4 chapter 4

early childhood adverse experiences

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I do not want this discussion of the impact and long term effects of severe abuse and neglect from birth, (or before) to be about the actual experiences we lived through and endured.  This is not about my mother suffering a psychotic break while delivering me so that she thought the devil sent me to kill her through making me come into the world butt first.  It is not about the particulars of how she treated me with abhorrence and violence for the next 18 years because she was nuts and believed I was the devil’s child.

It is not about every screaming battering assault upon my tiny body, or the assaults upon that body that should have landed her in prison for no less than 15,000 years.  I will recount some of those “dramas” simply as the gravel layer underlying the pavement of the highway we are about to take our journey down.

What matters to me is the common ground that all of us who were so abused find ourselves walking upon as we attempt to live a “normal” life, or any life at all.  In learning about this common underlying layer of affect we can join our voices into a perfect single note that carries around the globe, through time, across individual experiences.  We can no more “put our childhoods behind us and get on with our lives” than we can flap our arms and fly.  Our bodies built themselves to include adaptations and adjustments to the literally toxic conditions our bodies were formed in and by from conception.  They changed how our genes operate and manifest.  The stress of trauma places an unbearable burden upon the body, and it will show itself.  There is a cost for such an allostatic load.  There is a price to pay.  It is far too late to wish it otherwise.

Imagine trying to build a house in the midst of a powerful earthquake, or trying to fly a fragile paper kite in the midst of hurricane winds and rain.  Our body, nervous system, brain, immune system, all had to continue building themselves under the horrible and horrifying conditions we were born into.  How could we NOT expect and anticipate that the expression of our genes would change?

One must remove the largest wreckage after a disaster to find the bodies, dead or alive, that might be buried there.  Moving past all the psycho-babble, the prescription recommendations, the popular attitudes about “mental illness” and psychiatric labeling, “dysfunctional behavior” and “codependency” down through the layers, into the body we each live in and with, lets us learn about the actual changes we had to make, the alternative pathways our bodies had to take in order to survive and endure the overwhelming impossible catastrophe that was many of our infanthood and childhood experience.

The mediating factor for all of the difficulties of our childhoods had to be “adequate social support.”  If that support was there for us from birth through relationships with early caregivers, the long term disastrous consequences of our abuse and neglect could have been moderated through these mediators.  If that support was not available, we were left in essence completely alone in a world we were in no way prepared to deal with – except with the options made available to us on the level of our genetic potential.  This is both on the level of the actual DNA contained within our genes, and on the level of the machinery and mechanisms that tell our DNA what to do, when and how.  The WHAT of our DNA means nothing without the HOW.

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Weinreb et al 2002

Abstract – Department of Family Medicine and Community Health. Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA. weinrebl@ummhc.org

OBJECTIVE: Hunger, with its adverse consequences for children, continues to be an important national problem. Previous studies that document the deleterious effects of hunger among children cannot distinguish child from family hunger and do not take into account some critical environmental, maternal, and child variables that may influence child outcomes. This study examines the independent contribution of child hunger on children’s physical and mental health and academic functioning, when controlling for a range of environmental, maternal, and child factors that have also been associated with poor outcomes among children. METHODS: With the use of standardized tools, comprehensive demographic, psychosocial, and health data were collected in Worcester, Massachusetts, from homeless and low-income housed mothers and their children (180 preschool-aged children and 228 school-aged children). Mothers and children were part of a larger unmatched case-control study of homelessness among female-headed households. Hunger was measured by a set of 7 dichotomous items, each asking the mother whether she has or her children have experienced a particular aspect of hunger during the past year–1 concerns food insecurity for the entire family, 2 concern adult hunger, and 4 involve child hunger. The items, taken from the Childhood Hunger Identification Project measure, are summed to classify the family and divided into 3 categories: no hunger, adult or moderate child hunger, or severe child hunger (indicating multiple signs of child hunger). Outcome measures included children’s chronic health condition count using questions adapted from the National Health Interview Survey, Child Health Supplement, and internalizing behavior problems and anxiety/depression, measured by the Child Behavior Checklist. Additional covariates included demographic variables (ie, age, gender, ethnicity, housing status, number of moves, family size, income), low birth weight, child life events (ie, care and protection order, out of home placement, abuse, severe life events count), developmental problems (ie, developmental delay, learning disability, emotional problems), and mother’s distress and psychiatric illness. Multivariate regression analyses examined the effect of child hunger on physical and mental health outcomes.

RESULTS: The average family size for both preschoolers and school-aged children was 3; about one third of both groups were white and 40% Puerto Rican. The average income of families was approximately $11 000. Among the school-aged children, on average 10 years old, 50% experienced moderate child hunger and 16% severe child hunger. Compared with those with no hunger, school-aged children with severe hunger were more likely to be homeless (56% vs 29%), have low birth weights (23% vs 6%), and have more stressful life events (9 vs 6) when compared with those with no hunger.

School-aged children with severe hunger scores had parent-reported anxiety scores that were more than double the scores for children with no hunger and significantly higher chronic illness counts (3.4 vs 1.8) and internalizing behavior problems when compared with children with no hunger.

There was no relationship between hunger and academic achievement.

Among preschool-aged children, who averaged 4 years of age, 51% experienced moderate child hunger and 8% severe child hunger. For preschoolers, compared with children with no hunger, severe hunger was associated with homelessness (75% vs 48%), more traumatic life events (8.5 vs 6), low birth weight (23% vs 6%), and higher levels of chronic illness and internalizing behavior problems.

Mothers of both preschoolers and school-aged children

who reported severe hunger

were more likely to have a lifetime diagnosis

of posttraumatic stress disorder.

For school-aged children, severe hunger was a significant predictor of chronic illness after controlling for housing status, mother’s distress, low birth weight, and child live events. For preschoolers, moderate hunger was a significant predictor of health conditions while controlling for potential explanatory factors. For both preschoolers and school-aged children, severe child hunger was associated with higher levels of internalizing behavior problems. After controlling for housing status, mother’s distress, and stressful life events, severe child hunger was also associated with higher reported anxiety/depression among school-aged children. CONCLUSION: This study goes beyond previous research and highlights the independent relationship between severe child hunger and adverse physical health and mental health outcomes among low-income children. Study findings underscore the importance of clinical recognition of child hunger and its outcomes, allowing for preventive interventions and efforts to increase access to food-related resources for families.

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Seckl 2008

Abstract – Endocrinology Unit, Centre for Cardiovascular Science, Queen’s Medical Research Institute, Edinburgh, UK. J.Seckl@ed.ac.uk

Early life environmental events have persisting effects on tissue structure and function, a phenomenon called ‘developmental programming’. Exposure to stress and its glucocorticoid hormone mediators may underpin many such effects. Indeed, studies in animal models and observations in humans suggest that prenatal stress/glucocorticoid overexposure causes permanent cardiometabolic, neuroendocrine and behavioural effects in offspring. Such effects appear mediated via tissue-specific changes in gene expression. Underlying epigenetic changes in target gene promoters may ensure persistence of altered transcription long after the initial challenge.

Posttraumatic stress disorder and other affective diseases may both act as environmental challenges if present in early life and may themselves be more likely in individuals made ‘vulnerable’ by early life stress.

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Meaney, Szyf & Seckl 2007

Abstract – McGill Program for Study of Genes, Environment and Health, McGill University, Montreal, Canada. michael.meaney@mcgill.ca

EPIGENETICS

Environmental effects on the materno-foetal interaction determine birth outcomes that predict health over the lifespan. Thus, maternal undernutrition or stress associate with low birth weight, leading to an increased risk of metabolic and cardiovascular illness in the offspring. We argue that these effects are, in part, mediated by direct and indirect effects on the hypothalamic-pituitary-adrenal (HPA) axis such that (i) the effect of maternal adversity on foetal growth is mediated by adrenal glucocorticoids and (ii) environmental adversity alters maternal physiology and behavior, which then programs HPA activity in the offspring.

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Kiefer 2007

Abstract – Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, Utah 84132, USA. jkiefer@neuro.utah.edu

It has become increasingly evident in recent years that

development is under epigenetic control.

Epigenetics is the study of heritable changes

in gene function that occur independently of alterations

to primary DNA sequence.

The best-studied epigenetic modifications are DNA methylation, and changes in chromatin structure by histone modifications, and histone exchange. An exciting, new chapter in the field is the finding that long-distance chromosomal interactions also modify gene expression.

Epigenetic modifications are key regulators of important developmental events, including X-inactivation, genomic imprinting, patterning by Hox genes and neuronal development. This primer covers these aspects of epigenetics in brief, and features an interview with two epigenetic scientists.

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Kubicek et al 2006

Abstract – Research Institute of Molecular Pathology, The Vienna Biocenter, Austria. kubicek@imp.univie.ac.at

Epigenetic mechanisms control eukaryotic [A single-celled or multicellular organism whose cells contain a distinct membrane-bound nucleus] development beyond DNA-stored information.

DNA methylation, histone modifications and variants, nucleosome remodeling and noncoding RNAs all contribute to the dynamic make-up of chromatin [mass of genetic material composed of DNA and proteins that condense to form chromosomes in eukaryotic cell division] under distinct developmental options.

In particular, the great diversity of covalent histone tail modifications has been proposed to be ideally suited for imparting epigenetic information. While most of the histone tail modifications represent transient marks at transcriptionally permissive chromatin, some modifications appear more robust at silent chromatin regions, where they index repressive epigenetic states with functions also outside transcriptional regulation. Under-representation of repressive histone marks could be indicative of epigenetic plasticity in stem, young and tumor cells, while committed and senescent (old) cells often display increased levels of these more stable modifications. Here, we discuss profiles of normal and aberrant histone lysine methylation patterns, as they occur during the transition of an embryonic to a differentiated cell or in controlled self-renewal vs pro-neoplastic or metastatic conditions. Elucidating these histone modification patterns promises to have important implications for novel advances in stem cell research, nuclear reprogramming and cancer, and may offer novel targets for the combat of tumor cells, potentially leading to new diagnostic and therapeutic avenues in human biology and disease.

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Feng, Fouse & Fan 2007

Abstract – Department of Human Genetics, David Geffen School of Medicine, University of California at Los Angeles, CA 90095, USA.

Epigenetic regulation of neural gene expression and neuronal function.

The development and function of the CNS requires accurate gene transcription control in response to proper environmental signals.

Epigenetic mechanisms, including DNA methylation, histone modifications, and other chromatin-remodeling events, are critically important in mediating precise neural gene regulation.

This review focuses on discussing the role of DNA methylation and histone modifications in neural lineage differentiation, synaptic plasticity and neural behavior.

We postulate that DNA methylation- and histone

modification-mediated gene regulation

is not only important for neural cell differentiation

but also crucial for high-order cognitive functions

such as learning and memory.

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Levenson & Sweatt 2006

Abstract – Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.

In this review we address the idea that

conservation of

epigenetic mechanisms for information storage

represents a unifying model in biology,

with epigenetic mechanisms being utilized for cellular memory at levels from behavioral memory

to development

to cellular differentiation.

Epigenetic mechanisms typically involve alterations

in chromatin structure,

which in turn regulate gene expression.

An emerging idea is that the

regulation of chromatin structure

through histone acetylation and DNA methylation

may mediate long-lasting behavioral change

in the context of learning and memory.

This sure has some implications regarding stress and trauma – learning and memory – like I’ve been saying, the body will not let go until it makes us if at all possible of every experience we have

We find this idea fascinating

because similar mechanisms are used for triggering and storing long-term ‘memory’ at the cellular level,

for example when cells differentiate.

An additional intriguing aspect of the

hypothesis of a role for epigenetic mechanisms

in information storage is that lifelong behavioral memory storage may involve lasting changes in the physical, three-dimensional structure of DNA itself.

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Again, it is nearly impossible to know at this point where to draw the line between topics of interest.  I want to put some of the epigenetic information in memory chapter, but epigenetics is not only about what happens “down the line,” but is also crucially important when looking at ontogeny.  EVERYTHING our body does to manifest DNA is about epigenetics, and epigenetics IS about memory.  It is about what our body deems necessary for survival one fraction of an instant to the next as we move through this stream that is our LIFE.

Do we only want to think about memory in terms of what our self, our “ego self” might be able to consciously recall?  I suspect that information is almost of mute importance to our existence.

So for the time being I will include epigenetics under childhood because, though happening long before we inhale and exhale our first breath, it is already operating to best prepare us for what lies ahead once we exit our mother’s womb.  In the end, epigenetics will probably need its own chapter….

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Miller & Sweatt 2007

abstract – Department of Neurobiology and the Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

DNA methylation is a covalent chemical modification of DNA catalyzed by DNA methyltransferases (DNMTs).

DNA methylation is associated with transcriptional silencing and has been studied extensively as a lifelong molecular information storage mechanism put in place during development.

Here we report that DNMT gene expression is upregulated in the adult rat hippocampus following contextual fear conditioning and that DNMT inhibition blocks memory formation.

In addition, fear conditioning is associated with rapid methylation and transcriptional silencing of the

memory suppressor gene PP1

and demethylation and transcriptional activation of the synaptic plasticity gene reelin,

indicating both methyltransferase and demethylase activity during consolidation.

DNMT inhibition prevents the PP1 methylation increase, resulting in aberrant transcription of the gene during the memory-consolidation period.

These results demonstrate that DNA methylation

is dynamically regulated in the adult nervous system

and that this cellular mechanism is a crucial step

in memory formation.

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Albalat 2008

Abstract – Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, Av. Diagonal, 645, E-08028, Barcelona, Spain, ralbalat@ub.edu.

DNA methylation is an epigenetic mark

associated with gene regulation and cell memory,

silencing of transposable elements,

genomic imprinting,

and repression of spurious transcription of duplicated sequences.

These roles have varied widely during animal evolution and

current functions depend on the specific methylation pattern of the species

under consideration.

The patterns of methylation are

established, maintained, and translated into

appropriate functional states

by the DNA-methylation machinery,

which includes three groups of methyltransferase enzymes,

Dnmt1,

Dnmt2 and

Dnmt3, and

five methyl-DNA binding proteins,

Mbd1, Mbd2, Mbd3, Mbd4, and MeCP2.

In this study, I have identified the members of the Dnmt and the Mbd gene families in the cephalochordate amphioxus (Branchiostoma floridae), the most basal extant chordate and one of the closest sister groups of vertebrates. Database searches, phylogenetic studies and protein domain analyses revealed the presence of the three major groups of Dnmt enzymes in the cephalochordate genome, whereas only two Mbd members, Mbd2/3 and Mbd4, were found. Analysis of the amphioxus methylation machinery suggested that the complexity and the structural organization of cephalochordate methyltransferases do not differ substantially from those of current vertebrate enzymes, while new Mbd proteins arose in vertebrates, which perhaps minimized certain collateral effects associated with the major genomic changes that occurred during the invertebrate-vertebrate transition.

Again, this is looking into the eyeglass and mouthpiece of genesis itself, looking both back into the far reaches of time as we can imagine it, and looking at the same time into the immediate present.  This is an inclusive-exclusive diorama of creation in progress, in process.  Genesis is an ongoing procedure present in all species even though they may appear to us presently with clear cut delineations.

Every species must consistently and continually remember who and what it is, defining and redefining its own boundaries – and these boundaries determine from the inside and to the outside, exactly what the particular species is.  Among humans, the genetic manifestations also determine who and what the individual is in terms of behavior from cellular transactions outwards – growing into larger and larger manifestations until we see the behavior of the entire body in action, participating in conscious choice to whatever degree is possible for that person.

In the end, this is all about expectation and anticipation.  The organism prepares itself for life by using all the genetic memory stored within its DNA, and within the powers of differentiation contained in its genetic memory that determines how its manifestation machinery can operate.  In the end, it is all about potential and possibilities.

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Papaleo et al 2008

Abstract – Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, National Institute of Mental Health, Bethesda, Maryland 20892, USA.

The COMT (catechol-O-methyltransferase) gene

has been linked to a spectrum of human phenotypes,

including

cognition,

anxiety,

pain sensitivity and

psychosis.

Doubts about its clinical impact exist, however, because of the complexity of human COMT polymorphism and clinical variability. We generated transgenic mice overexpressing a human COMT-Val polymorphism (Val-tg), and compared them with mice containing a null COMT mutation.

Increased COMT enzyme activity in Val-tg mice

resulted in disrupted attentional set-shifting abilities, and

impaired working and recognition memory, but

blunted stress responses and pain sensitivity.

Conversely, COMT disruption

improved working memory, but

increased stress responses and pain sensitivity.

Does this tie in with “let’s hear it for the doves?”  Is this involved with the ability to pay very close, persistent and focused attention to whatever is happening or about to happen in the most minute detail in the near rather than the big, far, distant environment?

Amphetamine ameliorated recognition memory deficits in COMT-Val-tg mice but disrupted it in wild types, illustrating COMT modulation of the inverted-U relationship between cognition and dopamine. COMT-Val-tg mice showed increased prefrontal cortex (PFC) calcium/calmodulin-dependent protein kinase II (CaMKII) levels, whereas COMT deficiency decreased PFC CaMKII but increased PFC CaMKKbeta and CaMKIV levels,

suggesting the involvement of

PFC CaMK pathways in COMT-regulated

cognitive function and

adaptive stress responses.

Our data indicate a critical role for the

COMT gene

in an apparent evolutionary trade-off

between cognitive and affective functions.

Let me suggest that the sensitivities of the doves requires them to be able to feel, that is to recognize aspects of environmental interactions on the sensate level rather than detections based on thought or fore thought – which is, as we know, the slower way to both gain information and to react to it.

I would understand that early childhood adverse experiences further inform the dove end of the spectrum organisms that the environment is not only potentially dangerous, but certainly dangerous – based on experience as the teacher.

Here is epigenetics in process – experiential development – a skewing and amplification of possibilities and potential – an exaggeration of what can be the end result geared toward survival in the most flexible way possible – which unfortunately cannot retain at the same time enough flexibility to “change back again” in the future even if the environment were to change later on.

We can be as mad as we want about the limited flexibility abilities inherent within our species – and I mean that on the “innermost” level – into our cells themselves.  That we contain and retain enough flexibility to adapt to toxic and therefore dangerous environments in the first place is a miracle in itself.  But we are not made of play-do or silly putty!  Our plasticity, our “resiliency,” our protective factors can only reach so far.

In essence, this is who we are, right at the point of the intersection of our genesis, where IT is happening – the manifestation of our DNA on a continual, ongoing basis – to the limitations of our architecture and structure.

From this level the research moves up a notch and, to my thinking, loses its connection to the epigenetic factors in its consideration of actual polymorphisms in the genes themselves.  This level is not considering itself with the process of HOW the genes are expressing themselves and is more concerned with the genes and the polymorphisms in these genes.  I will include this information here and sort it out later….

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Smolka et al 2005

Abstract – Germany

Catechol-O-methyltransferase (COMT) degrades the catecholamine neurotransmitters dopamine, epinephrine, and norepinephrine.

A functional polymorphism in the COMT gene (val158met) accounts for a fourfold variation in enzyme activity.

The low-activity met158 allele has been associated with

…………… improved working memory but with

……………higher risk for anxiety-related behaviors.

Using functional magnetic resonance imaging, we assessed the effects of COMT genotype on brain activation by standardized affective visual stimuli (unpleasant, pleasant, and neutral) in 35 healthy subjects.

…………..The analysis of genotype effects was restricted to brain areas with robust activation by the task. To determine genedose effects, the number of met158 alleles (0, 1, or 2) was correlated with the blood oxygen level-dependent (BOLD) response elicited by pleasant or unpleasant stimuli compared with neutral stimuli.

……..COMT genotype had no significant impact on brain activation by pleasant stimuli

………but was related to the neural response to unpleasant stimuli:

reactivity to unpleasant stimuli was significantly positively correlated with the

…….number of met158 alleles in the limbic system (left hippocampus, right amygdala, right thalamus), connected prefrontal areas (bilateral ventrolateral prefrontal cortex, right dorsolateral prefrontal cortex), and the visuospatial attention system (bilateral fusiform gyrus, left inferior parietal lobule).

Genotype explained up to 38% of interindividual variance in BOLD response elicited by unpleasant stimuli.

We conclude that

………..(1) genetic variations can account for a substantial part of interindividual variance in task-related brain activation and that

……… (2) increased limbic and prefrontal activation elicited by unpleasant stimuli in subjects with more met158 alleles might contribute to the observed lower emotional resilience against negative mood states.

Are there environmental conditions, particularly as the brain develops, that create this situation?  Not the genes themselves, obviously, but how we experience life with these genes?

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Drabant et al 2006

Abstract – MD —need to get this one

Catechol O-methyltransferase (COMT), the

….major enzyme determining cortical dopamine flux, has a

….common functional polymorphism (val(158)met) that

…affects prefrontal function and working memory capacity

….and has also been associated with

anxiety and emotional dysregulation.

OBJECTIVES: To examine COMT val(158)met effects on corticolimbic circuitry reactivity and functional connectivity during processing of biologically salient stimuli, as well as the relationship to the temperamental trait of novelty seeking.

DESIGN: Within-subject functional magnetic resonance imaging study. SETTING: National Institute of Mental Health, Genes, Cognition, and Psychosis Program, Bethesda, Md. Patients One hundred one healthy subjects of both sexes.

RESULTS: We found that the met allele was associated with a dose-dependent increase in hippocampal formation and ventrolateral prefrontal cortex activation during viewing of faces displaying negative emotion.

In met/met homozygotes, limbic and prefrontal regions showed increased functional coupling.

……….Moreover, in these same subjects, the magnitude of amygdala-orbitofrontal coupling was inversely correlated with novelty seeking,

……….an index of temperamental inflexibility.

CONCLUSIONS: Our results indicate that heritable variation in dopamine neurotransmission associated with the met allele of the COMT polymorphism results in heightened reactivity and connectivity in corticolimbic circuits.

This may reflect a genetic predisposition for inflexible processing of affective stimuli, a mechanism possibly accounting for aspects of arousal and behavioral control that contribute to emotional dysregulation previously reported in met/met individuals.

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Bertolino et al 2006

Abstract – Italy —call this article in

Functional polymorphisms in the catechol-O-methyltransferase (COMT) and the dopamine transporter (DAT) genes modulate dopamine inactivation,

…………..which is crucial for determining neuronal signal-to-noise ratios in prefrontal cortex during working memory.

We show that the COMT Met158 allele and the DAT 3′ variable number of tandem repeat 10-repeat allele are

………independently associated in healthy humans

………with more focused neuronal activity … in the working memory cortical network, including the prefrontal cortex.

Moreover, subjects homozygous for the COMT Met allele and the DAT 10-repeat allele

…………have the most

focused

response,

………whereas the COMT Val and the DAT 9-repeat alleles have the least.

These results demonstrate additive genetic effects of genes regulating dopamine signaling on specific neuronal networks subserving

working memory.

I can’t help but wonder about this combination.  This is one thing I know about myself – I can focus.  I have tied this into dissociation for myself because I can be so focused on my immediate task that short of a bomb exploding I cannot be distracted.  While in this state nothing else exists but whatever it is I am focusing on.

I have also wondered if my focusing ability is part of what keeps me so loyal for so long – and contributes to my inflexibility and rigidity about moving off in another direction if something is not good for me or is not “bearing fruit.”  It is a form of “stick-to-it-ness” that is a concentrated application of focused effort – no matter what.

It is certainly an ability that probably served me as a child.  There was no way out or around of my 18 years of abuse except to go through it to the end.  There were no alternatives available to me.  Perhaps I have this genetic combination they are talking about here – and I marshaled and honed my abilities far beyond the usual.

If so, then this combination (of course along with others) could keep a person from giving up.  A strong work ethic involving working memory that allows us to apply ourselves in spite of overwhelming obstacles – even on those occasions and in those situations when doing so is not in our best interest.  Maybe it’s the “Little Engine that Could” gene, that keeps us raising our children when that act takes a whole lot of courage and application of focused commitment.  Maybe it’s the gene that keeps some of us trying and trying and trying to make relationships work that have been all down hill from the start.  We will push that relationship UP and over the top if it kills us – and for us, that is within our working memory capacities.  Maybe we used this gene so hard in surviving our contaminated, toxic childhoods that all related circuits became super strong as well in their participation and involvement with “solving” the task at hand.

Maybe for us there was no other way, and today in the present when this kind of focused work is not needed and our commitments to making things work no longer serves us – we are so entrenched in our application of effort based upon what worked for us in the past that we do not know how to deviate from our tried and true methods from the past.  They are built into our brain based on our successes, or we wouldn’t be here now to debate the issue.  “Never give up!  Never surrender!” is our motto. We can keep our nose to the grindstone until we’ve worn a hole through the back of our head.

Maybe this is a sort of perseverance gene that gives everyone in my family a peculiar form of intensity.  All my siblings share it, all six of us.  All three of my children have it.  It makes sense that the human species would have evolved a particular option to persevere, to work without ceasing to solve problems, to tackle the seemingly impossible task, to apply concentrated effort toward accomplishing a goal.  This work takes intense, concentrated application of working memory.  How could it not?

It makes sense to me that the dopamine circuits, which also control both liking and wanting, would be involved in working memory and concentration of focused effort.  I suppose people without histories of early severe abuse would utilize this genetic combination differently and actually have some fun with it.  Or, if they tip over into personality disorder, this combination would keep them focused on working for what they detect they need in the environment at the cost of all others.

I am equating tenacity with focus – not at all sure this is really the same thing.

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Tan et al 2007

Abstract – MD

Dopaminergic and glutamatergic systems are critical components responsible for prefrontal signal-to-noise tuning in working memory.

Recent functional MRI (fMRI) studies of genetic variation in these systems in catechol-O-methyltransferase (COMT) and in metabotropic glutamate receptor mgluR3 (GRM3), respectively, suggest that

…….. these genes influence prefrontal physiological signal-to-noise in humans.

Here, using fMRI, we extend these individual gene findings to examine the combined effects of COMT and GRM3 on dissociable components of the frontoparietal working memory network.

We observed an apparent epistatic interaction of these two genes on the engagement of prefrontal cortex during working memory.

Specifically, the GRM3 genotype putatively associated with suboptimal glutamatergic signaling

….was significantly associated with inefficient prefrontal engagement and altered prefrontal-parietal coupling on the background of COMT Val-homozygous genotype.

Conversely, COMT Met-homozygous background mediated against the effect of GRM3 genotype.

These findings extend putative brain dopaminergic and glutamatergic relationships indexed by COMT and GRM3 to a systems-level interaction in human cortical circuits implicated in working memory dysfunction such as in schizophrenia.

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Apud et al 2007

Abstract – Genes, Cognition and Psychosis Program, Clinical Brain Disorders Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20854, USA.

Prefrontal cortical dopamine (DA)

regulates various executive cognitive functions,

including attention and working memory.

Efforts to enhance prefrontal-related cognition, which have focused on catecholaminergic stimulant drugs, have been unsatisfactory. Recently, the demonstration that

a functional polymorphism in the

catecholamine-O-methyltransferase (COMT) gene

impacts prefrontal cognition

raises the possibility of a novel pharmacological approach for the treatment of prefrontal lobe executive dysfunction.

To explore in a proof of concept study the effects of

tolcapone,

a CNS penetrant specific COMT inhibitor,

we performed a randomized, double blind, placebo controlled, and crossover design of this drug in normal subjects stratified by

COMT (val158met) genotype.

COMT enzyme activity was determined in peripheral blood. Forty-seven normal volunteers with no family history of psychiatric disorders underwent neuropsychological testing and 34 of those subjects underwent physiological measurement of prefrontal information processing assessed by blood oxygen level-dependent functional magnetic resonance imaging (fMRI).

We found significant drug effects on measures of executive function and verbal episodic memory and a significant drug by genotype interaction on the latter, such that individuals with

val/val genotypes improved,

whereas individuals with met/met genotypes

worsened on tolcapone.

fMRI revealed a significant tolcapone-induced improvement in the efficiency of information processing in prefrontal cortex during a working memory test. This study demonstrates enhancement of prefrontal cortical function in normal human subjects with a nonstimulant drug having COMT inhibitory activity. Our results are consistent with data from animal studies and from computational models of the

effects of selective enhancement of DA [dopamine] signaling in the prefrontal cortex.

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Goldberg et al 2003

Abstract – Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA. goldbert@intra.nimh.nih.gov

Cognitive dysfunction in the working memory domain

seems to be under genetic control

and is a candidate intermediate phenotype in schizophrenia.

Genes that affect working memory processing may contribute to risk for schizophrenia. METHODS: Working memory and attentional processing were assessed in a large and unselected sample of schizophrenic patients, their healthy siblings, and controls (N = 250). We used the n-back task because it allows parametric analysis over increasing loads and delays and parsing of subcomponents of executive cognition and working memory, including temporal indexing and updating. Participants were genotyped for

catechol-O-methyltransferase (COMT) at the Val158Met locus,

which has been shown to

affect executive cognition and frontal lobe function, likely because of genetically determined variation in prefrontal dopamine signaling.

RESULTS: A significant COMT genotype effect was found:

Val/Val individuals had the lowest n-back performance,

and Met/Met individuals had the highest performance.

Effects were similar in the 1- and 2-back conditions and across all groups, whereas no effect on the Continuous Performance Test was seen, suggesting that genotype was not affecting working memory subprocesses related to attention, load, or delay. Siblings also performed significantly worse than controls on the 1- and 2-back conditions.

CONCLUSIONS: A prefrontal cognitive mechanism common to the 1- and 2-back conditions, probably executive processes involved in information updating and temporal indexing, is sensitive to the COMT genotype. Considering that the 3 participant groups were affected more or less linearly by the COMT genotype,

an additive genetic model

in which the effect of allele load is similar in its effects

on prefrontally based working memory

irrespective of the genetic or environmental background

in which it is expressed is suggested.

The findings also provide convergent evidence that

an intermediate phenotype

related to prefrontal cortical function

represents a viable approach to understanding

neuropsychiatric disorders with complex genetic etiologies

and individual differences in cognition.

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Northoff et al 2004

Abstract – Laboratory for Magnetic Brain Stimulation, Division of Behavioral Neurology, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. Georg.Northoff@Medizin.Uni-Magdeburg.DE

Everyday and clinical experience demonstrates strong interactions between emotions and cognitions. Nevertheless the neural correlates underlying emotional-cognitive interaction remain unclear. Using event-related fMRI, we investigated BOLD-signal increases and decreases in medial and lateral prefrontal cortical regions during emotional and non-emotional judgment of photographs taken from the International Affective Picture System (IAPS). Emotional and non-emotional judgment conditions were compared to each other as well as with baseline allowing for distinction between relative signal changes (comparison between conditions) and true signal changes (referring to baseline). We have found that:

(1) both emotional and non-emotional judgment of IAPS pictures were characterized by

signal increases in ventrally and dorsally located lateral prefrontal cortical areas and

concurrent signal decreases in ventro- and dorsomedial prefrontal cortex;

(2) direct comparison between emotional and non-emotional judgment showed relative signal increases in ventro- and dorsomedial prefrontal cortex,

and in contrast, relative signal increases were detected in ventrally and dorsally located lateral prefrontal cortical areas when comparing non-emotional to emotional judgment; and

(3) as shown in separate comparisons with baseline, these relative signal changes were due to smaller signal decreases in ventro- and dorsomedial prefrontal cortex and smaller signal increases in ventrally and dorsally located lateral prefrontal cortical areas during emotional judgment.

Therefore, the emotional load of a cognitive task

lead to both less deactivation of medial prefrontal regions

and, at the same time,

less activation of lateral prefrontal regions.

Analogous patterns of reciprocal modulation and attenuation have previously been described for other cortical regions such as visual and auditory areas.

Reciprocal modulation and attenuation

in medial and lateral prefrontal cortex

might constitute the neurophysiologic basis

for emotional-cognitive interaction

as observed in both healthy and psychiatric subjects.

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Northoff et al 2000

Abstract- Department of Psychiatry, Otto-von-Guericke University of Magdeburg, Düsseldorf, Germany. Georg.Northoff@Medizin.Uni-Magdeburg.de

The orbitofrontal cortex has been cytoarchitectonically and connectionally subdivided into a medial and a lateral part which are assumed to subserve distinct functions in emotional processing.

However the exact spatiotemporal mechanisms of negative and positive emotional processing in medial and lateral orbitofrontal cortex remain unclear. We therefore investigated spatiotemporal orbitofrontal and prefrontal cortical activation patterns during emotional stimulation in a combined fMRI/MEG study. We investigated 10 healthy subjects, 5 women and 5 men. Positive and negative pictures from the International Affective Picture system (IAPS) were used for emotional stimulation, whereas neutral and gray pictures were taken as control conditions. fMRI/MEG measurements covered the whole frontal lobe and a time window between -2000 and +200 ms around motor responses (right index finger extension) associated with each picture. Positively and negatively correlated activities were determined in various prefrontal/frontal cortical regions in fMRI. Isocontour maps and single dipoles in MEG were analyzed in 50 ms time windows ranging from -2000 to +200 ms. Dipoles and fMR images were mapped on three-dimensional anatomical MRI so that anatomical localization of single dipoles and regional fMRI activity could be compared.

Both negative and positive emotional conditions

differed from non-emotional control conditions by strong orbitofrontal and lateral prefrontal activation as well as by the presence of early magnetic fields (-1700 to +1100 ms).

Negative emotional processing

was characterized by strong medial orbitofrontal activation and earlier (-1700 ms), stronger and more medially oriented orbitofrontal dipoles.

In contrast positive emotional processing

showed a rather strong activation in lateral prefrontal cortex with later (-1500 ms), weaker and more laterally oriented orbito and prefrontal dipoles.

Negative emotional processing

can be characterized by strong and early medial orbitofrontal cortical activation,

whereas positive emotional processing

showed rather later and weaker activation in lateral orbitofrontal/prefrontal cortex.

Such a functional dissociation between medial and lateral orbito-frontal/prefrontal cortex during negative and positive emotional processing lends further support to the assumption of a functional subdivision in the orbitofrontal cortex.

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Siegle et al 2007

Abstract – Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. gsiegle@pitt.edu

Major depressive disorder

is characterized by increased and sustained emotional reactivity, which has been linked to sustained amygdala activity.

It is also characterized by disruptions

in executive control,

linked to abnormal dorsolateral prefrontal cortex (DLPFC) function.

These mechanisms have been hypothesized to interact

in depression.

This study explored relationships between amygdala and DLPFC activity during emotional and cognitive information processing in unipolar depression. METHOD: Twenty-seven unmedicated patients with DSM-IV unipolar major depressive disorder and 25 never-depressed healthy control subjects completed tasks requiring executive control (digit sorting) and emotional information processing (personal relevance rating of words) during event-related functional magnetic resonance imaging (fMRI) assessment. RESULTS: Relative to control subjects,

depressed subjects displayed sustained amygdala reactivity

on the emotional tasks and

decreased DLPFC activity on the digit-sorting task.

Decreased relationships between the time-series of amygdala and DLPFC activity were observed within tasks in depression, but different depressed individuals showed each type of bias. CONCLUSIONS:

Depression is associated with increased limbic activity in response to emotional information processing and decreased DLPFC activity in response to cognitive tasks though these may reflect separate mechanisms.

Depressed individuals also display decreased relationships between amygdala and DLPFC activity,

potentially signifying decreased functional relationships

among these structures.

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Wang et al 2008

Abstract – Brain Imaging and Analysis Center, Duke University Medical Center, Durham, NC, USA.

A dysfunction in the interaction

between executive function and mood regulation

has been proposed as the pathophysiology of depression.

We must be aware that our judgment of the “dysfunctionality” of this condition reflects our cultural biases.  If, in fact, this disequilibrium is a realistic alteration in the abilities of sensitive dove types to notice details in their environment.  In support of this variation between types of people geared to operate differently in their environment BECAUSE WE ARE NOT ALL THE SAME AND HAVE DIFFERENT GIFTS, is supported by the genetic and the epigenetic overlay, or more accurately the underlay of these same brain operational factors.

However, few studies have investigated the alteration in brain systems related to executive control over emotional distraction in depression. To address this issue, 19 patients with major depressive disorder (MDD) and 20 healthy controls were scanned using functional magnetic resonance imaging. Participants performed an emotional oddball task in which infrequently presented circle targets required detection while sad and neutral pictures were irrelevant novel distractors. Hemodynamic responses were compared for targets, sad distractors, and for targets that followed sad or neutral distractors (Target-after-Sad and Target-after-Neutral).

Patients with MDD revealed attenuated activation overall to targets in executive brain regions.

Behaviorally, MDD patients were slower in response to Target-after-Sad than Target-after-Neutra stimuli. Patients also revealed a

reversed activation pattern from controls in response

to this contrast in the

left anterior cingulate,

insula,

right inferior frontal gyrus (IFG), and

bilateral middle frontal gyrus.

Those patients who engaged the right inferior frontal gyrus (IFG), more during Target-after-Neutral stimuli responded faster to targets, confirming a role of this region in coping with emotional distraction.

The results provide direct evidence of an

alteration in the neural systems that interplay cognition

with mood in MDD.

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Wang et al 2008b

Abstract – Brain Imaging and Analysis Center, Duke University Medical Center, PO Box 3918, Rm. 163, Bell Building, Durham, NC 27710, USA. wang@biac.duke.edu

Geriatric depression has been associated with a heterogeneous neuropathology. Identifying both depressive state-related and disease-related alterations in brain regions associated with emotion and cognitive function could provide useful diagnostic information in geriatric depression. METHOD: Twelve late-onset acutely depressed patients, 15 patients fully remitted from major depression, and 20 healthy comparison subjects underwent event-related functional MRI. Brain activation and deactivation associated with executive and emotional processing were investigated using an emotional oddball task in which circles were presented infrequently as attentional targets and sad and neutral pictures as novel distractors. RESULTS: Significant changes in brain activation in patients were found mainly in response to attentional targets rather than to sad distractors.

Relative to healthy comparison subjects, the

depressed patients had

attenuated activation in the regions of the executive system, including the right middle frontal gyrus, the cingulate, and inferior parietal areas.

They do not mention the medial parietal region, or precuneus

Activity in the middle frontal gyrus revealed depressive state-dependent modulation,

whereas attenuated activation in the anterior portion of the posterior cingulate and inferior parietal regions persisted in the remitted subjects, suggesting a disease-related alteration.

Enhanced deactivation was observed in the

posterior portion of the posterior cingulate,

which was also state dependent.

The remitted group did not show this deactivation.

CONCLUSIONS: Our results indicate distinct roles for the right middle frontal gyrus and the anterior and posterior portions of the posterior cingulate cortex in geriatric depression. The deactivation of the posterior portion of the posterior cingulate could be informative for differentiation of cognitive dysfunction related to depression from other conditions, such as mild cognitive impairment.

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Grimm et al 2008

Abstract – Department of Psychiatry, University of Zurich, Switzerland.

Although recent neuroimaging and therapeutic transcranial magnetic cortex stimulation (TMS) studies suggest

imbalance between left and right dorsolateral prefrontal cortex (DLPFC) in major depressive disorder (MDD)

the fundamental neuropsychological characterization of

left DLPFC hypoactivity and

right DLPFC hyperactivity in MDD

remains poorly understood. METHODS: We used event-related functional magnetic resonance imaging (fMRI) to investigate neural activity in left and right DLPFC related to unattended (unexpected) and attended (expected) judgment of emotions. Participating in the study were 20 medication-free patients with MDD and 30 healthy subjects. RESULTS: The

MDD patients showed

hypoactivity in the left DLPFC

during both unattended and attended emotional judgment and hyperactivity in the right DLPFC

during attended emotional judgment.

In contrast to healthy subjects,

left DLPFC activity during emotional judgment

was not parametrically modulated by negative emotional valence and was inversely modulated by positive emotional valence

in MDD patients.

Hyperactivity in the right DLPFC

correlated with depression severity.

CONCLUSIONS: Results demonstrate that

left DLPFC hypoactivity is associated with

negative emotional judgment

rather than with emotional perception or attention while

right DLPFC hyperactivity is linked to attentional modulation.

Left-right DLPFC imbalance

is characterized in neuropsychological regard,

which bridges the gap

from resting metabolism

and therapeutic repetitive transcranial magnetic stimulation effects

to functional neuroanatomy of

altered emotional-cognitive interaction in MDD.

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Lee et al 2008b

Abstract – Department of Psychiatry, Hangang Sacred Heart Hospital, Hallym University Medical Center, Seoul, South Korea.

Mood abnormalities related to major depressive disorder (MDD)

seem to result from disturbances in pathways

connecting the fronto-limbic and subcortical,

both regions known to be involved in the

processing of emotional information.

Using functional magnetic resonance imaging (fMRI), we measured neural responses to viewing images of sad, angry and neutral faces in 21 patients with MDD and 15 healthy controls. When shown pictures of

sad faces,

patients with MDD relative controls

showed decreased activations

bilaterally in the dorsolateral prefrontal cortex,

inferior orbitofrontal cortex (OFC),

medial OFC,

caudate, and

hippocampus.

We also found significant group differences under the

angry face condition,

bilaterally, in the inferior OFC and medial OFC areas.

Our findings indicate that

decreased activations in the fronto-limbic and subcortical regions in response to affectively negative stimuli may be associated with pathophysiology of MDD.

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Lee et al 2007

Abstract – Department of Psychiatry, Hangang Sacred Heart Hospital, Hallym University Medical Center, Seoul, South Korea.

Previous studies examining neural responses to emotional stimuli in individuals with major depressive disorder (MDD) have indicated

increased responses within the left amygdala to sad faces, and increased activity within the visual cortex and striatum

to expressions of happiness.

Using functional magnetic resonance imaging (fMRI), the current study measured neural responses to neutral, positive and negative pictures of the International Affective Picture System in 15 healthy individuals and 15 patients with MDD. Depressed individuals demonstrated

lower activity in the right hippocampus and the

right insula to negative affective pictures,

whereas they showed

lower activity in the right anterior cingulate cortex and the

left insula to positive pictures.

However, within the MDD group, the

severity of depression correlated with the activity of the

left amygdala,

bilateral inferior orbitofrontal areas, and the

left insula to negative pictures,

whereas there were no clear indications of association between specific cerebral regions and positive pictures. Our findings indicate that

preferential decreases in the left amygdala in response to negative pictures might be involved in the processing of emotional stimuli in depressed individuals.

Also, these findings suggest that the

bilateral inferior orbitofrontal cortices and left amygdala

may be preferentially recruited in MDD patients,

but not in healthy individuals.

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Jollant et al 2008

Abstract – Université Montpellier I, Institut National de la Santé et de la Recherche Médicale U 888, Centre Hospitalier Universitaire, Montpellier, France. f-jollant@chu-montpellier.fr

OBJECTIVE: The authors sought to elucidate the functional neural basis of the neurobiological abnormalities underlying the vulnerability to suicidal behavior. METHOD: Event-related functional MRI was used to measure neural activity in response to angry and happy versus neutral faces. Thirteen currently euthymic men with a history of major depressive disorder and suicidal behavior were compared with 14 currently euthymic men with a history of major depressive disorder but not of suicidal acts (affective comparison subjects) and 16 healthy male comparison subjects. RESULTS: Relative to affective comparison subjects, suicide attempters showed greater activity in the right lateral orbitofrontal cortex (Brodmann’s area 47) and decreased activity in the right superior frontal gyrus (area 6) in response to prototypical angry versus neutral faces, greater activity in the right anterior cingulate gyrus (area 32 extending to area 10) to mild happy versus neutral faces, and greater activity in the right cerebellum to mild angry versus neutral faces. However, activation in these frontal regions did not differ between healthy individuals and either patient group. That makes no sense to me! Relative to healthy comparison subjects, both patient groups showed reduced activity in the right cerebellum to neutral faces and to mild happy versus neutral faces.

CONCLUSIONS: Suicide attempters were distinguished from nonsuicidal patients by responses to angry and happy faces that may suggest increased sensitivity to others’ disapproval, higher propensity to act on negative emotions, and reduced attention to mildly positive stimuli. These patterns of neural activity and cognitive processes may represent vulnerability markers of suicidal behavior in men with a history of depression.

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Mitterschiffthaler et al 2008

Abstract – Neuroimaging Research Group, Clinical Neuroscience, Institute of Psychiatry, King’s College London, UK. m.mitterschiffthaler@iop.kcl.ac.uk

A mood-congruent sensitivity towards negative stimuli has been associated with development and maintenance of major depressive disorder (MDD). The emotional Stroop task assesses interference effects arising from the conflict of emotional expressions consistent with disorder-specific self-schemata and cognitive color-naming instructions. Functional neuroimaging studies of the emotional Stroop effect advocate a critical involvement of the anterior cingulate cortex (ACC) during these processes. METHOD: Subjects were 17 medication-free individuals with unipolar MDD in an acute depressive episode (mean age 39 years), and 17 age-, gender- and IQ-matched healthy volunteers. In an emotional Stroop task, sad and neutral words were presented in various colors, and subjects were required to name the color of words whilst undergoing functional magnetic resonance imaging (fMRI). Overt verbal responses were acquired with a clustered fMRI acquisition sequence. RESULTS:

Individuals with depression showed greater increases in response time from neutral to sad words relative to controls. fMRI data showed a

significant engagement of

left rostral ACC (BA 32) and

right precuneus

during sad words in patients relative to controls.

Additionally, rostral ACC activation was positively correlated with latencies of negative words in MDD patients. Healthy controls did not have any regions of increased activation compared to MDD patients. CONCLUSIONS: These findings provide evidence for a behavioural and neural emotional Stroop effect in MDD and highlight the

importance of the ACC during monitoring of conflicting cognitive processes and

mood-congruent processing in depression.

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Fales et al 2008

Abstract – Department of Psychology, Washington University in St. Louis, St. Louis, Missouri 63110, USA.

Major depression is characterized by a negativity bias:

an enhanced responsiveness to, and memory for, affectively negative stimuli.

Just as a dove sensitive would even under normal conditions?

However, it is not yet clear whether this bias represents 1) impaired top-down cognitive control over affective responses, potentially linked to deficits in dorsolateral prefrontal cortex function; or 2) enhanced bottom-up responses to affectively laden stimuli that dysregulate cognitive control mechanisms, potentially linked to deficits in amygdala and anterior cingulate function. METHODS: We used an attentional interference task using emotional distracters to test for top-down versus bottom-up dysfunction in the interaction of cognitive-control circuitry and emotion-processing circuitry. A total of 27 patients with major depression and 24 control participants was tested. Event-related functional magnetic resonance imaging was carried out as participants directly attended to, or attempted to ignore, fear-related stimuli. RESULTS:

Compared with control subjects, patients with depression showed an enhanced amygdala response to unattended fear-related stimuli (relative to unattended neutral). By contrast,

control participants showed increased activity in

right dorsolateral prefrontal cortex (Brodmann areas 46/9) when ignoring fear stimuli (relative to neutral), which the patients with depression did not show.

In addition, the depressed participants failed to show evidence of error-related cognitive adjustments (increased activity in bilateral dorsolateral prefrontal cortex on posterior trials), but the control group did show them. CONCLUSIONS: These results suggest

multiple sources of dysregulation

in emotional and cognitive control circuitry in depression, implicating both

top-down and

bottom-up dysfunction.

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Holmes & Pizzagalli 2008

Abstract – Department of Psychology, Harvard University, Cambridge, MA 02138, USA.

Depression is characterized by executive dysfunctions and abnormal reactions to errors; however, little is known about the brain mechanisms that underlie these deficits. OBJECTIVE: To examine whether abnormal reactions to errors in patients with major depressive disorder (MDD) are associated with exaggerated paralimbic activation and/or a failure to recruit subsequent cognitive control to account for mistakes in performance. DESIGN: Between February 15, 2005, and January 19, 2006, we recorded 128-channel event-related potentials while study participants performed a Stroop task, modified to incorporate performance feedback. SETTING: Patients with MDD and healthy comparison subjects were recruited from the general community. PARTICIPANTS: Study participants were 20 unmedicated patients with MDD and 20 demographically matched comparison subjects. MAIN OUTCOME MEASURES: The error-related negativity and error positivity were analyzed through scalp and source localization analyses. Functional connectivity analyses were conducted to investigate group differences in the spatiotemporal dynamics of brain mechanisms that underlie error processing. RESULTS: Relative to comparison subjects,

patients with MDD displayed significantly lower accuracy after incorrect responses, larger error-related negativity, and higher current density in the rostral anterior cingulate cortex (ACC) and medial prefrontal cortex (PFC) (Brodmann area 10/32) 80 milliseconds after committing an error.

Functional connectivity analyses revealed that for the comparison subjects, but not the patients with MDD, rostral ACC and medial PFC activation 80 milliseconds after committing an error predicted left dorsolateral PFC (Brodmann area 8/9) activation 472 milliseconds after committing an error.

CONCLUSIONS: Unmedicated patients with MDD showed

reduced accuracy and potentiated error-related negativity immediately after committing errors, highlighting

dysfunctions in the automatic detection

of unfavorable performance outcomes.

New analytic procedures allowed us to show that

abnormal reaction

to committing errors

was accompanied by

hyperactivation in rostral ACC

and medial PFC regions

80 milliseconds after committing errors and a

failure to recruit dorsolateral PFC-based cognitive control.

Future studies are warranted to investigate whether these dysfunctions might foster the emergence and maintenance of negative processing biases and thus increase vulnerability to depression.

Are these changes orchestrated by epigenetic control?  If so, are they compensatory response patterns related to fear conditioning and hence to memory formation and retention?   One must also consider that these responses within the brain might be possible responses that were put in place far earlier than the time when language in words became a possibility for humans.

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Holmes & Pizzagalli 2008b

Abstract – Department of Psychology, Harvard University, Cambridge, MA 02138, USA.

Individuals with major depressive disorder (MDD) often exhibit impaired executive function, particularly in experimental tasks that involve

response conflict and require

adaptive behavioral adjustments.

Prior research suggests that these deficits might be

due to dysfunction within frontocingulate pathways

implicated in response conflict monitoring

and the recruitment of cognitive control.

However, the temporal unfolding of conflict monitoring impairments in MDD remains poorly understood. To address this issue, we recorded 128-channel event-related potentials while 20 unmedicated participants with MDD and 20 demographically matched, healthy controls performed a Stroop task. Compared to healthy controls, MDD subjects showed larger Stroop interference effects and reduced N2 and N450 amplitudes. Source localization analyses at the time of maximal N450 activity revealed that

MDD subjects had significantly reduced

dorsal anterior cingulate cortex (dACC; Brodmann area 24/32) and left dorsolateral prefrontal cortex (Brodmann area 10/46) activation to incongruent relative to congruent trials.

Interesting, the introduction of this term, congruency, in the MDD brain function considerations.  When Teicher talks about the brain developed in and for a malevolent world not being able to adjust down the road to a benevolent one, he is talking about a later appearing incongruency between response ability in match to the existing current environment.  This, to me, is a time issue, a timing issue, where a rupture and repair demand resulted in a possibly even epigenetic adjustment that remains “fixed” and unable to be moderated or modulated in a plastic fashion resulting in a rigid pattern that is incongruent with later environments.

Consistent with the heterogeneous nature of depression, follow-up analyses revealed that depressed participants with the lowest level of conflict-related dACC activation 620 ms post-stimulus were characterized by the largest Stroop interference effects (relatively increased slowing and reduced accuracy for incongruent trials). Conversely, MDD participants with relatively stronger dACC recruitment did not differ from controls in terms of interference effects. These findings suggest that

for some, but not all individuals,

MDD is associated with impaired performance

in trials involving

competition among different response options,

and reduced recruitment of frontocingulate pathways implicated in conflict monitoring and cognitive control.

An interesting and very useful addition to research structure at this point would be to include measures of dissociation.  My certain guess is that those with the highest difficulties with competition among different response options would show high dissociation patterns.

Not being able to choose, or to even recognize what the different response options might even be, is, to me, a key component of dissociation!

It might be possible that “nature” increases sensitivity without at the same time increasing the cognitive abilities necessary to choose response options.  I would also guess that in these individuals an extreme sensitivity to PTSD might simultaneously and concurrently exist.

This is also where the fissure could appear that allows hopelessness and helplessness to meet confusion – powerlessness and loss of control, loss of competence in the PAST to meet demands that match, are perceived to be congruent with present demands, only in the past the person was overwhelmed – what does Schore call that?  Faced with the “unsolvable paradox,” over and over and over again.  Being sensitive enough to detect when “danger” appears, but left without adequate responses to deal with it.

This must be tied to memory, and to working memory.  If nothing is remembered but the cue, and there was no adequate coping, one will be remembered but not, obviously, the other.

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Wagner et al 2006

Abstract – Department of Psychiatry, University of Jena, Jena, Germany. wagner.gerd@uni-jena.de

The present study is aimed to examine the neuronal correlates of Stroop interference in medication-free patients with major depressive disorder. METHODS: Sixteen patients fulfilling Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for unipolar depression and 16 healthy control subjects matched for age, gender, and education were included. All subjects underwent an event-related functional magnetic resonance imaging (fMRI) design with an adapted version of the Stroop task including congruent and incongruent task conditions. The fMRI experiment was conducted on a 1.5 T magnetic resonance (MR) scanner, and item responses were given manually by the subjects. RESULTS: With regard to behavioral performance, patients revealed no differences in both reaction time and accuracy relative to control subjects.

With regard to brain activations,

direct comparison of patients with control subjects

in the interference condition revealed

hyperactivity in rostral anterior cingulate gyrus (rACG) and

left dorsolateral prefrontal cortex (DLPFC)

in depressive patients,

which correlated strongly with the Stroop interference.

CONCLUSIONS: The study provides new evidence for the

functioning and dissociation of the anterior cingulate in depressed patients.

The greater prefrontal activation may reflect a cortical inefficiency due to hyperactivity in rACG

enhancing the cognitive interferences

from the emotional state.

That would mean the inefficiency is related and connected to the emotional state, sounding here like the emotional state is CAUSING the cognitive interferences.

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Smolka et al 2007

Abstract – Germany

Emotional reactivity and regulation

…………are fundamental to human behavior.

As inter-individual behavioral variation is affected by a multitude of different genes, there is intense interest to investigate gene-gene effects. Functional sequence variation at two genes has been associated with response and resiliency to emotionally unpleasant stimuli.

These genes are the catechol-O-methyltransferase gene (COMT Val158Met) and the regulatory region (5-HTTLPR) of the serotonin transporter gene.

Recently, it has been proposed that 5-HTT expression is not only affected by the common S/L variant of 5-HTTLPR but also by an A to G substitution.

Using functional magnetic resonance imaging, we assessed the effects of COMT Val(158)Met and both 5-HTT genotypes on brain activation by standardized affective visual stimuli (unpleasant, pleasant, and neutral) in 48 healthy subjects.

Based on previous studies, the analysis of genotype effects was restricted to limbic brain areas.

…………To determine allele-dose effects, the number of COMT Met158 alleles (i.e., lower activity of COMT) and the number of 5-HTT low expressing alleles (S and G) was correlated with the blood oxygen level-dependent (BOLD) response to pleasant or unpleasant stimuli compared to neutral stimuli.

We observed an additive effect of COMT and both 5-HTT polymorphisms, accounting for 40% of the inter-individual variance in the averaged BOLD response of amygdala, hippocampal and limbic cortical regions elicited by unpleasant stimuli.

Effects of 5-HTT and COMT genotypes did not affect brain processing of pleasant stimuli.

……………..These data indicate that functional brain imaging may be used to assess the interaction of multiple genes on the function of neuronal networks.

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Bertolino et al 2005

Abstract – Psychiatric Neuroscience Group, Section on Mental Disorders, Department of Psychiatric and Neurological Sciences, University of Bari, Bari, Italy. bertolia@psichiat.uniba.it

In the brain, processing of fearful stimuli engages the amygdala, and the variability of its activity is

associated with genetic factors

as well as with emotional salience.

The objective of this study was to explore the relevance of personality style for variability of amygdala response. Now this seems like a silly “which came first, the chicken or the egg” scenario!

METHODS: We studied two groups (n=14 in each group) of healthy subjects categorized by

contrasting cognitive styles

with which they attribute salience to fearful stimuli:

so-called phobic prone subjects who exaggerate potential environmental threat

versus so-called eating disorders prone subjects

who tend to be much less centered around fear.

That’s kind of a scary comparison, in more ways than one.  Firstly, this is a value judgment that would be more accurately be measured by anxiety scales.  Secondly, eating disordered subjects sound like vampires, me having been watching perhaps too many Buffy shows!  The ones who eat big things, perhaps, closer to the hawk traits, the predators and the carnivores versus the herbivores?  Do we have genetic predispositions based on ancient genetic memory of being more one or the other, and now both?

The two groups underwent functional magnetic resonance imaging (fMRI) at 3T during performance of a perceptual task of threatening stimuli and they were also matched for the genotype of the

5′ variable number tandem repeat (VNTR) polymorphism in the serotonin transporter. RESULTS: The fMRI results indicated that

phobic prone subjects selectively recruit the amygdala to a larger extent than eating disorders prone subjects.

Activity in the amygdala was also independently predicted by personality style and genotype of the serotonin transporter.

Moreover, brain activity during a working memory task did not differentiate the two groups. CONCLUSIONS:

The results of the present study suggest that

aspects of personality style

are rooted in biological responses of the fear circuitry associated with processing of environmental information.

Well, that would certainly indicate an open spot for epigenetics to enter and adjust!  But nothing is that simple, and this has to be a polygenetic condition – not ignoring vasopressin, the operation of the cannabinoid system, etc.  The doves and hawks, the “loomers” and the “flutterers.”

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Rubino et al 2007

Abstract – Psychiatric Neuroscience Group, Section on Mental Disorders, Department of Psychiatric and Neurological Sciences, University of Bari, Bari, Italy.

Cognitive evaluation of emotional stimuli involves a network of brain regions including the medial prefrontal cortex (mPFC).

However, threatening stimuli may be perceived with differential salience in different individuals.

The goal of our study was to evaluate how different personality styles are associated with differential modulation of brain activity during explicit recognition of fearful and angry facial expressions.

Twenty-eight healthy subjects [doesn’t say here any of them had eating disorders!?] underwent fMRI. Based on a cognitivist model, subjects were categorized according to how they attribute salience to emotional stimuli and how they regulate their emotional activation. Define “how.”

We compared 14 phobic prone (PP) subjects,

whose identity is more centered on the inner experience (“inward”) and around control of environmental threat,

and 14 eating disorders prone (EDP) subjects,

whose identity is more centered on external referential contexts (“outward”) and much less around control of threatening stimuli.

During fMRI subjects either matched the identity of one of two angry and fearful faces to that of a simultaneously presented target face or identified the expression of a target face by choosing one of two simultaneously presented linguistic labels. The fMRI results indicated that PP subjects had greater mPFC activation when compared with EDP subjects during cognitive labeling of threatening stimuli.

Activity in the mPFC also correlated with personality style scores.

These results demonstrate that

PP subjects

recruit greater neuronal resources in mPFC

whose activity is associated with cognitive aspects

that are closely intertwined with emotional processing.

These findings are consistent with the contention that

cognitive evaluation and salience of emotional stimuli

are associated with different personality styles.

In the OLD ways, ancient food finding patterns perhaps – things that loom versus things that flutter.  Both having a place in the ordering of the species, and in meeting the needs of the species for diversification of abilities and needs in finding and using resources.  The allostatic load people also tie these differences into how the immune system is geared to operate differently – in interaction with how the brain is processing information.

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Harenski & Hamann 2006

Abstract – Department of Psychology, Emory University, 532 North Kilgo Circle, Atlanta, GA 30322, USA.

Previous neuroimaging studies have identified several brain regions associated with regulating emotional responses. Different kinds of emotional stimuli, however, may recruit different regulatory processes and, in turn, recruit different regions. We compared emotion regulation for two types of negative emotional stimuli: those involving moral violations (moral stimuli), and those not involving moral violations (non-moral stimuli). In addition, we investigated whether activation in medial prefrontal cortex (MPFC), a region implicated previously in specifically moral processing, may instead reflect greater social and emotional content. Ten female subjects were scanned using fMRI while they passively viewed or were instructed to decrease emotional reactions to moral and non-moral pictures closely matched on social and emotional content. Passive viewing of both picture types elicited similar activations in areas related to the processing of social and emotional content, including MPFC and amygdala. During regulation, different patterns of activation in these regions were observed for moral vs. non-moral pictures. These results suggest that the neural correlates of regulating emotional reactions are modulated by the emotional content of stimuli, such as moral violations. In addition, the current findings suggest that

some brain regions previously implicated in moral processing reflect the processing of greater social and emotional content in moral stimuli.

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Phan et al 2003

Abstract – Department of Psychiatry, University of Michigan, Ann Arbor, Michigan 48109-0118, USA.

Activation of the medial prefrontal cortex and extended amygdala by individual ratings of emotional arousal: a fMRI study.

Significant differences between individual responses to emotional stimuli can be important for the study of emotion…

medial prefrontal cortex (MPFC) and

sublenticular extended amygdala (SLEA),

areas implicated in the processing of emotional salience.

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Kerestes et al 2008

Abstract – Behavioural Neuroscience Laboratory, School of Psychology, Psychiatry and Psychological Medicine, Monash University, Melbourne, Australia, Rebecca.Kerestes@med.monash.edu.au.

Serotonergic (SSRI) and noradrenergic (NRI) antidepressants modulate biases in emotional processing

such that perceptual bias is shifted away from negative and towards positive emotional material.

Well, isn’t that convenient!  Artificial, external editorship, censoring —  well, really, the effect seems to be to augment the emotion expression decoding of happy facial expressions in healthy male subjects.  This would be helpful as per research that shows depressed mother’s do not respond to their infant’s happy expressions and therefore the happy part of the infant’s brain does not form “correctly” – hence, passing it down the generations.  It has been shown in other research that depressed people do not see others’ happy expressions.  Sort of a “tuning out” of the happy information, I guess.  This research is not about depressed people, though – supposedly these subjects were healthy and normal.

However, the effects of serotonergic and noradrenergic modulation on the temporal course (occurring in milliseconds) of emotional processing, and in particular, the rapid physiological changes associated with the different stages of emotional processing, are unknown. OBJECTIVE: The current study assessed the effects of acute serotonergic (i.e. with citalopram) and noradrenergic (i.e. with reboxetine) augmentation on event-related potential (ERP) measures associated with ‘structural encoding’ (N170) and emotion expression decoding (N250 and late positive potential [LPP]) for positive (happy) and negative (sad) facial stimuli relative to neutral facial stimuli. MATERIALS AND METHODS: This study employed a double-blind, placebo-controlled, cross-over design in which 12 healthy male participants completed a facial expression recognition task tested under three acute conditions: (a) placebo, (b) citalopram (20 mg) and (c) reboxetine (4 mg). RESULTS: Both citalopram and reboxetine had no effect on the N170 ERP component associated with structural encoding, but potentiated the N250 associated with happy (relative to neutral) emotional facial expression decoding. Both drugs had no valence effects on later ERP measures of emotion expression decoding (LPP). CONCLUSIONS: Citalopram [acute serotonergic] and reboxetine [noradrenergic augmentation] have selective effects on the temporal course of emotional processing with evidence to suggest specific effects on emotion expression decoding of positive (happy) emotional facial stimuli as evidenced by changes in the attention-modulated N250 but not structural encoding. These findings provide physiological evidence that antidepressants may shift perceptual biases in emotional processing away from negative and towards positive stimuli. Hence, we could all live in the HAPPY world, forget the “negative” no matter how important or real?  Is this related to what avoidant insecure attachment people can do?  Or, do they not see the happy either?  This research is saying nothing, of course, about what the molecular or genetic level is doing with this alteration or process.

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Blau et al 2007

Abstract – Sackler Institute for Developmental Psychobiology, Weill Medical College of Cornell University, New York, USA. v.blau@psychology.unimaas.nl

According to the traditional two-stage model of face processing, the face-specific N170 event-related potential (ERP) is linked to structural encoding of face stimuli, whereas later ERP components are thought to reflect processing of facial affect. This view has recently been challenged by reports of N170 modulations by emotional facial expression. This study examines the time-course and topography of the influence of emotional expression on the N170 response to faces. METHODS: Dense-array ERPs were recorded in response to a set (n = 16) of fear and neutral faces. Stimuli were normalized on dimensions of shape, size and luminance contrast distribution. To minimize task effects related to facial or emotional processing, facial stimuli were irrelevant to a primary task of learning associative pairings between a subsequently presented visual character and a spoken word. RESULTS:

N170 [linked to structural encoding of face stimuli – but here shown to be “more than” this only] to faces showed a strong modulation by emotional facial expression.

A split half analysis demonstrates that this effect was significant both early and late in the experiment and was therefore not associated with only the initial exposures of these stimuli, demonstrating a form of robustness against habituation.

The effect of emotional modulation of the N170 to faces did not show significant interaction with the gender of the face stimulus, or hemisphere of recording sites. Subtracting the fear versus neutral topography provided a topography that itself was highly similar to the face N170. CONCLUSION: The face N170 response can be influenced by emotional expressions contained within facial stimuli. The topography of this effect is consistent with the notion that fear stimuli exaggerates the N170 response itself.

This finding stands in contrast to previous models

suggesting that N170 processes linked to structural analysis

of faces precede analysis of emotional expression,

and instead may reflect early top-down modulation from neural systems involved in rapid emotional processing.

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Blair et al 2007

Abstract – Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-2670, USA. peschark@mail.nih.gov <peschark@mail.nih.gov>

In this study, we examined the impact of goal-directed processing on the response to emotional pictures and the impact of emotional pictures on goal-directed processing. Subjects (N=22) viewed neutral or emotional pictures in the presence or absence of a demanding cognitive task.

Goal-directed processing disrupted the BOLD response to emotional pictures. In particular, the

BOLD response within bilateral amygdala and inferior frontal gyrus decreased during concurrent task performance. Moreover, the presence of both positive and negative distractors disrupted task performance, with

reaction times increasing for emotional relative to neutral distractors. With dissociation, the reaction time can extend into infinity – when no adequate response is available – or so says the trained trauma brain

Moreover, in line with the suggestion of the importance of lateral frontal regions in emotional regulation [Ochsner, K. N., Ray, R. D., Cooper, J. C., Robertson, E. R., Chopra, S., Gabrieli, J. D., et al. (2004). For better or for worse: neural systems supporting the cognitive down-and up-regulation of negative emotion. NeuroImage, 23(2), 483-499], connectivity analysis revealed

positive connectivity between

lateral superior frontal cortex and regions of middle frontal cortex previously implicated in emotional suppression [Beauregard, M., Levesque, J., and Bourgouin, P. (2001). Neural correlates of conscious self-regulation of emotion. J. Neurosci., 21 (18), RC165.; Levesque, J., Eugene, F., Joanette, Y., Paquette, V., Mensour, B., Beaudoin, G., et al. (2003). Neural circuitry underlying voluntary suppression of sadness. Biol. Psychiatry, 53 (6), 502-510.; Ohira, H., Nomura, M., Ichikawa, N., Isowa, T., Iidaka, T., Sato, A., et al. (2006). Association of neural and physiological responses during voluntary emotion suppression. NeuroImage, 29 (3), 721-733] and negative connectivity with bilateral amygdala. These data suggest that processes involved in emotional regulation are recruited during task performance in the context of emotional distractors.

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Koch et al 2007

Abstract – Department of Psychiatry and Psychotherapy, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany.

The interaction of emotion and cognition has become a topic of major interest. However, the influence of gender on the interplay between the two processes, along with its neural correlates have not been fully analyzed so far. In this functional magnetic resonance imaging (fMRI) study we induced negative emotion using negative olfactory stimulation while male (n=21) and female (n=19) participants performed an n-back verbal working memory task. Based on findings indicating increased emotional reactivity in women, we expected the female participants to exhibit stronger activation in characteristically emotion-associated areas during the interaction of emotional and cognitive processing in comparison to the male participants. Both groups were found to be significantly impaired in their working memory performance by negative emotion induction. However, fMRI analysis revealed distinct differences in neuronal activation between groups.

In men, cognitive performance under negative emotion induction

was associated with extended activation patterns in

mainly prefrontal and superior parietal regions.

In women, the interaction between emotion and working memory yielded a significantly stronger response in the amygdala and the orbitofrontal cortex (OFC) compared to their male counterparts.

Our data suggest that in

women the interaction of verbal working memory and negative emotion is associated with relative hyperactivation in more emotion-associated areas whereas in

men regions commonly regarded as important for cognition and cognitive control are activated.

These results provide new insights in gender-specific cerebral mechanisms.

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Vuilleumier & Pourtois 2007

Abstract – Laboratory for Behavioral Neurology & Imaging of Cognition, Clinic of Neurology, University Hospital of Geneva, Geneva, Switzerland. patrik.vuilleumier@medecine.unige.ch

Brain imaging studies in humans have shown that face processing in several areas is modulated by the affective significance of faces, particularly with fearful expressions, but also with other social signals such gaze direction. Here we review haemodynamic and electrical neuroimaging results indicating that

activity in the face-selective fusiform cortex

may be enhanced by emotional (fearful) expressions,

without explicit voluntary control,

and presumably through direct feedback connections

from the amygdala.

fMRI studies show that these increased responses in fusiform cortex to fearful faces are abolished by amygdala damage in the ipsilateral hemisphere, despite preserved effects of voluntary attention on fusiform; whereas emotional increases can still arise despite deficits in attention or awareness following parietal damage, and appear relatively unaffected by pharmacological increases in cholinergic stimulation.

Fear-related modulations of face processing driven by amygdala signals may implicate not only fusiform cortex, but also earlier visual areas in occipital cortex (e.g., V1) and other distant regions involved in social, cognitive, or somatic responses (e.g., superior temporal sulcus, cingulate, or parietal areas).

In the temporal domain, evoked-potentials show a widespread time-course of emotional face perception, with some increases in the amplitude of responses recorded over both occipital and frontal regions for fearful relative to neutral faces (as well as in the amygdala and orbitofrontal cortex, when using intracranial recordings), but with different latencies post-stimulus onset.

Early emotional responses may arise around 120ms, prior to a full visual categorization stage indexed by the face-selective N170 component, possibly reflecting rapid emotion processing based on crude visual cues in faces. Other electrical components arise at later latencies and involve more sustained activities, probably generated in associative or supramodal brain areas, and resulting in part from the modulatory signals received from amygdala.

Altogether, these fMRI and ERP results demonstrate that emotion face perception is a complex process that cannot be related to a single neural event taking place in a single brain regions, but rather implicates an interactive network with distributed activity in time and space.

Moreover, although traditional models in cognitive neuropsychology have often considered that facial expression and facial identity are processed along two separate pathways, evidence from fMRI and ERPs suggests instead that

emotional processing can strongly affect brain systems responsible for face recognition and memory.

The functional implications of these interactions remain to be fully explored, but might play an important role in the normal development of face processing skills and in some neuropsychiatric disorders.

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Noesselt et al 2005

Abstract – Institute of Cognitive Neuroscience, University College London, 17 Queen Square, London WC1N 3AR, United Kingdom. toemme@neuro2.med.uni-magdeburg.de

Traditional split-field studies and patient research indicate a privileged role for the right hemisphere in emotional processing [1-7], but there has been little direct fMRI evidence for this, despite many studies on emotional-face processing [8-10](see Supplemental Background). With fMRI, we addressed differential hemispheric processing of fearful versus neutral faces by presenting subjects with faces bilaterally [11-13]and orthogonally manipulating whether each hemifield showed a fearful or neutral expression prior to presentation of a checkerboard target. Target discrimination in the left visual field was more accurate after a fearful face was presented there. Event-related fMRI showed right-lateralized brain activations for fearful minus neutral left-hemifield faces in right visual areas, as well as more activity in the right than in the left amygdala. These activations occurred regardless of the type of right-hemifield face shown concurrently, concordant with the behavioral effect. No analogous behavioral or fMRI effects were observed for fearful faces in the right visual field (left hemisphere). Right or left handed subjects?

The amygdala showed enhanced functional coupling with right-middle and anterior-fusiform areas in the context of a left-hemifield fearful face.

These data provide behavioral and fMRI evidence for right-lateralized emotional processing during bilateral stimulation involving enhanced coupling of the amygdala and right-hemispheric extrastriate cortex.

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Pourtois & Vuilleumier 2006

Abstract – Neurology & Imaging of Cognition, Clinic of Neurology, University Hospital & Department of Neurosciences, University Medical Center, University of Geneva, Switzerland. gilles.pourtois@medecine.unige.ch

An efficient detection of threat is crucial for survival and requires an appropriate allocation of attentional resources toward the location of potential danger. Recent neuroimaging studies have begun to uncover the brain machinery underlying the reflexive prioritization of spatial attention to locations of threat-related stimuli. Here, we review functional brain imaging experiments using event-related potentials (ERPs) and functional magnetic resonance imaging (fMRI) in a dot-probe paradigm with emotional face cues, in which we investigated the spatio-temporal dynamics of attentional orienting to a visual target when the latter is preceded by either a fearful or happy face, at the same (valid) location or at a different (invalid) location in visual periphery. ERP results indicate that fearful faces can bias spatial attention toward threat-related location, and enhance the amplitude of the early exogenous visual P1 activity generated within the extrastriate cortex in response to a target following a valid rather than invalid fearful face. Furthermore, this gain control mechanism in extrastriate cortex (at 130-150 ms) is preceded by an earlier modulation of activity in posterior parietal regions (at 40-80 ms) that may provide a critical source of top-down signals on visual cortex.

Happy faces produced no modulation of ERPs in extrastriate and parietal cortex. fMRI data also show increased responses in the occipital visual cortex for valid relative to invalid targets following fearful faces, but in addition reveal significant decreases in intraparietal cortex and increases in orbitofrontal cortex when targets are preceded by an invalid fearful face,

suggesting that negative emotional stimuli

may not only draw but also hold spatial attention more strongly than neutral or positive stimuli.

These data confirm that threat may act as a powerful exogenous cue and trigger reflexive shifts in spatial attention

toward its location,

through a rapid temporal sequence of neural events

in parietal and temporo-occipital areas,

with dissociable neural substrates

for engagement benefits in attention

affecting activity in extrastriate occipital areas and increased disengagement costs affecting intraparietal cortex.

These brain-imaging results reveal how emotional signals related to threat can play an important role in modulating spatial attention to afford flexible perception and action.

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Pourtois et al 2006

Abstract – Neurology and Imaging of Cognition, Clinic of Neurology, University Hospital and Department of Neurosciences, University Medical Center, Switzerland. patrik.vuilleumier@medecine.unige.ch

Attention may reflexively shift towards the location of perceived threats, but it is still unclear how these spatial biases recruit the distributed fronto-parietal cortical networks involved in other aspects of selective attention. We used event-related fMRI to determine how brain responses to a neutral visual target are influenced by the emotional expression of faces appearing at the same location during a covert orienting task. On each trial, two faces were briefly presented, one in each upper visual field (one neutral and one emotional, fearful or happy), followed by a unilateral target (a small horizontal or vertical bar) replacing one of the faces. Participants had to discriminate the target orientation, shown on the same (valid) or opposite (invalid) side as the emotional face. Trials with faces but no subsequent target (cue-only trials) were included to disentangle activation due to emotional cues from their effects on target detection.

We found increased responses in bilateral temporo-parietal areas and right occipito-parietal cortex for fearful faces relative to happy faces, unrelated to the subsequent target and cueing validity. More critically, we found a selective modulation of intraparietal and orbitofrontal cortex for targets following an invalid fearful face, as well as an increased visual response in right lateral occipital cortex for targets following a valid fearful face. No such effects were observed with happy faces. These results demonstrate that

fearful faces can act as exogenous cues by increasing sensory processing in extrastriate cortex for a subsequent target presented at the same location, but also produce a cost in disengaging towards another location by altering the response of IPS to invalidly cued targets.

Neural mechanisms responsible for orienting attention

towards emotional vs. non-emotional stimuli

are thus partly shared in parietal and visual areas,

but also partly distinct.

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Pourtois et al 2005

Abstract – Department of Neuroscience, Neurology and Imaging of Cognition, Clinic of Neurology, University Medical Centre (CMU), Bat. A, Physiology, Geneva, Switzerland. gilles.pourtois@medecine.unige.ch

Visuo-spatial attention tends to be prioritized towards emotionally negative stimuli such as fearful faces, as opposed to neutral or positive stimuli. Here is the other side of the info on changing bias through antidepressants – the visual attention, at least, certainly has a survival component

Using a covert orienting task, we previously showed that a lateral occipital P1 component, with extrastriate neural sources, was selectively enhanced to lateralized visual targets replacing a fearful face (fear-valid trial) than the same targets replacing a neutral face (fear-invalid trial), providing evidence for

exogenous spatial orienting of attention towards threat cues.

Here, we describe a new analysis of these data, using topographic evoked potentials mapping methods combined with a distributed source localization technique. We show that an early field topography (40-80 ms post-target onset) with a centro-parietal negativity and a left posterior parietal source

distinguished fear-valid from fear-invalid trials,

whereas a distinct activity with anterior cingulate sources

was selectively evoked during fear-invalid trials.

At the same latency, or later, no difference in field topography was found for valid compared to invalid trials with happy faces. The early parietal map preceded a modulation in amplitude of the field strength (approximately 130 ms), corresponding to the enhanced lateral occipital P1 during valid trials in the fear condition. Furthermore, this early topography at 40-80 ms was positively correlated with the subsequent amplitude modulation of P1 at 130-160 ms in the fear condition, suggesting a possible functional coupling between these two successive events.

These data have important implications for models of

spatial attention and interactions with emotion.

They suggest two successive stages of neural activity

during exogenous orienting of attention towards visual targets following fearful faces,

including an early posterior parietal negativity,

followed by gain control mechanisms

enhancing visual responses in

extrastriate occipital cortex.

Well, what can I say.  I have seen more separate incidents of a fearful face than most people could see in several lifetimes – or more.  What affect those encounters had on my developing brain had to include the creation of a chasm, not a track or a rut, of a different kind of orienting of attention toward visual targets following fearful faces – Schore and all describe the disorganized, disoriented insecure attachment following mothering by either a frightened or a frightening mother – and it has been very hard for me to equate these two in my thoughts – and yet here is an area where it might not matter to the brain, certainly mattering little to the developing brain – if the face is full of terror or is so terrifying itself that it creates terror in its wake – something has to, had to have happened in these brain regions that is NOT NORMAL in a secure benevolent world.

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Holmes, Richards & Green 2006

Abstract – School of Psychology, Birkbeck University of London, UK. a.holmes@roehampton.ac.uk

This paper reports three studies in which stronger orienting to perceived eye gaze direction was revealed when observers viewed faces showing fearful or angry, compared with happy or neutral, emotional expressions.

Gaze-related spatial cueing effects to

laterally presented fearful faces and

centrally presented angry faces were also

modulated by the anxiety level of participants, with high- but not low-state anxious individuals revealing enhanced shifts of attention.

In contrast, both high- and low-state anxious individuals demonstrated enhanced orienting to averted gaze when viewing laterally presented angry faces. These results provide novel evidence for

the rapid integration of facial expression and

gaze direction information, and for the

regulation of gaze-cued attention by both the emotion conveyed in the perceived face and the

degree of anxiety experienced by the observer.

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Fox, Derakshan & Shoker 2008

Abstract – Department of Psychology, University of Essex, Colchester, Essex , UK. efox@essex.ac.uk

We investigated the electrophysiological markers of attentional bias for threat in anxiety. Low-anxiety and high-anxiety individuals performed a spatial-cueing task, in which an emotional facial expression (angry or happy) was presented alongside a neutral expression. Results revealed that angry expressions elicited an enhanced N2pc component, … true only for those reporting high levels of trait anxiety. These results confirm the early capture of spatial attention by threat-related stimuli, and demonstrate that this early bias is modulated by trait anxiety.

Enhanced P1 amplitudes to targets after presentations of angry expressions were also found; however, this effect was not modulated by trait anxiety levels. Our findings indicate that

individual differences in temperament

are an important determinant

of the early neural response to threat.

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Santesso et al 2008

Abstract – Department of Psychology, Harvard University, Cambridge, MA, USA.

The goal of this study was to examine behavioral and electrophysiological correlates of involuntary orienting toward rapidly presented angry faces in non-anxious, healthy adults using a dot-probe task in conjunction with high-density event-related potentials and a distributed source localization technique. Consistent with previous studies, participants showed hypervigilance toward angry faces, as indexed by facilitated response time for validly cued probes following angry faces and an enhanced P1 component.

An opposite pattern was found for happy faces suggesting that attention was directed toward the relatively more threatening stimuli within the visual field (neutral faces). Source localization of the P1 effect for angry faces indicated increased activity within the anterior cingulate cortex, possibly reflecting conflict experienced during invalidly cued trials. No modulation of the early C1 component was found for affect or spatial attention. Furthermore, the face-sensitive N170 was not modulated by emotional expression. Results suggest that the earliest modulation of spatial attention by face stimuli is manifested in the P1 component, and provide insights about mechanisms underlying attentional orienting toward cues of threat and social disapproval.

This social disapproval and cue of threat has to be connected to dominance and domination in the social hierarchy.  This would be about, in part, oxytocin and vasopressin.

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Pourtois et al 2004

Abstract – Neurology & Imaging of Cognition, University of Geneva, Switzerland. gilles.pourtois@medecine.unige.ch

We investigated the spatio-temporal dynamic of attentional bias towards fearful faces. Twelve participants performed a covert spatial orienting task while recording visual event-related brain potentials (VEPs). Each trial consisted of a pair of faces (one emotional and one neutral) briefly presented in the upper visual field, followed by a unilateral bar presented at the location of one of the faces. Participants had to judge the orientation of the bar. Comparing VEPs to bars shown at the location of an emotional (valid) versus neutral (invalid) face revealed an early effect of spatial validity: the lateral occipital P1 component (approximately 130 ms post-stimulus) was selectively increased when a bar replaced a fearful face compared to when the same bar replaced a neutral face. This effect was not found with upright happy faces or inverted fearful faces. A similar amplification of P1 has previously been observed in electrophysiological studies of spatial attention using non-emotional cues. In a behavioural control experiment, participants were also better at discriminating the orientation of the bar when it replaced a fearful rather than a neutral face. In addition, VEPs time-locked to the face-pair onset revealed a C1 component (approximately 90 ms) that was greater for fearful than happy faces. Source localization (LORETA) confirmed an extrastriate origin of the P1 response showing a spatial validity effect, and a striate origin of the C1 response showing an emotional valence effect. These data suggest that activity in primary visual cortex might be enhanced by fear cues as early as 90 ms post-stimulus, and that such effects might result in a subsequent facilitation of sensory processing for a stimulus appearing at the same location. These results provide evidence for neural mechanisms allowing rapid, exogenous spatial orienting of attention towards fear stimuli.

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Fox et al 2007

Abstract – Department of Psychology, University of Essex, Colchester, Essex, England. efox@essex.ac.uk

This study investigated the role of neutral, happy, fearful, and angry facial expressions in enhancing orienting to the direction of eye gaze. Photographs of faces with either direct or averted gaze were presented. A target letter (T or L) appeared unpredictably to the left or the right of the face, either 300 ms or 700 ms after gaze direction changed. Response times were faster in congruent conditions (i.e., when the eyes gazed toward the target) relative to incongruent conditions (when the eyes gazed away from the target letter). Facial expression did influence reaction times, but these effects were qualified by individual differences in self-reported anxiety.

High trait-anxious participants showed an enhanced orienting

to the eye gaze of faces with fearful expressions

relative to all other expressions.

In contrast, when the eyes stared straight ahead,

trait anxiety was associated with slower responding

when the facial expressions depicted anger.

Thus, in anxiety-prone people

attention is more likely to be held by an expression of anger, whereas attention is guided more potently by fearful facial expressions.

Maybe we need to find a different word to use other than anxiety.

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Putman, Hermans & van Honk 2006

Abstract – Affective Neuroscience Section, Helmholtz Institute, Utrecht University, Utrecht, Netherlands. P.Putman@fss.uu.nl

This study investigated in 2 experiments whether reflexive cuing of attention that occurs after perception of a gaze cue is greater for fearful than for happy faces in normal participants, as hypothesized from a social neuroscience perspective. To increase neuroecological validity, dynamic stimulus presentation was used to display faces that simultaneously morphed from a neutral expression into a happy or fearful one and shifted eye gaze from the center to the periphery. Shifts of attention resulting from a natural fearful gaze were expected to be related to participants’ anxiety traits, in agreement with the often found increased selective attention to threat in anxious participants.

Both hypotheses were confirmed: Fearful faces induced stronger gaze cuing than happy faces, and the strength of this cuing effect was correlated to participants’ anxiety levels. These results

suggest a

neural network,

which integrates

the processing of gaze, expression, and emotional states

to adaptively prime vigilance under threatening circumstances.

Is that all they can do, study the perception of emotion but not the expression of emotion?

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Putman, Saevarsson & van Honk 2007

Abstract – Affective Neuroscience, Helmholtz Institute, Utrecht University, Utrecht, The Netherlands. pputman@fsw.leidenuniv.nl

Hypomania

in bipolar disorders

is characterized by disinhibited, fearless and reward-seeking behavior.

This behavioral pattern suggests that early and automatic responding

to socio-emotional cues such as facial expressions

might be aberrant in hypomania.

The present study tested the predictions that participants selected on hypomania-like trait would show hypovigilant responses to facial cues of danger and increased responses to facial cues of reward. METHODS: From a group of 513, the 16 most trait-hypomanic individuals were selected by use of a shortened version of an established self-report instrument, the General Behavior Inventory (GBI). Their spatial-attentional responses after perception of dynamic fearful and happy facial gaze cues were compared with those of 12 controls. RESULTS: The group difference for full GBI hypomania scores was reliable (p=0.000).

Individuals with elevated hypomanic traits

clearly demonstrated attentional hypovigilance

after perception of fearful, laterally gazing faces

In addition, unlike controls, they demonstrated reliable attentional responding to happy gaze cues (p=0.007). CONCLUSIONS: These data provide the first experimental evidence that

hypomania-like trait

is associated with hypovigilant, fearless responding

to the social cue of an emotionally expressive gaze.

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Brosch et al 2008

Abstract – Swiss Centre for Affective Sciences, Department of Psychology, University of Geneva, Geneva, Switzerland. tobias.brosch@pse.unige.ch

There is much empirical evidence for

modulation of attention by negative — particularly fear-relevant — emotional stimuli.

This modulation is often explained in terms of a fear module.

Appraisal theories of emotion posit a more general mechanism, predicting attention capture by stimuli that are relevant for the needs and goals of the organism, regardless of valence. To examine the brain-activation patterns underlying attentional modulation, we recorded event-related potentials from 20 subjects performing a dot-probe task in which the cues were fear-inducing and nurturance-inducing stimuli (i.e., anger faces and baby faces). Highly similar validity modulation was found for the P1 time-locked to target onset, indicating

early attentional capture by both positive and negative emotional stimuli.

Topographic segmentation analysis and source localization indicate that

the same amplification process is involved

whether attention orienting is triggered by

negative, fear-relevant stimuli

or positive, nurturance-relevant stimuli.

These results confirm that

biological relevance,

and not exclusively fear,

produces an automatic spatial orienting

toward the location of a stimulus.

This is an important finding and lets us know that expenditure of energy in the brain is equal on the attentional level for the good and for the bad – what happens next, and which brain circuits are recruited to respond determine which neural circuits get reinforced, deepened, “firmed up” in the brain – from the beginning.  Orienting in physical space includes the space within our skull.

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Pourtois et al 2006b

Abstract – Neurology & Imaging of Cognition Laboratory, Department of Neuroscience & Neurology Clinic, University Medical Centre (CMU), Geneva, Switzerland. patrick.vuilleumier@medicine.unige.ch

People often remain “blind” to visual changes occurring during a brief interruption of the display.

The processing stages responsible for such failure remain unresolved. We used event-related potentials to determine the

time course of brain activity during conscious change detection versus change blindness.

Participants saw two successive visual displays, each with two faces, and reported whether one of the faces changed between the first and second displays.

Relative to blindness, change detection was associated with a distinct pattern of neural activity at several successive processing stages, including an enhanced occipital P1 response and a sustained frontal activity (CNV-like potential) after the first display, before the change itself. The amplitude of the N170 and P3 responses after the second visual display were also modulated by awareness of the face change. Furthermore, a unique topography of event-related potential activity was observed during correct change and correct no-change reports, but not during blindness, with a recurrent time course in the stimulus sequence and simultaneous sources in the parietal and temporo-occipital cortex.

These results indicate that

awareness of visual changes may depend on the attentional state subserved by coordinated neural activity in a distributed network,

before the onset of the change itself.

Another implication for dissociation in my book – if our attention cannot shift away from what it is “fixed” on easily and flexibly, we will “stagger” if not miss entirely changes that come up in our constantly changing environment.

This is not true only of visual changes.

What about auditory perceptions?

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Kim & Hamann 2007

Abstract – Psychology Department, Emory University, Atlanta, GA 30322, USA.

The ability to cope adaptively with emotional events

by volitionally altering one’s emotional reactions

is important for psychological and physical health

as well as social interaction.

This is the action abilities damaged with early abuse during brain development.  This is also one of the modulatory requirements of the empathy experience.

Cognitive regulation of emotional responses

to aversive events

engages prefrontal regions that modulate activity

in emotion-processing regions such as the amygdala.

Here, to, implications for avoidant insecure attachment patterns.

However,

the neural correlates of the regulation of positive emotions

remain largely unexplored. We used event-related functional magnetic resonance imaging to examine the neural correlates of cognitively increasing and decreasing emotional reactions to positive and negative stimuli. Participants viewed negative, positive, and neutral pictures while attempting to increase, decrease, or not alter their emotional reactions. Subjective reactions were assessed via on-line ratings. Consistent with previous studies,

increasing negative and positive emotion engaged primarily

left-lateralized prefrontal regions,

whereas decreasing emotion activated

bilateral prefrontal regions.

Different activations unique to increasing versus decreasing emotion were observed

for positive and negative stimuli:

Unique increase-related activations were observed only for positive stimuli,

whereas unique decrease-related activations were observed only for negative stimuli.

Regulation also modulated activity in the amygdala,

a key emotion-processing region.

Regulation effects on amygdala activity were larger for positive than for negative stimuli, potentially reflecting a greater malleability of positive emotional reactions.

Increasing and decreasing positive and negative emotion

can thus increase and decrease subjective reactions

and associated amygdala activity in line with regulatory goals,

and is associated with different patterns of prefrontal activation

as a function of emotional valence and regulatory goal.

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Ochsner et al 2004

Abstract – Department of Psychology, Columbia University, 369 Schermerhorn Hall, New York, NY 10027, USA. ochsner@psych.columbia.edu

Functional neuroimaging studies examining the

neural bases of the cognitive control of emotion

have found increased prefrontal and decreased amygdala activation for the reduction or down-regulation of negative emotion. This would probably show as a turning of the head, even slightly, to the right to activate the left regions of the brain?

It is unknown, however, (1) whether the same neural systems underlie the enhancement or up-regulation of emotion, and (2) whether altering the nature of the regulatory strategy alters the neural systems mediating the regulation. To address these questions using functional magnetic resonance imaging (fMRI), participants

up- and down-regulated negative emotion

either by focusing internally

on the self-relevance of aversive scenes

or by focusing externally on alternative meanings

for pictured actions and their situational contexts.

Results indicated

(1a) that both up- and down-regulating negative emotion recruited prefrontal and anterior cingulate regions implicated in cognitive control,

(1b) that amygdala activation was modulated up or down in accord with the regulatory goal, and

(1c) that up-regulation

uniquely recruited regions of left rostromedial PFC implicated in the retrieval of emotion knowledge, yet, I bet, another region implicated in dissociation

whereas down-regulation

uniquely recruited regions of

right lateral and orbital PFC implicated in behavioral inhibition.

self-focused regulation recruited

medial prefrontal regions

implicated in internally focused processing, this possibly including the precuneus [medial parietal region?]

whereas situation-focused regulation

recruited lateral prefrontal regions implicated in

externally focused processing.

These data suggest that both common and distinct neural systems support various forms of reappraisal and that

which particular prefrontal systems modulate the amygdala

in different ways

depends on the regulatory goal and strategy employed.

++++

Ochsner et al 2002

Abstract – Stanford University, USA.

The ability to cognitively regulate emotional responses to aversive events is important for mental and physical health. Little is known, however, about neural bases of the cognitive control of emotion. The present study employed functional magnetic resonance imaging to examine the neural systems used to reappraise highly negative scenes in unemotional terms. Reappraisal of highly negative scenes reduced subjective experience of negative affect.

Neural correlates of reappraisal

were increased activation of the lateral and medial prefrontal regions and

decreased activation of the amygdala and medial orbito-frontal cortex.

These findings support the hypothesis that

prefrontal cortex is involved in constructing

reappraisal strategies that can modulate activity

in multiple emotion-processing systems.

This is not accounting for the fact that much of this activity occurs automatically and unconsciously.

I am extremely uncomfortable if I cannot read someone’s emotions.  It is like they

Are emotionally dead to me and I am “with” a corpse.  To feel is to live to me.  Btu, then, I am not one of the people who can easily use cognition to change or control how I feel about anything.

++++

Eippert et al 2007

Abstract – Institute of Medical Psychology and Behavioral Neurobiology, University of Tuebingen, Germany. f.eippert@uke.uni-hamburg.de

The capacity to voluntarily regulate emotions is critical for mental health, especially when coping with aversive events.

Several neuroimaging studies of emotion regulation found the amygdala to be a target for downregulation and

prefrontal regions to be associated with downregulation.

To characterize the role of prefrontal regions in bidirectional emotion regulation and to investigate regulatory influences on amygdala activity and peripheral physiological measures, a functional magnetic resonance imaging (fMRI) study with simultaneous recording of self-report, startle eyeblink, and skin conductance responses was carried out. Subjects viewed threat-related pictures and were asked to up- and downregulate their emotional responses using reappraisal strategies. I would think that reappraisal strategies would be laborious and very slow compared to the innate automatic responses!  The laboratory is NOT a natural environment for threat

While startle eyeblink responses (in successful regulators) what makes a person a successful regulator? and skin conductance responses were amplified during upregulation, but showed no consistent effect during downregulation,

amygdala activity was increased and decreased according to the regulation instructions. Trial-by-trial ratings of regulation success correlated positively with activity in amygdala during upregulation and orbitofrontal cortex during downregulation.

Downregulation

was characterized by left-hemispheric activation peaks

in anterior cingulate cortex,

dorsolateral prefrontal cortex, and

orbitofrontal cortex

and upregulation

was characterized by a pattern of prefrontal activation

not restricted to the left hemisphere.

Further analyses showed significant overlap of prefrontal activation across both regulation conditions, possibly reflecting cognitive processes underlying both up- and downregulation, but also showed distinct activations in each condition.

The present study demonstrates that

amygdala responses to threat-related stimuli

can be controlled through the use of cognitive strategies depending on recruitment of prefrontal areas,

thereby changing the subject’s affective state.

This study is not about REAL threat – not in a natural situation.  Is this related to the process of detachment?  Of avoidance?  Whatever it is, it beats drugs in my opinion.  And yet for people whose brains formed under extremely adverse conditions, I suspect that there are complications and additive difficulties in implementing this process.  But we can all learn?  This report does not take into consideration the social context of our species, either, and seems to suggest that it is an independent process – which it is essentially, as it is an internal one.

++++

Sander et al 2005

Abstract – Geneva Emotion Research Group, Department of Psychology, University of Geneva, Switzerland. david.sander@pse.unige.ch

Multiple levels of processing

are thought to be involved in the appraisal

of emotionally relevant events,

with some processes

being engaged relatively independently of attention,

whereas other processes may depend on attention and current task goals or context.

We conducted an event-related fMRI experiment to examine how processing angry voice prosody,

an affectively and socially salient signal,

is modulated by voluntary attention.

Think here about an infant, or even one still in the womb, hears and responds to the sound of rage.  The fact that we have innate reactions to this “social signal” implicates genetic involvement – and plasticity or flexibility and adaptability

In this area is especially important to consider with abused children who in the beginning have no way, except biologically, to process these rage filled experiences.

To manipulate attention orthogonally to emotional prosody, we used a dichotic listening paradigm in which meaningless utterances, pronounced with either angry or neutral prosody, were presented simultaneously to both ears on each trial. In two successive blocks, participants selectively attended to either the left or right ear and performed a gender-decision on the voice heard on the target side.

Our results revealed a functional dissociation

between different brain areas.

We need to begin to understand that so-called dissociation

Has at its source very real functional dissociational abilities

Locked into the actual physiological operational processes

Of and within the brain itself.

Dissociation is NOT a mystery.  In all my thousands of hours of study I have yet to encounter an adequate description of what dissociation might ACTUALLY be.  It no more involves defense “mechanisms” than does the processes involved in remembering our name.

Whereas the

right amygdala and bilateral superior temporal sulcus responded to anger prosody irrespective of

whether it was heard from

a to-be-attended or to-be-ignored voice,

the orbitofrontal cortex and the cuneus in medial occipital cortex showed greater activation

to the same emotional stimuli when the angry voice

was to-be-attended rather than to-be-ignored.

So if we talk about the developing brain in this regard, an infant would learn very early on that the angry voice was connected to harm, threat, pain and therefore could not be ignored.  The orbitofrontal cortex and the cuneus in medial occipital cortex would be called into play very early, far earlier than it would need to either in an infant that never heard an angry voice, or heard one that was not connected to persona harm to itself.

Would the experts call this fear conditioning?  Pretty essential and natural response, I would say.  Of course I am not enough of an expert to follow my own trains of thoughts here, but if I were an expert, this is one of the places I would look for the genesis of dissociation!  And therefore for the epigenetic contributions to how these early disasters play themselves out in a persons body, brain, and life time.

Furthermore, regression analyses revealed

a strong correlation between orbitofrontal regions

and sensitivity

on a behavioral inhibition scale measuring

proneness to anxiety reactions.

I always sense a bias here that “sensitivity” and “anxiety proneness”

Are a BAD thing, undesirable – “dysfunctional”

Is this an American bias, in a country where we are all supposed to be TOUGH?

Our results underscore the importance of emotion and attention interactions in social cognition by demonstrating that multiple levels of processing are involved in the appraisal of emotionally relevant cues in voices, and by showing a modulation of some emotional responses by both the current task-demands and individual differences.

++++

some internet interplay around the word “anxiety”:

• S: (n) anxiety, anxiousness ((psychiatry) a relatively permanent state of worry and nervousness occurring in a variety of mental disorders, usually accompanied by compulsive behavior or attacks of panic)
• S: (n) anxiety (a vague unpleasant emotion that is experienced in anticipation of some (usually ill-defined) misfortune)

Definition

Anxiety is a multisystem response to a perceived threat or danger. It reflects a combination of biochemical changes in the body, the patient’s personal history and memory, and the social situation. As far as we know, anxiety is a uniquely human experience. Other animals clearly know fear, but human anxiety involves an ability, to use memory and imagination to move backward and forward in time, that animals do not appear to have. The anxiety that occurs in post-traumatic syndromes indicates that human memory is a much more complicated mental function than animal memory. Moreover, a large portion of human anxiety is produced by anticipation of future events. Without a sense of personal continuity over time, people would not have the “raw materials” of anxiety.

It is important to distinguish between anxiety as a feeling or experience, and an anxiety disorder as a psychiatric diagnosis. A person may feel anxious without having an anxiety disorder. Also a person facing a clear and present danger or a realistic fear is not usually considered to be in a state of anxiety. In addition, anxiety frequently occurs as a symptom in other categories of psychiatric disturbance.

Who decides what a “realistic clear and present danger” is?  Especially when a person is prepared not only through their DNA to be especially sensitive, but also through horrific early experiences that formed their entire body in the first place?

I bristle at the word anxious and anxiety.

Webster places anxiety at 1525 for introduction into our language.

Main Entry:

anx·ious

Pronunciation:

\ˈaŋ(k)-shəs\

Function:

adjective

Etymology:

Latin anxius; akin to Latin angere to strangle, distress – more at anger

Date:

circa 1616

1 : characterized by extreme uneasiness of mind or brooding fear about some contingency : worried <anxious parents> 2 : characterized by, resulting from, or causing anxiety : worrying <an anxious night> 3 : ardently or earnestly wishing <anxious to learn more>

Oh, that’s interesting.  Word origin strangle, distress, anger, even this word entering the language in 1616 is a newcomer.  How did we change anger into worry in our language?  In looking at “worry” the same I find the same connotation of restriction, strangulation, choking.  Yet if one follows “choke” it leads to what matters, either abiding or not abiding – e.g. life or death.

The streams, like blood vessels shifting into capillaries, rivers into streams back up to the headwaters, to the source – the whole “image” in the word anxiety is hard to define, hard to trace, hard to pin down – yet seems to head backwards into an area that concerns an ancient pattern of power versus no power – who has the power and who does not or is not allowed to have the power or be empowered, the disempowered.  The issue underlying the anxiety spectrum is about dominance and competence in the fight to stay alive, not to succumb to what is dangerous, not to be overwhelmed and eliminated by what one must fight.

It is connected in its origins to “reckless blindness in the darkness (temerity).”  It is about what we can withstand, tolerate, stand against.  It concerns acquiescing, giving in or giving up – or not.  About being daring, bold, fool hardy.  It is connected deeply to a sense and a concern with caution.  It is connected to waiting, continuance, continuing on, the sojourn (temporary stay in a place).  Through its connection to “bide” it goes directly to belief and trust.

Now I am getting the sense of the history of the human race in our recent history, at most 70,000 years ago when we began our journey out of Africa.  We traveled and we tarried for a time in one place or another.  Some of us continued to move more than other groups did.  What concepts do we, as humans, still retain in our languages that talk of time so far back?  What did we converse about 140,00 – 200,000 years ago when our FOXP2 gene became active and we began to talk to each other?  Before the traveling began?

When we go to bearing something, withstanding something, again the concept and image go back prior to the 12^th century.

Main Entry: ¹wor·ry

Function: verb

Inflected Form(s): wor·ried; wor·ry·ing

Etymology: Middle English worien, from Old English wyrgan; akin to Old High German wurgen to strangle, Lithuanian veržti to constrict

Date: before 12th century

transitive verb1dialect British : choke , strangle2 a: to harass by tearing, biting, or snapping especially at the throat b: to shake or pull at with the teeth <a terrier worrying a rat> c: to touch or disturb something repeatedly d: to change the position of or adjust by repeated pushing or hauling3 a: to assail with rough or aggressive attack or treatment : torment b: to subject to persistent or nagging attention or effort4: to afflict with mental distress or agitation : make anxious intransitive verb1dialect British : strangle , choke2: to move, proceed, or progress by unceasing or difficult effort : struggle3: to feel or experience concern or anxiety : fret <worrying about his health>

– wor·ried·ly \-(r)ēd-lē, -(r)əd-\ adverb

– wor·ri·er \-(r)ē-ər\ noun

– wor·ry·ing·ly adverb

synonyms worry , annoy , harass , harry , plague , pester , tease mean to disturb or irritate by persistent acts. worry implies an incessant goading or attacking that drives one to desperation <pursued a policy of worrying the enemy>. annoy implies disturbing one’s composure or peace of mind by intrusion, interference, or petty attacks <you’re doing that just to annoy me>. harass implies petty persecutions or burdensome demands that exhaust one’s nervous or mental power <harassed on all sides by creditors>. harry may imply heavy oppression or maltreatment <the strikers had been harried by thugs>. plague implies a painful and persistent affliction <plagued all her life by poverty>. pester stresses the repetition of petty attacks <constantly pestered with trivial complaints>. tease suggests an attempt to break down one’s resistance or rouse to wrath <children teased the dog>.

Main Entry: ¹choke

Function: verb

Inflected Form(s): choked; chok·ing

Etymology: Middle English, alteration of achoken, from Old English ācēocian, from ā-, perfective prefix + cēoce, cēace jaw, cheek – more at abide, cheek

Date: 14th century

Main Entry: abide

Function: verb

Inflected Form(s): abode \-ˈbōd\ or abid·ed; abid·ing

Etymology: Middle English, from Old English ābīdan, from ā-, perfective prefix + bīdan to bide; akin to Old High German ir-, perfective prefix – more at BIDE

Date: before 12th century

transitive verb1: to wait for : await2 a: to endure without yielding : withstand b: to bear patiently : tolerate <cannot abide such bigots>3: to accept without objection <will abide your decision>intransitive verb1: to remain stable or fixed in a state2: to continue in a place : sojourn

synonyms see bear, continue

– abid·er noun

– abide by

1: to conform to <abide by the rules>2: to acquiesce in <will abide by your decision>

Main Entry: ¹cheek

Function: noun

Etymology: Middle English cheke, from Old English cēace; akin to Middle Low German kāke jawbone

Date: before 12th century

1: the fleshy side of the face below the eye and above and to the side of the mouth ; broadly : the lateral aspect of the head2: something suggestive of the human cheek in position or form ; especially : one of two laterally paired parts3: insolent boldness and self-assurance4: buttock 1

synonyms see temerity

– cheek·ful \-ˌfu̇l\ noun

Main Entry: te·mer·i·ty

Function: noun

Inflected Form(s): plural te·mer·i·ties

Etymology: Middle English temeryte, from Latin temeritas, from temere blindly, recklessly; akin to Old High German demar darkness, Latin tenebrae, Sanskrit tamas

Date: 15th century

1 : unreasonable or foolhardy contempt of danger or opposition : rashness , recklessness 2 : an act or instance of temerity

synonyms temerity , audacity , hardihood , effrontery , nerve , cheek , gall , chutzpah mean conspicuous or flagrant boldness. temerity suggests boldness arising from rashness and contempt of danger <had the temerity to refuse>. audacity implies a disregard of restraints commonly imposed by convention or prudence <an entrepreneur with audacity and vision>. hardihood suggests firmness in daring and defiance <admired for her hardihood>. effrontery implies shameless, insolent disregard of propriety or courtesy <outraged at his effrontery>. nerve , cheek , gall, and chutzpah are informal equivalents for effrontery <the nerve of that guy> <has the cheek to call herself a singer> <had the gall to demand proof> <the chutzpah needed for a career in show business>.

Main Entry: bide

Function: verb

Inflected Form(s): bode \ˈbōd\ or bid·ed; bided; bid·ing

Etymology: Middle English, from Old English bīdan; akin to Old High German bītan to wait, Latin fidere to trust, Greek peithesthai to believe

Date: before 12th century

transitive verb1past usually bided : to wait for -used chiefly in the phrase bide one’s time2archaic : withstand <two men…might bide the winter storm – W. C. Bryant>3chiefly dialect : to put up with : tolerate intransitive verb1: to continue in a state or condition2: to wait awhile : tarry3: to continue in a place : sojourn

– bid·er noun

Main Entry: ²bear

Function: verb

Inflected Form(s): bore \ˈbȯr\ ; borne also born \ˈbȯrn\ ; bear·ing

Etymology: Middle English beren to carry, bring forth, from Old English beran; akin to Old High German beran to carry, Latin ferre, Greek pherein

Looking elsewhere, this is a fascinating connection: metaphor, from metapherein, to transfer : meta-, meta- + pherein, to carry.] —  “a carrying over,” from metapherein “transfer, carry over,” from meta- “over, across” (see meta- above, beyond) + pherein “to carry, bear” — “Metaphor” comes from the Greek meta, over, and pherein, to bear. The basic definition of metaphor thus has to do with movement, with a carrying over – Derived from the Greek verb meta-pherein, which means to transfer or to translate (the Latin word for metaphor being ‘translatio’)

Also: The term “pheromone” was introduced by Peter Karlson and Martin Lüscher in 1959, based on the Greek pherein (to transport) and hormon (to stimulate).  [chemical signaling, communication]

Also: Euphoria – New Latin, from Greek, from euphoros, healthy : eu-, eu- + pherein, to bear; … “bearing well,” from eu- “well” + pherein “to carry”

Also: Periphery – [Greek peri- around + pherein to bear] — The word “peripheral” comes from the Greek “peripheria” (“peri-“, around or about + “pherein“, to bear, carry).

Also: Christopher – Etymology: ME Christofre < LL(Ec) Christophorus < Gr(Ec) Christophoros, lit., bearing Christ < christos (see Christ) + pherein, to bear  [word Christ is related to Greek origins in “anointed” which is related to “grime” – smearing over – anointed – ointment – back to Sanskrit “he slaves” back to Greek oil flask]

Also:  connected on the internet to “right to bear arms”; also a discussion of Aristotle and emotions, “bearing or carrying a favor to someone else”

Date:  before 12th century

transitive verb1 a: to move while holding up and supporting b: to be equipped or furnished with c: behave , conduct <bearing himself well> d: to have as a feature or characteristic <bears a likeness to her grandmother> e: to give as testimony <bear false witness> f: to have as an identification <bore the name of John> g: to hold in the mind or emotions <bear malice> h: disseminate i: lead , escort j: render , give2 a: to give birth to b: to produce as yield c (1): to permit growth of (2): contain <oil-bearing shale>3 a: to support the weight of : sustain b: to accept or allow oneself to be subjected to especially without giving way <couldn’t bear the pain> <I can’t bear seeing you cry> c: to call for as suitable or essential <it bears watching> d: to hold above, on top, or aloft e: to admit of : allow f: assume , accept4: thrust , pressintransitive verb1: to produce fruit : yield2 a: to force one’s way b: to extend in a direction indicated or implied c: to be situated : lie d: to become directed e: to go or incline in an indicated direction3: to support a weight or strain -often used with up4 a: to exert influence or force b: apply , pertain -often used with on or upon<facts bearing on the question>

– bear a hand

: to join in and help out

– bear arms

1: to carry or possess arms2: to serve as a soldier

– bear fruit

: to come to satisfying fruition, production, or development

– bear in mind

: to think of especially as a warning : remember

– bear with

: to be indulgent, patient, or forbearing with

synonyms bear , suffer , endure , abide , tolerate , stand mean to put up with something trying or painful. bear usually implies the power to sustain without flinching or breaking <forced to bear a tragic loss>. suffer often suggests acceptance or passivity rather than courage or patience in bearing <suffering many insults>. endure implies continuing firm or resolute through trials and difficulties <endured years of rejection>. abide suggests acceptance without resistance or protest <cannot abide their rudeness>. tolerate suggests overcoming or successfully controlling an impulse to resist, avoid, or resent something injurious or distasteful <refused to tolerate such treatment>. stand emphasizes even more strongly the ability to bear without discomposure or flinching <unable to stand teasing>.

++++

Main Entry: ¹an·ger

Function: verb

Inflected Form(s): an·gered; an·ger·ing \-g(ə-)riŋ\

Date: 13th century

transitive verb : to make angry <he was angered by the decision> intransitive verb : to become angry

This word, anger, still is new to our language – 14^th century.  But now I think about a sort of emotional constriction even on the reality of our experience with this emotion, anger.  Looking into its relations, grief enters the picture – and narrow, strangling.  Perhaps a sort of choking or choking up over something?

The more I look into this strain of thought stemming from the word anxious, the less I like it.  I sense – being an “anxious” sensitive type – that there is a lie and a deception going on here, to disempower those of us who are “anxious trait types” and it reminds me of the witch hunts!

Main Entry: ²anger

Function: noun

Etymology: Middle English, affliction, anger, from Old Norse angr grief; akin to Old English enge narrow, Latin angere to strangle, Greek anchein

Date: 14th century

1 : a strong feeling of displeasure and usually of antagonism 2 : rage 2

– an·ger·less \-ləs\ adjective

synonyms anger , ire , rage , fury , indignation , wrath mean an intense emotional state induced by displeasure. anger, the most general term, names the reaction but in itself conveys nothing about intensity or justification or manifestation of the emotional state <tried to hide his anger>. ire, more frequent in literary contexts, may suggest greater intensity than anger, often with an evident display of feeling <cheeks flushed dark with ire>. rage suggests loss of self-control from violence of emotion <screaming with rage>. fury is overmastering destructive rage that can verge on madness <in her fury she accused us all of betrayal>. indignation stresses righteous anger at what one considers unfair, mean, or shameful <a comment that caused general indignation>. wrath is likely to suggest a desire or intent to revenge or punish <rose in his wrath and struck his tormentor>.

anginas

One entry found.

Main Entry: an·gi·na

Function: noun

Etymology: Latin, throat inflammation, from Greek anchonē strangling, from anchein to strangle

Date: 1578

: a disease marked by spasmodic attacks of intense suffocative pain: as a: a severe inflammatory or ulcerated condition of the mouth or throat b: angina pectoris

– an·gi·nal \an-ˈjī-n^əl, ˈan-jə-\ adjective

I’m going to look at strangle

Main Entry: stran·gle

Function: verb

Inflected Form(s): stran·gled; stran·gling \-g(ə-)liŋ\

Etymology: Middle English, from Anglo-French estrangler, from Latin strangulare, from Greek strangalan, from strangalē halter – more at strain

Date: 14th century

transitive verb1 a: to choke to death by compressing the throat with something (as a hand or rope) : throttle b: to obstruct seriously or fatally the normal breathing of c: stifle2: to suppress or hinder the rise, expression, or growth of <repression strangles free speech>intransitive verb1: to become strangled2: to die from or as if from interference with breathing

– stran·gler \-g(ə-)lər\ noun

Main Entry: ²strain

Function: verb

Etymology: Middle English, from Anglo-French estreindre, from Latin stringere to bind or draw tight, press together; akin to Greek strang-, stranx drop squeezed out, strangalē halter

Date: 14th century

transitive verb1 a: to draw tight : cause to fit firmly <strain the bandage over the wound> b: to stretch to maximum extension and tautness <strain a canvas over a frame>2 a: to exert (as oneself) to the utmost b: to injure by overuse, misuse, or excessive pressure <strained his back> c: to cause a change of form or size in (a body) by application of external force3: to squeeze or clasp tightly: as a: hug b: to compress painfully : constrict 4 a: to cause to pass through a strainer : filter b: to remove by straining <strain lumps out of the gravy>5: to stretch beyond a proper limit <that story strains my credulity>6obsolete : to squeeze out : extortintransitive verb1 a: to make violent efforts : strive <has to strain to reach the high notes> b: to pull against resistance <a dog straining at its leash> c: to contract the muscles forcefully in attempting to defecate -often used in the phrase strain at stool2: to pass through or as if through a strainer <the liquid strains readily>3: to make great difficulty or resistance : balk

– strain a point

: to go beyond a usual, accepted, or proper limit or rule

Main Entry: ¹hal·ter

Function: noun

Etymology: Middle English, from Old English hælftre; akin to Old High German halftra halter, Old English hielfe helve

Date: before 12th century

1 a: a rope or strap for leading or tying an animal b: a headstall usually with noseband and throatlatch to which a lead may be attached2: a rope for hanging criminals : noose ; also : death by hanging3: a woman’s blouse or top that leaves the back, arms, and midriff bare and that is typically held in place by straps around the neck and across the back

Main Entry: strive

Function: intransitive verb

Inflected Form(s): strove \ˈstrōv\ also strived \ˈstrīvd\ ; striv·en \ˈstri-vən\ or strived; striv·ing \ˈstrī-viŋ\

Etymology: Middle English, to quarrel, contend, fight, endeavor, from Anglo-French estriver to quarrel, from estri, estrif strife – more at strife

Date: 13th century

1 : to devote serious effort or energy : endeavor <strive to finish a project> 2 : to struggle in opposition : contend

synonyms see attempt

– striv·er \ˈstrī-vər\ noun

Main Entry: strife

Function: noun

Etymology: Middle English strif, from Anglo-French estrif, estri, of Germanic origin; akin to Middle Dutch striden to fight, Old High German strītan to quarrel – more at stride

Date: 13th century

1 a: bitter sometimes violent conflict or dissension <political strife> b: an act of contention : fight , struggle2: exertion or contention for superiority3archaic : earnest endeavor

synonyms see discord

– strife·less \ˈstrī-fləs\ adjective

++++

Mitchell 2006

abstract – School of Psychology and Clinical Language Sciences, University of Reading, Whiteknights Road, Reading, Berkshire RG6 6AL, UK. r.l.c.mitchell@rdg.ac.uk

We frequently encounter conflicting emotion cues. This study examined how the neural response to emotional prosody differed in the presence of congruent and incongruent lexico-semantic cues. Two hypotheses were assessed:

(i) decoding emotional prosody with conflicting lexico-semantic cues would activate

brain regions associated with

cognitive conflict

(anterior cingulate and dorsolateral prefrontal cortex)

or (ii) the increased attentional load of incongruent cues would modulate the activity of

regions that decode emotional prosody

(right lateral temporal cortex).

While the participants indicated the emotion conveyed by prosody, functional magnetic resonance imaging data were acquired on a 3T scanner using blood oxygenation level-dependent contrast. Using SPM5, the response to congruent cues was contrasted with that to emotional prosody alone, as was the response to incongruent lexico-semantic cues (for the ‘cognitive conflict’ hypothesis). The right lateral temporal lobe region of interest analyses examined modulation of activity in this brain region between these two contrasts (for the ‘prosody cortex’ hypothesis). Dorsolateral prefrontal and anterior cingulate cortex activity was not observed, and neither was attentional modulation of activity in right lateral temporal cortex activity. However,

decoding emotional prosody with incongruent lexico-semantic cues was strongly associated with

left inferior frontal gyrus activity.

This specialist form of conflict

is therefore not processed by the brain using the same neural resources as non-affective cognitive conflict

and neither can it be handled by associated sensory cortex alone.

The recruitment of inferior frontal cortex may indicate increased semantic processing demands but other contributory functions of this region should be explored

How does an infant’s developing brain learn about “matching” the look on its mother’s face with the sound of her words, and then as it progresses, determine the “matching” or congruency between her actual words and the sound of the words?

++++

Pourtois et al 2005b

Abstract – Donders Laboratory for Cognitive and Affective Neuroscience, University of Tilburg, Tilburg, The Netherlands. gilles.pourtois@medecine.unige.ch

Using positron emission tomography we explored brain regions activated during the perception of face expressions, emotional voices and combined audio-visual pairs.

A convergence region

situated in the left lateral temporal cortex

was more activated by bimodal stimuli

than by either visual only or auditory only stimuli.

Separate analyses for the emotions happiness and fear

revealed supplementary convergence areas

situated mainly

anteriorly in the left hemisphere for happy pairings

and in the right hemisphere for fear pairings

indicating

different neuro-anatomical substrates for multisensory integration of positive versus negative emotions.

Activation in the right extended amygdala

was obtained for fearful faces and fearful audio-visual pairs

but not for fearful voices only.

That’s interesting!  The visual information has to be put together with the audio part to trigger an amygdala involvement.  Does seeing a rageful face trigger this area even if the voice-only does not?

But what about fear contextual learning as the infant brain develops?  It had to happen quickly that I was terrified by the SOUND of my mother’s rageful voice, even if I could not see her.

These results suggest that

during the multisensory perception of emotion,

affective information from face and voice converge

in heteromodal regions of the human brain.

++++

Quadflieg et al 2008

Abstract – Department of Biological and Clinical Psychology, Friedrich-Schiller-University, Am Steiger 3//1, D-07743 Jena, Germany. s.quadflieg@abdn.ac.uk

Individuals with social phobia [very new in our language, 1786; phobic, 1897] display neural hyperactivation towards angry facial expressions.

However, it is uncertain whether they also show abnormal brain responses when processing angry voices. Well, that’s what I mean, “abnormal.”  How do we know that these reactions are not perfectly normal??

In an event-related functional magnetic resonance imaging study, we investigated brain responses to neutral and angry voices in 12 healthy control participants and 12 individuals with social phobia when emotional prosody was either task-relevant or task-irrelevant.

Regardless of task, both phobic and non-phobic participants recruited a network comprising

frontotemporal regions,

the amygdala,

the insula, and

the striatum,

when listening to angry compared to neutral prosody.

Across participants, increased activation in orbitofrontal cortex during task-relevant as compared to task-irrelevant emotional prosody processing was found. Compared to healthy controls,

individuals with social phobia

displayed significantly stronger orbitofrontal activation

in response to angry versus neutral voices

under both task conditions.

These results suggest a disorder-associated increased involvement of the orbitofrontal cortex in response to threatening voices in social phobia.

This makes me “defensive” and angry.  Disorder-associated?  Why?  Because we sense different things differently and process this information differently?  WE ARE NOT ALL THE SAME!

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The following information is in my hardcopy dictionary, but I could not access it online.  In my opinion, it is near ludicrous, and “mentally ill” of any professional who would blanket a fear, flight and flight reaction as indicated in the roots of this concept as wrong or sick.  There is a reason why the fear reaction exists, even if it seem “pathological” and creates difficulties in a person’s life.  Dishonoring the process is, to me, as faulty as dishonoring the person whose genes have prepared them to react in such a manner to a perception of threat.

Note in the origins of the word fear reference to sudden danger, ambush, peril – and attempt.

-phobia: a combined form [NL, fr. LL, fr. Gk, fr. –phobos fearing, fr. Phobos fear, flight, fr. Phebesthai to flee; akin to Lith begt to flee, OCS bezati]

1:  exaggerated fear of

2:  intolerance or aversion for

Main Entry: ²fear

Function: noun

Etymology: Middle English fer, from Old English fǣr sudden danger; akin to Old High German fāra ambush and perhaps to Latin periculum attempt, peril, Greek peiran to attempt

Date: 12th century

Look, see, hear, feel the images in the word, ambush.  Ancient awarenesses and sensitivities here.  Danger hiding and lurking in the dead wood!  Things lying in wait to do us harm, things we cannot see, and don’t know if we are prepared to attempt to conquer.

Main Entry: ¹am·bush

Function: verb

Etymology: Middle English embushen, from Anglo-French embuscher, from en in (from Latin in) + busche log, firewood

Date: 14th century

1 a: an unpleasant often strong emotion caused by anticipation or awareness of danger b (1): an instance of this emotion (2): a state marked by this emotion2: anxious concern : solicitude3: profound reverence and awe especially toward God4: reason for alarm : danger

synonyms fear , dread , fright , alarm , panic , terror , trepidation

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Ethofer et al 2006

Abstract – Section of Experimental MR of the CNS, Department of Neuroradiology, University of Tuebingen, Tuebingen, Germany. Thomas.Ethofer@med.uni-tuebingen.de

Emotional information can be conveyed by various means of communication, such as propositional content, speech intonation, facial expression, and gestures. Prior studies have demonstrated that inputs from one modality can alter perception in another modality. To evaluate the impact of emotional intonation on ratings of emotional faces, a behavioral study first was carried out. Second, functional magnetic resonance (fMRI) was used to identify brain regions that mediate crossmodal effects of emotional prosody on judgments of facial expressions. In the behavioral study, subjects rated fearful and neutral facial expressions as being more fearful when accompanied by a fearful voice as compared to the same facial expressions without concomitant auditory stimulus, whereas no such influence on rating of faces was found for happy voices. In the fMRI experiment, this shift in rating of facial expressions in presence of a fearfully spoken sentence was correlated with the hemodynamic response in the left amygdala extending into the periamygdaloid cortex, which suggests that crossmodal effects on cognitive judgments of emotional information are mediated via these neuronal structures. Furthermore, significantly stronger activations were found in the mid-portion of the right fusiform gyrus during judgment of facial expressions in presence of fearful as compared to happy intonations, indicating that enhanced processing of faces within this region can be induced by the presence of threat-related information perceived via the auditory modality. Presumably, these

increased extrastriate activations

[mid-portion of the right fusiform gyrus]

correspond to enhanced alertness,

whereas responses within the left amygdala

modulate cognitive evaluation

of emotional facial expressions.

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Kreifelts et al 2007

Abstract – Department of Psychiatry and Psychotherapy, University of Tuebingen, Osianderstrasse 24, 72076 Tuebingen, Germany. benjamin.kreifelts@med.uni-tuebingen.de

In a natural environment, non-verbal emotional communication is multimodal (i.e. speech melody, facial expression) and multifaceted concerning the variety of expressed emotions.

Understanding these communicative signals and integrating them into a common percept is paramount to successful social behavior.

While many previous studies have focused on the neurobiology of emotional communication in the auditory or visual modality alone, far less is known about multimodal integration of auditory and visual non-verbal emotional information. The present study investigated this process using event-related fMRI. Behavioural data revealed that

audiovisual presentation of non-verbal emotional information

resulted in a significant increase in correctly classified stimuli

when compared with visual and auditory stimulation.

This behavioral gain was paralleled by enhanced activation in

bilateral posterior superior temporal gyrus (pSTG)

and right thalamus,

when contrasting audiovisual to auditory and visual conditions

Further, a characteristic of these brain regions,

substantiating their role in

the emotional integration process,

is a linear relationship between the gain in classification accuracy and the strength of the BOLD response during the bimodal condition.

enhanced effective connectivity

Yet another area I would investigate for dissociation from when things went wrong during brain formation stages.  I don’t think my “associative auditory and visual cortices” are integrated the way they are supposed to be.  This is an area where I have difficulty in hearing a person’s words because on one level I am dissociated from WHAT they are saying and sensing what their intention is behind the words – what their emotional message is – what the message is behind the words – attempting to detect threat of harm, the ambush, to determine what is hiding and lying in wait in the woods.

My brain had to detect threat way before I knew words, or even knew visually what things were specifically – other than my crazy caregiver.

between audiovisual integration areas

and associative auditory and visual cortices

was observed during audiovisual stimulation,

offering further insight into the

neural process

accomplishing multimodal integration.

Finally, we were able to document an enhanced sensitivity of the putative integration sites to stimuli with emotional non-verbal content as compared to neutral stimuli.

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Wildgruber et al 2006

Abstract – Department of Psychiatry, University of Tübingen, Osianderstr. 24, 72076 Tübingen, Germany. dirk.wildgruber@med.uni-tuebingen.de

During acoustic communication in humans, information about a speaker’s emotional state is predominantly conveyed by modulation of the tone of voice (emotional or affective prosody). Based on lesion data,

a right hemisphere superiority for cerebral processing of emotional prosody has been assumed.

However, the available clinical studies do not yet provide a coherent picture with respect to interhemispheric lateralization effects of prosody recognition and intrahemispheric localization of the respective brain regions. To further delineate the cerebral network engaged in the perception of emotional tone, a series of experiments was carried out based upon functional magnetic resonance imaging (fMRI).

The findings obtained from these investigations allow for the separation of three successive processing stages during recognition of emotional prosody:

(1) extraction of suprasegmental acoustic information predominantly subserved by right-sided primary and higher order acoustic regions;

(2) representation of meaningful suprasegmental acoustic sequences within posterior aspects of the right superior temporal sulcus;

(3) explicit evaluation of emotional prosody at the level of the bilateral inferior frontal cortex.

Moreover, implicit processing of affective intonation seems to be bound to subcortical regions mediating automatic induction of specific emotional reactions such as activation of the amygdala in response to fearful stimuli.

As concerns lower level processing of the underlying suprasegmental acoustic cues, linguistic and emotional prosody seem to share the same right hemisphere neural resources.

Explicit judgment

of linguistic aspects of speech prosody

appears to be linked to left-sided language areas

bilateral orbitofrontal cortex has been found involved in

explicit evaluation

of emotional prosody.

These differences in hemispheric lateralization effects might explain that specific impairments in nonverbal emotional communication subsequent to focal brain lesions are relatively rare clinical observations as compared to the more frequent aphasic disorders.

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Ethofer et al 2008

Abstract – 1University of Tübingen, Tübingen, Germany, 2University Medical Center of Geneva, Geneva, Switzerland.

We investigated the functional characteristics of

brain regions implicated in processing of speech melody

by presenting words spoken in either neutral or angry prosody during a functional magnetic resonance imaging experiment using a factorial habituation design. Subjects judged either affective prosody or word class for these vocal stimuli, which could be heard for either the first, second, or third time.

Voice-sensitive temporal cortices,

as well as the amygdala, insula, and mediodorsal thalami, reacted stronger to angry than to neutral prosody.

These stimulus-driven effects were not influenced by the task, suggesting that these brain structures are

automatically engaged during processing of emotional information in the voice and operate relatively

independent of cognitive demands.

By contrast, the right middle temporal gyrus

and the bilateral orbito-frontal cortices (OFC)

responded stronger during emotion than word classification,

but were also sensitive to anger expressed by the voices, suggesting that

some perceptual aspects of prosody

are also encoded within these regions

subserving explicit processing of vocal emotion.

The bilateral OFC showed a selective modulation by emotion and repetition, with particularly pronounced responses to angry prosody during the first presentation only, indicating a

critical role of the orbito-frontal cortices (OFC)in detection of vocal information

that is both novel and behaviorally relevant.

These results converge with previous findings obtained for angry faces and suggest a

general involvement of the orbito-frontal cortices (OFC)

for recognition of anger

irrespective of the sensory modality.

Taken together, our study reveals that different aspects of voice stimuli and perceptual demands modulate distinct areas involved in the processing of emotional prosody.

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Bach et al 2008

Abstract – University Hospital of Psychiatry, University of Bern, Switzerland. d.bach@fil.ion.ucl.ac.uk

In visual perception of emotional stimuli,

low- and high-level appraisal processes

have been found to engage different neural structures.

Beyond emotional facial expression,

emotional prosody is an important auditory cue for social interaction.

Neuroimaging studies have proposed a network for emotional prosody processing that involves a right temporal input region and explicit evaluation in bilateral prefrontal areas.

However, the comparison of different appraisal levels has so far relied upon using linguistic instructions during low-level processing, which might confound effects of processing level and linguistic task. In order to circumvent this problem, we examined processing of emotional prosody in meaningless speech during

gender labeling

(implicit, — low-level appraisal) and

emotion labeling

(explicit, — high-level appraisal).

While bilateral amygdala,

left superior temporal sulcus and

right parietal areas [implicating the precuneus?]

showed stronger blood oxygen level-dependent (BOLD) responses during implicit processing,

areas with stronger BOLD responses during explicit processing included the left inferior frontal gyrus,

bilateral parietal,

anterior cingulate and

supplemental motor cortex.

Emotional versus neutral prosody

evoked BOLD responses in

right superior temporal gyrus,

bilateral anterior cingulate,

left inferior frontal gyrus,

insula and

bilateral putamen.

Basal ganglia and

right anterior cingulate responses to emotional versus neutral prosody were particularly pronounced during

explicit processing.

These results are in line with an

amygdala-prefrontal-cingulate network

controlling different appraisal levels,

and suggest a specific role of the left inferior frontal gyrus in explicit evaluation of emotional prosody.

In addition to brain areas commonly related to prosody processing, our results suggest specific functions of

anterior cingulate and basal ganglia

in detecting emotional prosody, particularly when explicit identification is necessary.

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Rymarczyk & Grabowska 2007

Abstract – Department of Neurophysiology, Nencki Institute of Experimental Biology, Pasteur 3, 02-093 Warsaw, Poland. k.rymarczyk@nencki.gov.pl

Affective (emotional) prosody is a neuropsychological function that encompasses non-verbal aspects of language that are necessary for recognizing and conveying emotions in communication,

whereas non-affective (linguistic) prosody indicates whether the sentence is a question, an order or a statement.

Considerable evidence points to a dominant role for the right hemisphere in both aspects of prosodic function. However, it has yet to be established whether separate parts of the right hemisphere are involved in processing different kinds of emotional intonation.

The aim of this study was to answer this question. In addition, the issue of sex differences in the ability to understand prosody was considered. Fifty-two patients with damage to frontal, temporo-parietal or subcortical (basal) parts of the right hemisphere and 26 controls were tested for their ability to assess prosody information in normal (well-formed) sentences and in pseudo-sentences. General impairment of prosody processing was seen in all patient groups but the effect of damage was more apparent for emotional rather than linguistic prosody. Interestingly, appreciation of emotional prosody appeared to depend on the type of emotional expression and the location of the brain lesion.

The patients with frontal damage were mostly impaired in comprehension of happy intonations;

those with temporo-parietal damage in assessment of sad intonations,

while subcortical lesions mostly affected comprehension of angry intonations.

Differential effects of lesion location on the performance of men and women were also observed.

Frontal lesions were more detrimental to women,

whereas subcortical lesions led to stronger impairment in men. This suggests sex differences in brain organization of prosodic functions.

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Wildgruber et al 2004

Abstract – Department of General Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Germany. dirk.wildgruber@med.uni-tuebingen.de

In addition to the propositional content of verbal utterances, significant linguistic and emotional information is conveyed by the tone of speech. To differentiate brain regions subserving processing of linguistic and affective aspects of intonation, discrimination of sentences differing in linguistic accentuation and emotional expressiveness was evaluated by functional magnetic resonance imaging. Both tasks yielded rightward lateralization of hemodynamic responses at the level of the dorsolateral frontal cortex as well as bilateral thalamic and temporal activation. Processing of linguistic and affective intonation, thus, seems to be supported by overlapping neural networks comprising partially right-sided brain regions.

Comparison of hemodynamic activation during the two different tasks, however, revealed bilateral orbito-frontal responses restricted to the affective condition

as opposed to activation of the left lateral inferior frontal gyrus confined to evaluation of linguistic intonation. These findings indicate that

distinct frontal regions contribute to higher level processing of intonational information depending on its communicational function.

In line with other components of language processing,

discrimination of linguistic accentuation

seems to be lateralized to the left inferior-lateral frontal region whereas bilateral orbito-frontal areas subserve

evaluation of emotional expressiveness.

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Nakashima et al 2008

Abstract – Department of Clinical Neurophysiology, Neurological Institute, Faculty of Medicine Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Japan Society for the Promotion of Science (JSPS), Tokyo, Japan.

It is generally accepted that the N170 component of an event-related potential (ERP) reflects the structural encoding of faces and is specialized for face processing. Recent neuroimaging and ERP studies have demonstrated that spatial frequency is a crucial factor for face recognition. To clarify which early ERP components reflect either coarse (low spatial frequency, LSF) or fine (high spatial frequency, HSF) processing of faces, we recorded ERPs induced by manipulated face stimuli. By filtering the original grayscale faces (broadband spatial frequency) spatially, we created LSF and HSF face stimuli. Next, we created physically equiluminant (PEL) face stimuli to eliminate the effects of lower order information, such as luminance and contrast. The P1 amplitude at the occipital region was augmented by LSF faces, while the N170 amplitude increased for HSF faces. The occipital P1 amplitude for PEL faces was relatively unaffected compared with that for PEL houses. In addition, the occipital N2 for PEL faces was spatiotemporally separable from N170 in a time-window between P1 and N170. These results indicate that P1 reflects coarse processing of faces, and that the face robustness further assures face-specific processing in the early component. Moreover, N2 reflects the early contrast processing of faces whereas N170 analyzes the fine facial features. Our findings suggest the presence of spatial frequency-and-contrast detectors for face processing.  Not sure what this means, maybe only shop talk for those in the know who perform these tests

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Malhi et al 2007

Abstract – CADE Clinic, Royal North Shore Hospital, University of Sydney, Australia. gmalhi@med.usyd.edu.au

To determine the neural responses invoked in the recognition of facial fear and disgust in euthymic [Word origin: Greek “eu” (good, well) + Greek “thumos” (spirit, soul)] bipolar patients as compared with healthy subjects.

METHODS: This study examined 10 female euthymic bipolar patients, and 10 suitably matched healthy subjects using functional magnetic resonance imaging (fMRI) while subjects were engaged in an explicit facial emotion recognition task involving fear, disgust and neutral expressions. The activation paradigm involved nominating the facial expression using specified response keys. Behavioural data were collected and analyzed and both within-group (Fear versus Neutral; Disgust versus Neutral) and random-effects between-group analyses were performed on fMRI data using BrainVoyager (Brain Innovations, Maastricht, the Netherlands). RESULTS: Patients were equally accurate in identifying facial expressions as healthy subjects but were slower to respond, especially with respect to fear and disgust.

Responses to fear and disgust (within-group analyses) resulted in activation of anticipated brain regions such as amygdala and insula, respectively.

However, between-group random effects analysis revealed differential responses to both disgust and fear in both healthy subjects and euthymic bipolar patients such that euthymic bipolar patients responded largely to fear and healthy subjects responded more so to disgust.

This partitioning of responsiveness was reflected by differential activation involving the hippocampus and amygdala.

CONCLUSIONS: Greater responsiveness to fear with hippocampal activation in patients perhaps reflects recollection of traumatic events associated with past experiences of illness or simply the use of a more

mnemonic (hippocampal)

as opposed to affective (amygdala) approach

when performing the task.

It is possible that in bipolar disorder, prefrontal-subcortical network dysfunction that relegates neural processing to limbic regions is impaired and that clinically

euthymic bipolar patients,

although able to accurately and effectively identify emotions such as fear and disgust,

are limited in their ability to interpret their salience.

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Lemche et al 2007

Abstract – Section of Neuroscience and Emotion, Brain Image Analysis Unit, Neuroimaging Research Group, Centre for Neuroimaging Sciences, Institute of Psychiatry, London, UK. e.lemche@iop.kcl.ac.uk

Depersonalization disorder,

characterized by emotional detachment,

has been associated with

increased prefrontal cortical and

decreased autonomic activity

to emotional stimuli.

Event-related fMRI with simultaneous measurements of skin conductance levels occurred in nine depersonalization disorder patients and 12 normal controls to neutral, mild and intense happy and sad facial expressions. Patients, but not controls, showed

This is perhaps the opposite of what I experience with my heightened perception, threat detection radar – how is this effect they are presenting different from avoidant detachment?  How is it different from the “healthy” detachment from emotions?  Perhaps because the choice is not consciously controlled, rather the automatic response is to shut it all down?

decreases in subcortical limbic activity to increasingly intense happy and sad facial expressions, respectively.

For both happy and sad expressions, negative correlations between skin conductance measures in bilateral dorsal prefrontal cortices occurred only in

depersonalization disorder patients.

Abnormal decreases

in limbic activity to increasingly intense emotional expressions,

and increases in dorsal prefrontal cortical activity to emotionally arousing stimuli

may underlie the emotional detachment of depersonalization disorder.

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Lemche et al 2008

Abstract – Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK. e.lemche@iop.kcl.ac.uk

Depersonalization disorder is

characterized by emotion suppression,

but the cerebral mechanisms of this symptom are not yet fully understood. AIMS: To compare brain activation and autonomic responses of individuals with the disorder and healthy controls. METHOD: Happy and sad emotion expressions in increasing intensities (neutral to intense) were presented in an implicit event-related functional magnetic resonance imaging (fMRI) design with simultaneous measurement of autonomic responses. RESULTS:

Participants with depersonalization disorder

showed fMRI signal decreases,

whereas the control group showed signal increases

in response to emotion intensity increases

in both happy and sad expressions.

The analysis of evoked haemodynamic responses from

regions exhibiting functional connectivity between central and autonomic nervous systems indicated that

in depersonalization disorder

initial modulations of haemodynamic response occurred significantly earlier (2 s post-stimulus) than in the control group (4-6 s post-stimulus).

Wee are supposed to be able, except in extreme situations and under dangerous conditions, be able to consciously modulate our emotions BY CHOICE.  When there is a “too much” condition of being under unconscious control, or not being able at all to consciously control our emotions, there is trouble.

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Herba et al 2008

Abstract – Department of Psychological Medicine, Institute of Psychiatry, KCL, London, UK. c.herba@erasmusmc.nl

The impact of personal familiarity upon children’s developing emotion-processing has been largely ignored in previous research, yet may prove particularly important given the emotional salience of such stimuli and children’s greater exposure to familiar others compared to strangers. We examined the impact of personal familiarity upon developing facial expression recognition (FER). METHODS: Participants included 153 children, 4-15 years old. We employed dynamic expressions of

five emotions (happy, sad, anger, fear, disgust),

posed by familiar (parents, teachers) and unfamiliar identities.

RESULTS: Accuracy improved with age for recognizing sad and fear expressions, but not anger.

Children tended to correctly recognize happiness and fear at lower intensities.

The impact of familiarity on FER depended on emotion-category.

Familiarity did not affect recognition of sad expressions,

but children were less accurate at recognizing anger, fear, and disgust in familiar individuals compared to strangers.

CONCLUSION: Personal familiarity may exert a distracting effect on children’s performance. Findings highlight the importance of incorporating different emotion-categories and familiarity when examining the development of FER. Does this vary with attachment – secure4 versus insecure?

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Herba et al 2006

Abstract – Department of Psychological Medicine, Institute of Psychiatry, KCL, UK. c.herba@erasmusmc.nl

This study examined the effects of age and two novel factors (intensity and emotion category) on healthy children’s developing emotion-processing from 4 to 15 years using two matching paradigms. METHODS: An explicit emotion-matching task was employed in which children matched the emotion of a target individual, and an implicit task whereby participants ignored the emotive facial stimulus and matched identity. Four intensities (25%, 50%, 75%, and 100%) for each of five emotion categories (sad, anger, happy, fear, and disgust) were included and provided a novel avenue of emotion-processing exploration. RESULTS: Increasing age significantly improved children’s performance on both tasks, particularly for fear and disgust.

Age was not associated with more subtle processing (i.e., lower intensity of expression).

When explicitly matching emotion expressions, increasing intensity was associated with improved performance. When matching identities (implicit emotion-matching), emotion category and intensity influenced task performance. Sex effects were minimal. CONCLUSIONS: In children, age, facial expression intensity and emotion category are important for predicting accuracy on emotion-processing tasks. Emotion category and expression intensity differentially affect performance on explicit and implicit emotion-processing tasks.

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Richards et al 2007

Abstract – School of Psychology, Birkbeck College, University of London, London, UK. a.richards@bbk.ac.uk

The relationship between children’s anxiety and cognitive biases was examined in two tasks. A group of 50 children aged 10 to 11 years (mean = 11 years, SD = 3.71 months) was given two tasks. The first tested children’s selective attention (SA) to threat in an emotional Stroop task. The second explored facial processing biases using morphed angry-neutral and happy-neutral emotional expressions that varied in intensity. Faces with varying levels of emotion (25% emotion-75% neutral, 50% emotion-50% neutral, 100% emotion-0% neutral [prototype] and 150% emotion-0% neutral [caricature]) were judged as being angry or happy. Results support previous work highlighting a link between anxiety and selective attention (SA) to threat In addition,

increased anxiety in late childhood

is associated with

decreased ability to discriminate facial expression.

One would think the increased anxiety would be designed by nature to facilitate an increased rather than a decreased ability to detect – accurately – facial expressions as an indicator of safety or threat.

Is this same effect found in adulthood?

Is this a form of “dissociation” where there is a split of some kind resulting from the fear that interferes with the discrimination?

lack of discrimination in the emotional expression task

was related to lack of inhibition to threat in the Stroop task.

Is this effect from higher anxiety creating a lack of competence in reaction to the perception or reality of threat in the environment, then?  Is this a consequence of being overwhelmed, of having been pushed past a sensitivity threshold?

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Masten et al 2008

Abstract – Department of Psychology, University of California, 1285 Franz Hall, Box 951563, Los Angeles, CA 90095, USA.

The purpose of this study is to examine processing of facial emotions in a sample of maltreated children showing high rates of post-traumatic stress disorder (PTSD).

Maltreatment during childhood

has been associated independently with both

atypical processing of emotion

and the development of PTSD.

However, research has provided little evidence indicating how high rates of PTSD might relate to maltreated children’s processing of emotions. METHOD: Participants’ reaction time and labeling of emotions were measured using a morphed facial emotion identification task. Participants included a diverse sample of maltreated children with and without PTSD and controls ranging in age from 8 to 15 years. Maltreated children had been removed from their homes and placed in state custody following experiences of maltreatment. Diagnoses of PTSD and other disorders were determined through combination of parent, child, and teacher reports. RESULTS:

Maltreated children

displayed faster reaction times than controls

when labeling emotional facial expressions,

and this result was most pronounced for

fearful faces.

Relative to children who were not maltreated, maltreated children both with and without PTSD showed enhanced response times when identifying fearful faces.

There was no group difference in labeling of emotions when identifying different facial emotions. CONCLUSIONS:

Maltreated children show heightened ability

to identify fearful faces,

evidenced by faster reaction times relative to controls.

This association

between maltreatment and atypical processing of emotion

is independent of PTSD diagnosis

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Famularo, Fenton & Kinscherff 1993

Abstract – Boston Juvenile Court Clinic, Massachusetts Department of Mental Health, Boston, MA 02108.

The purpose of this study was to compare the relative effects of various forms of maltreatment on the development of posttraumatic stress disorder (PTSD) in children. DESIGN–Children were randomly selected from a population of court-involved maltreated children. The children were then assigned to a PTSD group and a non-PTSD group on the basis of their responses to a structured interview. SETTING–A juvenile/family court in a large urban area. PARTICIPANTS–This study examined 101 children who were before a juvenile/family court because of severe child maltreatment. All children had been removed from parental custody as a result of the maltreatment. INTERVENTIONS–None. MEASUREMENTS AND RESULTS–Structured clinical psychiatric interviews were administered to each child and each parent, and all court records were reviewed. The major analyses assessed the extent to which the presence and duration of the most common types of severe maltreatment were associated with a diagnosis of PTSD. Thirty-nine children met criteria for PTSD.

Those who were sexually maltreated and those who witnessed family violence had a much greater likelihood of developing PTSD than did those whose histories of maltreatment did not include these types of events.

The duration of emotional abuse (psychological terror)

also proved to be a significant factor in discriminating children diagnosed as having PTSD from other severely maltreated children.

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Famularo et al 1996

Abstract – Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA.

One-hundred and fifty-six children were randomly evaluated at an inner-city juvenile/family court. These children were removed from their parent’s custody subsequent to a finding of severe child maltreatment. From our original sample of 156 children, 62 met strict criteria for Post Traumatic Stress Disorder (PTSD). Fifty-two of these 62 were successfully recruited and participated in the 2 year re-examination. Each PTSD diagnosis was conferred by the Diagnostic Interview for Children and Adolescents (DICA). From our sample of 52 PTSD children re-examined after 2 years, 17 (32.7%) retained the full PTSD diagnosis, while 67.3% did not meet criteria.

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Famularo & Fenton 1994

Abstract – Boston Juvenile Court, Massachusetts Department of Mental Health.

OBJECTIVE: To determine which factors from the early developmental histories of maltreated children are associated with the risk of developing posttraumatic stress disorder (PTSD). DESIGN: Retrospective cohort analytic study. SETTING: A county juvenile/family court (not a criminal court). SAMPLE: The sample consisted of 117 severely maltreated children, aged 5 to 12 years, whose maltreatment was so severe that they were removed from parental custody. Forty-one (35%) of these children met criteria of the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition, for PTSD. MAIN OUTCOME MEASURES: Individual developmental and temperament-independent variables were used to compare children with PTSD and the maltreated children who did not reach PTSD inclusion criteria. The child’s PTSD status was the primary dependent variable.

RESULTS: Variables representing the three factors from the early developmental history, along with markers for sex and race (black vs other), were entered into a logistic regression, with PTSD status as the outcome variable. Indicators of five different types of child maltreatment were also entered as predictors, to control for previously discovered effects associated with the type of trauma suffered by the children. This analysis disclosed that, while we controlled for the other predictors, one of the developmental factors remained statistically significant, one was marginally significant (P = .07), and one made no contribution toward predicting the probability of PTSD. Sex did not make a significant contribution to the logistic model, but

being black

continued to be associated with a lower probability of developing PTSD.

CONCLUSIONS: We conclude that PTSD may be caused by factors

[that’s a stupid statement – not caused by these!  These are very likely not a cause, but a correlational effect, though abuse and early life trauma CAN cause these difficulties]

discernible in the first year of life that leave a maltreated child vulnerable to this disorder. These include birth weight less than 2.25 kg, jaundice, vomiting, diarrhea, infections, sleep problems, frequent crying, poor weight gain, fussiness, jumpiness, and distress when moved.

How would researchers know this info without getting it from the same family that caused the abuse in the first place?  How accurate would those parental reports be on ANYTHING, in my book.

The seemingly protective effect of being black was an unexpected, although provocative, finding whose interpretation will require further investigation.  One thing to look for is adequate social support as a mediating and moderating factor

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Famularo et al 1996b

Abstract – Boston Juvenile Court, Massachusetts Department of Mental Health, USA.

OBJECTIVE: The purpose of this study was to examine the psychiatric comorbidity between children presenting with Post Traumatic Stress Disorder (PTSD) and traumatized children not developing this disorder. DESIGN: One-hundred and seventeen severely maltreated children were examined for evidence of PTSD. Analyses probed for diagnostic relationship, between PTSD and other formal diagnoses on The Diagnostic Interview for Children and Adolescents, Revised Version (DICA-CR). PARTICIPANTS: All children presented before a juvenile/family court due to severe child maltreatment and psychological trauma. These children had been ordered removed from parental custody due to the trauma suffered by the child. For the purposes of analyses, this entire group of maltreated and traumatized children were dichotomized into a PTSD group and a non-PTSD group. Thirty-five percent (41 of 117) of the children met strict DICA criteria for PTSD. MEASUREMENTS: The children were examined by means of a structured clinical interview. The Diagnostic Interview for Children and Adolescents, revised version (DICA-Child-R), along with a more general psychiatric interview. The DICA-Child-R responses provided the only determination of whether the children met formal PTSD criteria. Data gathering on the sample also included a comprehensive review of risk factors for the development of PTSD, including demographics, and type(s) of trauma suffered. RESULTS: Findings revealed that the

PTSD diagnosis was significantly correlated with:

1. Attention Deficit Hyperactivity Disorder (ADHD)

2. Other anxiety disorders

3. Brief Psychotic Disorder or Psychotic Disorder NOS

4. The presence of suicidal ideation

5. A trend toward mood disorders.

There were no differences between the two samples on measures of age, race, and family income. CONCLUSIONS:

Pediatric PTSD is a severe psychiatric disorder. In this study, PTSD was statistically related to other formal psychiatric diagnoses. The investigators attended to the issues relating to true comorbidity versus inaccurate diagnosis secondary to symptom overlap between different conditions. Applying strict criteria, the results suggest that

the presence of PTSD in children confers a substantial likelihood of other formal diagnosis. Moreover, the symptom of suicidal ideation was overrepresented among PTSD subjects. Given these additional conditions, more extensive evaluation and specialized, multi-modal treatment should be considered in children presenting with PTSD.

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Famularo et al 1994

Abstract – Boston Juvenile Court Clinic, MA 02108.

The purpose of this study was to examine the rates of posttraumatic stress disorder (PTSD) among a sample of severely maltreated children and their mothers, and to investigate the age of onset of documented maltreatment in these children. The sample consisted of 109 pairs of women and their children who were before a juvenile/family court due to maltreatment of sufficient severity to warrant removal of the child from parental custody. Children were examined using the PTSD Section of the Diagnostic Interview for Children and Adolescents, Revised 6th Version (DICA-6-R). The PTSD Module of the Structured Clinical Interview for DSM-III-R (SCID) was administered to all mothers. Clinical psychiatric interviews were also administered to all children and mothers. From the sample of 109 cases, 15.6% of the mothers met SCID criteria for a current presentation of PTSD, while 36.7% had a past history of PTSD.

Of the 109 evaluated children, 35.8% met current DICA criteria for PTSD.

Posttraumatic stress disorder is significantly overrepresented in the children of mothers diagnosed with PTSD (p = .001).

The average age of maltreatment onset was 46.4 months among the children diagnosed as PTSD, and was 61.3 months in the group of seriously maltreated children who did not develop PTSD (p = .038).

The onset of maltreatment is significantly earlier among children whose mothers meet PTSD criteria than among other maltreated children (p = .025).

Intergenerational transmission of violence and developmental effects of traumatic experiences upon the young child are discussed.

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Shaffer, Huston & Egeland 2008

Abstract – Institute of Child Development, University of Minnesota, 51 East River Road, Minneapolis, MN 55455, USA.

One of the greatest methodological problems in the study of childhood maltreatment is the discrepancy in methods by which cases of child maltreatment are identified. The current study compared incidents of maltreatment identified prospectively, retrospectively, or through a combination of both methods. METHOD: Within a cohort of 170 participants followed from birth to age 19, incidents of maltreatment which occurred prior to age 17.5 were identified via prospective case review and interviewer ratings of retrospective self-reports. Multi-informant measures of behavior problems were obtained at age 16, and diagnostic assessments of psychopathology were completed at age 17.5. RESULTS: While the maximal number of maltreatment cases was identified by using a combination of all available identification methods, the prospective method was the single most comprehensive method for identifying the most cases of childhood physical abuse, sexual abuse, and neglect.

Those who were identified as maltreated by a combination of both prospective and self-report methods experienced the greatest number of incidences of maltreatment (i.e., 49% of this group experienced more than one type of maltreatment) and displayed the most emotional and behavioral problems in late adolescence (i.e., 74% met diagnostic criteria for a clinical disorder). CONCLUSIONS: This study emphasizes the variability in the incidence rates of maltreatment and the psychological outcomes that result from utilizing different methods of identification. The most severe cases of maltreatment are likely to be identified by both prospective and retrospective methods; however, cases that are identified solely through retrospective self-report may have unique relations to psychopathology in late adolescence. PRACTICE IMPLICATIONS: Reliance on a single method to identify childhood maltreatment incidents often overlooks many cases. Comparing both prospective case reviews and retrospective self-reports in late adolescence, the most severe cases of multiple incidents of abuse were most likely to be identified by both methodologies. The less severe maltreatment incidents were more likely to be missed, either by prospective methods or, more frequently, by self-report methods. Practitioners must be continually sensitive to possible abuse histories among their clients, seeking out information from multiple sources whenever feasible. Additionally, the potential effects of abuse disclosure on pre-existing or developing psychopathology should be considered.

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Cohen, Brown & Smaile 2001

Abstract – New York State Psychiatric Institute, New York 10032, USA.

Child abuse and neglect have repeatedly been shown to be risks for psychiatric and personality disorders. However, much of this evidence is based on retrospective reports of adults. In addition, little is known about the developmental course of psychopathology among those exposed to child maltreatment. In this study, we report mental disorders assessed from early childhood to adulthood in those later identified as victims of abuse or neglect by official or self-report.

Findings show elevated rates of mental disorders and symptoms in each of four groups relative to the normative sample. Groups included those who had been victims of physical abuse or neglect according to official report and those who had been victims of physical or sexual abuse by self-report.

As expected, the maltreated groups were quite different demographically from the community comparison sample, especially those with official reports.

The group with retrospective self-reports of physical abuse differed only modestly from the comparison group on the symptom and disorder measures, while the sexually abused group showed the most consistently elevated patterns, even after controls for demographic differences were taken into account. The disorder and symptom patterns differed both by group and by age: neglect cases showed a partial remission in adulthood, while

official physical abuse cases showed an increasingly consolidated pattern of antisocial and impulsive behavior.

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Johnson et al 1999

Abstract – Columbia University, New York, USA.

BACKGROUND: Data from a community-based longitudinal study were used to investigate whether childhood abuse and neglect increases risk for personality disorders (PDs) during early adulthood. METHODS: Psychosocial and psychiatric interviews were administered to a representative community sample of 639 youths and their mothers from 2 counties in the state of New York in 1975, 1983, 1985 to 1986, and 1991 to 1993. Evidence of childhood physical abuse, sexual abuse, and neglect was obtained from New York State records and from offspring self-reports in 1991 to 1993 when they were young adults. Offspring PDs were assessed in 1991 to 1993. RESULTS:

Persons with documented childhood abuse or neglect were more than 4 times as likely as those who were not abused or neglected to be diagnosed with PDs during early adulthood after age, parental education, and parental psychiatric disorders were controlled statistically.

Childhood physical abuse, sexual abuse, and neglect were each associated with elevated PD symptom levels during early adulthood after other types of childhood maltreatment were controlled statistically.

Of the 12 categories of DSM-IV PD symptoms, 10 were associated with childhood abuse or neglect. Different types of childhood maltreatment were associated with symptoms of specific PDs during early adulthood. Would need article to know which ones, is a 1999 article, probably won’t call it in

CONCLUSIONS: Persons in the community who have experienced childhood abuse or neglect are considerably more likely than those who were not abused or neglected to have PDs and elevated PD symptom levels during early adulthood. Childhood abuse and neglect may contribute to the onset of some PDs.  How vague is this?

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Johnson et al 2001

Abstract – Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, NY 10032, USA.

Data from a community-based longitudinal study were used to investigate whether childhood verbal abuse increases risk for personality disorders (PDs) during adolescence and early adulthood. Psychiatric and psychosocial interviews were administered to a representative community sample of 793 mothers and their offspring from two New York State counties in 1975, 1983, 1985 to 1986, and 1991 to 1993, when the mean ages of the offspring were 5, 14, 16, and 22 years, respectively. Data regarding childhood abuse and neglect were obtained from the psychosocial interviews and from official New York State records.

Offspring who experienced maternal verbal abuse

during childhood were more than three times as likely

as those who did not experience verbal abuse

to have borderline, narcissistic, obsessive-compulsive, and paranoid PDs during adolescence or early adulthood.

This is correlational and does not prove cause and effect.  The same difficulties and factors that made the children sick may have made the mothers mean.

These associations remained significant after offspring temperament, childhood physical abuse, sexual abuse, neglect, physical punishment during childhood, parental education, parental psychopathology, and co-occurring psychiatric disorders were controlled statistically.

In addition, youths who experienced childhood verbal abuse had elevated borderline, narcissistic, paranoid, schizoid, and schizotypal PD symptom levels during adolescence and early adulthood after the covariates were accounted for.

These findings suggest that childhood verbal abuse may contribute to the development of some types of PDs, independent of offspring temperament, childhood physical abuse, sexual abuse, neglect, physical punishment during childhood, parental education, parental psychopathology, and co-occurring psychiatric disorders.

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Johnson et al 2006

Abstract – Department of Psychiatry, Columbia University and the New York State Psychiatric Institute, New York 10032, USA. jjohnso@pi.cpmc.columbia.edu

CONTEXT: Research has suggested that some types of parental child-rearing behavior may be associated with risk for offspring personality disorder (PD), but the association of parenting with offspring PD has not been investigated comprehensively with prospective longitudinal data. OBJECTIVE: To investigate the association of parental child-rearing behavior with risk for offspring PD during adulthood. DESIGN: The Children in the Community study, a prospective longitudinal investigation. SETTING AND PARTICIPANTS: A community-based sample of 593 families interviewed during childhood (mean age, 6 years), adolescence (mean ages, 14 and 16 years), emerging adulthood (mean age, 22 years), and adulthood (mean age, 33 years) of the offspring. MAIN OUTCOME MEASURE: The Structured Clinical Interview for DSM-IV Personality Disorders. RESULTS: Ten types of parenting behavior that were evident during the child-rearing years were associated with elevated offspring risk for PD during adulthood when childhood behavioral or emotional problems and parental psychiatric disorders were controlled statistically.

Parental behavior in the home during the child-rearing years was associated with elevated risk for offspring PD at mean ages of 22 and 33 years. Risk for offspring PD at both assessments increased steadily as a function of the number of problematic parenting behaviors that were evident.

Low parental affection or nurturing was associated with elevated risk for offspring antisocial (P = .003), avoidant (P = .01), borderline (P = .002), depressive (P = .02), paranoid (P = .002), schizoid (P = .046), and schizotypal (P<.001) PDs.

Aversive parental behavior (eg, harsh punishment) was associated with elevated risk for offspring borderline (P = .001), paranoid (P = .004), passive-aggressive (P = .046), and schizotypal (P = .02) PDs.

CONCLUSIONS: Parental behavior during the child-rearing years may be associated with risk for offspring PD that endures into adulthood. This risk may not be attributable to offspring behavioral and emotional problems or parental psychiatric disorder, and it may not diminish over time. Low parental nurturing and aversive parental behavior during child rearing may both be associated with elevated risk for offspring PDs.

I need to call this article in to find out what the 10 parental behaviors are

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Pine et al 2005

Abstract – Section on Development and Affective Neuroscience, National Institute of Mental Health Intramurral Research Program, Bethesda, MD 20817-2670, USA. daniel.pine@nih.gov

OBJECTIVE: Previous research in adults implicates attention bias in posttraumatic stress disorder (PTSD). To study attention bias in children, the authors used picture-based versions of the visual-probe attention bias task previously used with adults. They tested the hypothesis that attention bias to threatening facial photographs is associated with maltreatment and PTSD. METHOD: A visual-probe task that manipulated threat levels was used to test 34 children who had been maltreated and 21 children who had not been maltreated. The visual-probe task involved showing photographs of actors with faces depicting neutral, angry/threatening, or happy expressions for 500 msec each. RESULTS:

Attention bias away from threat

was associated with severity of physical abuse

and diagnosis of PTSD.

This association reflected the tendency for high levels of abuse or PTSD to predict attention avoidance of threatening faces.

CONCLUSIONS: Previous studies examined the engagement of specific brain regions associated with attention orientation to angry/threatening faces. The current study used similar methods to document associations between attention bias and maltreatment in children. This sets the stage for studies examining relationships in children among perturbed brain function, psychopathology, attention bias, and maltreatment.

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Monk et al 2006

Abstract – Department of Psychology, University of Michigan, 2000 East Hall, 530 Church St., Ann Arbor, MI 48109, USA. csmonk@umich.edu

OBJECTIVE: While adolescent anxiety disorders represent prevalent, debilitating conditions, few studies have explored their brain physiology. Using event-related functional magnetic resonance imaging (fMRI) and a behavioral measure of attention to angry faces, the authors evaluated differences in response between healthy adolescents and adolescents with generalized anxiety disorder. METHOD: In the primary trials of interest, 18 adolescents with generalized anxiety disorder and 15 comparison subjects of equivalent age/gender/IQ viewed angry/neutral face pairs during fMRI acquisition. Following the presentation of each face pair, subjects pressed a button to indicate whether a subsequent asterisk appeared on the same (congruent) or opposite (incongruent) side as the angry face. Reaction time differences between congruent and incongruent face trials provided a measure of attention bias to angry faces. RESULTS: Relative to the comparison subjects, patients with generalized anxiety disorder manifested greater right ventrolateral prefrontal cortex activation to trials containing angry faces.

Patients with generalized anxiety disorder also showed greater attention bias away from angry faces.

Ventrolateral prefrontal cortex activation differences remained evident when differences in attention bias were covaried. Finally, in an examination among patients of the association between degree of anxiety and brain activation, the authors found that

as ventrolateral prefrontal cortex activation increased,

severity of anxiety symptoms diminished.

CONCLUSIONS: Adolescents with generalized anxiety disorder show greater right ventrolateral prefrontal cortex activation and attentional bias away from angry faces than healthy adolescents. Among patients, increased ventrolateral prefrontal cortex activation is associated with less severe anxiety, suggesting that this activation may serve as a compensatory response.

Avoidance or detachment?

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Famularo, Kinscherff & Fenton 1992

Abstract – Boston Juvenile Court Clinic, Massachusetts 02108.

The Structured Clinical Interview for DSM-III-R diagnoses of 54 mothers who had maltreated their children were compared with those of 37 controls. The maltreatment group showed a significantly greater incidence of both current and past diagnoses. Maltreating mothers exhibited a significantly greater incidence of current mood disorder, alcohol abuse, and personality disorder than did controls. The results indicate that past abuse of cocaine, alcohol, other substances and past mood disorders were significantly more prevalent among the maltreatment sample than among controls.

Mothers who had maltreated their children were significantly more likely to have histories of posttraumatic stress disorder than were controls.

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Johnson et al 2000

Abstract – Columbia University, New York, NY, USA.

Data from a community-based longitudinal study were used to investigate the association between childhood neglect and personality disorder (PD) symptom levels during adolescence and early adulthood. Psychosocial and psychiatric interviews were administered to a representative sample of 738 youths and their mothers from upstate New York in 1975, 1983, 1985-1986, and 1991-1993. Evidence of childhood cognitive, emotional, physical, and supervision neglect was obtained from the maternal interviews that were conducted in 1975, 1983, and 1985-1986, and from New York State records. PDs were assessed among the youths in 1985-1986, when they were adolescents, and in 1991-1993, when they were young adults.

Findings indicated that childhood emotional, physical, and supervision neglect were associated with increased risk for PDs and with elevated PD symptom levels during adolescence and early adulthood, after age, sex, childhood physical or sexual abuse, other types of childhood neglect, and cooccurring PD symptoms were controlled statistically.

Childhood emotional neglect was associated with increased risk for avoidant PD and with paranoid and Cluster A PD symptom levels during adolescence and early adulthood.

Childhood physical neglect was associated with increased risk for schizotypal PD and with Cluster A PD symptom levels during adolescence and early adulthood.

Childhood supervision neglect was associated with increased risk for passive-aggressive and Cluster B PDs and with borderline, paranoid, and passive-aggressive PD symptom levels during adolescence and early adulthood.

The present findings suggest that childhood emotional, physical, and supervision neglect may play a role in the etiology of some PDs.

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Guyer et al 2006

Abstract – Mood and Anxiety Program, National Institute of Mental Health, Bethesda, MD 20892-2670, USA. amandaguyer@mail.nih.gov

OBJECTIVE: To examine in children the influence of maltreatment and associated psychiatric sequelae on behavioral responses to reward stimuli. METHOD: A computerized two-choice decision-making task involving probabilistic monetary gains was used to probe elemental processes of goal-directed actions. Using different risk contingencies, the authors examined decision-making, expectations of outcomes, and affective responses to rewards in 38 maltreated children and 21 demographically matched controls (8-14 years old). RESULTS:

Maltreated children selected risk options faster than controls; however, whereas controls responded more quickly as the chance of winning increased, maltreated children did not vary in response speed as a function of the likelihood of winning.

When choosing between high- and low-risk options,

maltreated children with depressive disorders

more frequently selected safe over risky choices

than did controls.

No group differences emerged in self-report ratings of positive or negative reactions to winning or not winning, respectively. CONCLUSIONS: This initial experimental study of responses to reward lays the groundwork for subsequent research on neurodevelopmental aspects of reward processes in relationship to maltreatment and psychopathology. Clinical applications of these data may be relevant for developing treatment plans for maltreated children, particularly those with depression.

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Monk et al 2008b

Abstract – Department of Psychology, University of Michigan, Ann Arbor, MI 48109, USA. csmonk@umich.edu

OBJECTIVE: Offspring of parents with major depressive disorder face a threefold higher risk for major depression than offspring without such family histories.

Although major depression is a significant cause of morbidity and mortality, neural correlates of risk for major depression remain poorly understood. This study compares amygdala and nucleus accumbens activation in children and adolescents at high and low risk for major depression under varying attentional and emotional conditions. METHOD: Thirty-nine juveniles, 17 offspring of parents with major depression (high-risk group) and 22 offspring of parents without histories of major depression, anxiety, or psychotic disorders (low-risk group) completed a functional magnetic resonance imaging study. During imaging, subjects viewed faces that varied in intensity of emotional expressions across blocks of trials while attention was unconstrained (passive viewing) and constrained (rate nose width on face, rate subjective fear while viewing face).

RESULTS: When attention was unconstrained, high-risk subjects showed greater amygdala and nucleus accumbens activation to fearful faces and lower nucleus accumbens activation to happy faces (small volume corrected for the amygdala and nucleus accumbens).

No group differences emerged in amygdala or nucleus accumbens activation during constrained attention. Exploratory analysis showed that constraining attention was associated with greater medial prefrontal cortex activation in the high-risk than in the low-risk group.

CONCLUSIONS:

Amygdala and nucleus accumbens responses to affective stimuli may reflect vulnerability for major depression.

Constraining attention may normalize emotion-related neural function

possibly by engagement of the medial prefrontal cortex;

face-viewing with unconstrained attention may engage aberrant processes associated with risk for major depression.

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Wildgruber et al 2005

Abstract – Department of General Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany. dirk.wildgruber@med.uni-tuebingen.de

During acoustic communication among human beings, emotional information can be expressed both by the propositional content of verbal utterances and by the modulation of speech melody (affective prosody). It is well established that linguistic processing is bound predominantly to the left hemisphere of the brain. By contrast, the encoding of emotional intonation has been assumed to depend specifically upon right-sided cerebral structures. However, prior clinical and functional imaging studies yielded discrepant data with respect to interhemispheric lateralization and intrahemispheric localization of brain regions contributing to processing of affective prosody. In order to delineate the cerebral network engaged in the perception of emotional tone, functional magnetic resonance imaging (fMRI) was performed during recognition of prosodic expressions of five different basic emotions (happy, sad, angry, fearful, and disgusted) and during phonetic monitoring of the same stimuli. As compared to baseline at rest, both tasks yielded

widespread bilateral hemodynamic responses within frontal, temporal, and parietal areas,

the thalamus, and the cerebellum.

A comparison of the respective activation maps, however, revealed

comprehension of affective prosody to be bound to a distinct right-hemisphere pattern of activation, encompassing posterior superior temporal sulcus (Brodmann Area [BA] 22), dorsolateral (BA 44/45), and orbitobasal (BA 47) frontal areas.

Activation within left-sided speech areas, in contrast, was observed during the phonetic task. These findings indicate that

partially distinct cerebral networks

subserve processing of phonetic and intonational information during speech perception.

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Lemche et al 2004

Abstract – Department of Psychotherapy and Psychosomatic Medicine, Dresden University of Technology, Dresden, Germany. erwin.lemche@mailbox.tu-dresden.de

The construct of alexithymia

implies a deficit in symbolization for

emotional, somatic, and mental states.

However, the etiologic factors for alexithymia have not yet been fully elucidated. The present study investigated the use of mentalizing language, i.e. the utterance of internal states, from a developmental perspective according to attachment organization and disorganization. METHODS: A longitudinal design across 4 time points was applied to a volunteer We must understand that a truly dangerous parent will not volunteer for this kind of research or for any other research – so the worst attachment scenarios will NOT be represented!!

sample of 42 children. At 12 months, children were tested with the strange situation procedure, the standard measure of attachment at the optimal age, and attachment classifications were taken of videotapes. At ages 17, 23, 30 and 36 months, mother and child were observed in simplified separation episodes of 30 min duration. Transcripts of the sessions were subject to coding of internal state words. RESULTS: During the investigated span,

securely attached children

rapidly acquired emotion, physiology, cognition and emotion-regulatory language, whereas

insecurely attached and disorganized children either completely lacked internal state language or displayed a considerable time lag in the use of emotion and cognition vocabulary.

CONCLUSION: The results raise the possibility that alexithymia might be a consequence of deficits in the development of internal state language in the context of insecure or disorganized childhood attachment relationships.

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Levenson & Sweatt 2005

Abstract – Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, S607, Houston, Texas 77030, USA.

Discoveries concerning the molecular mechanisms of cell differentiation and development have dictated the definition of a new sub-discipline of genetics known as epigenetics.

Epigenetics refers to a set of

self-perpetuating, God making God!?

post-translational modifications of DNA and nuclear proteins that produce lasting alterations in chromatin structure

as a direct consequence,

and lasting alterations in patterns of gene expression

as an indirect consequence.

The area of epigenetics is a burgeoning subfield of genetics in which there is considerable enthusiasm driving new discoveries. Neurobiologists have only recently begun to investigate the possible roles of epigenetic mechanisms in behavior, physiology and neuropathology.

Strikingly, the relevant data from the few extant

neurobiology-related studies have already indicated a theme – epigenetic mechanisms probably have an important role

in synaptic plasticity and memory formation.

It seems a sort of divine synchronicity that I would encounter epigenetics tied specifically to memory. But, of course, epigenetics is about memory – as DNA is itself.  I found one of the doorways into the study of epigenetics – interesting that memory is it.  Tying epigenetics, memory, traumatic stress and the HPA axis together will be challenging – along with connection to the sex hormones – because of course it is all finally about survival to reproduce, anyway.  Nature will forgo the finer trappings of a happy life if it needs to.

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Allen 2008

Abstract – School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3US, UK. allennd@cf.ac.uk

The anticipated therapeutic uses of neural stem cells depend on their ability to retain a certain level of developmental plasticity.

In particular, cells must respond to developmental manipulations designed to specify precise neural fates.

Studies in vivo and in vitro have shown that the developmental potential of neural progenitor cells changes and becomes progressively restricted with time. For in vitro cultured neural progenitors, it is those derived from embryonic stem cells that exhibit the greatest developmental potential.

It is clear that both extrinsic and intrinsic mechanisms

determine the developmental potential of neural progenitors

and that

epigenetic, or chromatin

structural, changes

regulate and coordinate hierarchical changes

in fate-determining gene expression.

Here, we review the temporal changes in developmental plasticity of neural progenitor cells and discuss the epigenetic mechanisms that underpin these changes.

We propose that understanding the processes of epigenetic programming within the neural lineage is likely to lead to the development of more rationale strategies for cell reprogramming that may be used to expand the developmental potential of otherwise restricted progenitor populations.

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Kuwabara et al 2004

Abstract – Laboratory of Genetics, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.

Discovering the molecular mechanisms that regulate neuron-specific gene expression remains a central challenge for CNS research. Here, we report that

small, [define small!] noncoding double-stranded (ds) RNAs

play a critical role in mediating neuronal differentiation.

The sequence defined by this dsRNA is NRSE/RE1,

which is recognized by NRSF/REST,

known primarily as a negative transcriptional regulator

that restricts neuronal gene expression

to neurons.

The NRSE dsRNA can trigger gene expression of neuron-specific genes through interaction with NRSF/REST transcriptional machinery, resulting in the

Transition

from neural stem cells with neuron-specific genes silenced by NRSF/REST

into cells with neuronal identity

that can express neuronal genes.

The mechanism of action appears to be mediated through a dsRNA/protein interaction, rather than through siRNA or miRNA. The

discovery of small modulatory dsRNAs (smRNAs)

extends the important contribution of noncoding RNAs

as key regulators of cell behavior at both

transcriptional and posttranscriptional levels.

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Watanabe et al 2004

Abstract – Department of Molecular Genetics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA

Repressor element 1 (RE1)-silencing transcription factor (REST)/neuron-restrictive silencer factor (NRSF)

can repress several terminal neuronal differentiation genes

by binding to a specific DNA sequence (

RE1/neuron-restrictive silencer element [NRSE])

present in their regulatory regions.

REST-VP16 binds to the same RE1/NRSE, but activates these REST/NRSF target genes. However, it is unclear whether REST-VP16 expression is sufficient to cause formation of functional neurons either from neural stem cells or from heterologous stem cells. Here we show that the

expression of REST-VP16 in myoblasts

grown under muscle differentiation conditions

blocked entry into the muscle differentiation pathway,

countered endogenous REST/NRSF-dependent repression, activated the REST/NRSF target genes, and, surprisingly,

activated other neuronal differentiation genes

and converted the myoblasts to a physiologically active neuronal phenotype.

Furthermore, in vitro differentiated neurons

produced by REST-VP16-expressing myoblasts,

when injected into mouse brain,

survived,

incorporated into the normal brain,

and did not form tumors.

This is the first instance in which myoblasts

were converted to a neuronal phenotype.

Our results suggest that direct activation of REST/NRSF target genes with a single transgene, REST-VP16,

is sufficient to activate other

terminal neuronal differentiation genes

and to override the muscle differentiation pathways,

and they suggest that this approach provides an efficient way of triggering neuronal differentiation in myoblasts and possibly other stem cells.

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Ballas & Mandel 2005

Abstract – ward Hughes Medical Institute, Department of Neurobiology and Behavior, State University of New York, Stony Brook, NY 11794, USA.

Nervous system development relies on a complex signaling network to engineer the orderly transitions that lead to the acquisition of a neural cell fate.

Progression from the non-neuronal pluripotent stem cell

to a restricted neural lineage is characterized by distinct patterns of gene expression,

particularly the restriction of neuronal gene expression to neurons.

Concurrently, cells outside the nervous system acquire and maintain a non-neuronal fate that permanently excludes expression of neuronal genes.

See Watanabe et al 2004

Studies of the transcriptional repressor REST, which regulates a large network of neuronal genes, provide

a paradigm for elucidating the link between epigenetic mechanisms and neurogenesis.

REST orchestrates a set of epigenetic modifications

that are distinct between non-neuronal cells

that give rise to neurons

and those that are destined to remain

as nervous system outsiders.

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Ballas et al 2005

Abstract – Howard Hughes Medical Institute, Dept. of Neurology and Behavior, The State University of New York at Stony Brook, Stony Brook, NY 11794, USA. nballas@notes.cc.sunysb.edu

Regulation of neuronal gene expression is critical to central nervous system development. Here, we show that

REST regulates the transitions from pluripotent

to neural stem/progenitor cell

and from progenitor to mature neuron.

In the transition to progenitor cell,

REST is degraded to levels just sufficient to maintain

neuronal gene chromatin in an inactive state

that is nonetheless poised for expression.

As progenitors differentiate into neurons,

REST and its co-repressors dissociate from the RE1 site,

triggering activation of neuronal genes.

In some genes, the level of expression is adjusted further in neurons by CoREST/MeCP2 repressor complexes that remain bound to a site of methylated DNA distinct from the RE1 site. Expression profiling based on this mechanism indicates that

REST defines a gene set subject to plasticity in mature neurons. Thus, a multistage repressor mechanism

controls the orderly expression of genes

during development

while still permitting fine tuning in response to specific stimuli.

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Lunyak & Rosenfeld 2005

Abstract – comment on Cell. 2005 May 20;121(4):645-57.

Epigenetic strategies control the orderly acquisition and maintenance of neuronal traits. Phenotypes

A complex network of transcriptional repressors and co-repressors mediates gene specificity for these strategies. In this issue of Cell, a study by Ballas and coworkers (Ballas et al., 2005) provides insight into the early lineage commitment events during neurogenesis. This study demonstrates that regulation of the REST/NRSF transcriptional repressor plays a fundamental role in the progression of pluripotent cells to lineage-restricted neural progenitors.

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Hamby, Coskun & Sun 2008

Abstract – Mental Retardation Research Center, David Geffen School of Medicine, University of California Los Angeles, USA.

The transcriptional programs of neural progenitor cells change dynamically during neurogenesis, a process regulated by both intrinsic and extrinsic factors.

Although many of the transcription factors required for neuronal differentiation have long been identified, we are only at the brink of understanding how epigenetic mechanisms influence transcriptional activity and the accessibility of transcription factors to bind consensus cis-elements.

Herein, we delineate the chief epigenetic modifications and the machinery responsible for these alterations. Further, we review the epigenetic modifications presently known to participate in the maintenance of the neural progenitor cell state and in the regulation of neuronal differentiation.

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Hsieh & Gage 2005

Abstract – Department of Molecular Biology and Cecil H and Ida Green Center for Reproductive Biology Sciences, UT Southwestern Medical Center, 6001 Forest Park Road, Dallas, Texas 75390, USA. Jenny.Hsieh@UTSouthwestern.edu

Neural stem cells generate distinct cell types

for tissue formation and cell replacement

during development and throughout adulthood.

Neural development and plasticity are determined by both extrinsic and intrinsic factors that interface to regulate gene programs for controlling neuronal cell fate and function.

Recent reports have shown that chromatin remodeling

and epigenetic gene regulation

play an important role in such diverse areas as neural cell fate specification and synaptic development and function.

These epigenetic mechanisms include

cell-type-specific transcriptional regulators,

histone modifications and

chromatin remodeling enzymes, and the

activity of retrotransposons.

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Miller, Campbell & Sweatt 2008

Abstract – Department of Neurobiology, Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, 1074 Shelby Building, 1825 University Boulevard, Birmingham, AL, USA. cmiller@nrc.uab.edu

A clear understanding is developing concerning the

importance of epigenetic-related molecular mechanisms

in transcription-dependent long-term memory formation.

My guess is that most mental health problems are connected HERE – including incoherent insecure attachment life histories

And dissociation

Chromatin modification,

in particular histone acetylation,

is associated with transcriptional activation,

and acetylation of histone 3 (H3) occurs in Area CA1 of the hippocampus following contextual fear conditioning training.

Conversely, DNA methylation is associated with transcriptional repression, but is also dynamically regulated in Area CA1 following training. We recently reported that inhibition of the enzyme responsible for DNA methylation,

DNA methyltransferase (DNMT),

in the adult rat hippocampus blocks behavioral memory formation.

Here, we report that DNMT inhibition also blocks the concomitant memory-associated H3 acetylation, without affecting phosphorylation of its upstream regulator, extracellular signal-regulated kinase (ERK).

Interestingly, the DNMT inhibitor-induced deficit in memory consolidation, along with deficits in long-term potentiation, can be rescued by pharmacologically increasing levels of histone acetylation prior to DNMT inhibition.

These observations suggest that DNMT activity is not only necessary for memory and plasticity, but that DNA methylation may work in concert with histone modifications to regulate plasticity and memory formation in the adult rat hippocampus.

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If epigenetic mechanisms can enable bodies to communicate through the generations that there “used to be” a famine, or that there “used to be fungicides” in the environment, why couldn’t it communicate transgenerationally that there is risk to attachment, which is the social foundation of our species?  Broken attachment systems HURT.  I think this pain is permanently hardwired into us – yet in the cases of my and my siblings’ children, I think we provided strong enough “earned secure” attachment in the here and now to avert the carry over of the pain to our offspring.

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Seckl & Meaney 2006

Abstract – Endocrinology Unit, Centre for Cardiovascular Science, Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK. J.Seckl@ed.ac.uk

Epidemiological data have linked an adverse fetal environment with increased risks of cardiovascular, metabolic, neuroendocrine, and psychiatric disorders in adulthood.

Prenatal stress and/or glucocorticoid excess might underlie this link. In animal models, prenatal stress, glucocorticoid exposure or inhibition/knockout of 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD-2), the feto-placental barrier to maternal glucocorticoids, reduces birth weight and causes permanent hypertension, hyperglycemia, increased hypothalamic-pituitary-adrenal (HPA) axis activity and behavior resembling of anxiety. In humans, 11 beta-HSD-2 gene mutations cause low birth weight and placental 11 beta-HSD-2 activity correlates directly with birth weight and inversely with infant blood pressure. Low birth weight babies have higher plasma cortisol levels throughout adult life, indicating HPA programming.

In human pregnancy, severe maternal stress affects the offspring HPA axis and associates with neuropsychiatric disorders. Posttraumatic stress disorder (PTSD) appears to be a variable in the effects.

Intriguingly, some of these effects appear to be ‘inherited’ into a further generation, itself unexposed to exogenous glucocorticoids at any point in the lifespan from fertilization, implying epigenetic marks persist into subsequent generation(s).

Overall, the data suggest that prenatal exposure to excess glucocorticoids programs peripheral and CNS functions in adult life, predisposing to some pathologies, perhaps protecting from others, and these may be transmitted perhaps to one or two subsequent generations.

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Seckl & Meaney 2004

Abstract – Endocrinology Unit, University of Edinburgh, Molecular Medicine Centre, Western General Hospital, Edinburgh, EH4 2XU, UK. J.Seckl@ed.ac.uk

Epidemiological evidence suggests that an adverse fetal environment permanently programs physiology, leading to increased risks of cardiovascular, metabolic, and neuroendocrine disorders in adulthood. Prenatal glucocorticoid excess or stress might link fetal maturation and adult pathophysiology. In a variety of animal models, prenatal glucocorticoid exposure or inhibition of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), the fetoplacental “barrier” to maternal glucocorticoids, reduces birth weight and causes permanent hypertension, hyperglycemia, and increased hypothalamic-pituitary-adrenal axis (HPA) activity and behavior resembling anxiety. In humans, 11beta-HSD2 gene mutations cause low birth weight and reduced placental 11beta-HSD2 activity associated with intrauterine growth retardation. Low birth weight babies have higher plasma cortisol levels throughout adult life, indicating HPA programming. The molecular mechanisms may reflect permanent changes in the expression of specific transcription factors; key is the glucocorticoid receptor itself. Differential programming of the glucocorticoid receptor in different tissues reflects effects upon one or more of the multiple tissue-specific alternate first exons/promoters of the glucocorticoid receptor gene. Overall, the data suggest that either pharmacological or physiological exposure to excess glucocorticoids prenatally programs pathologies in adult life.

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Seckl 2001

Abstract – Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK. j.seckl@ed.ac.uk

It has been long recognized that the glucocorticoid administration to pregnant mammals (including humans) reduces offspring birth weight. Epidemiologically, low weight or thinness at birth is associated with an increased risk of cardiovascular and metabolic disorders in adult life. So, does fetal exposure to glucocorticoids produce such ‘programming’ of adult disorders? Here data are reviewed which show, in rodents and other model species, that antenatal exposure to glucocorticoids reduces offspring birth weight and produces permanent hypertension, hyperglycaemia, hyperinsulinaemia, altered behavior and neuroendocrine responses throughout the lifespan.

This occurs with exogenous (dexamethasone) or endogenous glucocorticoids, the latter achieved by inhibiting 11 beta-hydroxysteroid dehydrogenase type 2, the feto-placental enzymic barrier to maternal glucocorticoids.

Processes underlying fetal programming

include determination of the

‘set point’

of the hypothalamic-pituitary-adrenal axis

and of tissue glucocorticoid receptor expression.

Detailed molecular mechanisms are being dissected. Analogous stress axis hyperreactivity occurs in lower birth weight humans and may be an early manifestation and indicate approaches to

manipulation or prevention of the phenotype.

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Seckl 2004

Abstract – Endocrinology Unit, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK. J.Seckl@ed.ac.uk

Epidemiological evidence suggests that low birth weight is associated with an increased risk of cardiovascular, metabolic and neuroendocrine disorders in adult life. Glucocorticoid administration during pregnancy reduces offspring birth weight and alters the maturation of the lung and other organs. We hypothesized that prenatal exposure to excess glucocorticoids or stress might represent a mechanism linking foetal growth with adult pathophysiology. In rats, birth weight is reduced following prenatal exposure to the synthetic steroid dexamethasone, which readily crosses the placenta, or to carbenoxolone, which inhibits 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), the physiological feto-placental ‘barrier’ to maternal glucocorticoids. As adults, the offspring exhibit permanent hypertension, hyperglycaemic, increased hypothalamic-pituitary-adrenal (HPA) axis activity and behavior reminiscent of anxiety. Physiological variations in placental 11beta-HSD2 activity correlate directly with foetal weight. In humans, 11beta-HSD2 gene mutations cause low birth weight. Moreover, low-birth-weight babies have higher plasma cortisol levels throughout adult life, indicating HPA axis programming. The molecular mechanisms may reflect permanent changes in the expression of specific transcription factors, key among which is the glucocorticoid receptor (GR) itself.

The differential programming of the GR in different tissues reflects effects upon one or more of the multiple tissue-specific alternate first exons/promoters of the GR gene. Overall, the data suggest that both pharmacological and physiological exposure prenatally to excess glucocorticoids programs cardiovascular, metabolic and neuroendocrine disorders in adult life.

I need the link for this with early postnatal stress causing similar changes.

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Seckl & Homes 2007

Abstract – College of Medicine and Veterinary Medicine, University of Edinburgh, UK.

Epidemiological evidence suggests that an adverse prenatal environment permanently ‘programs’ physiology and increases the risk of cardiovascular, metabolic, neuroendocrine and psychiatric disorders in adulthood.

Prenatal stress or exposure to excess glucocorticoids might provide the link between fetal maturation and adult pathophysiology. In a variety of animal models, prenatal stress, glucocorticoid exposure and inhibition (or knockout of) 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2)–the fetoplacental barrier to maternal glucocorticoids–reduce birth weight and cause increases in adult blood pressure, glucose levels, hypothalamic-pituitary-adrenal (HPA) axis activity and anxiety-related behaviors. In humans, mutations in the gene that encodes 11beta- hydroxysteroid dehydrogenase type 2 are associated with low birth weight. Babies with low birth weight have higher plasma cortisol levels throughout life, which indicates HPA-axis programming.

In human pregnancy, severe maternal stress affects the offspring’s HPA axis and is associated with neuropsychiatric disorders; moreover, maternal glucocorticoid therapy alters offspring brain function.

The molecular mechanisms that underlie prenatal programming might reflect permanent changes in the expression of specific transcription factors, including the glucocorticoid receptor; tissue specific effects reflect modification of one or more of the multiple alternative first exons or promoters of the glucocorticoid receptor gene. Intriguingly,

some of these effects seem to be inherited by subsequent generations that are unexposed to exogenous glucocorticoids at any point in their lifespan from fertilization, which implies that these epigenetic effects persist.

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O’Reagan et al 2001

Abstract – Endocrinology Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK.

Increasing epidemiological evidence supports the notion that adverse events in fetal life permanently alter the structure and physiology of the adult offspring, a phenomenon dubbed ‘fetal programming’.

In particular, low weight or thinness at birth in humans is associated with an increased risk of cardiovascular and metabolic disorders as well as neuroendocrine dysfunction in adult life.

Glucocorticoid administration during pregnancy is well-documented to both reduce offspring birth weight and alter the maturation of organs (hence their use to accelerate fetal lung maturation in premature labor). Here data are reviewed which show, in rodents and other models, that antenatal exposure to endogenous or exogenous glucocorticoids reduces offspring birth weight and produces permanent hypertension, hyperglycaemia, hyperinsulinaemia, altered behavior and neuroendocrine responses throughout the lifespan.

Processes underlying fetal programming include determination of the ‘set point’ of the hypothalamic-pituitary-adrenal (HPA) axis and of tissue glucocorticoid receptor (GR) expression. Similar HPA axis hyperreactivity occurs in lower birth weight humans and may be an early manifestation of the ‘low birth weight’ phenotype.

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Wells 2007

Abstract – Childhood Nutrition Research Centre, Institute of Child Health, 30 Guilford Street, London WC1N 1EH. J.Wells@ich.ucl.ac.uk

Human diseases in adulthood are increasingly associated with growth patterns in early life, implicating early-life nutrition as the underlying mechanism. Cannot ignore effects of epigenetics

The thrifty phenotype hypothesis

proposed that early-life metabolic adaptations

promote survival, with the developing organism responding to cues of environmental quality by selecting an appropriate trajectory of growth.

Reminds me of Teicher’s evolutionarily altered brain – early stress does effect metabolism, and how nutrition is handled in the brain.  In a wholeness scenario, metabolism, immune system, brain all being affected with adjustments toward thrift

Recently, some authors have proposed that the thrifty phenotype is also adaptive in the longer-term, by preparing the organism for its likely adult environment. However,

windows of plasticity close early during human development,

and subsequent environmental changes

may result in the selected trajectory becoming inappropriate, leading to adverse effects on health.

This paradox generates uncertainty as to whether the thrifty phenotype is indeed adaptive for the offspring in humans. The

thrifty phenotype should not be considered a dichotomous concept, rather it refers to the capacity of all offspring to respond to environmental information during early ontogenetic development.

This article argues that the thrifty phenotype is the consequence of three different adaptive processes – niche construction, maternal effects, and developmental plasticity – all of which in humans are influenced by our large brains. While developmental plasticity represents an adaptation by the offspring, both niche construction and parental effects are subject to selection on parental rather than offspring fitness.

The three processes also operate at different paces.

Human offspring do not become net calories-producers until around 18 years of age, such that the high energy costs of the human brain are paid primarily by the mother, even after weaning.

………The evolutionary expansion of human brain volume occurred in environments characterized by high volatility, inducing strong selective pressure on maternal capacity to provision multiple offspring simultaneously.

………The thrifty phenotype is therefore best considered as a manipulation of offspring phenotype for the benefit of maternal fitness.

The information that enters offspring phenotype

during early development

does not predict the likely future environment of the offspring, but rather reflects the mother’s own developmental experience and the quality of the environment

during her own maturation.

This is fascinating – implications for child abuse such as mine

Offspring growth trajectory thus becomes aligned with long-term maternal capacity to provision.

……..In contemporary populations, the sensitivity of offspring development to maternal phenotype exposes the offspring to adverse effects, through four distinct pathways.

………The offspring may be exposed to

(1) poor maternal metabolic control (e.g. gestational diabetes), (

2) maternally derived toxins (e.g. maternal smoking), or

(3) low maternal social status (e.g. small size). Adverse consequences of these effects may then be exacerbated by

(4) exposure either to the “toxic” western environment in postnatal life, in which diet and physical activity levels are mismatched with metabolic experience in utero, or at the other extreme to famine. Even emotionally

The rapid emergence of the epidemic of the metabolic syndrome in the 20th Century reflects the rapid acceleration in the pace of niche construction relative to the slower physiological combination of developmental plasticity and parental effects

This fits in with what I have been thinking for some time, that once the evolutionary scenario is implemented in early development that the world is a malevolent place, all the adaptations that occur during development are designed to operate in adulthood for survival in the same kind of world.  In the end, when things go far off kilter, mother’s kill their offspring, males mate more, kill more enemies, find more food – all fitting in the “thrifty phenotype” model.

Early social interventions that change the developing phenotype and moderate its understanding of the famine world would logically change the resulting phenotype – as they are finding with genes for depression being modulated in childhood by adequate social support interventions.  Quite clear and simple.  As Schore notes, early stress changes the nutritional environment in the brain and changes how it develops.  Stress equals famine from the brain’s point of view.

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Wells 2003

Abstract – MRC Childhood Nutrition Research Centre, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. j.well@ich.ucl.ac.uk

Medical research is increasingly focusing on the contribution of nutritional programming to disease in later life.

Programming is a process whereby a stimulus during a critical window of time permanently affects subsequent structure, function or developmental schedule of the organism.

The thrifty phenotype hypothesis is widely used to interpret such studies, with

early growth restriction seen as

adaptation to environmental deprivation.

However, such permanent adjustment is less beneficial

than maintaining flexibility

so as to recover

from early growth deficits if the environment improves.

Thus, the existing thrifty phenotype hypothesis fails to explain why plasticity is lost so early in development in species with extended growth. Extremes of deprivation in the environment, I would think, signal special circumstances – really bad ones where the body has to take over – doomsday world

One explanation is that the developing organism

simply cannot maintain phenotypic plasticity

throughout the period of organ growth.

This article adds a life history perspective, arguing that programming of the offspring may in some species benefit maternal fitness more than it does that of individual offspring. Perfect place to include the concept that the intergenerational transmission of “unresolved trauma” comes down through the mother to the offspring – communication through her about the condition of the present, but more importantly, about the FUTURE of the world the offspring are growing into.  Epigenetic factors can include not only emotional but also toxic environment poisons – the body does not care about “psychological.”  The body will take over and the luxury of having a self or a “psychology” can be eliminated – ontogeny recapitulates phylogeny

Closing the critical window early in development

allows the preservation of maternal strategy in offspring phenotype, which in humans benefits the mother by constraining offspring demand after weaning.

The offspring gains by being buffered against environmental fluctuations during the most sensitive period of development,

allowing coherent adaptation of organ growth including brain and nervous system

to the state of the environment.

The critical window is predicted to close when offspring physiology becomes independent of maternal physiology, the timing of which depends on offspring trait.

Because placental nutrition and lactation buffer against short-term environmental fluctuations, maternal strategy is predicted to derive from long-term experience, encapsulated in maternal size and nutritional status. Including in humans the stress-response pattern

Such an approach implies that public health programs for improving birth weight may be more effective if they target maternal development rather than nutrition during pregnancy. Equally, aggressive nutritional management of infants born small or pre-term may induce the very environmental fluctuations that are naturally softened by maternal nutrition.

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Gluckman et al 2005

Abstract – Liggins Institute, University of Auckland and National Research Centre for Growth and Development, 2-6 Park Avenue, Grafton, Private Bag 92019, Auckland, New Zealand.

Early experience has a particularly great effect on most organisms. Normal development may be disrupted by early environmental influences; individuals that survive have to cope with the damaging consequences. Additionally, the responses required to cope with environmental challenges in early life may have long-term effects on the adult organism.

A further set of processes,

those of developmental plasticity,

may induce a phenotype that is adapted to the adult environment predicted by the conditions of early life.

I think all the rest of the “issues” fit under this umbrella

A mismatch between prediction and subsequent reality

can cause severe health problems in those human societies where economic circumstances and nutrition are rapidly improving. Don’t just think food – neurotransmission is a feeding on the cellular levels – and operates within these same parameters

Understanding the underlying mechanisms of plasticity is, therefore, clinically important.

However, to conduct research in this area,

developmental plasticity

must be disentangled from

disruption and the

adverse long-term effects of coping.

The paper reviews these concepts and explores ways in which such distinctions may be made in practice.

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Kuzawa 2005

Abstract – Department of Anthropology, Northwestern University, Evanston, Illinois 60208, USA. kuzawa@northwestern.edu

Evidence that fetal nutrition triggers permanent adjustments in a wide range of systems and health outcomes is stimulating interest in the evolutionary significance of these responses. This review evaluates the

postnatal adaptive significance of fetal developmental plasticity from the perspective of life history theory

and evolutionary models of energy partitioning.

Birthweight is positively related to multiple metabolically costly postnatal functions, suggesting that the

fetus has the capacity to distribute the burden of energy insufficiency

when faced with a nutritionally challenging environment.

As Schore says, stress in the developing brain changes the nutritional environment and affects genetic factors

Lowering total requirements

may reduce the risk of negative energy balance,

which disproportionately impacts functions

that are not essential for survival

but that are crucial for reproductive success.

Having a self is not essential for anything from an evolutionary standard.  It is a luxury that results from an adequate or a usually-predictable excess of basic survival essentials.  Nutrition availability to the developing brain cues it for its eventual life circumstances

The long-term benefit of these metabolic adjustments is contingent upon the fetus having access to a cue that is predictive of its future nutritional environment, a problem complicated in a long-lived species by short-term ecologic fluctuations like seasonality.   How does the body know what to predict in a life as long as ours has become?  How can it know all the changes that are possible?  Best educated guess from early signals and cues – cutting the line through the middle of up and down variations, even in the middle ground of essential balance between MR and GR activation in the HPA axis

Evidence is reviewed suggesting that the

flow of nutrients reaching the fetus [and the postnatal brain] provides an integrated signal of nutrition as experienced by recent matrilineal ancestors, which effectively limits the responsiveness to short-term ecologic fluctuations during any given pregnancy.

This capacity for fetal nutrition to minimize the growth response to transient ecologic fluctuations is defined here as intergenerational “phenotypic inertia,” and is hypothesized

to allow the fetus [and young neonate]

to cut through the “noise” of seasonal

or other stochastic influences to

read the “signal” of longer-term ecologic trends. Cut through the temporary like finding the best middle ground, and aiming a trajectory toward that end – what it responds to and how

As a mode of adaptation, phenotypic inertia may

help the organism cope with ecologic trends

too gradual to be tracked by conventional developmental plasticity,

but too rapid to be tracked by natural selection.

Sounds like epigenetics could fit here

From an applied perspective, if a trait like fetal growth is designed to minimize the effects of short-term fluctuations by integrating information across generations,

public health interventions may be most effective if focused not on the individual but on the

matriline.

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Horton 2005

Abstract – Department of Neurobiology and Physiology and the Centers for Reproductive Science, Northwestern University, Evanston, Illinois 60208, USA. thorton@northwestern.edu

The interaction of the genetic program with the environment shapes the development of an individual.

Accumulating data from animal models indicate that prenatal and early-postnatal events (collectively called “early-life events”) can

initiate long-term changes in the expression of the genetic program which persist, or may only become apparent, much later in the individual’s life.

Researchers working with humans or animal models of human diseases often view the effects of early-life events through the lens of pathology, with a focus on whether the events increase the risk for a particular disease. Alternatively, comparative biologists often view the effects of early-life events through the lens of evolution and adaptation by natural selection; they investigate the

processes by which environmental conditions

present early in life may prompt the adoption of different developmental pathways

leading to alternative life histories.

Examples of both approaches are presented in this article. This article reviews the concepts of phenotypic plasticity, natural selection, and evidence from animal models that early-life events can program the activity of the neuroendocrine system, at times altering life history patterns in an adaptive manner. Adaptive to the “best guess” during critical windows of development, with corresponding lack of flexibility to adapt, during a long life, to changes for the extreme better or worse that might be encountered.

Data from seasonally breeding rodents are used to illustrate the use of maternally derived information to alter the life history of young. In several species, the maternal system transfers photoperiodic information to the young in utero. And very early on during nervous system and brain development of the neonate

This maternally derived information

alters the response of young to photoperiods

encountered later and life, producing

seasonally distinct life histories.

Now that’s an interesting concept – seasonally distinct life histories. Perhaps it is here that we could look biologically to the human characteristic of both dissociation and incoherent life stories – as if each segment (see working memory) of life that represents a “shock” or extreme contrast having to do with biological availability on the continuum of “famine” or “toxic” results in an inability to link these extremes of “seasonally distinct life histories” together.  A season of safety, a season of danger, a season of scarcity, a season of plenty – If we stick to what the body knows, this makes perfect sense!

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Worthman & Kuzara 2005

Abstract – Department of Anthropology, Emory University, Atlanta, Georgia 30322, USA. worthman@emory.edu

Current epidemiologic models concerning the fetal [and neonate] origins of later health risk are evaluated from the perspectives of evolutionary and developmental biology. Claims of adaptive value for and biological status of fetal programming are critically examined.

Life history theory is applied to identify

key trade-offs in adaptive strategies

that constrain developmental design

to use information from the environment

to guide ontogeny and establish cost-benefit trade-offs

that weigh early survival advantage

against remote or unlikely future costs.

Or remote and unlikely changes in the “known environmental factors” even if they should be less costly, more beneficial – there are limitations in what the organism can grow up expecting from in the womb. And limitations to the developmental possibilities it can accomplish!

Expectable environments of evolutionary adaptedness, please don’t limit it here – neonate experiences are crucial, also, in this process – particularly of gestation, are characterized and their impact on human adaptive design discussed.

The roles of neuroendocrine mechanisms in scaffolding life course development, negotiating ongoing cost-benefit trade-offs, and mediating their long-term impacts on function and health are reviewed in detail.

Overviews of gestational biology and the postnatal physiologic, cognitive-affective, and behavioral effects of gestational stress identify a

shared central role for the hypothalamic-pituitary-adrenal (HPA) axis.

Rather than merely mediating stress responses,

the axis emerges an agent of resource allocation

that draws a common thread among conditions of gestation, postnatal environments, and functional and health-related outcomes.

The preponderance of evolutionary and developmental analysis identifies environments as agents on both sides

of the health risk equation, by influencing vulnerabilities

and capacities established in early and later life course development, and determining exposures and demands encountered over the life course.

These people have it right!  All the other strategies of research focus on what’s already wrong with the systems, and only begin to look down into the origins of how this all happened in the first place.  Just throw a drug at the problem – never mind how things got to be this way.  I believe that the light of understanding, education and insight allow people to focus some healing energy into themselves, transgenerationally – and that this light of understanding can help, partly because it can enlighten us on the flexibility and adativeness of human life – and what we evolved to include over the wide array of possibilities in our environments – with the best case, optimal being development under conditions of plenty, of play, of joy.

We can also learn to see the bigger picture which includes information on what heals us – including language, social contact, dance, music – and we can quit blaming the victim.  We are talking evolutionary capacities – the life history of our species, not only our own personal life histories.  We can learn the language to talk about what we can learn to understand – the big and the tiny picture of adaptation in interaction with our environment

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Crespi & Denver 2005

Abstract – Department of Molecular, Cellular and Developmental Biology, The University of Michigan, Ann Arbor, Michigan 48109, USA.

Animals have the ability to alter development, physiology, growth, and behavior in response to different environmental conditions.

These responses represent critical assessments of both external and internal factors. For example, the timing of metamorphosis, hatching, or birth depends on the trade-offs between growth opportunity and mortality risk in the developmental habitat. Physiological sensors compute these trade-offs as a function of energy balance and environmental stress, and effectors initiate physiological, developmental, and behavioral responses to these determinations.

The neuroendocrine stress axis

provides a means for animals to integrate information from multiple sources and to respond accordingly.

Considerable evidence now supports the view that the

secretion of hormones critical to development

(corticosteroid and thyroid hormones)

is controlled by a common neuroendocrine stress pathway involving corticotropin-releasing factor (CRF)

and related peptides.

CRF produced in the hypothalamus

stimulates the biosynthesis and secretion of both

thyroid and corticosteroid hormones,

leading to accelerated tadpole metamorphosis. Similarly, in mammals CRF of fetal and placental origin has been shown to influence the timing of birth. Studies in several experimental animal models and in humans show that early life experience can have long-term phenotypic consequences. No may about it – early life experience makes us, no matter what the details of the experience are – for good or for ill or for middle of the road it shapes all of us

Furthermore, there is evidence that

phenotypic expression

is strongly influenced by the actions of

stress hormones produced during development.

The integrated neuroendocrine response to stress,

and its role in timing critical life history transitions

and establishing long-term phenotypic expression,

arose early in the evolution of vertebrates.

Now I would go one step further and look for the link between this process and the immune response.  Once we have even one cell, our immune system response goes into operation – that it could influence development might be hard for people to think about, because it would be saying the truth, that development requires a best guess projection into the future in order to guide development for better survival odds once we get there.  This connection between immune system response and guided organism development requires future-think – remembering the future – evolution can do that, or we would not be here, plain and simple.

We need to work together as a whole, which means we need to consider all the individual areas of human concern that are being researched, and look for how the research links together.  We need to stop wasting time, energy and resources.  We need not wonder like children would about how some people end up depressed, or bipolar, or borderline, or with PTSD, or without a “conscience” or low on empathy or anxious or not anxious, etc.  Nature is logical.  There are projections that are resulting consequences of incoming information about the environment with resulting best guess adaptations.  All of this happens in interaction with gene manifestation and plasticity.  Risk and protective factors.

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Jones 2005

Abstract – Department of Anthropological Sciences, Stanford University, Stanford, California, USA. jhj1@stanford.edu

Fetal [and neonate] programming is an ontogenetic phenomenon of increasing interest to human biologists. Because the downstream consequences of fetal programming have clear impacts on specific life-history traits (e.g., age at first reproduction and the general age-pattern of reproductive investments), a number of authors have raised the question of the adaptive significance of fetal programming.

In this paper, I review in some detail several classical models in life-history theory and discuss their relative merits and weaknesses for human biology. I suggest that

an adequate model of human life-history evolution must account for the highly structured nature of the human life cycle, with its late age at first reproduction, large degree of iteroparity, highly overlapping generations, and extensive, post-weaning parental investment.

I further suggest that an understanding of stochastic demography is essential for answering the question of the adaptive significance of fetal programming, and specifically the finding of low birth weight on smaller adult body size and earlier age at first reproduction. Using a stage-structured stochastic population model, I show that the downstream consequences of early deprivation may be “making the best of a bad start” rather than an adaptation per se.

When a high-investment strategy entails survival costs,

the alternate strategy of early reproduction with relatively low investment

may have higher fitness than trying to play the high-investment strategy

and failing.

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Ellison 2005

Abstract – Department of Anthropology, Harvard University, Cambridge, Massachusetts 02138, USA. AJHB@fas.harvard.edu

The fetal origins hypothesis, or Barker hypothesis, is both stimulating and challenging for evolutionary human biologists. While evidence of a correlation between conditions around the time of birth and later health outcomes has been presented before, the more recent evidence of a connection between fetal growth and chronic disease risk later in life Including mental health disease has attracted considerable attention among epidemiologists and human biologists. Several themes that are fundamental to human biology emerge from an engagement with the fetal origins hypothesis.

Among them are the tension between concepts of pathology, constraint, and adaptation; the importance of a life history perspective that embraces the notion of trade-offs; the question of environmental predictability; and the mechanisms of energy mobilization and allocation.

Bringing the insights of evolutionary biology to bear on the fetal origins hypothesis illustrates the value of the field now known as evolutionary medicine.

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van Goozen & Fairchild 2008

abstract – School of Psychology, Cardiff University, Cardiff, UK. vangoozens@cardiff.ac.uk

Children with severe antisocial behavior have an increased risk of showing violently aggressive and other forms of problem behavior in adolescence and adulthood. It is well established that both biological and social factors are involved in the development of antisocial behavior. The primary aim of this paper is to discuss the evidence that specific neurobiological systems are involved in the etiology of childhood-onset antisocial behavior. These factors are responsible for the severity of the behavioral problems observed in antisocial children, but they also play a role in their persistence, because they influence children’s interactions with their environment. We will discuss the possible causes of disruptions in neurobiological systems in childhood antisocial behavior and point out the implications of these findings for theory and clinical practice.

We will argue that

familial factors

(e.g., genetic influences, early childhood adversity)

are linked to negative behavioral outcomes

(e.g., antisocial behavior problems)

through the mediating and transactional interplay

with neurobiological deficits.

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see this in mutant genes

Stein, Schork & Gelernter 2008

Abstract – Anxiety and Traumatic Stress Disorders Program, Departments of Psychiatry and Family & Preventive Medicine, University of California San Diego, La Jolla, CA 92093-0855, USA. mstein@ucsd.edu

Stein MB, Schork NJ, Gelernter J.

Gene-by-environment (serotonin transporter and childhood maltreatment) interaction for anxiety sensitivity, an intermediate phenotype for anxiety disorders.

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de Kloet et al 2005b – call in this article

abstract – Department of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research and Leiden University Medical Center, P.O. Box 9502, 2300 RA Leiden, The Netherlands. e.kloet@lacdr.leidenuniv.nl

Adverse conditions during early life

are a risk factor for stress-related diseases

such as depression and post-traumatic stress disorder (PTSD).

How this long-term effect of early adversity occurs is not known, although evidence accumulates that the action of stress hormones is an important determinant.

In rodents after a variety of experiences, even minor ones, during postnatal life permanent changes in emotional and neuroendocrine reactivity have been observed.

Also stressful events occurring prenatally and even the pre-implantation hormonal conditions can have permanent consequences.

Here we will focus on evidence obtained from

(i) the blastocyst implantation during conditions of ovarian hyperstimulation, which is commonly used in the generation of transgenic mice;

(ii) the stress system activity in the newborn under various conditions of maternal care;

(iii) the long-term consequences of maternal separation procedures.

The results clearly demonstrate that

early experiences trigger immediate changes

in the stress system that may

permanently alter brain and behavior.

These changes happen within the context of the early attachment experience – maternal separation for rodents creates irreversible stress responses

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Susman 2006

Abstract – Biobehavioral Transitions Laboratory, Department of Biobehavioral Health, The Pennsylvania State University, E.108 Health & Human Developement Building, University Park, PA 16802, USA. ejs5@psu.edu

Stress experienced during the sensitive prenatal, postnatal and early childhood periods of brain development can have damaging consequences for developing biological systems.

Stressors imposed by early physical vulnerabilities and an adverse care giving environment is proposed to set in motion early precursors of later persistent antisocial behavior. The purpose of this report is to present an integrated theoretical perspective of potential mechanisms involved in the development of persistent antisocial behavior with an emphasis on early stressors and the neuroendocrinology of stress.

The attenuation of endocrine physiology of the stress system is considered a key mechanism involved in persistent antisocial behavior.

The amygdala is considered a structure/process linking subjective experiences,

emotional learning,

brain development and

stress physiology.

Attenuated cortisol level

subsequent to early vulnerabilities is considered a

risk marker for

persistent antisocial behavior.

Interesting – lowered cortisol, not raised, for antisocial

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van Goozen et al 2007

abstract – School of Psychology, Cardiff University, Cardiff, UK. vangoozens@cardiff.ac.uk

Children with persistent antisocial and aggressive behavior are diagnosed as having disruptive behavior disorder. The authors review evidence that antisocial children, and especially those who persist with this behavior as they grow older, have a range of neurobiological characteristics.

It is argued that serotonergic functioning and stress-regulating mechanisms are important in explaining individual differences in antisocial behavior. Moreover, low fear of punishment and physiological underactivity may predispose antisocial individuals to seek out stimulation or take risks and may help to explain poor conditioning and socialization. The authors propose a theoretical model highlighting the interplay between neurobiological deficits and cognitive and emotional functioning as mediators of the link between early adversity and antisocial behavior problems in childhood.

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van Goozen & Fairchild 2006

abstract – School of Psychology, Cardiff University, PO Box 901, Cardiff CF10 3AT, UK. VangoozenS@cardiff.ac.uk

When antisocial behavior becomes a persistent pattern that affects diverse domains of children’s functioning, psychiatrists refer to oppositional defiant disorder (ODD) or conduct disorder (CD). The term disruptive behavior disorder (DBD) covers both ODD and CD. Research shows that in the absence of effective interventions, the prognosis for DBD children is relatively unfavorable: their disorder can extend into adolescence, manifest itself in delinquency, and convert into other psychiatric symptoms, such as addiction or personality disorders. Although environmental factors have traditionally attracted most attention in explaining the origin and persistence of DBDs, it is important not to overlook the vulnerability of the child in the development of antisocial behavior. Risk in the environment is a vulnerability factor – interactions

Relatively few studies have been conducted on the neurobiological factors involved in the development of DBDs in children. In this paper, we explain how problems in hypothalamic-pituitary-adrenal (HPA) axis and serotonergic system functioning could be important factors in the behavioral problems of DBD children. Low fear of punishment and physiological underactivity may predispose antisocial individuals to seek out stimulation or take risks and may explain poor (social) conditioning and socialization. Findings consistent with this hypothesis are presented. Finally, we explain how stress in general, and adverse early life experiences in particular, could have an impact on the development of the HPA and serotonergic systems. An investigation of the neurobiological factors involved in antisocial behavior disorder might ultimately guide the development of new forms of intervention.

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Connor & Zhang 2006

Abstract – Anxiety and Traumatic Stress Program, Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.

In human terms, resilience is an ability to cope with stress and varies with context, time, age, gender, and cultural origin.

Resilience shifts the focus of psychological investigation onto increasing the positive rather than reducing the negative. We have to realize that this factor influences our genes and cannot be separated from it – positive or negative

Inquiry into resilience has evolved from

descriptions of resilient qualities,

to discovery of the process to attain resilience,

to uncovering the motivation to reintegrate in a resilient manner.

Much of the research on resilience has focused on children in settings such as family violence, extreme poverty, war, and natural disasters. A coherent pattern of characteristics associated with successful adaptation has emerged.

Salient characteristics include

commitment,

dynamism,

humor in the face of adversity,

patience,

optimism,

faith, and

altruism.

We have to be very careful not to “blame the victim” in the considerations of resiliency.  There is a point where situations are so overwhelming – and this is also in interaction with genetics – that nobody can come out and win – no matter how optimistic they are – literally, for crying out loud!

As such, resilience may represent an important target of treatment in anxiety, depression, and stress reactions. Resilience can be quantified, but available measures need to be validated transculturally. There exist many possible determinants of resilience, including neurobiologic,

genetic, temperament, and environmental influences. These are so closely intertwined and connected they cannot be separated

Resilience is modifiable on individual and cultural levels. Posttraumatic stress disorder is an example of a serious disorder associated with impaired stress coping that can improve with treatment.

This sounds like a pretty simplistic article, but I don’t have the whole thing to read it, so can’t judge

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Betancourt & Khan 2008 – called for this article

Abstract – Harvard School of Public Health, Cambridge, MA 02115, USA. Theresa_Betancourt@Harvard.edu

This paper examines the concept of resilience in the context of children affected by armed conflict. Resilience has been frequently viewed as a unique quality of certain ‘invulnerable’ children. In contrast, this paper argues that a number of protective processes contribute to resilient mental health outcomes in children when considered through the lens of the

child’s social ecology.

While available research has made important contributions to understanding risk factors for negative mental health consequences of war-related violence and loss, the focus on trauma alone has resulted in inadequate attention to factors associated with resilient mental health outcomes. This paper presents key studies in the literature that address the

interplay between risk and protective processes

in the mental health of war-affected children from an ecological, developmental perspective. It suggests that further

research on war-affected children should pay particular attention to

coping and

meaning making at the individual level; the

role of attachment relationships,

caregiver health,

resources and connection in the family, and

social support available in peer and extended social networks.

Cultural and community influences such as attitudes towards mental health and healing as well as the meaning given to the experience of war itself are also important aspects of the larger social ecology.

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McAllister 2000

Article – U of C, Davis

synaptogenesis and dendritic growth

“Nervous system development comprises several stages.  First, neurons are born and migrate to their final positions in the nervous system.  Subsequently, neurons elaborate their axons and dendrites in patterns characteristic for each cell type.  Finally, highly specific connections between neurons – synapses – are formed.  In many cases, these early synaptic connections are sculpted and remodeled by neuronal activity to achieve the mature pattern of connectivity in the brain….Such precise interconnections between neurons suggest a high degree of cellular and molecular regulation during development.”  McAllister 2000, – 963

“…evidence is rapidly accumulating that dendrites are remarkably responsive to environmental signals….growth of dendrites is highly dynamic, rather than passive.  Moreover, dendritic growth is locally regulated by synaptic activity and other molecular signals from neighboring cells.  Activity-dependent structural changes in postsynaptic cells act together with changes in presynaptic axonal arbors to shape specific patterns of connectivity in the nervous system.  Thus, the growth of dendrites is a dynamic process influenced by, and integral to, the formation of connections in the nervous system.”  McAllister 2000, – 963

“Dendritic arbors develop in a highly choreographed manner…..First, primary basal dendrites extend directly from the cell body; higher order dendrites appear by branching from the primary dendrites.  For most neuronal types, dendritic growth is slow at first but then dramatically increases with a transient overproduction of dendrites to achieve the mature dendritic arborization.”  McAllister 2000, – 963

Recent “…technical advances in our ability to label and image living neurons in real-time has dramatically changed the pervading view of how dendrites grow…Rather than the steady growth implied from studies of fixed tissue, real-time imaging has demonstrated that dendritic elaboration occurs through a net growth of highly dynamic filopodia that each extend and (p 963) retract many times a minute….dendritic filopodia rapidly extend toward nearby axonal growth cones to form synaptic connections, implying that dendrites may be a much more active force in synapse formation than previously imagined….As the neurons mature, these filopodia become much less dynamic and eventually retract into dendritic shaft just before dendritic spines are formed….Thus, dendritic filopodia may serve to increase the likelihood of synapse formation and to physically pull axons toward the dendrite…..Although these spines have classically been considered stable structures, recent imaging experiments clearly demonstrate that spines undergo rapid structural alterations in response to synaptic activity…..”  McAllister 2000, – 964

“The final form and extent of dendritic arbors result from interactions between intrinsic developmental programs and local environmental cues, including levels and patterns of activity….all neurons have an intrinsic ability to produce branched dendrites….environmental signals work with intrinsic mechanisms to regulate proper dendritic arborization.  In fact, evidence for a potent role for environmental signals, including neuronal activity, in regulating dendritic growth is overwhelming.”  McAllister 2000, – 964

“Electrical activity of neurons shapes patterns of synaptic connectivity during early development of the nervous system….Although most studies have focused on the role of activity in sculpting axonal arbors, there is increasing evidence that neuronal activity also fine-tunes dendritic growth and branching.  Dendritic differentiation occurs concurrently with synapse formation, suggesting that afferent [carrying toward] axon terminals might stimulate dendritic growth.  In general, most neurons must receive a particular level and/or pattern of afferent activity for characteristic adult patterns of dendrites to develop.”  McAllister 2000, – 964

“…dendritic structure is rapidly responsive to changes in afferent activity.”  McAllister 2000, – 964

“Increasing afferent activity by raising either young or adult rats in enriched environments also has potent effects on dendritic arbors.  In many cortical areas, exposure to an enriched environment can increase dendritic branching of pyramidal neurons….These results are intriguing and have been used to support the hypothesis that experience alters dendritic form dynamically in both the developing and the mature animal as it interacts with its environment.  However, raising animals in enriched environments is likely to have complex effects on the nervous system, including nutritional and hormonal changes.”  McAllister 2000, – 964

each protein has   “…distinct effects on dendritic growth and branching.”  McAllister 2000, – 969

.mediate rapid effects of synaptic activity to alter dendritic morphology

“The protein synthesis and post-translational modification of proteins required from the growth of dendrites may be facilitated by polyribosomes located at the base of dendritic spines….Polyribosome clusters are sites of protein synthesis.  The location of polyribosomes at the base of dendritic spines may enable protein synthesis to be regulated by activity at individual synapses….As protein synthesis may be required for long-term synaptic changes…dendritic mRNA and local protein synthesis at spines could facilitate local production of proteins necessary for activity-dependent synaptic strengthening and spine formation.”  McAllister 2000, – 969

“Immediate early genes (IEGs) are also likely to be involved in the fast, activity-dependent  dendritic dynamics described above.  These genes are rapidly and transiently expressed in response to synaptic activity and growth factors [e.g. Arc – activity regulated cytoskeleton-associated protein, implicated in activity- and growth-factor-dependent dendritic plasticity, isolated in 1995; Narp – neuronal activity-regulated pentraxin, stimulates dendritic growth, “…may be one of the molecular signals that regulates concurrent dendritic growth and synapse formation.”]  McAllister 2000, – 969

“…overwhelming evidence that afferent innervation is necessary for proper formation of dendrites….”  McAllister 2000, – 969

“Activity-dependent dendritic growth implies that dendritic arborization is not only determined by the intra-cellular components of the dendrite but is also influenced by (969) both the molecular components of the synapse and the axon, and by the signals that influence synaptic stability.  This large number of molecular players acting in concert may enable dendrites to be exquisitely responsive to changes in local signals from connected neurons – a capability necessary for activity-dependent development and also perhaps for adult plasticity.”  McAllister 2000, – 970

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McAllister 2002

Abstract – Davis

The mammalian cerebral cortex requires the proper formation of exquisitely precise circuits to function correctly. These neuronal circuits are assembled during development by the formation of synaptic connections between hundreds of thousands of differentiating neurons. Although the development of the cerebral cortex has been well described anatomically, the cellular and molecular mechanisms that guide neuronal differentiation and formation of connections are just beginning to be understood. Moreover, despite evidence that coordinated patterns of activity underlie reorganization of brain circuits during critical periods of development, the molecular signals that translate activity into structural and functional changes in connections remain unknown.

Recently, the neurotrophins have emerged as attractive candidates not only for regulating neuronal differentiation in the developing brain, but also for mediating activity-dependent synaptic plasticity.

The neurotrophins meet many of the criteria required for molecular signals involved in neuronal differentiation and plasticity.

…………They are present in the cerebral cortex during development and

……….. their expression is regulated by synaptic activity.

….. In turn, the neurotrophins themselves strongly influence both short-term synaptic plasticity and long-term potentiation and depression.

In addition to their functional effects, the neurotrophins also

….profoundly regulate the structural changes that underlie axonal and dendritic differentiation.

…..Finally, the neurotrophins have been implicated in mediating synaptic competition required for activity-dependent plasticity during the critical period. …………This chapter presents and discusses the rapidly accumulating evidence that the neurotrophins are critical for neuronal differentiation and that they may be involved in activity-dependent synaptic refinement in the developing cerebral cortex.

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Cirulli et al 2008

Abstract – Italy

Early adverse events can enhance stress responsiveness and lead to greater susceptibility for psychopathology at adulthood.

The epigenetic factors involved in transducing specific features of the rearing environment into stable changes in brain and behavioural plasticity have only begun to be elucidated.

Neurotrophic factors, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), are affected by stress and play a major role in brain development and in the trophism [acting on something specified] of specific neuronal networks involved in cognitive function and in mood disorders.

In addition to the central nervous system, these effectors are produced by peripheral tissues, thus being in a position to integrate the response to external challenges. In this paper we will review data, obtained from animal models, indicating that early maternal deprivation stress can affect neurotrophin levels, suggesting that they might be involved in the mechanisms underlying the mother-infant relationship. Maladaptive or repeated activation of NGF and BDNF, early during postnatal life, may influence stress sensitivity at adulthood and increase vulnerability for stress-related psychopathology.

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Alleva  & Santucci  2001

Abstract – Italy

Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are well-studied polypeptide growth factors involved in the development and maintenance of specific peripheral and central populations of neuronal cells.

In addition to its role as a neurotrophic agent, NGF controls very complex functions in vertebrate physiology.

…………A variety of cells outside the nervous system are in fact able to synthesize NGF including epithelial cells, fibroblasts, lymphocytes, and macrophages. Implicating immune system here

NGF target cells have been identified in the nervous, immune, and endocrine systems, suggesting that NGF

……..may operate through multiple paths to ultimately regulate physiological homeostasis and behavioral coping.

We used a mouse model of social stress to demonstrate that NGF levels increase both in plasma and in the hypothalamus following intermale aggressive interactions. In both the aggressor and the subordinate?

The investigation has been extended to other species, including humans, to show that

………..labour, lactation,

………and the anticipation of the first jump with a parachute also result in increased NGF plasma levels and in changes in the distribution of NGF receptors on lymphocytes.

BDNF activation is caused by both physical and social stress events. The aim of this review is to

(1) outline the current understanding of the roles of NGF and BDNF in stress-related physiological changes in vertebrates, in particular for physical vs. psychological stressors, which may activate both similar and different neurobiological pathways, and

(2) summarize recent efforts to derive pharmacological strategies from the increasing body of BDNF and NGF neurobehavioral data.

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Branchi, Francia & Alleva 2004

Abstract – Italy

Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are two neurotrophins involved in the differentiation, growth and maintenance of selected peripheral and central populations of neuronal cells, during development and at adulthood.

Furthermore, neuronal activity enhances expression and action of these neurotrophins, modifying synaptic transmission and connectivity. Neurotrophin production has been shown to be experience-dependent. In particular, during early developmental phases, experiences such as maternal deprivation or exposure to an enriched environment markedly affect NGF and BDNF levels.

At adulthood, psychosocial stress has been shown to markedly alter NGF and BDNF levels, both in plasma and selected brain areas, including the hypothalamus and hippocampus.

………….. These results have been extended to humans, showing that NGF levels are enhanced by emotional stress induced by parachute jumping. Overall, these findings suggest a role of neurotrophins as factors mediating both short- and long-term effects of experience on brain structure and function.

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Mendell, Albers & Davis 1999

Abstract – NY

Neurotrophins and pain

It is now well established that neurotrophins play a crucial role in the development of the nervous system.

……….However, there is increasing evidence that the function of neurotrophins persists throughout adulthood.

………The broad scope of neurotrophin action is well documented in the case of nerve growth factor (NGF) and its effect on nociceptors and nociception. …………Here, we review the evidence for these multiple roles for NGF. Two manipulations influencing NGF levels are discussed in detail. The first involves the use of transgenic mice that overexpress or underexpress neurotrophins. ……….A second strategy involves administration of NGF or its antibody in vivo to increase or decrease its level.

During prenatal development, NGF is required for survival of nociceptors. In the early postnatal period, NGF is required for expression of the appropriate nociceptor phenotype.

This must be tied to the opioid system, and probably to the immune system

In adults, NGF acts as an important intermediate in inflammatory pain, contributing to both peripheral and central sensitization

…… The sensitization of peripheral nociceptors can be very rapid and can involve non-neural cells such as mast cells, neutrophils, fibroblasts, and macrophages.

……….Recent evidence indicates that other neurotrophins also play key supporting roles in the development of nociceptors (e.g., NT-3) and in inflammatory pain (e.g., BDNF, NT-4/5).

……….Furthermore, molecules from other superfamilies (e.g., GDNF) also are required to assure survival of certain classes of nociceptors.

……….The diverse effects of neurotrophins on nociceptive processing emphasize their broad importance in the development and function of the nervous system.

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Cirulli, Berry & Alleva 2003

Abstract – Italy

Early environmental manipulations can impact on the developing nervous system, contributing to shape individual differences in physiological and behavioral responses to environmental challenges.

………In particular, it has been shown that disruptions in the mother-infant relationship result in neuroendocrine, neurochemical and behavioural changes in the adult organism, although the basic mechanisms underlying such changes have not been completely elucidated.

……….Recent data suggest that neurotrophins might be among the mediators capable of transducing the effects of external manipulations on brain development.

…………Nerve growth factor and brain-derived neurotrophic factor are known to play a major role during brain development,

……..while in the adult animal they are mainly responsible for the maintenance of neuronal function and structural integrity.

Changes in the levels of neurotrophic factors during critical developmental stages might result in long-term changes in neuronal plasticity and lead to increased vulnerability to aging and to psychopathology.

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Macrì  & Würbel 2006

Abstract – Italy

Developmental plasticity of HPA and fear responses in rats has been proposed to be mediated by environment-dependent variation in active maternal care.

Here, we review this maternal mediation hypothesis based on the postnatal manipulation literature and on our own recent research in rats. We show that developmental plasticity of HPA and fear responses in rats cannot be explained by a linear single-factor model based on environment-dependent variation in active maternal care.

……… However, by adding environmental stress as a second factor to the model, we were able to explain the variation in HPA and fear responses induced by postnatal manipulations.

In this two-factor model, active maternal care and environmental stress (as induced, e.g., by long maternal separations or maternal food restriction) exert independent, yet opposing, effects on HPA reactivity and fearfulness in the offspring.

………This accounts well for the finding that

…………completely safe and stable,

………..as well as, highly stressful maternal environments

………..result in high HPA reactivity and fearfulness

………..compared to moderately challenging maternal environments.

First that I’ve seen reference to this!  Makes sense, though…

Furthermore, it suggests that the downregulation of the HPA system in response to stressful maternal environments could reflect adaptive developmental plasticity based on the increasing costs of high stress reactivity with increasingly stressful conditions.

By contrast, high levels of environmental stress induced by environmental adversity might constrain such adaptive plasticity, resulting in non-adaptive or even pathological outcomes.

Alternatively, however, developmental plasticity of HPA and fear responses in rats might be a function of maternal HPA activation (e.g., levels of circulating maternal glucocorticoid hormones).

….. Thus, implying a U-shaped relationship

….between maternal HPA activation

……and HPA reactivity and fearfulness

………in the offspring,

increasing maternal HPA activation with increasing environmental adversity would explain the effects of postnatal manipulations equally well.

This raises the possibility that variation in active maternal care is an epiphenomenon [A secondary phenomenon that results from and accompanies another]:, rather than a causal factor in developmental plasticity of HPA and fear responses in rats.

Developmental plasticity of HPA and fear responses in rats and other animals has important implications for the design of animal experiments and for the well-being of experimental animals, both of which depend on the exact underlying mechanism(s).

Importantly, however, more naturalistic approaches are needed to elucidate the adaptive significance of environment-dependent variation of HPA reactivity and fearfulness in view of discriminating between effects reflecting adaptive plasticity, phenotypic mismatch and pathological outcomes, respectively.

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Macrì, Mason & Wurbel 2004

Abstract – Switzerland

The development of the hypothalamic-pituitary-adrenal (HPA) response to stress is influenced by the early mother-infant relationship. In rats, early handling (brief daily mother-offspring separations) attenuates the adult offspring’s HPA and fear responses compared to both nonhandling (no separations) and maternal separation (prolonged daily separations).

It has been proposed that variation in the amount of maternal care mediates these effects of neonatal manipulations on the adult offspring’s stress and fear responses. Here we tested this hypothesis by assessing maternal care and the adult offspring’s HPA and fear responses in Lister hooded rats which were subjected to either early handling (EH) or maternal separation (MS) from postnatal day 1-13, or were left completely undisturbed (nonhandled, NH) throughout this period.

………. Both EH and MS induced a more active nursing style and elevated levels of maternal care compared to NH.

………….Total levels of maternal care were indistinguishable between EH and MS, but diurnal distribution differed.

……….MS dams showed elevated levels of maternal care following the 4-h separation period, thereby fully compensating for the amount of maternal care provided by EH dams during the time MS dams were separated from their pups

. ………..However, while EH resulted in reduced HPA and fear responses in the adult offspring compared to NH, MS and NH offspring did not differ.

………Our findings therefore demonstrate dissociation in the effects of EH and MS on maternal care and on the stress and fear responses in the offspring.

This indicates that maternal care cannot be the sole mediator of these effects.

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Macrì, Chiarotti & Würbel 2008

Abstract – Switzerland

Postnatal manipulations such as brief (early handling, EH) and long, daily mother-offspring separations (maternal separation, MS) in rats are used to study the mechanisms underlying developmental plasticity of stress and fear responses, and to model stress-related disorders in humans and in non-human animals.

Current evidence suggests that, compared to non-handled rats, EH reduces hypothalamic-pituitary-adrenal (HPA) reactivity in the adult offspring through stimulating increased levels of active maternal care.

……….In contrast, despite a similar increase in active maternal care, MS does not reduce HPA reactivity, thus suggesting that long mother-offspring separations may counteract the effects of increased active maternal care.

………..We therefore attempted to selectively manipulate levels of active maternal care and durations of mother-offspring separations in neonate rats. Rat pups were exposed to different combinations of EH and MS from postnatal day (PND) 2 to 10 using a split-litter design. Maternal behaviour was recorded from PND 2 to 8 and behavioural and endocrine responses to stress were studied in adult male offspring.

Low levels of maternal care combined with long mother-offspring separations increased HPA-reactivity

……..compared to both high maternal care combined with long mother-offspring separations

……and low maternal care combined with brief separations.

…………These findings further support the hypothesis that active maternal care and long mother-offspring separation act independently,

………..and exert opposing effects, on adult offspring’s HPA responses,

………. but that increased maternal care may buffer the adverse consequences of long separations.

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Moles, Rizzi & D’Amato 2004

Abstract – Italy

Short- and long-term effects of brief maternal separation, maternal exposure to novel male odor, and standard rearing were compared in NMRI mice. The first condition consisted of 15 min of daily exposure of pups to clean bedding (CB), and the second condition consisted of 15 min of mothers’ exposure to the odor of strange males (SM), for 14 days after birth starting from postnatal Day 1. Thus, both conditions entailed the same period of maternal separation. A control mother-offspring group was left undisturbed (nonhandled, N-H). Corticosterone levels of mothers and pups were measured at the end of the last manipulation session.

…..Corticosterone levels were higher in SM mothers, differing from both those of CB and of control dams;

….CB pups showed the highest corticosterone levels in comparison with the pups belonging to the other groups.

Maternal behavior observed as furthest as possible from the daily separation session did not differ among the three groups. The behavioral response to 0.5 mg/kg of apomorphine in 15-day-old pups was enhanced in both CB and SM animals, which suggests an alteration of dopaminergic functioning.

Finally, adult CB and SM male mice showed an increase in the percentage of time and entries into the open arms of the plus-maze in comparison to nonhandled males.

………..This study indicates that exposure to ecologically relevant stimuli elicited a stress response in lactating dams.

…………This “social stress” brings about short- and long-term effects in the offspring, even in the absence of any direct manipulation of the pups.

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Moles et al 2008

Abstract – Italy

BACKGROUND: Early adverse experiences are preeminent factors for the development of affective disorders.

In the present study, we analyzed the effects of different postnatal manipulations applied either on the mother or on the offspring in mice. Maternal behavior and adrenocortical activity of both mothers and offspring at the end of postnatal stress and at adulthood were considered. METHODS: From postnatal day (PND) 1 to 14 mice underwent 15min of: (a) brief (15min) pups’ exposure to clean bedding (CB: clean bedding), (b) mothers’ exposure to the odor of a novel male (SM: stressed mother) or (c) mothers’ exposure to a clean cage (CSM: control stressed mother), and (d) standard rearing (N-H: non-handled). The behavior of mouse dams during and after stress sessions was analyzed. Serum corticosterone of mothers and pups at the end of the stress session and 30min after reunion was assessed on PND 14. Moreover, anxiety levels and HPA-axis inhibitory feedback in response to dexamethasone administration were evaluated in adult male offspring. RESULTS: Overall, during the 14 days of treatment CB mothers when reunited with their pups showed higher maternal behavior than other dams. After the last stress (PND 14) SM and CSM maternal corticosterone levels increased as well as those of CB pups. While 30min of mother-infant interaction restored baseline corticosterone levels in SM and CSM mothers and in CB pups,

…………SM and CSM offspring showed a decrease of corticosterone under baseline levels. Like a pre-PTSD condition?

At adulthood, SM and CSM males did not show the suppressive hormonal response to dexamethasone treatment.

……….Moreover, adult CB and SM male mice displayed decreased anxiety in the open field.

CONCLUSIONS: Maternal psychosocial stress during lactation seems to permanently affect the offspring’s HPA functioning.

These effects may be dissociated from the behavioral response

……….as suggested by the decrease of anxiety in SM and CB adult mice.

I don’t understand the implications of this without the article

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Vanbesien-Mailliot et al 2007

Abstract – France

PRENATAL STRESS – PRO-INFLAMMATORY CHANGES IN IMMUNE SYSTEM IN PUPS

The in utero environment is critical for initiating the ontogeny of several physiological systems, including the immune surveillance. Yet, little is known about adverse early experiences on the offspring’s immunity and vulnerability to disease. The present work aimed at investigating the impact of restraint prenatal stress (PS) on the development and responsiveness of in vitro and in vivo cellular and humoral immunity of male progeny aged 7 weeks and 6 months. In adult 6-month-old rats, we detected increased circulating CD8(+)-expressing and NK cells in PS rats as compared to controls, associated with higher mRNA expression of IFN-gamma.

……….In addition, in vitro stimulation with phytohemagglutinin-A induced an increase in both the proliferation of T lymphocytes and the secretion of IFN-gamma in PS rats. Interestingly, these alterations were undetectable in younger PS rats (7-week old), except for a slight increase in the mRNA expression of several pro-inflammatory cytokines in peripheral blood mononuclear cells. Moreover, in vivo neutralization of IFN-gamma in young rats had no effects in PS group. In conclusion, we report for the first time long-lasting pro-inflammatory [capable of promoting inflammation. For example, air pollution may have proinflammatory effects] consequences of PS in rats.

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Kraszpulski, Dickerson & Salm 2006

Abstract – Poland

PRENATAL STRESS – CHANGES AMYGDALA

The amygdala plays a critical role in generating the emotion of fear, and alterations in amygdala fear processing are thought to underlie the acquisition and maintenance of anxiety disorders.

The prenatally stressed (PS) rat displays hormonal, behavioral and brain anatomical similarities to anxious humans and is useful to study the neurobiological underpinnings of pathological anxiety. We studied PS and control male rats at postnatal days 7 (P7), P25, P45 and P60. Using unbiased stereological analyses we examined the volumes, anterior-posterior lengths and total numbers of neurons and glia of the basolateral (BL), central (Ce) and lateral (La) amygdalar nuclei.

We found prenatal stress-associated differences in the developmental trajectories of each nucleus. These were apparent in some measures as early as P7, most extensive at P25 and resolved by P45, at least as seen by Nissl staining. These changes were not a result of differential brain growth.

This early divergence in developmental trajectories seen here may be the harbinger of PS rat amygdalas that ultimately function very differently in adulthood.

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Dickerson et al 2005

Abstract – WV

We have been studying the mildly prenatally stressed (PS) rat as a potentially useful animal model of anxiety disorders.

Previously we have demonstrated that there are anatomical and biochemical alterations in the amygdalas of adult PS offspring and that these offspring show increased fearful behaviors.

………However, human data indicate that anxiety disorders often present first in early childhood and then persist throughout adolescence and adulthood.

To determine if PS rats also model this characteristic of human anxiety disorders, here we asked whether behavioral indices of increased fear would be detectable at an early age. We tested the hypotheses that young PS rats would show increased behavioral fearfulness in response to an acute stressor and that this would increase with age. A mild prenatal stressor, consisting of removal of the dam from the home cage and administration of a subcutaneous injection of 0.1 ml of 0.9% saline daily, was administered during the last week of pregnancy. Offspring were tested in the defensive-withdrawal apparatus before and after exposure to restraint stress at 25, 45 and 60 days of age.

……… PS animals showed increased defensive-withdrawal behavior following the stressor and were more fearful following restraint when compared to controls (CON). This was significant at P45 and increased to P60. ………Hence, fearful behaviors in PS rats emerge prior to sexual maturation and increase in magnitude thereafter, further validating our model as a means to investigate the underpinnings of anxiety disorders.

Too bad they didn’t measure vasopressin in these studies – were these rats high or low anxiety trait rats to start with before the prenatal stress?

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Van der Hove et al 2005

Abstract – The Netherlands

Chronic or repeated stress during critical periods of human fetal brain development has been associated with various learning, behavioral and/or mood disorders in later life.

In this investigation, pregnant Fischer 344 rats was individually restrained three times a day for 45 min during the last week of gestation in transparent plastic cylinders while at the same time being exposed to bright light. Control pregnant females were left undisturbed in their home cages. Anxiety and depressive-like behavior was measured in the offspring at an age of 6 months using the open field test, the home cage emergence test and the forced swim test.

Prenatally stressed rats spent more time in the corners and less time along the walls of an open field, while no difference in total distance moved was observed.

…….. In addition, prenatally stressed rats took more time to leave their home cage in the home cage emergence test.

……..On the other hand, no differences in immobility were observed in the forced swim test.

……Moreover, prenatally stressed rats showed lower stress-induced plasma corticosterone levels compared with control rats.

……Prenatal stress (PS) had no effect on the number of 5-bromo-2-deoxyuridine-positive cells – used as a measure for cell proliferation – in the dentate gyrus of these rats.

……..These data further support the idea that

……..PS may perturb normal anxiety-related development.

………… However, the present data also suggest that an adaptive or protective effect of PS should not be ignored.

………..Genetic factors are likely to play a role in this respect.

To be useful, they need to see what these rats are like when they are older!

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Pallares et al 2007

Abstract – Argentina

Stressor presence during the last weeks of gestation has been associated with behavioral disorders in later life. In this study we support further research on the long term effects of prenatal stress on Swiss mice descendant’s behavior. Prenatal stress procedure consisted on restraining the dams under bright light for 45 min, three times per day from the 15th day of pregnancy, until birth. After weaning, offspring’s motor performance and spontaneous exploratory behavior were measured by the tight-rope and T-maze tests, respectively. We also evaluated anxiety behavior using elevated plus maze test.

We found that maternal stress improves the performance of the animals in the tight rope test and that this effect was sex and age dependent: prenatal stressed males obtained the best scores during the first month of life, while in females the same was achieved at the second month.

Spontaneous exploratory behavior analysis revealed that it was elevated in prenatal stressed males and that this effect persisted on time.

…………However, we did not find significant differences on this behavioral response among both females groups.

Finally, differences on anxiety behavior were found only in females: prenatally stressed animals showed a higher proportion of entries into the open arms of a plus maze (reduced anxiety) compared to the control group.

Our results show that prenatal stress modifies the normal behavior of the progeny: prenatal stressed animals have a better performance in the carried out test. These notably results suggest the existence of an adaptive response to prenatal stress

Again, they need to follow to adulthood to see the long-term effects

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Estanislau & Morato 2005

Abstract – Brazil

anxiogenic effects

Prenatal stress and maternal separation are used in a large number of studies on early adversity consequences and present some similarities in their effects. The present work investigates the behavioral effects of these two procedures on two models of anxiety: the elevated plus-maze and the elevated T-maze. During pregnancy, female rats were submitted to uncontrollable electric foot shock sessions every other day or kept undisturbed. After delivery, litters from undisturbed dams were submitted to either 180-min daily periods of maternal separations from the 3-14th postnatal days or maintained with the dams all the time. Litters from the stressed dams were left undisturbed from the 3-14th postnatal days. Only males were tested. In adulthood, rats were tested in the elevated T-maze or in the elevated plus-maze. In the latter procedure half the subjects were submitted to a 60-min period of restraint immediately before being tested. The following measures were taken in the elevated plus-maze: frequency and time spent in entries into the arms, stretching, rearing, grooming and head dipping. In the T-maze measures of avoidance and escape latencies were used.

Our data indicated that prenatal stress had more pronounced anxiogenic effects than maternal separation, as judged by reduced exploration of the open arms of the elevated plus-maze, but mainly after the restraint stress, and increase in avoidance latencies in the elevated T-maze. The other measures not directly involved in the elevated plus-maze arm exploration yielded similar results. Our data indicate that prenatal stress causes more anxiogenic effects in adulthood than maternal separation but, in the elevated plus-maze, these anxiogenic effects are better seen immediately after an acute stress.

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Estanislau & Morato 2006

Abstract – Brazil

anxiogenic effects

Prenatal stress is a putative model for studying some psychopathological disorders. Indeed, submitting pregnant animals to stress leads to enhanced anxiety in the adult offspring. Conflictual study results

However, little is known about how prenatal stress effects interact with anxiety throughout development. To study this issue, prenatally stressed rats were tested in the elevated plus-maze at different ages. During pregnancy female rats were submitted to uncontrollable electric foot shock sessions every other day or kept undisturbed (controls). After delivery, litters from control and stressed dams were left undisturbed from the 3rd to the 14th postnatal days. Male and female rats were tested in the elevated plus-maze at the ages of 30, 45 or 60 days. The following measures were taken in the elevated plus-maze: number of entries and time spent in the arms (or their extremities) and frequency and time spent in naturalistic behaviors (stretching, rearing, end exploring, grooming and head dipping). Decreases in the percentage of entries into and in the time spent (only females) in the open arms were shown by 60-day-old prenatally stressed rats, but not by 30- and 45-day old. Increased open arm ends exploration was shown by 45-day-old prenatally stressed males. Rearing behavior was found to increase with age, a phenomenon more pronounced in females. Additionally, at the younger ages prenatally stressed rats were heavier than controls, an effect which disappeared at young adulthood. In conclusion, anxiogenic prenatal stress effects in the elevated plus-maze could only be detected at early adulthood, not before. Nonetheless, at late adolescence (45 days of age)

prenatal stress leaded to an anxiolytic-like effect which can be interpreted as increased risk-taking behavior.  Anxiolytic [any substance taken to reduce anxiety]

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Ward et al 2000

Abstract – WV

increased activity of CRFergic systems in the amygdala.

Exposure of pregnant rats to stress results in offspring that exhibit abnormally fearful behavior and have elevated neuroendocrine responses to novelty and aversive stimuli.

…………..This study examined the effects of prenatal stress on plasma corticosterone, adrenal weight, defensive withdrawal behavior, and the density of receptors for corticotropin releasing factor (CRF) in the amygdala.

Pregnant Sprague-Dawley rats were stressed by daily handling and saline injection (s.c., 0.9%, 0.1 mL) during the last week of gestation. Male offspring were studied at adulthood (60-120 days of age). Adrenal hypertrophy and increased plasma corticosterone were observed in the prenatally stressed offspring.

………. Defensive withdrawal, an ethological measure of the conflict between exploratory behavior and retreat, was quantified in naive offspring, and in offspring exposed to restraint stress (2 h).

……….. Restraint stress increased defensive withdrawal in both control and prenatally stressed offspring. Both naive and restraint-stressed prenatally stressed offspring exhibited increased defensive withdrawal compared to control offspring.

………..There was a significant interaction between prenatal stress and restraint stress, suggesting increased vulnerability of prenatally stressed offspring.

The effects of restraint in the defensive withdrawal test were reduced by intracerebroventricular administration of the CRF antagonists, alpha-helical CRF9-41 (20 microg every hour) or D-phe(12), Nle(21, 38), C(alpha)-MeLeu(37)]-CRF((12-41)) (5 microg every hour) during the restraint period. The difference between control and prenatally stressed offspring was abolished by the CRF antagonists,

suggesting that increased activation of CRF receptors may be a factor in the behavioral abnormalities of prenatally stressed rats.

Measurement of CRF receptors in amygdala revealed a 2.5-fold increase in binding in prenatally stressed offspring.

……….In light of previous work from this laboratory demonstrating increased content and release of CRF in amygdala from prenatally stressed offspring, the present study suggests that

the increased fearfulness of prenatally stressed rats may be a consequence of increased activity of CRFergic systems in the amygdala.

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Viltart  & Vanbesien-Mailliot 2007b

Abstract – France

Since life emerged on the Earth, the development of efficient strategies to cope with sudden and/or permanent changes of the environment has been virtually the unique goal pursued by every organism in order to ensure its survival and thus perpetuate the species. In this view, evolution has selected tightly regulated processes aimed at maintaining stability among internal parameters despite external changes, a process termed homeostasis.

……Such an internal equilibrium relies quite heavily on three interrelated physiological systems:

…the nervous,

…immune, and

….endocrine systems,

….which function as a permanently activated watching network, communicating by the mean of specialized molecules: neurotransmitters, cytokines, and hormones or neurohormones.

……..Potential threats to homeostasis might occur as early as during in utero life, potentially leaving a lasting mark on the developing organism. ………..Indeed, environmental factors exert early-life influences on the structural and functional development of individuals, giving rise to changes that can persist throughout life. This organizational phenomenon, encompassing prenatal environmental events, altered fetal growth, and development of long-term pathophysiology, has been named early-life programming.

Over the past decade, increased scientific activities have been devoted to deciphering the obvious link between states of maternal stress and the behavioral, cognitive, emotional, and physiological reactivity of the progeny.

………This growing interest has been driven by the discovery of a tight relationship between prenatal stress and development of short- and long-term health disorders.

……….Among factors susceptible of contributing to such a deleterious programming, nutrients and hormones, especially steroid hormones, are considered as powerful mediators of the fetal organization since they readily cross the placental barrier.

In particular, variations in circulating maternal glucocorticoids are known to impact this programming strongly, notably when hormonal surges occur during sensitive periods of development, so-called developmental windows of vulnerability.

………….Stressful events occurring during the perinatal period may impinge on various aspects of the neuroendocrine programming, subsequently amending the offspring’s growth, metabolism, sexual maturation, stress responses, and immune system.

……..Such prenatal stress-induced modifications of the phenotypic plasticity of the progeny might ultimately result in the development of long-term diseases, from metabolic syndromes to psychiatric disorders.

………Yet, we would like to consider the outcome of this neuroendocrine programming from an evolutionary perspective.

………Early stressful events during gestation might indeed shape internal parameters of the developing organisms in order to adapt the progeny to its everyday environment and thus contribute to an increased reproductive success, or fitness, of the species.

…………..Moreover, parental care, adoption, or enriched environments after birth have been shown to reverse negative long-term consequences of a disturbed gestational environment.

In this view, considering the higher potential for neonatal plasticity within the brain in human beings as compared to other species, long-term consequences of prenatal stress might not be as inexorable as suggested in animal-based studies published to date.

This idea is mirrored in the vasopressin research in attachment chapter about the low and high anxiety pups exposed to stress in utero – each come up or down a few notches on the anxiety spectrum as a result

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Hodyl et al 2007

Abstract – Australia

Growing evidence suggests that maternal health during the prenatal period is a critical determinant of adult immuno-competence. This study aimed to characterise the innate immune response to bacterial exposure in rat offspring following maternal exposure to a pro-inflammatory stimulus. The offspring’s innate immune responses were investigated at four developmental timepoints in the rat by determination of immune cell subtypes and TNF-alpha and IL-1beta response to in-vivo LPS exposure.

…….The pre-weaned offspring of exposed dams demonstrated no immune response to the LPS challenge, whereas control offspring responded with a typical elevation in cytokine levels.

….. In pubescence no differences were observed between the responses of the control and exposed offspring.

…….In adulthood and senescence, offspring of endotoxin treated dams had significantly less monocytes in circulation than control offspring and differential sex effects were only evident in these older animals.

………The developmental profile of immune functioning following prenatal immune activation has not previously been demonstrated. This study highlights the prenatal period as one of importance in determining later immune function.

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Ashdown et al 2006

Abstract – Quebec

Maternal infections with bacterial or viral agents during pregnancy are associated with an increased incidence of schizophrenia in the offspring at adulthood

,,,,,,,,,although little is known about the mechanism by which maternal infection might affect fetal neurodevelopment.

Exposure of pregnant rodents to the bacterial endotoxin, lipopolysaccharide (LPS), results in behavioral deficits in the adult offspring that are relevant to schizophrenia.

……… It is however unknown whether these effects are due to the direct action of the inflammatory stimulus on the developing fetus,

………or due to secondary immune mediators (cytokines) activated at maternal/fetal sites.

In this study we sought to elucidate the site of action of LPS, following a single intraperitoneal (i.p.) injection, in pregnant rats at gestation day 18. Animals received 5 muCi of iodinated LPS ((125)I-LPS) and its distribution was assessed in maternal/fetal tissues (1-8 h). In addition, induction of the inflammatory cytokines, TNF-alpha, IL-1beta and IL-6, was measured in maternal/fetal tissues following maternal LPS challenge (0.05 mg/kg, i.p.) (2-8 h). (125)I-LPS was detected in maternal tissues and placenta, but not the fetus. This distribution was accompanied by significant increases in TNF-alpha, IL-1beta and IL-6 in maternal plasma and placenta, but not in fetal liver or brain. A significant increase in IL-1beta was however detected in fetal plasma, possibly due to transfer from the maternal circulation or placenta.

Collectively, these data suggest that effects of maternal LPS exposure on the developing fetal brain are not mediated by the direct action of LPS, but via indirect actions at the level of the maternal circulation or placenta.

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Shen et al 2008

Abstract – China

Exposure to prenatal undernutrition or malnutrition increases the risk of schizophrenia, although little is known about the mechanism.

Pro-inflammatory factors are critical in brain development, and are believed to play an important role in neurodevelopmental disorders associated with prenatal exposure to infection, including schizophrenia.

However it is not known whether pro-inflammatory factors also mediate the effects on the fetus of prenatal malnutrition or undernutrition. In this study, we established a new prenatal undernourished rat model induced by maternal exposure to a diet restricted to 50% of the low (6%) protein diet (RLP50). We observed the disappearance of maternal nest-building behavior in the RLP50 dams, increased levels of TNFA and IL6 in the placentas (P<0.001; P=0.879, respectively) and fetal livers (P<0.001; P<0.05, respectively), and a decrease in the fetal brains (P<0.05; P<0.01, respectively).

Our results are similar to previous studies of maternal infection, which implies that

….a common pathway mediated by pro-inflammatory factors may contribute to the brain development,

…….consequently increasing the risk of schizophrenia and other psychiatric diseases

…..programmed by varied maternal adversities.

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Ngom et al 2004

Abstract – UK – Gambian research

BACKGROUND: In rural Gambians, the season of birth strongly predicts adult mortality. Those born during the harvest season have longer life spans than do those born during the hungry season, and the deaths associated with infectious diseases suggest permanent early-life influences on immunity. Thymic measurements showed significantly smaller thymuses in infants born during the hungry season than in those born during the harvest season. The differences were greatest at 8 wk of age, a time when all infants were exclusively breastfed, which suggests the involvement of breast milk factors. OBJECTIVE: This study tested whether thymic size differences reflect thymic output and ascertained whether thymic output is associated with breast milk interleukin 7 (IL-7) concentrations. DESIGN: We studied thymic size and output in a prospective cohort of 138 Gambian infants born in either the hungry or the harvest season by measuring signal-joint T cell receptor-rearrangement excision circles (sjTRECs) at birth and at 8 wk of age. IL-7 concentrations in breast milk were measured by using an enzyme-linked immunosorbent assay. RESULTS: By age 8 wk, those born in the hungry season had significantly lower sjTREC counts than did those born in the harvest season (0.97 and 2.12 sjTRECs/100 T cells, respectively; P = 0.006). At 1 wk postpartum, the breast milk of mothers of infants born in the hungry season had significantly lower IL-7 than did that of mothers of infants born in the harvest season (79 and 100 pg/mL, respectively; P = 0.02). The findings were similar at 8 wk postpartum. CONCLUSION: These data show a plausible pathway linking external seasonal insults to mothers with thymic development in their infants, which suggests possible implications for long-term programming of immunity.

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Moore et al 2004

Abstract – UK – Bangladesh research

BACKGROUND: Analysis of data from rural Gambia has previously shown that being born during the annual hungry season strongly influences susceptibility to mortality from infectious disease in young adulthood, possibly through an influence on immune function. In rural Bangladesh pregnancies are exposed to similar seasonality. The current paper uses data from a large demographic survey in the Matlab region of Bangladesh to retest the Gambian-derived hypothesis that early life exposures correlated with season of birth predict later patterns of mortality. METHODS: Since 1966, a continuous demographic surveillance system has been in operation in the rural Matlab region of Bangladesh. The current analysis is based on 172 228 births and 24 697 deaths between 1974 and 2000. Season of birth was defined as ‘harvest’ (January-June) and ‘hungry’ (July-December), based on monthly variations in rates of conception and neonatal mortality within the same dataset. RESULTS: Birth during the hungry season resulted in excess mortality during the first year of life. However, for adult mortality (deaths >15 years), there was no excess in individuals born during the annual hungry season: ratio of hazard July-December versus January-June = 1.12; 95% CI: 0.87, 1.45. CONCLUSIONS: The current study found no excess mortality in young adults born during the ‘hungry’ season in rural Bangladesh. This differing pattern in survival when compared with The Gambia may be a consequence of the greatly reduced incidence of young adult deaths in Bangladesh (0.1%) compared with The Gambia (3%). Under such conditions possible differences in immune function may not be detectable with early adult death as the outcome. However, it also remains possible that our Gambian observation could be a highly discrete phenomenon localized in either time or place, and as such, will not be replicated in other populations.

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Enel et al 2006

Abstract – France – article in French

Undernutrition in young children in developing countries is associated with an increased risk of death. But in several studies, a decrease in mortality was not associated with any decrease in the prevalence of undernutrition. STUDY AREA: A rural population of Casamance (Senegal) has been under yearly demographic surveillance by The French National Institute of Demographic Studies (INED) since 1985. Between 1960-1964 and 1990-1994, under-5 and child (1-4 years) mortality rates dropped from 312 to 127 and from 201 to 68 per 1,000, respectively. Since 1961, French Catholic nuns who are also professional nurses have been in charge of a private village dispensary located in a rural area of Casamance. This dispensary delivers permanent, high quality service and is widely attended. GROWTH MONITORING PROGRAMME: A growth-monitoring programme, supported by Cathwell, was initiated in 1969 for 0-5-year-old children (0-3 from 1985). Children were weighed wearing light clothes to the nearest 10g. Weights were recorded in a register that also contained information concerning identity (name, sex, date of birth) and address. All weights were plotted on growth charts kept by the mothers. During the sessions, the nurses provided nutrition education messages (i.e., preparation of high-energy and nutrient-dense infant gruels using local foods), advice on illness management (oral rehydration during diarrhoea) and hygiene (well and water-jar disinfection, construction of pit-latrines), importance of vaccination. From 1975, they also distributed free chloroquine during the malaria transmission season (May-November) for prevention and early presumptive treatment. Most likely thanks to this programme, infant and child mortality reached a low level at the end of the 1980s. In 1990, plasmodium resistance to chloroquine appeared, increasing malaria mortality. METHODS: All weight measurements taken in 1969-1994 were entered into a database. This paper presents an analysis of weight measurements taken at 3-23 months of age from 1969-1992. A total of 4,636 infants were weighed at least once, but only 3,912 infants (1,983 boys and 1,929 girls) were available for the analysis, 724 being excluded due to missing data. RESULTS: The average coverage of the programme during the month of February was 88% for infants aged 3-23 months. Mean weight was examined at three target ages: 5, 11 and 15 months. Not only did the nutritional status not improve between 1969 and 1989, it even deteriorated in some years for all three age-cohorts. The nutritional status of infants in this community did not differ significantly from that of 12-23 month-old Senegalese children in the 1992-1993 Demographic and Health Survey (DHS). Seasonal differences in mean weight and the prevalence of underweight became significant in the rainy season since 1975. Underweight for the 15-month-old children increased over time during the rainy season. These findings were unexpected, since malaria morbidity is thought to be at least partially responsible for seasonal variations in the nutritional status of young children, and despite the fact that the nurses began a malaria control programme in 1975. CONCLUSION: The rapid transition towards lower childhood mortality observed in this rural area of Casamance (Senegal), was not concomitant with any improvement in infants’ nutritional status from 1969 through 1992. Focused public health interventions such as vaccinations and malaria prevention probably did not improve the nutritional status. Paradoxically, growth monitoring may have been more helpful in improving health than growth. Targeted specific nutritional interventions are needed to significantly improve growth of children in this community.

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Hamilton et al 2007

Abstract – U of MN

Much is known about the immunomodulatory effects of opiate exposure and withdrawal in adult rats. However, little research has delved into understanding the immunological consequences of prenatal opiate exposure and postnatal withdrawal. The purpose of the current study was to measure changes in responding to immune stimulation in adult rats following prenatal opiate exposure. Further, we sought to characterize the role of interleukin (IL)-1beta in these changes. Following prenatal exposure to the long-acting opiate l-alpha-acetylmethadol (LAAM), adult male and female rats were assessed for their fever response to lipopolysaccharide (LPS). Blood and tissue samples were collected to measure circulating IL-1beta and IL-1beta protein in the hypothalamus and spleen. Prenatal LAAM exposure resulted in a blunted fever response to LPS injection without any changes in basal body temperature or in response to saline injection. Circulating IL-1beta was not affected by prenatal LAAM exposure, nor was IL-1beta protein in the spleen. Interestingly, mature IL-1beta protein was elevated in the hypothalamus of prenatally LAAM-treated rats. These results indicate that prenatal opiate exposure blunts the fever response of adult offspring. Direct action of IL-1beta is likely not the cause of the dysfunction reported here. However, alterations in signaling mechanisms downstream from IL-1beta may play a role in the altered fever response in adult rats treated prenatally with opiates.

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Kay et al 1998

Abstract – Israel

The aim of the present study was to determine the effect of prenatal stress on immune function in rats. Pregnant rats were stressed by noise and light, three times weekly throughout pregnancy. Experiments were performed on male and female offspring aged 2 months. Cellular immune responses of splenic lymphocytes to B-cell (pokeweed mitogen (PWM) and T-cell (phytohemagglutinin (PHA)) mitogens were measured by [3H]thymidine uptake, and natural killer (NK) cell cytotoxicity in blood and splenic lymphocytes was measured against the murine T-cell lymphoma, YAC-1, by a 4-h [51Cr] release assay.

Prenatal stress suppressed immune function as shown by

a) decreased NK cytotoxicity in splenic and blood lymphocytes, indicating that the effect was not confined to a particular immune compartment, and

b) decreased rate of proliferation of splenic lymphocytes to PWM and a smaller depressant effect on their response to PHA.

……….The suppression of B-cell proliferation was more marked in the female and that of NK cell cytoxicity, in the male.

………Prenatal stress did not alter the distribution of subsets of lymphocytes, in either the spleen or blood, indicating that the reduction in proliferative and cytotoxic activity resulted from functional modifications of effector mechanisms in the cells rather from alterations in their migration between immune compartments.

………..The mechanisms underlying this effect of prenatal stress are not clear but could result from an action of maternal stress hormones on the developing fetal neuroendocrine system.

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Kaur & Salm 2008

Abstract – WV

Smad1 is the downstream effector for bone morphogenetic protein, part of the anti-inflammatory cytokine family.

Glucocorticoids (GCs) increase the production of anti-inflammatory cytokines

………..to oppose the actions of pro-inflammatory cytokines.

.. protective mechanism in the amygdala

Here we used the prenatally stressed (PS) rat to see if chronic GC activation affects this protective mechanism in the amygdala. Male PS and control offspring were either left undisturbed or exposed to a 2-week regimen of intruder stress. One week later, half of these animals were further subjected to restraint stress for 3 days. Nuclear and cytoplasmic phosphorylated (p)-Smad1 were visualized by immunocytochemistry and quantified in the lateral and basolateral amygdala and in the hind limb primary somatosensory (S1HL) cortex. PS rats showed significantly greater baseline p-Smad1 per cell than controls.

……..However, intruder stress increased p-Smad1 nuclear staining in the control rats only: no further increases in either compartment were observed in the PS group. With repeated restraint stress,

……….attenuation of both cytoplasmic and nuclear p-Smad1 responses was significantly greater in controls.

……….Thus, the overall p-Smad1 responsiveness of amygdala neurons of PS rats to life stressors is blunted.

………We hypothesize that the amygdala may play an essential role in initiating the cytokine response to stress in the adult rat brain.

Basal p-Smad1 staining was unaffected by prenatal stress in the S1HL cortex but became elevated in the cytoplasm following intruder stress. The significance of this is unknown, but

……….may point to a means by which stress can generally affect cells whose functions are unrelated to driving the sympathoadrenal system.

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Allen & Dawbarn 2006

Abstract – UK

The neurotrophins are growth factors

…..required by discrete neuronal cell types for survival and maintenance,

…..with a broad range of activities in the central and peripheral nervous system in the developing and adult mammal.

This review examines their role in diverse disease states, including Alzheimer’s disease, depression, pain and asthma.

….. In addition, the role of BDNF (brain-derived neurotrophic factor) in synaptic plasticity and memory formation is discussed.

Unlike the other neurotrophins, BDNF is secreted in an activity-dependent manner that allows the highly controlled release required for synaptic regulation.

Evidence is discussed which shows that sequestration of NGF (nerve growth factor) is able to reverse symptoms of inflammatory pain and asthma in animal models.

Both pain and asthma show an underlying pathophysiology linked to increases in endogenous NGF and subsequent NGF-dependent increase in BDNF.

Conversely, in Alzheimer’s disease, there is a role for NGF in the treatment of the disease and a recent clinical trial has shown benefit from its exogenous application. In addition, reductions in BDNF, and changes in the processing and usage of NGF, are evident and it is possible that both NGF and BDNF play a part in the aetiology of the disease process.

This highly selective choice of functions and disease states related to neurotrophin function, although in no way comprehensive, illustrates the importance of the neurotrophins in the brain, the peripheral nervous system and in non-neuronal tissues. Ways in which the neurotrophins, their receptors or agonists/antagonists may act therapeutically are discussed.

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Branchi et al 2006

Abstract – Italy

BACKGROUND: Early experiences produce persistent changes in brain and behavioral function. We investigate whether being reared in a communal nest (CN), a form of early social enrichment that characterizes the natural ecological niche of many rodent species including the mouse,

……..has effects on adult social/aggressive behavior and nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) levels in mice.

METHODS: The CN consisted of a single nest where three mothers kept their pups together and shared care-giving behavior from birth to weaning (postnatal day 25). RESULTS: Compared to standard laboratory conditions, in CN condition, mouse mothers displayed higher levels of maternal care.

……..At adulthood, CN mice displayed higher propensity to interact socially and achieved more promptly the behavioral profile of either dominant or subordinate male.

…. Furthermore, CN adult mice showed higher NGF levels, which were further affected by social status, and higher BDNF levels in the brain. CONCLUSIONS: Our findings indicate that CN, a highly stimulating early social environment,

………..produces differences in social behavior later in life associated with marked changes of neurotrophin levels in selected brain areas,

……… including hippocampus and hypothalamus.

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Kaufman et al 2000

Abstract

Child abuse, associated with markedly elevated rates of major depression and other psychiatric disorders in adulthood

….”This article reviews preclinical studies examining the effects of early stress, factors that modify the impact of these experiences, and neurobiological changes associated with major depression.”

“Preclinical studies demonstrate that early stress can alter the development of the hypothalamic-pituitary-adrenal axis, hypothalamic and extrahypothalamic corticotropin releasing hormone, monoaminergic, and gamma-aminobutyric acid/benzodiazepine systems.”

“Emerging data suggest, however, that the long-term effects of early stress can be moderated by genetic factors and the quality of the subsequent caregiving environment.  These effects also can be prevented or reversed with various pharmacological interventions.”

……..interactions between genes and environments in determining individual sensitivity to stress

……how inherent factors interact with experience of abuse and other psychosocial factors to confer vulnerability to developing depression

everyone has their limits – trauma thresholds – amount and kind of resources available, timing of the abuse – take no Pollyanna perspective under tendency to minimize risk or damage!

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see genetics in learning chapter

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Black et al 2002

Abstract – Baltimore

OBJECTIVE:  “To investigate whether living in a 3-generation household (grandmother-mother-child) is associated with fewer behavior problems and better cognitive development among preschool children of mothers who gave birth during adolescence and whether it protects children from the behavior and developmental problems associated with maltreatment and maternal depression.”

Low-income families from East, Northwest, Midwest, South, part of LONGSCAN longitudinal study of children’s health, development, and maltreatment

CONCLUSIONS

194 adolescent mothers age less than 19 at delivery – gathered data when their children were 4-5 years old

…26% lived in 3-generation households

…39% had history of maltreatment

….32% of mothers had depression scores in clinical range

RESULTS

….”…children who had been reported for maltreatment and had mothers with depressive symptoms had more externalizing behavior problems, compared with children who experienced neither risk or only 1 risk.”  — measure attachment, you guys!  Externalizing is a symptom of disorganized attachment!  Empathizing pathologies likely

………”…when residential status was considered, children with the greatest number of externalizing behavior problems were those who experienced both maltreatment and maternal depressive symptoms and lived in 3-generation households.”

…. “Children who had been reported for maltreatment or had mothers with depressive symptoms were more likely to have internalizing problems, compared with children with neither risk.  Residential status was not related to children’s internalizing behavior problems or cognitive development.”  Internalizing, to me, reflects lack of boundary formation and interference with development of a clear sense of self – empathizing pathologies likely also

CONCLUSIONS

“Living in a 3-generation household did not protect preschool children from the behavior problems associated with maltreatment and depression.”

“In contrast, living in a 3-generation household was associated with more behavior problems among the highest risk group of children – those who had been maltreated and had mothers with symptoms of depression.”   This is coming down the generations and may be actually, to my thinking, compounded by the presence of a maternal conflict with grandmother that contributed to mother’s problems in the first place

“Although 3-generation families may provide an important source of support and stability for adolescent mothers and their infants early in the parenting process, it may not be advisable to rely on 3-generation households as young mothers enter adulthood, particularly among those with a history of maltreatment or depression.”  Maternal depression has a huge impact on an infant’s growing brain – powerfully so in regard to stimulation of the “happy” emotions – and mirroring capacities of the mothers in all regards.  Why didn’t they measure the mental health status of the grandmothers?  That would have been very helpful/useful information to have in such a study – as well as the attachment patterns of all 3 generations

“Children with the fewest number of behavior problems were living with their mothers in their own household (often with the father), had not been maltreated, and had mothers with few symptoms of depression.”

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Levendosky, Okun & Parker 1995

Abstract – Ann Arbor, MI

Depression and maltreatment were used in this study to predict social competence and social problem-solving skills – 68 children, most high-risk either due to poverty, physical abuse and neglect, or exposure to negative life events

Depression predicted social competence and parents’ ratings of peer rejection

Depression predicted childrens’ ratings of social competence and social problem-solving skills

Maltreatment predicted parents’ and teachers’ ratings of social competence and parents’ ratings of peer rejection

Gender predicted teachers’ ratings of peer rejection and social competence

“An additive effect of depression and maltreatment was found such that children who are depressed and maltreated have the lowest social competence as rated by parents and teachers.  These children are, therefore, doubly at risk for problems in future relationships.”

Parents’ perceptions of abused kids would be unreliable in my book

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Teicher, Tomoda & Andersen 2006

Abstract – Developmental Biopsychiatry Research Program, McLean Hospital, 115 Mill Street Belmont, MA 02478, USA. martin_teicher@hms.harvard.edu

Recent studies have reported an association between exposure to childhood abuse or neglect and alterations in brain structure or function. One limitation of these studies is that they are correlational and do not provide evidence of a cause-effect relationship. Preclinical studies on the effects of exposure to early life stress can demonstrate causality, and can enrich our understanding of the clinical research if we hypothesize that the consequences of early abuse are predominantly mediated through the induction of stress responses.

Exposure to early abuse and early stress has each been associated with the emergence of epileptiform electroencephalogram (EEG) abnormalities, alterations in corpus callosum area, and reduced volume or synaptic density of the hippocampus.

Further, there is evidence that different brain regions have unique periods when they are maximally sensitive to the effects of early stress. To date, preclinical studies have guided clinical investigations and will continue to provide important insight into studies on molecular mechanisms and gene-environment interactions.

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De Bellis & Kuchibhatia 2006

Abstract – Healthy Childhood Brain Development and Developmental Traumatology Research Program, Duke University Medical Center, Durham, North Carolina 27710, USA. debel002@mc.duke.edu

BACKGROUND: The results of previous studies suggest structural brain differences in pediatric maltreatment-related posttraumatic stress disorder (PTSD) However, posterior fossa volumes were not examined, despite the consensus that the cerebellum is important in emotional and cognitive development. We investigated the relationship between structural volumes of the cerebellum hemispheres,

vermis,

brainstem, and clinical variables in pediatric maltreatment-related PTSD. METHODS: Fifty-eight psychotropic-naïve maltreated children and adolescents with DSM-IV PTSD were compared with two groups of pediatric subjects who had no DSM-IV criteria A trauma histories: 1) 13 with pediatric generalized anxiety disorder, and 2) 98 healthy non-abused children and adolescents. Subjects underwent a comprehensive psychiatric assessment and an anatomical magnetic resonance image brain scan. RESULTS: Unadjusted means of the left, right, and total cerebellum were smaller in the PTSD group. The group differences remained significant in the left cerebellum, right cerebellum, and total cerebellum in the analyses adjusted for cerebral volume, sociodemographic, and IQ variables.

Cerebellar volumes positively correlated with age of onset of the trauma that lead to PTSD and negatively correlated with the duration of the trauma that lead to PTSD.

Cerebellar volumes were larger in boys versus girls, but there was no group x gender interaction. There were significant positive correlations between IQ measures and volumetric variables. CONCLUSIONS: The results support

cerebellar volume differences in maltreated children and adolescents with PTSD. Further studies are warranted.

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Andersen et al 2008

Abstract – Department of Psychiatry, Harvard Medical School, Belmont, MA 02478, USA.

Very specific brain developmental changes in regions per ages of sexual abuse

Volumetric MRI scans from 26 women with repeated episodes of childhood sexual abuse and 17 healthy female comparison subjects (ages 18-22 years) were analyzed for sensitive period effects on hippocampal and amygdala volume, frontal cortex gray matter volume and corpus callosum area.

Hippocampal volume was reduced in association with childhood sexual abuse at ages 3-5 years and ages 11-13 years.

Corpus callosum was reduced with childhood sexual abuse at ages 9-10 years, and

frontal cortex was attenuated in subjects with childhood sexual abuse at ages 14-16 years.

Brain regions have unique windows of vulnerability to the effects of traumatic stress

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Kitayama et al 2007

Abstract – Division of Adult Mental Health, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan. norikita@fd6.so-net.ne.jp

Magnetic resonance imaging (MRI) studies in children with maltreatment-related posttraumatic stress disorder (PTSD) have demonstrated

smaller corpus callosum area,

with the greatest magnitude of change in posterior portions

of the corpus callosum.

The purpose of this study was to measure corpus callosum area in adult female patients with childhood abuse-related PTSD and comparison subjects. MRI was used to measure the midsagittal area of the corpus callosum as well as subregions of the corpus callosum in 9 female subjects with abuse-related PTSD and 9 healthy female subjects.

No differences were found in total area of the corpus callosum or in individual subregions, but the subregion/total area ratio was significantly smaller in posterior midbody in PTSD compared with the healthy subjects. These results suggest that relatively smaller areas of the

posterior midbody of the corpus callosum

are associated with childhood abuse

related PTSD in adults;

these findings are consistent with findings in children with abuse-related PTSD.

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Villarreal et al 2004

Abstract – New Mexico VA Healthcare System, PTSD Program (116A), 1501 San Pedro Drive SE, Albuquerque, NM 87108, USA. Gerardo.Villarreal@med.va.gov

Magnetic resonance imaging (MRI) studies have revealed decreases in the mid-sagittal area of the corpus callosum (CC) [a white-matter bundle of 200-300 million nerve fibers that connect the left and right hemispheres] in pediatric posttraumatic stress disorder (PTSD), but at present no data are available in adult PTSD patients. We have previously reported decreased whole-brain white matter (WM) volume in adults with PTSD and now report corpus callosum area from the same sample. MRI was used to obtain whole-brain images in 12 adult patients with PTSD and 10 matched controls. Total parenchyma (white matter plus gray matter [GM]) volume, mid-sagittal area of the CC and seven sub-regions of this structure were calculated. In PTSD patients, the total CC area, absolute and normalized to total brain parenchyma, was smaller compared with control values. Several absolute and normalized CC sub-regions were also smaller in PTSD patients: genu (region 2), mid-body (region 5) and isthmus (region 6).

There was also a trend for the anterior mid-body (area 4) to be smaller in PTSD patients.

No differences were found in the rostrum (region 1), rostral body (region 3) or splenium (region 7).

Adult patients with PTSD had decreased CC area after correcting for total brain tissue, indicating that these differences are not attributable to generalized white matter atrophy. These findings are similar to previous results in children with PTSD and suggest specific changes in the CC.

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De Bellis & Kreshavan 2003

Abstract – Healthy Childhood Brain Development and Developmental Traumatology Research Program, Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Box 3613, Durham, NC 27710, USA. debel002@mc.duke.edu

BACKGROUND: Recent investigations suggested that pediatric posttraumatic stress disorder (PTSD) is associated with adverse brain development. However, sex differences are poorly understood. METHODS: In this study, 61 medically healthy children and adolescents (31 males and 30 females) with chronic PTSD secondary to abuse, who had similar trauma and mental health histories, and 122 healthy controls (62 males and 60 females) underwent comprehensive psychiatric assessments and an anatomical MRI brain scan. RESULTS: When gender groups were analyzed separately, findings of

larger prefrontal lobe CSF volumes and

smaller midsagittal area of the corpus callosum subregion 7 (splenium) were seen in both boys and girls with

maltreatment-related PTSD

compared to their gender-matched comparison subjects.

Subjects with PTSD did not show the normal age related increases

in the area of the total corpus callosum and its region 7 (splenium)

compared to non-maltreated subjects; however, this finding was more prominent in males with PTSD. Significant sex by group effects demonstrated

smaller cerebral volumes and

corpus callosum regions 1 (rostrum) and 6 (isthmus)

in PTSD males and

greater lateral ventricular volume increases in maltreated

males with PTSD than maltreated females with PTSD. CONCLUSIONS: These data suggest that there are sex differences in the brain maturation of boys and girls with maltreatment-related PTSD. Longitudinal MRI brain investigations of childhood PTSD and the relationship of gender to psychosocial outcomes are warranted.

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Thomas & De Bellis 2004

Abstract – Child and Adolescent Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.

BACKGROUND: Previous findings suggest that

corticotrophin-releasing hormone (CRH)

is elevated in adults with posttraumatic stress disorder (PTSD), maltreated children, and

children with maltreatment-related PTSD.

METHODS: Magnetic resonance imaging was used to measure pituitary volumes in 61 medication-naïve maltreated subjects with PTSD (31 male and 30 female subjects) and 121 nontraumatized healthy comparison subjects (62 male and 59 female subjects). RESULTS: Overall, no differences were seen between PTSD and control subjects in pituitary volumes. There was a significant age-by-group effect for PTSD subjects to have greater differences in pituitary volume with age than control subjects. Post hoc analyses revealed that

pituitary volumes were significantly larger in pubertal and postpubertal maltreated subjects with PTSD

than control subjects but were similar in prepubertal maltreated subjects with PTSD and control subjects.

Pituitary volumes were larger in the PTSD subjects

with history of suicidal ideation.

CONCLUSIONS: These findings may suggest

developmental alterations in pituitary volume in maltreatment-related pediatric PTSD.

This finding may be associated with stress-related differences in CRH and may be more pronounced in pediatric patients with PTSD comorbid with suicidal ideation.

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Pilowsky et al 2006

Abstract – Columbia U

Assessed current and lifetime prevalence of psychiatric disorders among children of currently depressed mothers and assessed association of clinical features of maternal depression (i.e., severity, chronicity, and clinical features) with child psychopathology

………… “Maternal features assessed for this study were history of MDEs, severity of current MDE, comorbid conditions, depressive symptom features, and social functioning.”

Treatment-seeking mothers with current diagnosis of MDD, children 7 – 17

72% of mothers were severely depressed

34% of children had a current psychiatric disorder, including disruptive behavior (22%), anxiety (16%), and depressive (10%) disorders.  Nearly half (45% had a lifetime psychiatric disorder, including disruptive behavior (29%), anxiety (20%), and depressive (19%) disorders.

Atypical depressive features in the mother were associated with a 3-fold increase in odds of having a child with depressive or anxiety disorders

A history of maternal suicide attempts and presence of comorbid panic disorder with agoraphobia were associated with a 3-fold increase and an 8-fold increase in the odds of depressive disorders in the offspring, respectively.

Associations between the following characteristics of maternal depression and offspring disorders:  maternal comorbid panic disorder with agoraphobia and offspring depressive and anxiety disorders, maternal irritable depression and offspring disruptive behavior disorders and any disorder, and maternal substance use disorders and any disorder

CONCLUSIONS

“Children of mothers in the midst of a current [major depressive episode] MDE are at high risk for disruptive behavior and anxiety disorders.  The elevated risk of psychopathology among children of depressed mothers may recommend assessment of these children when clinically suggested.  Children of depressed mothers with comorbid panic disorder with agoraphobia are at high risk for depressive and anxiety disorders and deserve special attention from clinicians.”

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Kaufman 1991

Abstract – Yale

Examined prevalence of depressive disorders in sample of 56 7-12 year old maltreated children

………18% met diagnostic criteria for major depression

……..25% met criteria for dysthymia, with majority of children who met criteria for major depression also meeting criteria for dysthymia

“Ratings of the different types of maltreatment children experienced, together with measures of the children’s social supports, attributional style, and cortisol secretion were examined to determine which maltreated children were most likely to evidence a depressive disorder.”

…analysis of subset of these measures correctly classified 91% of sample in terms of their diagnostic status

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Beardslee et al 2003

Abstract – Boston —-  — TREATMENT

PREVENTION STUDY — Depression in parents – prevalent and impairing illness – children of depressed parents are at risk for psychopathology and other difficulties

……….evaluation of 2 preventive intervention strategies that target children living in homes with depressed parents

……….public health approaches – designed to be used by wide range of Practioners from variety of disciplines

…….adolescence is age of highest risk for depression onset

……family-based approach to prevention, reduce risk factors and enhance protective factors for early adolescents by increasing positive interactions between parents and children, increasing understanding of the illness for everyone in the family

…provided information about mood disorders to parents…open dialogue with children about effects of parental depression

………. “…psychoeducational material about mood disorders, risk, and resilience was presented and efforts were made to decrease feelings of guilt and blame in children.  Parents were helped to build resilience in their children through encouraging their friendships, their success outside of the home, and their understanding of parental illness and of themselves….efforts made to link the psychoeducational material presented to the family’s own unique illness experience.”

……assessed 1 year postintervention and again 2.5 years postintervention

………..parents who had changed the most in response to intervention had children who also changed the most

children’s internalizing scores decreased with increased time since intervention

females had higher internalizing scores than males

programs had long-standing positive effects in how families problem solve around parental illness – changes in parents perceptions translated directly into changes in children’s own understanding of parental illness –

“Parental behavior and attitude changes and their connection to child changes in understanding identify an important mediating variable:  family change.  By increasing children’s understanding of parental mood disorder our interventions were found to promote resilience-related qualities in these children at risk.”

…….support for a family-based approach to preventive intervention – demonstrated a significant reduction in risk factors and increase in protective factors in these families over a long time interval 2(1/2) years

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Austin, Leader & Reilly 2005

Abstract – Australia

“Although it has long been acknowledged that chronic HPA axis dysregulation impacts on adult neural function, little attention has been paid to the impact that disturbances of the maternal HPA axis may have on the developing fetal brain.”

……examines associations between prenatal stress, neuroendocrine functioning, and behavioural outcome in both animal and human offspring, with particular focus on relationship between prenatal stress and human fetal and infant neurobehaviour.

……growing evidence that prenatal stress impacts on offspring neural function and behaviour in animal populations

……potential importance of the timing of pregnancy stress is being increasingly highlighted

……”There is a pressing need for more research into the role of maternal stress and anxiety during pregnancy on human fetal and infant outcomes.  Future studies should prospectively pair physiological and psychological measures both pre- and postnatally if the HPA axis function of the mother and her infant is to be more fully understood.”

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Davis et al 2007

Abstract – Department of Psychiatry and Human Behavior, University of California, Irvine, USA. edavis@uci.edu

BACKGROUND: Accumulating evidence indicates that prenatal maternal and fetal processes can have a lasting influence on infant and child development. Results from animal models indicate that

prenatal exposure to maternal stress and stress hormones

has lasting consequences for development of the offspring.

Few prospective studies of human pregnancy have examined the consequences of prenatal exposure to stress and stress hormones. METHOD: In this study the effects of prenatal maternal psychosocial (anxiety, depression, and perceived stress) and endocrine (cortisol) indicators of stress on infant temperament were examined in a sample of 247 full-term infants. Maternal salivary cortisol and psychological state were evaluated at 18-20, 24-26, and 30-32 weeks of gestation and at 2 months postpartum. Infant temperament was assessed with a measure of negative reactivity (the fear subscale of the Infant Temperament Questionnaire) at 2 months of age. RESULTS: Elevated maternal cortisol at 30-32 weeks of gestation, but not earlier in pregnancy, was significantly associated with greater maternal report of infant negative reactivity.

Prenatal maternal anxiety and depression additionally predicted infant temperament.

The associations between maternal cortisol and maternal depression remained after controlling for postnatal maternal psychological state. CONCLUSIONS: These data suggest that prenatal exposure to maternal stress has consequences for the development of infant temperament.

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de Weerth & Buitelaar 2007

abstract – Developmental Psychology, Radboud University Nijmegen, P.O. Box 9104, 6500 HE, Nijmegen, The Netherlands. C.deWeerth@psych.ru.nl

BACKGROUND: The process of childbirth and its complications have been related to the newborn’s condition and to development at later ages. In this study, we examine how mode of delivery and delivery complications are related to the behavior and cortisol reactivity of infants during the first 2 months. METHODS: Delivery factors (i.e. mode, duration, fetal heart function, and 5-min Apgar score) were determined in 116 healthy, term, firstborn infants. The infants’ behavioral and cortisol reactivity to stressors were assessed during a physical examination at 11 days and an inoculation at 2 months. Daily behavior at 6 weeks was followed by means of a four-day parental diary. RESULTS: Indicators of a more stressful delivery were linked to more crying/fussing in the infant and to more difficulties in regulating the infants’ behavior (i.e., more unsoothability and longer crying bouts). Specific delivery complications rather than mode of delivery were linked to infants’ behavior. No significant associations however, were found between childbirth and the infants’ cortisol reactivity to a physical examination and an inoculation. CONCLUSIONS: Childbirth complications, even when mild, can apparently affect early infant behavior. These effects extend over different types of situations, and last at least until the age of 2 months, and should be taken into account in studies on infant behavior. Earlier findings of relations between childbirth complications and infant cortisol reactivity could not be replicated in this study, possibly due to the confounding effect of parity, and to the important intra-individual variability present in the infants’ cortisol.

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Barnett 2005

Abstract – Wellcome Trust Centre for the History of Medicine at University College London, UK. ucgarba@ucl.ac.uk

Historians of medicine frequently marginalize or completely ignore the importance of linguistics in the development and dissemination of medical theories and clinical techniques, both in professional culture and in society at large. This is particularly true in the history of pain relief in labor, despite the significant role played by popular attitudes to birth and pain relief in the development of clinical services. This paper uses a simple form of citation analysis to examine shifts in the usage of terms related to regional nerve block techniques in The Lancet and The Times from 1900 to 1999. Graphical representations of these data are used to relate changes in the incidence of citations to key events in the 20th century history of obstetric anaesthesia in Britain. A study of the rise and fall of ‘twilight sleep’ in the early part of the century is used to demonstrate the advantages and disadvantages associated with this approach to medical history. Conclusions from this analysis are used to suggest (tentative) models for the acceptance and diffusion of medical words in professional and popular vocabularies.

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Marx 1987

Abstract – Department of Anesthesiology, Albert Einstein College of Medicine, Bronx, New York.

Article in German

Pain is a primary component of normal childbirth as evidenced by the behavior of parturients in primitive societies. Methods of pain relief such as the use of herbs and plant extracts were described in ancient writings. Modern obstetric analgesia employing ether began in 1847, three months after the first successful surgical anesthetic. Administration of chloroform and nitrous oxide followed. Twilight sleep, a combination of morphine and scopolamine, became popular in the beginning of the twentieth century as did regional analgesia, first single injection and later continuous blockade via catheter. Simultaneously, psychologic methods were propagated, but were not uniformly successful. Continuous lumbar extradural analgesia has evolved as the optimal method of bsotetric pain relief, both subjectively and objectively, and its combination with childbirth education is considered to be complementary. The increasing utilization of obstetric analgesia and the recognition of marked physiologic and pharmacologic differences between pregnant and nonpregnant patients has led to the development of the subspecialty of obstetric anesthesia as well as to the foundation of obstetric anesthesia societies.

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Pitcock & Clark 1992

Abstract – Division of Medical Humanities, University of Arkansas for Medical Sciences.

Obstetric anesthesia has been the object of public interest and patient advocacy from its introduction in the 1840s to the present. Early arguments concerned the significance of pain in childbearing and became a popular issue involving physicians, clergymen, and journalists. The first obstetric anesthesia, either, given in the United States was administered in Cambridge, Massachusetts, in 1847. For the next several decades general anesthesia was the only feasible means of relieving labor pain. At the turn of the century a combination of scopolamine and morphine was introduced in the United States by a popular women’s magazine; the National Twilight Sleep Association was launched. After the decline of this movement, the “natural” childbirth method came into national prominence. In spite of their differing pharmacologic characteristics, there are sociologic parallels between the patient advocacy of Twilight Sleep and that of psychoprophylaxis. This study focuses on the public perception of these movements, which were begun by physicians and subsequently endorsed by militant lay groups.

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Ward et al 2004

Article – National Institute of Child Health and Human Development, Bethesda, MD

This information needs to be paired with Schore’s information about how stress heats up the infant developing brain and alters the way the mitochondria do their job as the heat interferes with the nutritional environment and starves the growing brain

Prenatal insults have been shown to affect HPA activity independently of birth weight

…………refers to a Scottish experiment where the mothers at high protein – 1 lb of red meat per day and/or fish, low carbohydrate diet in late pregnancy- was associated with raised cortisol concentrations when the offspring were 30 years old

Fetal programming of the HPA axis has been proposed as an intermediary in the association between reduced fetal growth and adult cardiovascular and metabolic diseases

…..small birth size associated with increased fasting plasma cortisol and adrenal responsiveness to ACTH stimulation

……study examines at age 60-69, N=65 men who were either high or low birth weight in the UK – low birth weight men were significantly shorter and lighter but no difference in any obesity measure, or any other lifestyle measure –

…….provides further evidence of dysregulation of the HPA axis in people who were small at birth

biological forerunners of adult cardiovascular disease – associated with thinness at birth

….hypertension, impaired glucose tolerance, insulin resistance (the metabolic syndrome)

“This phenomenon may be explained by programming, a process whereby a stimulus or insult at a critical period in development results in permanent adaptation of the organism’s structure or physiology.”  Ward et al 2004, p 1227

“…fetal programming of the hypothalamic-pituitary-adrenal (HPA) axis may be one of the long-term changes that link reduced fetal growth with adult metabolic disease.  In animal models, prenatal stress, maternal malnutrition, or glucocorticoid exposure in pregnancy have produced offspring with alterations of either basal [bottom line – resting] or stimulated HPA activity and lifelong hypertension or glucose intolerance….”  Ward et al 2004, p 1227

hypothesis:  hypercortisolemia in people who were small at birth was due to increased hypothalamic secretion of CRH.  “A similar abnormality has been suggested in depressed patients….”  Ward et al 2004, p 1227

……..no relationship between birth weight and the nonstr5essed rhythm of cortisol secretion

……CYP3A4 metabolizes dexamethasone [a synthetic steroid – does not pass blood-brain barrier, major target is the pituitary gland] used in the DEX/CRH test used to investigate subtle HPA dysfunction, particularly in depression and related pathological conditions

…depression is associated with increased CRH responses after dexamethasone…..imply a decreased pituitary sensitivity to dexamethasone, possibly a result of increased vasopressin action at the corticotroph which attenuates [lessens] the inhibitory effect of glucocorticoids on CRH-stimulated ACTH secretion

…study result – may reflect the reverse, i.e. increased pituitary sensitivity to dexamethasone or reduced vasopressingergic drive — Ward et al 2004, p 1231

“Previous studies carried out by ourselves and others have suggested that people who were small at birth have high urinary excretion of glucocorticoids in childhood, raised fasting plasma cortisol concentrations in adult life, and increased adrenal responsiveness to synthetic ACTH administration….Because similar abnormalities in melancholic depression are thought to be due to abnormal central regulation of the pituitary-adrenal axis, we hypothesized that the responses to CRH testing would be similar to those seen in depressed patients.  However, the pattern we observed bears closer resemblance to the alterations in HPA activity associated with chronic fatigue and atypical depressive syndromes, such as seasonal affective disorder, than with melancholic depression.”  Ward et al 2004, p 1231

…..reduced ACTH and cortisol response to CRH suggesting impaired central drive to the pituitary – found in chronic fatigue syndrome and seasonal affective disorder by other researchers [there are genetic serotonin relationships here…]

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Huizink et al 2002

Abstract – The Netherlands

Examined whether psychological and endocrinological measures of stress during pregnancy predicted developmental outcome of human infants

……….”Self-report data about daily hassles, pregnancy-specific anxiety and perceived stress, salivary cortisol levels and adrenocorticotrophic hormone (ACTH) levels were collected in nulliparous [first time mothers] women throughout pregnancy.  Infant development was measured at 3 and 8 months….Infant temperament was rated…”

RESULTS

“High levels of pregnancy-specific anxiety in early pregnancy predicted both temperamental and developmental difficulties.”

“High amounts of daily hassles in early pregnancy were associated with lower mental developmental scores.  Perceived stress in early pregnancy was related to more difficult behavior and adaptational problems.”

“Early morning values of cortisol in late pregnancy were negatively related to both mental and motor development, whereas higher ACTH levels were related to more adaptational problems.”

CONCLUSION

“Increased maternal prenatal stress seems to be one of the determinants of temperamental and developmental variation of infants.  The hypothalamic-pituitary-adrenal (HPA) axis may be involved in the harmful effects of prenatal maternal stress on infant development and temperament.

There are many possible complicating factors here – if a mother is that stressed carrying the baby she is likely to be just as stressed raising it, and her behavioral interaction with the infant will also affect the baby’s development.

Such a study design would be perfect for adding in measurements of attachment – pre and post birth.

I think I wrote this elsewhere in here, that it isn’t really the unresolved traumas that are being transmitted intergenerationally, it is the epigenetic changes and the alterations in the HPA axis operational capacities – and this study supports that – but what is cause and what is consequence needs to be better clarified than it is in this study.  These studies, along with testing for attachment patterns, also need to be longitudinal to study the offspring over the lifetime.

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Binder et al 2008

Article – GA

Prevalence rates of PTSD in US population 7% – 8%

……higher among combat veterans and those living in high violence areas

……..critical roles for predisposing genetic and environmental influences “in differentially mediating psychological risk to the traumatized individual….”  Binder et al 2008, p 1291

CHILDABUSE

.high rates, major public health problem

..significantly increases risk for impaired physical and psychological health, reduces adaptive functioning in adulthood

….”…well-established relationship of child abuse with adult PTSD…” Binder et al 2008, p 1292

“…PTSD in adults may represent a prolonged symptomatic reaction to traumatic child abuse.”  Binder et al 2008, p 1292

Also proved link to adult lifelong depression from gene interaction with child abuse

“The experience of child abuse is associated with an increased number of traumatic experiences across the lifespan.  Child abuse may also increase vulnerability for later development of PTSD by

altering psychological (eg. attachment) and

biological (eg, hypothalamic-pituitary-adrenal [HPA] axis function) developmental processes, including interaction with genetic factors.”  Binder et al 2008, p 1292

Here is where I take issue under attachment-pain – that attachment is a biological, physiological, hormone brain driven system that is the basis of all other systems and influences all of them – not “psychological”

“…the most robust research to date points to child abuse and related family/interpersonal stressful life events in predicting a wide range of later psychological and physical health problems.”  Binder et al 2008, p 1292

“Our study focuses on the interplay between child abuse and polymorphisms in the FKBP5 gene, which is involved in the glucocorticoid-mediated stress response, in the prediction of adult PTSD.”  Binder et al 2008, p 1292

distinct endophenotypes [any hereditary characteristic that is normally associated with some condition but is not a direct symptom of that condition]and influences from environmental factors – interplay

“A number of studies suggest that genetic factors contribute to the development of PTSD, with heritability estimates ranging from 30% to 40%….Candidate gene studies, however, have been inconclusive so far, usually limited by extremely low power to detect any but the strongest possible genetic effects [sample sizes less than 100].”  Binder et al 2008, p 1292

(other studies – 5HTTLPR polymorphism (serotonin transporter influence) interaction with stressful life events including child abuse, in predicting depression)

“From a developmental perspective, HPA axis genes are strong candidates with respect to altering susceptibility to PTSD.  Exposure to trauma and stress increase HPA axis activity, and PTSD has been associated with long-lasting alterations in HPA axis reactivity …and specifically higher GR sensitivity [the stop end of stress response]….Polymorphisms in genes regulating GR activity may impact the acute effects of trauma on the HPA axis and thereby possibly impact long-term HPA axis regulation affecting the development of PTSD [and my guess, depression also – no possibly about it without the right intervening variables being present – and if not affecting HPA toward PTSD, then look at all the rest of the problems HPA dysregulation are related to].”  Binder et al 2008, p 1292

studies

….suggest child abuse and neglect affect HPA axis functioning, reviewed by Watts-English et al 2006 below  – http://www.pubpol.duke.edu/centers/child/publications/articles/wattsenglish12-06.pdf —

………. I have been working on this idea, here are the articles –

…………suggest that depression-related HPA axis functioning as hyperactivity may be related to early life stress

……”For example, plasma corticotropin and cortisol, as well as cerebrospinal fluid corticotropin-releasing hormone (CRH) concentrations, correlate with perceived early life stress more than with current depression….”  Binder et al 2008, p 1292

……….”…persistent hyperactivity of the HPA axis associated with early life stress is mediated by a hyperactive CRH receptor 1 (CRHR1) system, with chronic overactivity of the CRHR1 in limbic brain regions…”  Binder et al 2008, p 1292  (see below Plotsky et al 2005)

“FKBP5 is a co-chaperone of hsp90.  It directly interacts with hsp90, which binds to the GR.  FKBP5 also has been shown to regulate GR sensitivity.  FKBP5 is part of the mature GR heterocomplex.  On hormone biding, FKBP5 is replaced by FKBP4, which then recruits dynein into the complex, allowing translocation into the nucleus where the complex regulates expression of glucocorticoid-responsive genes by functioning as a transcription factor.  FKPB5 expression is induced by glucocorticoids as part of an intracellular ultra-short negative feedback loop for GR activity.”  Binder et al 2008, p 1293

.overexpression of human FKBP5 reduces hormone binding affinity and nuclear translocation of GR

…naturally overexpression of FKBP5 in New World monkeys causes GR resistance, accompanied by increased plasma cortisol levels

…..”…potentially functional single-nucleotide polymorphisms (SNPs), or SNPs in very strong linkage disequilibrium with a functional variant, appear to alter FKBP5 function.”  Binder et al 2008, p 1293

….alleles of rs3800373 and rs1360780 associated with increased peritraumatic dissociation in children after medical trauma

“Higher levels of peritraumatic dissociation have been shown to be predictors of PTSD in adults.”  Binder et al 2008, p 1292  [this is controversial – see with dissociation]

HYPOTHESIS

“…the putative functional SNPs in FKBP5 moderate the development of PTSD.  Because early trauma, PTSD, and FKBP5 SNPs have all been shown to influence GR resistance, we also hypothesize that variants in this gene may alter the impact of early trauma or PTSD on GR sensitivity and address this by investigating the dexamethasone suppression test (DST) in a subsample of individuals.”  Binder et al 2008, p 1293

sample – 900 highly traumatized, inner city sample – urban, low-income, predominantly black men and women – “…we address whether these polymorphisms interact with increasing levels of child abuse and increasing levels of non-child abuse trauma exposure to predict PTSD symptomatology during adulthood.”  Binder et al 2008, p 1293

…17.6% of the sample reported a history of childhood physical abuse

…18.8% reported history of childhood sexual abuse

…70.5% reported no abuse

…22.7% reported either physical or sexual abuse

…6.8% reported both physical and sexual abuse  Binder et al 2008, p 1294

exposure to trauma other than child abuse –

…19.9% of participants – primarily happened in adulthood

RESULTS

Non-child abuse trauma exposure and PTSD symptoms:  found gender effect and very robust non-child abuse trauma exposure effect

….group reporting none compared to group with 4 or more, found continuous increases by more than 5-fold up to 16.74

Child abuse trauma exposure and PTSD symptoms:  found significant effect in presence of child abuse – experience of child abuse increased – nearly doubled with 1 type and 2.5-fold in 2 types of child abuse group

Non-child abuse trauma exposure, child abuse and PTSD symptoms:  exposure to child abuse increases risk for higher levels of PTSD symptoms in response to non-child abuse trauma exposure

Genotyped for 3 potentially functional SNPs (rs4713916, rs1360780, and rs3800373 – and 5 others spanning the locus

And 3 SNPs within the CRHR1 gene (rs110402, rs242924 and rs7209436 shown with strong interaction with childhood abuse on adult depression symptoms  Binder et al 2008, p 11295

PRIMARY GENETIC ANALYSES

Based on previous data supporting a clear role of FKBP5 in modulating the glucocorticoid response to stress, with evidence supporting association of FKBP5 variants with risks for and rate of recovery from affective disorders , hypothesized that genetic variation at FKBP5 may influence liability to PTSD

….found no significant main effect of FKBP5 genotypes on PSTD symptom measurement

INTERACTION OF FKBP5 PLYMORPHISMS WITH NON-CHILD ABUSE TRAUMA TO PREDICT PTSD SYMPTOMS

…..fkbp5 POLYMORPHISMS DO NOT APPEAR TO HAVE A SIMPLE ROLE IN MODERATING THE EFFECTS OF NON-CHILD ABUSE TRAUMA EXPOSURE ON PTSD SYMPTOMS

interaction of fkbp5 polymorphisms with child abuse to predict PTSD symptoms

……….identified 4 SNPs that showed significant interactions with child abuse

….all 4 associated SNPs are in fairly high linkage disequilibrium

…….most significant SNP – rs9296158

…two of the SNPs – rs3800373 and rs1360780 – previously reported to associate with differential glucocorticoid-mediated responses

… “For all 4 significant SNPs, we observed a similar additive mode of interaction, and there appears to be a gene dose-dependent protection from severe child abuse-associated increases in adult PTSD scores….In the group of individuals with 2 types of child abuse, individuals homozygous for the protective G allele of rs9296158 had a mean (SEM) PSS [PTSD symptom score] of 13.54…; in the heterozygous group, the mean PSS score was 21.25…; and in the group homozygous for the risk allele A, the mean PSS score was 31.11….  The PSS scores of more than 20 indicate clinical significant PTSD and higher scores indicate more severe PTSD, with a maximum of 51 points that can be reached in that scale….” Binder et al 2008, p 1298

“Interestingly, the genotypes previously associated with a  higher number of previous depressive episodes and faster response to antidepressant treatment were the genotypes with the high- (1298) est level of adult PTSD symptoms in the presence of child abuse.”  Binder et al 2008, p 1299

“…these data suggest that the DKBP5 genotype may interact with childhood trauma to predict adult PTSD severity, even when controlling for age, sex, non-child abuse trauma level, and severity of depressive symptoms.”  Binder et al 2008, p 1299

..found significant interactions between risk allele carrier status and PTSD with repeated measure of cortisol [over day/night], but no significant main effects…data suggest that majority of patients with risk alleles with PTSD showed enhanced suppression to dexamethasone or enhanced GR sensitivity, which has been reported to be a possible endocrine signature of PTSD

“In contrast, those individuals with the putative resilience genotype with PTSD appear to show the opposite effect.”  Binder et al 2008, p 1302

COMMENT

“Our results indicate that levels of child abuse and non-child abuse trauma eaxh independently predicted the level of adult PTSD symptomatology.  Although polymorphisms in FKBP5 did not directly predict the level of PTSD symptoms or interact with the level of non-child abuse trauma to predict PTSD symptoms, SNPs within the FKBP5 locus robustly interacted with the level of child abuse to predict the level of adult PTSD symptoms.”  Binder et al 2008, p 1302

“The most novel and important finding of our study was the interaction between FKBP5 polymorphisms and child abuse history to predict the levels of adult PTSD symptoms.  The polymorphisms seem to belong to the same bin of SNPs all in high linkage disequilibrium, which is associated with functional differences in FKBP5 expression and consequent alterations in GR function.  Notably, all 4 SNPs showing a significant interaction effect had either been reported to be associated with higher KFBP5 protein levels or a stronger induction of FKBP5 mRNA by cortisol in healthy probands (rs1360780 and rs3800373), or were in strong linkage disequilibrium with these SNPs (rs9296158 and rs9470080).”  Binder et al 2008, p 1302

“The SNP genotypes that were associated with the highest FKBP5 mRNA induction in peripheral blood mononuclear cells by cortisol were also the ones that were associated with the highest vulnerability to PTSD symptoms following child abuse.”  Binder et al 2008, p 1302

“Individuals carrying the other allele seemed to be protect4ed from the development of PTSD symptoms in a gene-dose dependent manner.”  Binder et al 2008, p 1302

“FKBP5 expression is induced by glucocorticoids as part of an intracellular ultrashort negative feedback loop for GR activity, with increased expression of FKBP5 reducing glucocorticoid binding affinity and nuclear translocation of the GR, resulting in resistance to glucocorticoid activation.  Thus, the alleles previously associated with high FKBP5 protein/mRNA expression should be associated with GR resistance.  This is precisely what we observed in individuals without PTSD symptoms.  The healthy carriers of these alleles showed less dexamethasone suppression and thus more GR resistance.”  Binder et al 2008, p 1302

“This functional association appears to be switched in patients with PTSD symptoms.  These same alleles were associated with a higher dexamethasone suppression ration and thus increased GR sensitivity, which is associated with PTSD, while the protective genotype was associated with relative GR resistance in patients with PTSD symptoms.”

“This environment-dependent reversal of the functional association may be similar to the effects previously reported in patients with depression, where less cortisol response in the dexamethasone-CRH text (an indication of increased GR sensitivity) was observed with the same alleles that had been associated with more FKBP5 protein and thus presumably GR resistance in healthy controls.”  Binder et al 2008, p 1302

“Our study is the first to our knowledge to provide evidence directly supporting a developmental or symptom-dependent difference in the functional consequences of these FKBP5 SNPs on GR sensitivity.”

……………specific FKBP5 alleles may enhance the effects of acutely released cortisol following child abuse on FKBP5 mRNA expression

……abnormal FKBP5 expression leads to maladaptive changes in GR sensitivity

………result in long-term alterations of HPA axis sensitivity, such as GR hypersensitivity that effect adult response to trauma

..alterations of HPA axis responsiveness are risk factors for PTSD

“PTSD has been suggested to result in part from initial overconsolidation of traumatic memories or, conversely, abnormal extinction of such memories.  Thus, alterations in FKBP5 function could conceivably be involved in abnormal GR-mediated signaling in neurons involved with stress response and memory formation.”  Binder et al 2008, p 1302

“Polymorphisms within the FKBP5 gene that lead to altered GR responsiveness could promote sensitization of the neural systems involved in stress response and emotional memory processing, thereby placing children who have been abused with specific genetic variants at higher (p 13023) risk for PTSD …when exposed to other types of traumas.”  Binder et al 2008, p 1303

alleles rs3800373 and rs1360780 associated with higher risk for dissociation

“It is presently not clear if the associated polymorphisms represent the actual functional variants that lead to the differential FKBP5 expression patterns or are in linkage disequilibrium with a so far untyped, potential functional variant….studies may allow definitive identification of the genetic variants mechanistically responsible for the interactions and associations observed herein.”  Binder et al 2008, p 1303

interaction of FKBP5 genotypes with child abuse history might influence PTSD symptoms not shared with depression – separate gene X environment interactions for depression and PTSD symptomatology

also lack of interaction in the CRHR1 gene and child abuse and PTSD found in other studies

“…the mechanisms accounting for the relationship of child abuse to increased risk for PTSD in adulthood are not well understood.  It may be that child abuse directly impacts psychological and biological developmental processes or that child abuse is associated with other variables (child/parental temperament, broader family environment, attachment) that impact psychological and biological development or an interaction of the 2.”  Binder et al 2008, p 1303

CONCLUSIONS

“Our genetic results support the hypothesis that the glucocorticoid response system moderates the effects of early life stress on adult PTSD symptoms and that GR hypersensitivity may be important in the pathophysiology of this disorder.  These results suggest the possibility that heritable differences in glucocorticoid-mediated neural functioning exacerbate or dampen the effects of child abuse on the stress hormone system, thus altering HPA axis sensitivity and risk for PTSD in adulthood.”  Binder et al 2008, p 1304

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Alkon et al 2003

Abstract – San Francisco

Studies of cardiovascular reactivity in young children … Preejection period (PEP) and respiratory sinus arrythmia (RSA) were measured as indices of sympathetic and parasympathetic nervous system reactivity, respectively, and autonomic profiles were created to offer summative indices of PEP and RSA response. Results confirmed the protocol’s validity and reliability, and showed differences in autonomic reactivity by age and study context, but not by gender. The studies’ findings offer guidelines for future research on autonomic reactivity in middle childhood and support the feasibility of examining sympathetic and parasympathetic responses to challenge in 3- to 8-year-old children.

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Alkon et al 2006

Abstract – San Francisco

The purpose of this study was to develop a standardized protocol to measure preejection period (PEP), a measure of sympathetic nervous system, and respiratory sinus arrhythmia (RSA), a measure of parasympathetic nervous system, during resting and challenging states for 6- and 12-month-old infants and to determine developmental changes and individual stability of these measures.

A 7-min reactivity protocol was administered to Latino infants at 6 months (n=194) and 12 months (n=181). Results showed: (1) it is feasible to measure PEP and RSA in infants, (2) the protocol elicited significant autonomic changes, (3) individual resting autonomic measures were moderately stable from 6 to 12 months, but reactivity measures were not stable, and (4) heart rate and RSA resting and challenge group means changed significantly from 6 to 12 months. Findings suggest that although infants’ autonomic responses show developmental changes, individuals’ rank order is stable from 6 to 12 months of age.

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Carpenter et al 2004

Abstract – RI

Previous studies have reported elevated concentrations of cerebrospinal fluid (CSF) corticotropin-releasing factor (CRF) in patients with major depression.

Elevations of CSF CRF have also been reported in adult laboratory animals exposed to the stress of brief maternal deprivation or maternal neglect in the neonatal or preweaning period.

The present study was designed to determine whether major depression and a history of perceived early adversity in childhood are independently associated with elevated CSF CRF concentrations in adults. In this case-control study, 27 medication-free adults with major depression and 25 matched controls underwent standardized lumbar puncture for collection of a single CSF sample at 1200. Subjects provided data about significant adverse early-life experiences and rated their global perceived level of stress during pre-school and preteen years on a six-point Likert scale..

In a regression model, perceived early-life stress was a significant predictor of CSF CRF, but depression was not.

Perinatal adversity and perceived adversity in the preteen adversity years (ages 6-13 years) were both independently associated with decreasing CSF CRF concentrations.

The relationship observed between perceived early-life stress and adult CSF CRF concentrations in this study closely parallels recent preclinical findings. More work is needed to elucidate the critical nature and timing of early events that may be associated with enduring neuroendocrine changes in humans.

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from Wickipedia

Cortisol is a corticosteroid hormone produced by the adrenal gland (in the Zona fasciculata of the adrenal cortex). It is often referred to as the “stress hormone” as it is involved in response to stress. It increases blood pressure and blood sugar, and reduces immune responses. In pharmacology, the synthetic form of cortisol is referred to as hydrocortisone, and is used to treat allergies and inflammation, and to supplement natural cortisol when its production is too low.

When first introduced as a treatment for rheumatoid arthritis, it was referred to as Compound E.

Physiology

The amount of cortisol present in the blood undergoes diurnal variation, with the highest levels present in the early morning, and the lowest levels present around midnight, 3-5 hours after the onset of sleep. Information about the light/dark cycle is transmitted from the retina to the paired suprachiasmatic nuclei in the hypothalamus. The pattern is not present at birth (estimates of when it starts vary from two weeks to 9 months).^[1]

Changed patterns of serum cortisol levels have been observed in connection with abnormal ACTH levels, clinical depression, psychological stress, and such physiological stressors as hypoglycemia, illness, fever, trauma, surgery, fear, pain, physical exertion or extremes of temperature.

There is also significant individual variation, although a given person tends to have consistent rhythms.

Effects

See also Medical uses and effects of high dose glucocorticoids

In normal release, cortisol (like other glucocorticoid agents) has widespread actions which help restore homeostasis after stress. (These normal endogenous functions are the basis for the physiological consequences of chronic stress – prolonged cortisol secretion.). It has been proposed that its primary function is to inversely mobilize the immune system to fight potassium-depleting diarrhea diseases.^[2] Its odd attributes all support this.

Insulin

Cortisol counteracts insulin by increasing gluconeogenesis and promotes breakdown of lipids (lipolysis), and proteins, and mobilization of extrahepatic amino acids and ketone bodies. This leads to increased circulating glucose concentrations (in the blood) by increasing gluconeogenesis. There is an increased glycogen breakdown in the liver.^[3] Prolonged cortisol secretion causes hyperglycemia. Cortisol has no effect on insulin.^[4] The reason why in vivo experiments seem to deny this is that cortisone (a cortisol metabolite) greatly inhibits insulin. So the cortisone-cortisol equilibrium may explain why in vivo experiments contradict the cortisol effect.^[5] Cortisol does cause serum glucose to rise, but this is probably an indirect effect caused by stimulation of amino acid degradation, especially that derived from collagen in the skin. Loss of collagen from skin by cortisol is ten times greater than from all other tissue in the rat.^[6]

Amino acids

Cortisol raises the free amino acids in the serum. It does this by inhibiting collagen formation, decreasing amino acid uptake by muscle, and inhibiting protein synthesis.^[7] Cortisol (as opticortinol) probably inversely inhibits IgA precursor cells in the intestines of calves.^[8] Cortisol also inhibits IgA in serum, as it does IgM, but not IgE.^[9]

Gastric secretion

Cortisol stimulates gastric acid secretion.^[10] Gastric acid secretion would increase loss of potassium into the stomach during diarrhea as well as acid loss. Cortisol’s only direct effect on the hydrogen ion excretion of the kidneys is to stimulate excretion of ammonium ion by inactivation of renal glutaminase enzyme.^[11] Net chloride secretion in the intestines is inversely decreased by cortisol in vitro (methylprednisolone).^[12]

Sodium

Cortisol inhibits loss of sodium from small intestines of mammals.^[13] However, sodium depletion does not affect cortisol,^[14] so cortisol is not used to regulate serum sodium. Cortisol’s purpose may originally have been centered around moving sodium because cortisol is used to stimulate sodium inward for fresh water fish and outward for salt-water fish.^[15]

Potassium

Sodium load augments the intense potassium excretion by cortisol, and corticosterone is comparable to cortisol in this case.^[16] In order for potassium to move out of the cell, cortisol moves in an equal number of sodium ions.^[17] It can be seen that this should make pH regulation much easier, unlike the normal potassium deficiency situation in which about 2 sodium ions move in for each 3 potassium ions that move out, which is closer to the deoxycorticosterone effect. Nevertheless, cortisol consistently causes alkalosis of the serum, while in a deficiency pH does not change. Perhaps this may be for the purpose of bringing serum pH to a value most optimum for some of the immune enzymes during infection in those times when cortisol declines. Potassium is also blocked from loss in the kidneys directly somewhat by decline of cortisol (9 alpha fluorohydrocortisone).^[18]

Water

Cortisol also acts as a water diuretic hormone. Half the intestinal diuresis is so controlled.^[19] Kidney diuresis is also controlled by cortisol in dogs. The decline in water excretion upon decline of cortisol (dexamethasone) in dogs is probably due to inverse stimulation of antidiuretic hormone (ADH or arginine vasopressin), the inverse stimulation of which is not overridden by water loading.^[20] Humans also use this mechanism^[21] and other different animal mechanisms operate in the same direction.

Copper

It is probable that increasing copper availability for immune purposes is the reason why many copper enzymes are stimulated to an extent which is often 50% of their total potential by cortisol.^[22] This includes lysyl oxidase, an enzyme which is used to cross link collagen and elastin.^[23] Particularly valuable for immunity is the stimulation of superoxide dismutase by cortisol^[24] since this copper enzyme is almost certainly used by the body to permit superoxide to poison bacteria. Cortisol causes an inverse four- or fivefold decrease of metallothionein, a copper storage protein, in mice^[25] (however rodents do not synthesize cortisol themselves). This may be to furnish more copper for ceruloplasmin synthesis or release of free copper. Cortisol has an opposite effect on alpha aminoisobuteric acid than on the other amino acids.^[26] If alpha aminoisobuteric acid is used to transport copper through the cell wall, this anomaly would possibly be explained.

Immune system

Cortisol can weaken the activity of the immune system. Cortisol prevents proliferation of T-cells by rendering the interleukin-2 producer T-cells unresponsive to interleukin-1 (IL-1), and unable to produce the T-cell growth factor.^[27] Cortisol has a negative feedback effect on interleukin-1^[28] which must be especially useful in combating diseases, such as the endotoxin bacteria, that gain an advantage by forcing the hypothalamus to secrete a hormone called CRH. The suppressor cells are not affected by GRMF,^[29] so that the effective set point for the immune cells may be even higher than the set point for physiological processes. It reflects leukocyte redistribution to lymph nodes, bone marrow, and skin. Acute administration of corticosterone (the endogenous Type I and Type II receptor agonist), or RU28362 (a specific Type II receptor agonist), to adrenalectomized animals induced changes in leukocyte distribution. Natural killer cells are not affected by cortisol.^[30]

Bone metabolism

It lowers bone formation thus favoring development of osteoporosis in the long term. Cortisol moves potassium out of cells in exchange for an equal number of sodium ions as mentioned above.^[31] This can cause a major problem with the hyperkalemia of metabolic shock from surgery.

Memory

It cooperates with epinephrine (adrenaline) to create memories of short-term emotional events; this is the proposed mechanism for storage of flash bulb memories, and may originate as a means to remember what to avoid in the future. However, long-term exposure to cortisol results in damage to cells in the hippocampus. This damage results in impaired learning. The desirability of inhibiting activity during infection is no doubt the reason why cortisol is responsible for creating euphoria.^[32] The desirability of not disturbing tissues weakened by infection or of not cutting off their blood supply could explain the inhibition of pain widely observed for cortisol.

Additional effects

• It increases blood pressure by increasing the sensitivity of the vasculature to epinephrine and norepinephrine. In the absence of cortisol, widespread vasodilation occurs.

• It inhibits the secretion of corticotropin-releasing hormone (CRH), resulting in feedback inhibition of ACTH (Adrenocorticotropic hormone or corticotropin) secretion. Some researchers believe that this normal feedback system may break down when animals are exposed to chronic stress.

• It increases the effectiveness of catecholamines.

• It allows for the kidneys to produce hypotonic urine.

• It has anti-inflammatory effects by reducing histamine secretion and stabilizing lysosomal membranes. The stabilization of lysosomal membranes prevents their rupture, thereby preventing damage to healthy tissues.

• It stimulates hepatic detoxification by inducing tryptophan oxygenase (to reduce serotonin levels in the brain), glutamine synthase (reduce glutamate and ammonia levels in the brain), cytochrome P-450 hemoprotein (mobilizes arachidonic acid), and metallothionein (reduces heavy metals in the body).

• In addition to the effects caused by cortisol binding to the glucocorticoid receptor, because of its molecular similarity to aldosterone, it also binds to the mineralocorticoid receptor. Aldosterone and cortisol have similar affinity for the mineralocorticoid receptor however, glucocorticoids circulate at roughly 100 times the level of mineralocorticoids. An enzyme exists in mineralocorticoid target tissues to prevent overstimulation by glucocorticoids and allow selective mineralocorticoid action. This enzyme, 11-beta hydroxysteroid dehydrogenase type II (Protein:HSD11B2), catalyzes the deactivation of glucocorticoids to 11-dehydro metabolites.

Binding

Most serum cortisol, all but about 4%, is bound to proteins including corticosteroid binding globulin (CBG), and serum albumin. Only free cortisol is available to most receptors.

Regulation

The primary control of cortisol is the pituitary gland peptide, adrenocorticotropic hormone (ACTH). ACTH probably controls cortisol by controlling movement of calcium into the cortisol secreting target cells.^[33]. ACTH is in turn controlled by the hypothalamic peptide, corticotropin releasing hormone (CRH), which is under nervous control. CRH acts synergistically with arginine vasopressin, angiotensin II, and epinephrine ^[34].

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Schmidt et al 2005

Abstract – Leiden-Amsterdam Center for Drug Research/Leiden University Medical Center, Leiden University, Leiden, The Netherlands. mschmidt@mpipsykl.mpg.de

During postnatal development, mice undergo a period of reduced responsiveness of the pituitary-adrenal axis, the stress hyporesponsive period (SHRP), which is largely under control of maternal signals. The present study was designed to test the hypothesis that this quiescence in hypothalamic-pituitary-adrenal (HPA) activity is mediated by glucocorticoid feedback. For this purpose, the role of mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) in control of HPA activity was examined during the SHRP and in response to 24 h of maternal deprivation. Nondeprived or deprived (24 h) CD1 mice on postnatal d 8 were injected sc at 16 and 8 h before testing with the MR antagonist RU28318 or the GR antagonist RU38486. The results showed that, in nondeprived mice, blockade of GR rather than MR triggered a profound increase in anterior pituitary proopiomelanocortin mRNA, circulating ACTH, and corticosterone concentrations. In contrast, CRH mRNA in hypothalamus and GR mRNA in hippocampus and hypothalamus were decreased. Blockade of the GR during the deprivation period amplified the rise in corticosterone induced by maternal deprivation, whereas it reversed the deprivation effect on the other HPA markers, leading to profound increases in plasma ACTH, proopiomelanocortin mRNA expression in the anterior pituitary, CRH mRNA expression in the paraventricular nucleus, and MR mRNA expression in the hippocampus, but not in GR mRNA expression in the hippocampus and paraventricular nucleus. In conclusion, the data suggest that control of postnatal pituitary-adrenal activity during the SHRP involves GR-mediated feedback in the anterior pituitary, which is further potentiated in the absence of the mother.

Considering the capacity for developmental brain stress, having this lowered is a good thing, higher, not so good

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