Cortisol

Manufacturing PTSD evidence with machine learning

gettingwell4 < 0 Detracted from science, Beliefs, Brain development, Cerebrum, Cortisol, Epigenetics, Hypothalamus, Limbic system, Memory, Neurochemicals, Stress

What would you do if you were a scientist who had strong beliefs that weren’t borne out by experimental evidence?

Would you be honest with yourself about the roots of the beliefs? Would you attempt to discover why the beliefs were necessary for you, and what feelings were associated with the beliefs?

Instead of the above, the researchers of this 2017 New York human study reworked negative findings of two of the coauthors’ 2008 study until it fit their beliefs:

“The neuroendocrine response contributes to an accurate predictive signal of PTSD trajectory of response to trauma. Further, cortisol provides a stable predictive signal when measured in conjunction with other related neuroendocrine and clinical sources of information.

Further, this work provides a methodology that is relevant across psychiatry and other behavioral sciences that transcend the limitations of commonly utilized data analytic tools to match the complexity of the current state of theory in these fields.”

1. The limitations section included:

“It is important to note that ML [machine learning]-based network models are an inherently exploratory data analytic method, and as such might be seen as ‘hypotheses generating’. While such an approach is informative in situations where complex relationships cannot be proposed and tested a priori, such an approach also presents with inherent limitations as a high number of relationships are estimated simultaneously introducing a non-trivial probability of false discovery.”

2. Sex-specific impacts of childhood trauma summarized why cortisol isn’t a reliable biological measurement:

“Findings are dependent upon variance in extenuating factors, including but not limited to, different measurements of:

  • early adversity,
  • age of onset,
  • basal cortisol levels, as well as
  • trauma forms and subtypes, and
  • presence and severity of psychopathology symptomology.”

Although this study’s authors knew or should have known that review’s information, cortisol was the study’s foundation, and beliefs in its use as a biomarker were defended.

3. What will it take for childhood trauma research to change paradigms? described why self-reports of childhood trauma can NEVER provide direct evidence for trauma during the top three periods when humans are most sensitive to and affected by trauma:

“The basic problem prohibiting the CTQ (Childhood Trauma Questionnaire) from discovering likely most of the subjects’ historical traumatic experiences that caused epigenetic changes is that these experiences predated the CTQ’s developmental starting point.

Self-reports were – at best – evidence of experiences after age three, distinct from the experience-dependent epigenetic changes since conception.”

Yet the researchers’ beliefs in the Trauma History Questionnaire’s capability to provide evidence for early childhood traumatic experiences allowed them to make such self-reports an important part of this study’s findings, for example:

“The reduced cortisol response in the ER [emergency room] was dependent on report of early childhood trauma exposure.”

https://www.nature.com/articles/tp201738 “Utilization of machine learning for prediction of post-traumatic stress: a re-examination of cortisol in the prediction and pathways to non-remitting PTSD”

How well do single-mother rodent studies inform us about human fathers?

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Two items before getting to the review:

This 2018 Australian review subject was paternal intergenerational and transgenerational transmission of biological and behavioral phenotypes per this partial outline:

“Evidence for non-genetic inheritance of behavioral traits in human populations

  • Intergenerational inheritance modulating offspring phenotypes following paternal exposure to trauma
  • Epigenetic inheritance via the germline following paternal environmental exposures
  • Limitations of research on epigenetic inheritance in human populations

The transgenerational impact of stressful paternal environments

  • Impact of paternal stress on affective behaviors and HPA-axis regulation of progeny
  • Influence of paternal stress exposure on offspring cognition
  • Role of sperm-borne microRNAs in the epigenetic inheritance of stress

Sexually dimorphic aspects of paternal transgenerational epigenetic inheritance”

The review was comprehensive, and filled in the above outline with many details towards the goal of:

“This exciting new field of transgenerational epigenomics will facilitate the development of novel strategies to predict, prevent and treat negative epigenetic consequences on offspring health, and psychiatric disorders in particular.”

The reviewers also demonstrated that current intergenerational and transgenerational research paradigms exclude a father’s child care behavior.

The fact that studies use rat and mouse species where fathers don’t naturally provide care for their offspring has warped the translation of findings to humans. The underlying question every animal study must answer is: how can its information be used to help humans? I asked in A limited study of parental transmission of anxiety/stress-reactive traits:

“How did parental behavioral transmission of behavioral traits and epigenetic changes become a subject not worth investigating? These traits and effects can be seen everyday in real-life human interactions, and in every human’s physiology.”

Who among us doesn’t still have biological and behavioral consequences from our experiences of our father’s child care actions and inactions? Why can’t researchers and sponsors investigate these back to their sources that may include grandparents and great-grandparents?

Such efforts weren’t apparent in the review’s 116 cited references that included:

The reviewer in the latter has been instrumental in excluding behavioral inheritance mechanisms from these research paradigms, leading to my questions:

  1. “If the experimental subjects had no more control over their behavioral stress-response effects than they had over their DNA methylation, histone modification, or microRNA stress-response effects, then why was such behavior not included in the “epigenetic mechanisms” term?
  2. How do behavioral inheritance mechanisms fall outside the “true epigenetic inheritance” term when behavioral stress-response effects are shown to be reliably transmitted generation after generation?
  3. Wouldn’t the cessation of behavioral inheritance mechanisms confirm their status by falsifiability as was similarly done with studies such as the 1995 Adoption reverses the long-term impairment in glucocorticoid feedback induced by prenatal stress?”

Translating rodent studies into human mothers’ behavioral transmission of biological and behavioral phenotypes isn’t hampered by the studied species’ traits as it is for human fathers. But sponsors have to have the guts to support human research that may not produce politically-correct findings.

http://www.translatingtime.org provides an inter-species comparative timeline. For example, an input of:

  • Species 1: Human
  • Process: Lifespan
  • Location: Whole Organism
  • Days (post-conception): 270
  • Species 2: Mouse

produces a list of event predictions. Note how many significant events occur before humans are born at day 270, assuming everything goes right with our developmental processes! Also, the model predictions for humans end at post-conception day 979, three weeks short of when we celebrate our second birthday.

https://www.nature.com/articles/s41380-018-0039-z “Transgenerational epigenetic influences of paternal environmental exposures on brain function and predisposition to psychiatric disorders” (not freely available) Thanks to Dr. Shlomo Yeshurun for providing a full copy.

What will it take for childhood trauma research to change paradigms?

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This 2018 German human study found:

“DNA methylation in a biologically relevant region of NR3C1-1F [glucocorticoid receptor gene] moderates the specific direction of HPA-axis dysregulation (hypo- vs. hyperreactivity) in adults exposed to moderate-severe CT [childhood trauma].

In contrast, unexposed and mildly-moderately exposed individuals displayed moderately sized cortisol stress responses irrespective of NR3C1-1F DNA methylation. Contrary to some prior work, however, our data provides no evidence for a direct association of CT and NR3C1-1F DNA methylation status.”

The study was an example of why researchers investigating the lasting impacts of human traumatic experiences won’t find causes, effects, and productive therapies until their paradigms change.

1. Limited subject histories

A. Why weren’t the subjects asked for historical information about their parents, grandparents, and great-grandparents?

The researchers had no problem using animal studies to guide the study design, EXCEPT for animal studies of the etiologic bases of intergenerational and transgenerational transmission of biological and behavioral phenotypes. Just the approximate places and dates of three generations of the German subjects’ ancestors’ births, childhoods, adolescences, and early adulthoods may have provided relevant trauma indicators.

B. Why are studies still using the extremely constrained Childhood Trauma Questionnaire? Only one CTQ aspect was acknowledged as a study design limitation:

“Our findings rely on retrospective self-report measures of CT, which could be subject to bias.”

But bias was among the lesser limiting factors of the CTQ.

The study correlated epigenetic changes with what the subjects selectively remembered, beginning when their brains developed sufficient cognitive functionalities to put together the types of memories that could provide CTQ answers – around age four. The basic problem that kept the CTQ from discovering likely most of the subjects’ traumatic experiences causing epigenetic changes was that these experiences predated the CTQ’s developmental starting point:

  1. A human’s conception through prenatal period is when both the largest and the largest number of epigenetic changes occur, and is when our susceptibility and sensitivity to our environment is greatest;
  2. Birth through infancy is the second-largest; and
  3. Early childhood through the age of three is the third largest.

CTQ self-reports were – at best – evidence of experiences after age three, distinct from the  experience-dependent epigenetic changes since conception. If links existed between the subjects’ early-life DNA methylation and later-life conditions, they weren’t necessarily evidenced by CTQ answers about later life that can’t self-report relevant early-life experiences that may have caused DNA methylation.

2. Limited subject selection

The researchers narrowed down the initial 622 potential subjects to the eventual 200 subjects aged 18 to 30. An exclusion criteria that was justified as eliminating confounders led to this limitation statement:

“Our results might be based on a generally more resilient sample as we had explicitly excluded individuals with current or past psychopathology.”

Was it okay for the researchers to assert:

“Exposure to environmental adversity such as childhood trauma (CT) affects over 10% of the Western population and ranges among the best predictors for psychopathology later in life.”

but not develop evidence for the statement by letting people who may have been already affected by age 30 and received treatment participate in the study?

Was the study design so fragile that it couldn’t adjust to the very people who may be helped by the research findings?

3. Limited consequential measurements

The current study design conformed to previous studies’ protocols. The researchers chose cortisol and specific DNA methylation measurements.

A. Here’s what Sex-specific impacts of childhood trauma had to say about cortisol:

“Findings are dependent upon variance in extenuating factors, including but not limited to, different measurements of:

  • early adversity,
  • age of onset,
  • basal cortisol levels, as well as
  • trauma forms and subtypes, and
  • presence and severity of psychopathology symptomology.”

The researchers knew or should have known all of the above since this quotation came from a review.

B. What other consequential evidence for prenatal, infancy, and early childhood experience-dependent epigenetic changes can be measured? One overlooked area was including human emotions as evidence.

There are many animal studies from which to draw inferences about human emotions. There are many animal models of creating measurable behavioral and biological phenotypes of human emotion correlates, with many methods, including manipulating environmental variables during prenatal, infancy, and early childhood periods.

Studies that take detailed histories may arrive at current emotional evidence for human subjects’ earliest experience-dependent changes. Researchers who correlate specific historical environments and events, stress measurements, and lasting human emotions expressed as “I’m all alone” and “No one can help me” will better understand causes and effects.

CTQ answers weren’t sufficiently detailed histories.

4. Limited effective treatments and therapies

The current study only addressed this area in the final sentence:

“Given their potential reversibility, uncovering epigenetic contributions to differential trajectories following childhood adversity may serve the long-term goal of delivering personalized prevention strategies.”

Researchers – if your paradigms demonstrate these characteristics:

  • Why are you spending your working life in efforts that can’t make a difference?
  • Aren’t your working efforts more valuable than that?
  • What else could you investigate that could make a difference in your field?

I hope that researchers will value their professions enough to make a difference with their expertise. And that sponsors won’t thwart researchers’ desires for difference-making science by putting them into endless funding queues.

http://www.psyneuen-journal.com/article/S0306-4530(17)31355-0/pdf “Glucocorticoid receptor gene methylation moderates the association of childhood trauma and cortisol stress reactivity” (not freely available)

Sex-specific impacts of childhood trauma

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This 2018 Canadian paper reviewed evidence for potential sex-specific differences in the lasting impacts of childhood trauma:

“This paper will provide a contextualized summary of neuroendocrine, neuroimaging, and behavioral epigenetic studies on biological sex differences contributing to internalizing psychopathology, specifically posttraumatic stress disorder and depression, among adults with a history of childhood abuse.

Given the breadth of this review, we limit our definition [of] trauma to intentional and interpersonal experiences (i.e., childhood abuse and neglect) in childhood. Psychopathological outcomes within this review will be limited to commonly explored internalizing disorders, specifically PTSD and depression.

Despite the inconsistent and limited findings in this review, a critical future consideration will be whether the biological effects of early life stress can be reversed in the face of evidence-based behavioral interventions, and furthermore, whether these changes may relate to potentially concurrent reductions in susceptibility to negative mental health outcomes.”

It was refreshing to read a paper where the reviewers often interrupted the reader’s train of thought to interject contradictory evidence, and display the scientific method. For example, immediately after citing a trio of well-respected studies that found:

“Psychobiological research on relationships linking impaired HPA axis functioning and adult internalizing disorders are suggestive of lower basal and afternoon levels of plasma cortisol in PTSD phenotype.”

the reviewers stated:

“However, a recent meta-analysis suggests no association between basal cortisol with PTSD.”

and effectively ended the cortisol discussion with:

“Findings are dependent upon variance in extenuating factors, including but not limited to, different measurements of:

  • early adversity,
  • age of onset,
  • basal cortisol levels, as well as
  • trauma forms and subtypes, and
  • presence and severity of psychopathology symptomology.”

The reviewers also provided good summaries of aspects of the reviewed subject. For example, the “Serotonergic system genetic research, childhood trauma and risk of psychopathology” subsection ended with:

“Going forward, studies must explore the longitudinal effects of early trauma on methylation as well as comparisons of multiple loci methylation patterns and interactions to determine the greatest factors contributing to health outcomes. Only then, can we start to consider the role of sex in moderating risk.”

I didn’t agree with the cause-ignoring approach of the behavior therapy mentioned in the review. Does it make sense to approach one category of symptoms:

“the biological effects of early life stress”

by treating another category of symptoms?

“can be reversed in the face of evidence-based behavioral interventions.”

But addressing symptoms instead of the sometimes-common causes that generate both biological and behavioral effects continues to be the direction.

After receiving short-term symptom relief, wouldn’t people prefer treatments of originating causes so that their various symptoms don’t keep bubbling up? Why wouldn’t research paradigms be aligned accordingly?

I was encouraged by the intergenerational and transgenerational focus of one of the reviewer’s research:

“Dr. Gonzalez’s current research focus is to understand the mechanisms by which early experiences are transmitted across generations and how preventive interventions may affect this transmission.”

This line of hypotheses requires detailed histories, and should uncover causes for many effects that researchers may otherwise shrug off as unexplainable individual differences. Its aims include the preconception through prenatal periods when both the largest and the largest number of epigenetic changes occur, and is when our susceptibility and sensitivity to our environment is greatest. There are fewer opportunities for effective “preventive interventions” in later life compared with these early periods.

Unlike lab rats, women and men can reach some degree of honesty about our early lives’ experiential causes of ongoing adverse effects. Experiential therapies that allow humans to potentially change their responses to these causes deserve more investigation than do therapies that apply external “interventions.”

https://www.sciencedirect.com/science/article/pii/S0272735817302647 “Biological alterations affecting risk of adult psychopathology following childhood trauma: A review of sex differences” (not freely available) Thanks to lead author Dr. Ashwini Tiwari for providing a copy.

DNA methylation and childhood adversity

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This 2017 Georgia human review covered:

“Recent studies, primarily focused on the findings from human studies, to indicate the role of DNA methylation in the associations between childhood adversity and cardiometabolic disease in adulthood. In particular, we focused on DNA methylation modifications in genes regulating the hypothalamus-pituitary-adrenal axis as well as the immune system.”

Recommendations in the review’s Epigenetics inheritance and preadaptation theory section included:

“Twin studies offer another promising design to explore the mediation effect of DNA methylation between child adversity and cardiometabolic outcomes..which could rule out heterogeneity due to genetic and familia[l]r environmental confounding.”

As it so happened, the below 2018 study provided some evidence.

http://www.sciencedirect.com/science/article/pii/S0167527317352762 “The role of DNA methylation in the association between childhood adversity and cardiometabolic disease” (not freely available) Thanks to lead author Dr. Guang Hao for providing the full study.

This 2018 UK human study:

“Tested the hypothesis that victimization is associated with DNA methylation in the Environmental Risk (E-Risk) Longitudinal Study, a nationally representative 1994-1995 birth cohort of 2,232 twins born in England and Wales and assessed at ages 5, 7, 10, 12, and 18 years. Multiple forms of victimization were ascertained in childhood and adolescence (including physical, sexual, and emotional abuse; neglect; exposure to intimate-partner violence; bullying; cyber-victimization; and crime).

Hypothesis-driven analyses of six candidate genes in the stress response (

  1. NR3C1 [glucocorticoid receptor],
  2. FKBP5 [a regulator of the stress hormone system],
  3. BDNF [brain-derived neurotrophic factor],
  4. AVP [arginine vasopressin],
  5. CRHR1 [corticotropin-releasing hormone receptor 1],
  6. SLC6A4 [serotonin transporter]

) did not reveal predicted associations with DNA methylation.

Epigenetic epidemiology is not yet well matched to experimental, nonhuman models in uncovering the biological embedding of stress.”

One of the sad findings was that as the types of trauma inflicted by other people on the subjects increased, so did the percentage of subjects who hurt themselves by smoking. Two-thirds of teens who reported three or more of the seven adolescent trauma types also smoked by age 18:

Polyvictimization

Self-harming behaviors other than smoking weren’t considered.

Another somber finding was:

“Childhood sexual victimization is associated with stable DNA methylation differences in whole blood in young adulthood. These associations were not observed in relation to sexual victimization in adolescence.”

The researchers guided future studies regarding the proxy measurements of peripheral blood DNA methylation:

“The vast majority of subsequent human studies, including the present one, have relied on peripheral blood. This choice is expedient, but also scientifically reasonable given the aim of detecting effects on stress-related physical health systems that include peripheral circulating processes (immune, neuroendocrine).

But whole blood is heterogeneous, and although cell-type composition can be evaluated and controlled, as in the present study, it does raise the question of whether peripheral blood is a problematic surrogate tissue for research on the epigenetics of stress.

Comparisons of methylomic variation across blood and brain suggest that blood-based EWAS may yield limited information relating to underlying pathological processes for disorders where brain is the primary tissue of interest.”

1. The comment on “epigenetic epidemiology” overstated the study’s findings because the epigenetic analysis, although thorough, was limited to peripheral blood DNA methylation. Other consequential epigenetic effects weren’t investigated, such as histone modifications and microRNA expression.

2. An unstated limitation was that the DNA methylation analyses were constrained by budgets. Studies like The primary causes of individual differences in DNA methylation are environmental factors point out restrictions in the methodology:

“A main limitation with studies using the Illumina 450 K array is that the platform only covers ~1.5 % of overall genomic CpGs, which are biased towards promoters and strongly underrepresented in distal regulatory elements, i.e., enhancers.

WGBS [whole-genome bisulfite sequencing] offers single-site resolution CpG methylation interrogation at full genomic coverage.

Another advantage of WGBS is its ability to access patterns of non-CpG methylation.”

I’d expect that in the future, researchers with larger budgets would reanalyze the study samples using other techniques.

3. The researchers started and ended the study presenting their view of human “embedding of stress” as a fact rather than a paradigm. Epigenetic effects of early life stress exposure compared and contrasted this with another substantiated view.

4. The study focused on the children’s intergenerational epigenetic effects. An outstanding opportunity to advance science was missed regarding transgenerational epigenetic inheritance:

  • Wouldn’t the parents’ blood samples and histories – derived from administering the same questionnaires their twins answered at age 18 – likely provide distant causal evidence for some of the children’s observed effects?
  • And lay the groundwork for hypotheses about aspects of future generations’ physiologies and behaviors?

https://ajp.psychiatryonline.org/doi/full/10.1176/appi.ajp.2017.17060693 “Analysis of DNA Methylation in Young People: Limited Evidence for an Association Between Victimization Stress and Epigenetic Variation in Blood” (not freely available) Thanks to coauthor Dr. Helen Fisher for providing the full study.

Make consequential measurements in epigenetic studies

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The subject of this 2017 Spanish review was human placental epigenetic changes:

“39 papers assessing human placental epigenetic signatures in association with either

  • (i) psychosocial stress,
  • (ii) maternal psychopathology,
  • (iii) maternal smoking during pregnancy, and
  • (iv) exposure to environmental pollutants,

were identified.

Their findings revealed placental tissue as a unique source of epigenetic variability that does not correlate with epigenetic patterns observed in maternal or newborn blood.“

Each study’s confounders were summarized by a column in Table 1. Some of the reviewers’ comments included:

“33 out of 39 papers reviewed (85%) reported significant associations between either placental DNA methylation or placental miRNA expression and exposure to any of the risk factors assessed. However, the methodological heterogeneity present throughout the studies reviewed does not allow meta-analytic exploration of reported findings.

Heterogeneity regarding the origin of biological tissues analyzed confounds the replicability and validity of reported findings and their potential synthesis.”

Sponsors and researchers really have to take their work seriously if the developmental origins of health and disease hypothesis can advance to a well-evidenced theory. Study designers should:

  1. Sample consequential dimensions. “There were no studies examining histone modifications.” Why were there no human studies in this important category of epigenetic changes in the placenta, the “barrier protecting the fetus“?
  2. Correct methodological deficiencies in advance. Eliminate insufficiencies like “Once collected, processing and storage of placental samples also differed across studies and was not reported in all of them.”
  3. Stop using convenient but non-etiologic proxy assays such as global methylation. How can a study advance the DOHaD hypothesis if everyone knows ahead of time that its outcome will be yet another finding that epigenetic changes “are associated with” non-causal factors?
  4. Forget about non-biological measurements like educational attainment per Does a societal mandate cause DNA methylation?.

Every human alive today has observable lasting epigenetic effects caused by environmental factors during the earliest parts of our lives, and potentially even before we’re conceived. Isn’t this sufficient rationale to expect serious efforts by research sponsors and designers?

https://www.sciencedirect.com/science/article/pii/S0892036217301769 “The impact of prenatal insults on the human placental epigenome: A systematic review” (click the Download PDF link to read the paper)

How to cure the ultimate causes of migraines?

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Most of the spam I get on this blog comes in as ersatz comments on The hypothalamus couples with the brainstem to cause migraines. I don’t know what it is about the post that attracts internet bots.

The unwanted attention is too bad because the post represents a good personal illustration of “changes in the neural response to painful stimuli.” Last year I experienced three three-day migraines in one month as did the study’s subject. This led to me cycling through a half-dozen medications in an effort to address the migraine causes.

None of the medications proved to be effective at treating the causes. I found one that interrupted the progress of migraines – sumatriptan, a serotonin receptor agonist. I’ve used it when symptoms start, and the medication has kept me from having a full-blown migraine episode in the past year.

1. It may be argued that migraine headache tendencies are genetically inherited. Supporting personal evidence is that both my mother and younger sister have migraine problems. My father, older sister, and younger brother didn’t have migraine problems. Familial genetic inheritance usually isn’t the whole story of diseases, though.

2. Migraine headaches may be an example of diseases that are results of how humans have evolved. From Genetic imprinting, sleep, and parent-offspring conflict:

“Evolutionary theory predicts: that which evolves is not necessarily that which is healthy.

Why should pregnancy not be more efficient and more robust than other physiological systems, rather than less? Crucial checks, balances and feedback controls are lacking in the shared physiology of the maternal–fetal unit.“

Both migraine causes and effects may be traced back to natural lacks of feedback loops. These lacks demonstrate that such physiological feedback wasn’t evolutionarily necessary in order for humans to survive and reproduce.

3. Examples of other processes occurring during prenatal development that also lack feedback loops, and their subsequent diseases, are:

A. Hypoxic conditions per Lack of oxygen’s epigenetic effects are causes of the fetus later developing:

  • “age-related macular degeneration
  • cancer progression
  • chronic kidney disease
  • cardiomyopathies
  • adipose tissue fibrosis
  • inflammation
  • detrimental effects which are linked to epigenetic changes.”

B. Stressing pregnant dams per Treating prenatal stress-related disorders with an oxytocin receptor agonist caused fetuses to develop a:

and abnormalities:

  • in social behavior,
  • in the HPA response to stress, and
  • in the expression of stress-related genes in the hippocampus and amygdala.”

1. What would be a treatment that could cure genetic causes for migraines?

I don’t know of any gene therapies.

2. What treatments could cure migraines caused by an evolved lack of feedback mechanisms?

We humans are who we have become, unless and until we can change original causes. Can we deal with “changes in the neural response to painful stimuli” without developing hopes for therapies or technologies per Differing approaches to a life wasted on beliefs?

3. What treatments could cure prenatal epigenetic causes for migraines?

The only effective solution I know of that’s been studied in humans is to prevent adverse conditions like hypoxia from taking place during pregnancy. The critical periods of our physical development are over once we’re adults, and we can’t unbake a cake.

Maybe science will offer other possibilities. Maybe researchers could do more than their funding sponsors expect?

Differing approaches to a life wasted on beliefs

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Let’s start by observing that people structure their lives around beliefs. As time goes on, what actions would a person have taken to ward off non-confirming evidence?

One response may be that they would engage in ever-increasing efforts to develop new beliefs that justified how they spent their one precious life’s time so far.

Such was my take on beliefs embedded in https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5684598/pdf/PSYCHIATRY2017-5491812.pdf “Epigenetic and Neural Circuitry Landscape of Psychotherapeutic Interventions”:

“Animal models have shown the benefits of continued environmental enrichment (EE) on psychopathological phenotypes, which carries exciting translational value.

This paper posits that psychotherapy serves as a positive environmental input (something akin to EE).”

The author conveyed his belief that wonderful interventions were going to happen in the future. However, when scrutinized, most human studies have demonstrated NULL effects of psychotherapeutic interventions on causes. Without sound evidence that treatments affect causes, his belief seemed driven by something else.

The author cited findings of research like A problematic study of oxytocin receptor gene methylation, childhood abuse, and psychiatric symptoms as supporting external interventions to tamp down symptoms of patients’ presenting problems. Did any of the 300+ cited references concern treatments where patients instead therapeutically addressed their problems’ root causes?

For an analogous religious example, a person’s belief caused him to spend years of his life trying to convince men to act so that they could get their own planet after death, and trying to convince women to latch onto men who had this belief. A new and apparently newsworthy belief developed from his underlying causes:

“The founder and CEO of neuroscience company Kernel wants “to expand the bounds of human intelligence.” He is planning to do this with neuroprosthetics; brain augmentations that can improve mental function and treat disorders. Put simply, Kernel hopes to place a chip in your brain.

He was raised as a Mormon in Utah and it was while carrying out two years of missionary work in Ecuador that he was struck by what he describes as an “overwhelming desire to improve the lives of others.”

He suffered from chronic depression from the ages of 24 to 34, and has seen his father and stepfather face huge mental health struggles.”

https://www.theguardian.com/small-business-network/2017/dec/14/humans-20-meet-the-entrepreneur-who-wants-to-put-a-chip-in-your-brain “Humans 2.0: meet the entrepreneur who wants to put a chip in your brain”

The article stated that he had given up Mormonism. There was nothing to suggest, though, that he had therapeutically addressed any underlying causes for his misdirected thoughts, feelings, and behavior.

So he developed other beliefs instead.

What can people do to keep their lives from being wasted on beliefs? As mentioned in What was not, is not, and will never be:

“The problem is that spending our time and efforts on these ideas, beliefs, and behaviors won’t ameliorate their motivating causes. Our efforts only push us further away from our truths, with real consequences: a wasted life.”

The goal of the therapeutic approach advocated by Dr. Arthur Janov’s Primal Therapy is to remove the force of presenting problems’ motivating causes. Success in reaching this goal is realized when patients become better able to live their own lives.

Epigenetic effects of microRNA on fetal heart development

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This 2017 Australian review’s subject was epigenetic impacts involving microRNA in adverse intrauterine environments, and how these affected fetal heart tissue development:

“We describe how an adverse intrauterine environment can influence the expression of miRNAs (a sub-set of non-coding RNAs) and how these changes may impact heart development. Potential consequences of altered miRNA expression in the fetal heart include; Hypoxia inducible factor (HIF) activation, dysregulation of angiogenesis, mitochondrial abnormalities and altered glucose and fatty acid transport/metabolism.

This feedback network between miRNAs and other epigenetic pathways forms an epigenetics–miRNA regulatory circuit that organizes the whole gene expression profile. The human heart encodes over 700 miRNAs.”

A 2016 review Lack of oxygen’s epigenetic effects also provided a details about hypoxia. Those reviewers importantly pointed out the natural lack of a feedback mechanism to the HIF-1α signaling source, and how this evolutionary lack contributed to diseases.

http://www.mdpi.com/1422-0067/18/12/2628/htm “Adverse Intrauterine Environment and Cardiac miRNA Expression”

Do you have your family’s detailed medical histories?

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Imagine that you were a parent who puzzled over the mystery of your pre-teen daughter’s hyperactive behavior. Without detailed family medical histories, would anyone recognize this as a preprogammed phenotype?

Could anyone trace the daughter’s behavior back to her maternal great-grandmother being treated with glucocorticoids near the end of the second trimester of carrying her grandfather?

Such was a finding of a 2017 Canadian guinea pig study that was undertaken to better inform physicians of the transgenerationally inherited epigenetic effects of glucocorticoid treatments commonly prescribed during human pregnancies:

“This study presents the first evidence that prenatal treatment with sGC [synthetic glucocorticoid] results in transgenerational paternal transmission of hyperactivity and altered hypothalamic gene expression through three generations of young offspring. Female offspring appear to be more sensitive than male offspring to the programming effects of sGC, which suggests an interaction between sGC and sex hormones or sex-linked genes. Paternal transmission to F3 strongly implicates epigenetic mechanisms in the process of transmission, and small noncoding RNAs likely play a major role.”

Some details of the study included:

Veh[icle] was the control group initially treated with saline.

The study was informative and conclusive for the aspects studied. From the Methods section:

“Data from same-sex littermates were meaned to prevent litter bias. Sample sizes (N) correspond to independent litters, and not to the total number of offspring across all litters.

Power analyses based on previous studies determined N ≥ 8 sufficient to account for inter-litter variability and detect effects in the tests performed.”

https://www.nature.com/articles/s41598-017-11635-w “Prenatal Glucocorticoid Exposure Modifies Endocrine Function and Behaviour for 3 Generations Following Maternal and Paternal Transmission”

Experience-induced transgenerational programming of neuronal structure and functions

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The second paper of Transgenerational epigenetic inheritance week was a 2017 German/Israeli review focused on:

“The inter- and transgenerational effects of stress experience prior to and during gestation..the concept of stress-induced (re-)programming in more detail by highlighting epigenetic mechanisms and particularly those affecting the development of monoaminergic transmitter systems, which constitute the brain’s reward system.

We offer some perspectives on the development of protective and therapeutic interventions in cognitive and emotional disturbances resulting from preconception and prenatal stress.”

The reviewers noted that human studies have difficulties predicting adult responses to stress that are based on gene expression and early life experience. Clinical studies that experimentally manipulate the type, level and timing of the stressful exposure aren’t possible. Clinical studies are also predicated on the symptoms being recognized as disorders and/or diseases.

The researchers noted difficulties in human interventions and treatments. Before and during pregnancy, and perinatal periods are where stress effects are largest. But current human research hasn’t gathered sufficient findings to develop practical guidelines for early intervention programs.

I’m not persuaded by arguments that cite the difficulties of performing human research on transgenerational epigenetic inheritance. There are overwhelming numbers of people who have obvious stress symptoms: these didn’t develop in a vacuum.

Researchers:

  • Design human studies to test what’s known from transgenerational epigenetic inheritance animal studies that will include documenting the subjects’ detailed histories with sufficient biometric samples and data obtained from their lineage.
  • Induce pregnant subjects to at least temporarily avoid what’s harmful for them and/or the offspring, in favor of what’s beneficial.
  • Document the subjects’ actions with history and samples.

I acknowledge that economic incentives may not be enough to get people to participate. I’m familiar with a juvenile sickle-cell study that didn’t get enough subjects despite offering free transportation and hundreds of dollars to the caregivers per visit. The main problem seemed to be that the additional income would be reported and threaten the caregivers’ welfare benefits.

Stop whining that your jobs are difficult, researchers. Society doesn’t owe you a job. EARN IT – get yourself and the people in your organization motivated to advance science!

http://www.sciencedirect.com/science/article/pii/S014976341630731X “Experience-induced transgenerational (re-)programming of neuronal structure and functions: Impact of stress prior and during pregnancy” (not freely available)

Transgenerational effects of early environmental insults on aging and disease

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The first paper of Transgenerational epigenetic inheritance week was a 2017 Canadian/Netherlands review that’s organized as follows:

“First, we address mechanisms of developmental and transgenerational programming of disease and inheritance. Second, we discuss experimental and clinical findings linking early environmental determinants to adverse aging trajectories in association with possible parental contributions and sex-specific effects. Third, we outline the main mechanisms of age-related functional decline and suggest potential interventions to reverse negative effects of transgenerational programming.”

A transgenerational phenotype was defined as an epigenetic modification that was maintained at least either to F2 grandchildren in the paternal lineage, or to F3 great-grandchildren in the maternal lineage.

The reviewers noted that mechanisms of transgenerational programming are complex and multivariate.  Severity, timing, and type of exposure; lineage of transmission; germ cell exposure; and gender of an organism were the main factors that may determine consequences. Mechanisms reviewed were:

  1. Parental exposure to an adverse environment;
  2. Altered maternal behavior and care of offspring; and
  3. Experience-dependent modifications of the epigenome.

There was a long list of diseases and impaired functionalities that were consequences of ancestral experiences and exposures. Most studies were of animals, but a few were human, such as those done on effects of extended power outages during a Quebec ice storm of January 1998.

One intervention that was effective in reversing a transgenerational phenotype induced by deficient rodent maternal care was to place pups with a caring foster female soon after birth. It’s probably unacceptable in human societies to preemptively recognize all poor-care human mothers and remove the infant to caring foster mothers. But researchers could probably find enough instances to develop studies of the effectiveness of such placements in reversing a transgenerational phenotype.

The review didn’t have suggestions for reversing human transgenerational phenotypes, just “potential interventions to reverse negative effects of transgenerational programming.” Interventions suggested for humans – exercise, enriched lifestyle, cognitive training, dietary regimens, and expressive art and writing therapies – only reduced impacts of transgenerational epigenetic effects.

Tricky wording of “reverse negative effects of transgenerational programming” showed that research paradigms weren’t aimed at resolving causes. The review was insufficient for the same reasons mentioned in How one person’s paradigms regarding stress and epigenetics impedes relevant research, prompting my same comment:

Aren’t people interested in human treatments of originating causes so that their various symptoms don’t keep bubbling up? Why wouldn’t research paradigms be aligned accordingly?

When reversals of human phenotypes aren’t researched, problems may compound by being transmitted to the next generations.

http://www.sciencedirect.com/science/article/pii/S014976341630714X “Transgenerational effects of early environmental insults on aging and disease incidence” (not freely available)

Does living near a forest keep your amygdala healthier?

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A thought-provoking post from A Paper a Day Keeps the Scientist Okay entitled “Living Near a Forest Keeps Your Amygdala Healthier” referenced a 2017 German human study which found:

“..a relationship between place of residence and brain health: those city dwellers living close to a forest were more likely to show indications of a physiologically healthy amygdala structure and were therefore presumably better able to cope with stress.”

The researchers accomplished the imperative of meeting the study’s stated objective:

“We set out to identify and characterize the geographical elements of a city that are associated with these brain structures following a suggestion by Kennedy and Adolph that studies should begin to derive recommendations for urban planning and architecture.

The results of our study may suggest that forests in and around the cities are a valuable resource that should be promoted. However future longitudinal studies are needed to investigate the causal directionality of the effect in order to disentangle whether more forest in ones habitat facilitates brain structural integrity or potentially those people with better brain structural integrity choose to live closer to forests. Moreover we need to investigate whether living close to the forest is associated with an absence of risk factors such as noise, air pollution or stress and thereby has beneficial effects or whether the forest itself constitutes a salutary factor that promotes well-being.”

https://www.nature.com/articles/s41598-017-12046-7 “In search of features that constitute an “enriched environment” in humans: Associations between geographical properties and brain structure”

A major limitation of this study’s methodology was intentional non-use of an available data source. Referring to Do we need to study the brain to understand the mind? posted earlier this week:

“Self-report is still the gold standard for assessing emotional experience and the contents of thought. Isn’t it easier just to ask?”

These researchers put the forest before the trees, and designed a study that didn’t ask subjects important questions such as why they lived where they lived. The researchers inferred sketchy fMRI-geography associations because they didn’t solicit relevant primary information via individual self-reports.

I don’t live in Berlin, and I’m not part of the selected cohort, but I otherwise generally meet this study’s subject parameters. Something in my past causes me to actively select housing that isn’t in a noisy environment. If I were asked why I lived where I lived, my answer would have included:

  • A deciding factor in why I sold my second house was traffic noise in wintertime;
  • A deciding factor in why I bought my fourth house was its location in the housing development’s center, away from street noise; and
  • A deciding factor in why I live where I now live is the house’s orientation away from both direct and reflective traffic noise sources.

Processing my hypothetical fMRI data with my self-reported historical housing choices may or may not have found:

“Geographical features in the proximal participants’ habitat are associated with brain integrity.”

Using better-quality information of self-reports, though, it’s unlikely that an association this study would have found to be significant – a chance fact that I live within one kilometer of a forest – would have been deemed significant.

Epigenetic effects of early life stress exposure

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This 2017 Netherlands review subject was the lasting epigenetic effects of early-life stress:

“Exposure to stress during critical periods in development can have severe long-term consequences.

One of the key stress response systems mediating these long-term effects of stress is the hypothalamic-pituitary-adrenal (HPA) axis.

Early life stress (ELS) exposure has been reported to have numerous consequences on HPA-axis function in adulthood.

ELS is able to “imprint” or “program” an organism’s neuroendocrine, neural and behavioral responses to stress. Research focuses along two complementary lines:

  1. ELS during critical stages in brain maturation may disrupt specific developmental processes (by altered neurotransmitter exposure, gene transcription, or neuronal differentiation), leading to aberrant neural circuit function throughout life.
  2. ELS may induce modifications of the epigenome which lastingly affect brain function.

These epigenetic modifications are inducible, stable, and yet reversible, constituting an important emerging mechanism by which transient environmental stimuli can induce persistent changes in gene expression and ultimately behavior.”

In early life, the lower brain and limbic system brain structures are more developed and dominant, whereas the cerebrum is less developed (use the above rodent graphic as a rough guide). Stress and pain generally have a greater impact on a fetus than an infant, and a greater impact on an infant than an adult.

The reviewers cited 50+ studies from years 2000-2015 in the “Early Life Stress Effects in a “Matching” Stressful Adult Environment” section to argue for the match / mismatch theory:

“Encountering ELS prepares an organism for similar (“matching”) adversities during adulthood, while a mismatching environment results in an increased susceptibility to psychopathology, indicating that ELS can exert either beneficial or disadvantageous effects depending on the environmental context.

Initial evidence for HPA-axis hypo-reactivity is observed for early social deprivation, potentially reflecting the abnormal HPA-axis function as observed in post-traumatic stress disorder.

Experiencing additional (chronic) stress in adulthood seems to normalize these alterations in HPA-axis function, supporting the match / mismatch theory.”

Evidence for this theory was contrasted with the allostatic load theory presented in How one person’s paradigms regarding stress and epigenetics impedes relevant research.

The review mainly cited evidence from rodent studies that mismatched reactions in adulthood may be consequences of early-life events. These events:

“Imprint or program an organism’s neuroendocrine, neural and behavioral responses..leading to aberrant neural circuit function throughout life..which lastingly affect brain function.”

Taking this research to a personal level:

  • Have you had feelings that you were unsafe, although your environment was objectively safe?
  • Have you felt uneasy when people are nice to you?
  • Have you felt anxious when someone pays attention to you, even after you’ve acted to gain their attention?

Mismatched human feelings are one form of mismatched reactions. These may be consequences of early-life experiences, and indicators of personal truths.

If researchers can let go of their biases and Advance science by including emotion in research, they may find that human subjects’ feelings produce better evidence for what actually happened during the subjects’ early lives than do standard scientific methods of:

Incorporating feeling evidence may bring researchers and each individual closer to discovering the major insults that knocked their development processes out of normally robust pathways and/or induced “persistent changes in gene expression and ultimately behavior.”

https://www.frontiersin.org/articles/10.3389/fncel.2017.00087/full “Modulation of the Hypothalamic-Pituitary-Adrenal Axis by Early Life Stress Exposure”

I came across this review as a result of it being cited in http://www.sciencedirect.com/science/article/pii/S1084952117302884 “Long-term effects of early environment on the brain: Lesson from rodent models” (not freely available)

How one person’s paradigms regarding stress and epigenetics impedes relevant research

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This 2017 review laid out the tired, old, restrictive guidelines by which current US research on the epigenetic effects of stress is funded. The reviewer rehashed paradigms circumscribed by his authoritative position in guiding funding, and called for more government funding to support and extend his reach.

The reviewer won’t change his beliefs regarding individual differences and allostatic load pictured above since he helped to start those memes. US researchers with study hypotheses that would develop evidence beyond such memes may have difficulties finding funding except outside of his sphere of influence.

Here’s one example of the reviewer’s restrictive views taken from the Conclusion section:

“Adverse experiences and environments cause problems over the life course in which there is no such thing as “reversibility” (i.e., “rolling the clock back”) but rather a change in trajectory [10] in keeping with the original definition of epigenetics [132] as the emergence of characteristics not previously evident or even predictable from an earlier developmental stage. By the same token, we mean “redirection” instead of “reversibility”—in that changes in the social and physical environment on both a societal and a personal level can alter a negative trajectory in a more positive direction.”

What would happen if US researchers proposed tests of his “there is no such thing as reversibility” axiom? To secure funding, the prospective studies’ experiments would be steered toward altering “a negative trajectory in a more positive direction” instead.

An example of this influence may be found in the press release of Familiar stress opens up an epigenetic window of neural plasticity where the lead researcher stated a goal of:

“Not to ‘roll back the clock’ but rather to change the trajectory of such brain plasticity toward more positive directions.”

I found nothing in citation [10] (of which the reviewer is a coauthor) where the rodent study researchers even attempted to directly reverse the epigenetic changes! The researchers under his guidance simply asserted:

“A history of stress exposure can permanently alter gene expression patterns in the hippocampus and the behavioral response to a novel stressor”

without making any therapeutic efforts to test the permanence assumption!

Never mind that researchers outside the reviewer’s sphere of influence have done exactly that, reverse both gene expression patterns and behavioral responses!!

In any event, citation [10] didn’t support an “there is no such thing as reversibility” axiom.

The reviewer also implied that humans respond just like lab rats and can be treated as such. Notice that the above graphic conflated rodent and human behaviors. Further examples of this inappropriate rodent / human merger of behaviors are in the Conclusion section.

What may be a more promising research approach to human treatments of the epigenetic effects of stress? As pointed out in The current paradigm of child abuse limits pre-childhood causal research:

“If the current paradigm encouraged research into treatment of causes, there would probably already be plenty of evidence to demonstrate that directly reducing the source of the damage would also reverse damaging effects. There would have been enough studies done so that the generalized question of reversibility wouldn’t be asked.

Aren’t people interested in human treatments of originating causes so that their various symptoms don’t keep bubbling up? Why wouldn’t research paradigms be aligned accordingly?”

http://journals.sagepub.com/doi/full/10.1177/2470547017692328 “Neurobiological and Systemic Effects of Chronic Stress”