This 2019 McGill paper reviewed human and animal studies on brain-shaping influences from the fetal period through childhood:
“In neonates, regions of the methylome that are highly variable across individuals are explained by the genotype alone in 25 percent of cases. The best explanation for 75 percent of variably methylated regions is the interaction of genotype with different in utero environments.
A meta-analysis including 45,821 individuals with attention-deficit/hyperactivity disorder and 9,207,363 controls suggests that conditions such as preeclampsia, Apgar score lower than 7 at 5 minutes, breech/transverse presentations, and prolapsed/nuchal cord – all of which involve some sort of poor oxygenation during delivery – are significantly associated with attention-deficit/hyperactivity disorder. The dopaminergic system seems to be one of the brain systems most affected by perinatal hypoxia-ischemia.
Exposure to childhood trauma activates the stress response systems and dysregulates serotonin transmission that can adverselyimpact brain development. Smaller cerebral, cerebellar, prefrontal cortex, and corpus callosum volumes were reported in maltreated young people as well as reduced hippocampal activity.
Environmental enrichment has a series of beneficial effects associated with neuroplasticity mechanisms, increasing hippocampal volume, and enhancing dorsal dentate gyrus-specific differences in gene expression. Environmental enrichment after prenatal stress decreases depressive-like behaviors and fear, and improves cognitive deficits.”
The reviewers presented strong evidence until the Possible Factors for Reversibility section, which ended with the assertion:
“All these positive environmental experiences mentioned in this section could counterbalance the detrimental effects of early life adversities, making individuals resilient to brain alterations and development of later psychopathology.”
The review’s penultimate sentence recognized that research is seldom done on direct treatments of causes:
“The cross-sectional nature of most epigenetic studies and the tissue specificity of the epigenetic changes are still challenges.”
Cross-sectional studies won’t provide definitive data on cause-and-effect relationships.
The question that remains to be examined is: How can humans best address these early-life causes to ameliorate their lifelong effects?
A subset of memory recall–induced neurons in the DG [dentate gyrus] becomes reactivated after memory attenuation,
The degree of fear reduction positively correlates with this reactivation, and
The continued activity of memory recall–induced neurons is critical for remote fear memory attenuation.
Although other brain areas such as the prefrontal cortex and the amygdala are likely to be implicated in remote fear memories and remain to be investigated, these results suggest that fear attenuation at least partially occurs in memory recall–induced ensembles through updating or unlearning of the original memory trace of fear.
These data thereby provide the first evidence at an engram-specific level that fear attenuation may not be driven only by extinction learning, that is, by an inhibitory memory trace different from the original fear trace.
Rather, our findings indicate that during remote fear memory attenuation both mechanisms likely coexist, albeit with the importance of the continued activity of memory recall–induced neurons experimentally documented herein. Such activity may not only represent the capacity for a valence change in DG engram cells but also be a prerequisite for memory reconsolidation, namely, an opportunity for learning inside the original memory trace.
As such, this activity likely constitutes a physiological correlate sine qua non for effective exposure therapies against traumatic memories in humans: the engagement, rather than the suppression, of the original trauma.”
The researchers also provided examples of human trauma:
“We dedicate this work to O.K.’s father, Mohamed Salah El-Dien, and J.G.’s mother, Wilma, who both sadly passed away during its completion.”
So, how can this study help humans? The study had disclosed and undisclosed limitations:
1. Humans aren’t lab rats. We can ourselves individually change our responses to experiential causes of ongoing adverse effects. Standard methodologies can only apply external treatments.
2. It’s a bridge too far to go from neural activity in transgenic mice to expressing unfounded opinions on:
“A physiological correlate sine qua non for effective exposure therapies against traumatic memories in humans.”
Human exposure therapies have many drawbacks, in addition to being applied externally to the patient on someone else’s schedule. A few others were discussed in The role of DNMT3a in fear memories:
“Inability to generalize its efficacy over time,
Potential return of adverse memory in the new/novel contexts,
Context-dependent nature of extinction which is widely viewed as the biological basis of exposure therapy.”
3. Rodent neural activity also doesn’t elevate recall to become an important goal of effective human therapies. Clearly, what the rodents experienced should be translated into human reliving/re-experiencing, not recall. Terminology used in animal studies preferentially has the same meaning with humans, since the purpose of animal studies is to help humans.
4. The researchers acknowledged that:
“Other brain areas such as the prefrontal cortex and the amygdala are likely to be implicated in remote fear memories and remain to be investigated.”
“The findings imply that in response to traumatic stress, some individuals, instead of activating the glutamate system to store memories, activate the extra-synaptic GABA system and form inaccessible traumatic memories.”
The study I curated yesterday, Organ epigenetic memory, demonstrated organ memory storage. It’s hard to completely rule out that other body areas may also store traumatic memories.
The wide range of epigenetic memory storage vehicles is one reason why effective human therapies need to address the whole person, the whole body, and each individual’s entire history.
This 2017 UC Irvine human review subject provided details of how fetalhypothalamic-pituitary-adrenal components and systems develop, and how they are epigenetically changed by the mother’s environment:
“The developmental origins of disease or fetal programming model predicts that intrauterine exposures have life-long consequences for physical and psychological health. Prenatal programming of the fetal hypothalamic-pituitary-adrenal (HPA) axis is proposed as a primary mechanism by which early experiences are linked to later disease risk.
Development of the fetal HPA axis is determined by an intricately timed cascade of endocrine events during gestation and is regulated by an integrated maternal-placental-fetal steroidogenic unit. Mechanisms by which stress-induced elevations in hormones of maternal, fetal, or placental origin influence the structure and function of the emerging fetal HPA axis are discussed.
Human gestational physiology and fetal HPA axis development differ even from that of closely related nonhuman primates, thereby limiting the generalizability of animal models. This review will focus solely on studies of prenatal stress and fetal HPA axis development in humans.”
Every time I read a prenatal study I’m in awe of all that has to go right, and at the appropriate time, and in sequence, for a fetus to be undamaged. Add in what needs to happen at birth, during infancy, and throughout early childhood, and it seems impossible for any human to escape epigenetic damage.
1. The reviewers referenced human research performed with postnatal subjects, as well as animal studies, despite the disclaimer:
This review will focus solely on studies of prenatal stress and fetal HPA axis development in humans.”
This led to blurring of what had been studied or not with human fetuses regarding the subject.
2. The reviewers uncritically listed many dubious human studies that had both stated and undisclosed severe limitations on their findings. It’s more appropriate for reviewers to offer informed reviews of cited studies, as Sex-specific impacts of childhood trauma summarized with cortisol:
“Findings are dependent upon variance in extenuating factors, including but not limited to, different measurements of:
presence and severity of psychopathology symptomology.”
3. It would have been preferable had the researchers stayed with their stated intention and critically reviewed only a few dozen studies with solid evidence of the review title: “Developmental origins of the human hypothalamic-pituitary-adrenal axis.” Let other reviews cover older humans, animals, and questionable evidence.
I asked the reviewers to provide a searchable file so that their work could be better used as a reference.
“Genome-wide technology has facilitated epigenome-wide association studies (EWAS), permitting ‘hypothesis-free’ examinations in relation to adversity and/or mental health problems. Results of EWAS are in fact conditional on several a priori hypotheses:
EWAS coverage is sufficient for complex psychiatric problems;
Peripheral tissue is meaningful for mental health problems; and
1. CpG sites were chosen as potentially biologically informative based on consultation with a consortium of DNA methylation experts. Selection was, in part, based on data from a number of phenotypes (some medical in nature such as cancer), and thus is not specifically targeted to brain-based, stress-related complex mental health phenotypes.
2. The assumption is often that distinct peripheral tissues are interchangeable and equally suited for biomarker detection, when in fact it is highly probable that peripheral tissues themselves correspond differently to environmental adversity and/or disease state.
3. Analyses result in general statements such as ‘neurodevelopment’ or the ‘immune system’ being involved in the aetiology of a given phenotype. Whether these broad categories play indeed a substantial role in the aetiology of the mental health problem is often hard to determine given the post hoc nature of the interpretation.”
The reviewers mentioned in item #2 the statistical flaw of assuming that measured entities are interchangeable with one another. They didn’t mention that the problem also affected item #1 methodologies of averaging CpG methylation measurements in fixed genomic bins or over defined genomic regions, as discussed in:
The reviewers offered suggestions for reducing the impacts of these three hypotheses. But will doing more of the same, only better, advance science?
Was it too much to ask of researchers whose paychecks and reputations depended on a framework’s paradigm – such as the “biomarker” mentioned a dozen and a half times – to admit the uselessness of gathering data when the framework in which the data operated wasn’t viable? They already knew or should have known this.
“Blood-based EWAS may yield limited information relating to underlying pathological processes for disorders where brain is the primary tissue of interest.”
The truth about complex traits and GWAS added another example of how this framework and many of its paradigms haven’t produced effective explanations of “the aetiology of the mental health problem”
“The most investigated candidate gene hypotheses of schizophrenia are not well supported by genome-wide association studies, and it is likely that this will be the case for other complex traits as well.”
Researchers need to reevaluate their framework if they want to make a difference in their fields. Recasting GWAS as EWAS won’t make it more effective.
This 2018 McGill paper reviewed findings from animal and human studies on the relationships between drug-seeking behavior and epigenetic DNA methylation:
“Although there is an increasing line of evidence from preclinical models of addiction, there are only a few human studies that systematically assessed DNA methylation in addiction. Most of the studies were done on small cohorts and focused on one or a few candidate genes, except in the case of alcohol use where larger studies have been carried out.
A long line of evidence suggests that abnormal patterns of gene expression occur in brain regions related to drug addiction such as the nucleus accumbens, prefrontal cortex, amygdala, and the ventral tegmental area.
Using the “incubation of craving” model in rats trained to self-administer cocaine, and treated with either SAM or RG108, the genome-wide DNA methylation and gene expression landscape in the nucleus accumbens after short (1 day) and long (30 days) abstinence periods and the effects of epigenetic treatments were delineated. The main findings are:
A long incubation period results in robust changes in methylation;
Direct accumbal infusion of SAM that is paired with a “cue” after long incubation times increases drug-seeking behavior,
Whereas a single treatment with RG108 decreases this behavior.
Importantly, the effects of these single administrations of a DNA methylation inhibitor remain stable for 30 more days. These data suggest that DNA methylation might be mediating the impact of “incubation” on the craving phenotype and that this phenotype could be reprogrammed by a DNA demethylation agent.”
The review covered neither human dimensions of the impacts of unfulfilled needs nor investigations of exactly what pain may impel human drug-seeking behavior. The “Implications for Diagnostic and Therapeutics” were largely at the molecular level.
This 2018 Loma Linda review subject was gestational hypoxia:
“Of all the stresses to which the fetus and newborn infant are subjected, perhaps the most important and clinically relevant is that of hypoxia. This review explores the impact of gestational hypoxia on maternal health and fetal development, and epigenetic mechanisms of developmental plasticity with emphasis on the uteroplacental circulation, heart development, cerebral circulation, pulmonary development, and the hypothalamic-pituitary-adrenal axis and adipose tissue.
An understanding of the specific hypoxia-induced environmental and epigenetic adaptations linked to specific organ systems will enhance the development of target-specific inhibition of DNA methylation, histone modifications, and noncoding RNAs that underlie hypoxia-induced phenotypicprogramming of disease vulnerability later in life.
A potential stumbling block to these efforts, however, relates to timing of the intervention. The greatest potential effect would be accomplished at the critical period in development for which the genomic plasticity is at its peak, thus ameliorating the influence of hypoxia or other stressors.
With future developments, it may even become possible to intervene before conception, before the genetic determinants of the risk of developing programmed disease are established.”
Table 3 “Antenatal hypoxia and developmental plasticity” column titles were Species | Offspring Phenotypes of Disorders and Diseases | Reference Nos.
This review was really an ebook, with 94 pages and 1,172 citations in the pdf file. As I did with Faith-tainted epigenetics, I read it with caution toward recognizing 1) the influence of the sponsor’s biases, 2) any directed narrative that ignored evidence contradicting the narrative, and 3) any storytelling.
One review topic that was misconstrued was transgenerational epigenetic inheritance of hypoxic effects. The “transgenerational” term was used inappropriately by several of the citations, and no cited study provided evidence for gestational hypoxic effects through the F2 grandchild and F3 great-grandchild generations.
“One substance that fetuses are frequently exposed to is caffeine, which is a non-selective adenosine receptor antagonist. We discovered that in utero alteration in adenosine action leads to adverse effects on embryonic and adult murine hearts. We find that cardiac A1ARs [a type of adenosine receptor] protect the embryo from in utero hypoxic stress, a condition that causes an increase in adenosine levels.
After birth in mice, we observed that in utero caffeine exposure leads to abnormal cardiac function and morphology in adults, including an impaired response to β-adrenergic stimulation. Recently, we observed that in utero caffeine exposure induces transgenerational effects on cardiac morphology, function, and gene expression.”
Why was this review and its studies omitted? It was on target for both gestational hypoxia and transgenerational epigenetic inheritance of hypoxic effects!
It was alright to review smoking, cocaine, methamphetamine, etc., but the most prevalent drug addiction – caffeine – couldn’t be a review topic?
The Loma Linda review covered a lot, but I had a quick trigger due to the sponsor’s bias. I started to lose “faith” in the reviewers after reading the citation for the review’s last sentence that didn’t support the statement.
My “faith” disappeared after not understanding why a few topics were misconstrued and omitted. Why do researchers and sponsors ignore, misrepresent, and not continue experiments through the F3 generation to produce evidence for and against transgenerational epigenetic inheritance? Where was the will to follow evidence trails regardless of socially acceptable beverage norms?
The review acquired the taint of storytelling with the reviewers’ assertion:
“..timing of the intervention. The greatest potential effect would be accomplished at the critical period in development for which the genomic plasticity is at its peak, thus ameliorating the influence of hypoxia or other stressors.”
Contradictory evidence was in the omitted caffeine study’s graphic above which described two gestational critical periods where an “intervention” had opposite effects, all of which were harmful to the current fetus’ development and/or to following generations. Widening the PubMed link’s search parameters to “caffeine hypoxia” and “caffeine pregnancy” returned links to human early life studies that used caffeine in interventions, ignoring possible adverse effects on future generations.
This is my final curation of any paper sponsored by this institution.