Limbic system

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)

It’s transgenerational epigenetic inheritance week!

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Transgenerational epigenetic inheritance is a subject whose time has come. This week I sequentially curated two 2017 reviews and two 2016 studies of the subject, and ended with a meta-analysis of human preventive treatments:

It’s the opposite of advancing science for those in the funding chain to give lip service to the subject, and then create an atmosphere where proposals to extend experiments to subsequent generations to study possible transgenerational epigenetic effects are neither encouraged nor funded.

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.

Do we need to study the brain to understand the mind?

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A coauthor of the studies referenced in:

offered an opinion piece in A Paper a Day Keeps the Scientist Okay entitled “Do We Need To Study The Brain To Understand The Mind?”

“The emerging consensus appears to be that implementation is important. Interestingly, the inverse question is also being asked by neurobiologists—do we need consider the mind to understand the brain?—and answered largely and increasingly in the affirmative.

Is pain different from negative emotions such as sadness and anger, or are they variants on a common theme? Pain appears to be distinct from negative emotion, but commonalities suggest ways in which they may share underlying processes such as heightened attention.

One of the biggest pitfalls is the temptation to observe brain activity and make inferences about the psychological state—for example, to infer:

  • Episodic memory retrieval from hippocampal activity,
  • Fear from amygdala activity, or
  • Visual processing from activity in the ‘visual cortex.’

These inferences ignore the scope of processes which may activate each of these areas and involve a fallacy in reasoning: “if memory then hippocampus” is not the same thing as “if hippocampus then memory.”

The fact that few brain areas, including the ‘visual cortex,’ are dedicated to one process means that self-report is still the gold standard for assessing emotional experience and the contents of thought. This is a serious challenge for those who would like, for example, to assess your brand preferences or your political affiliation from a brain scan. (And isn’t it easier just to ask?)”

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)

Epigenetic effects of THC differ between female adolescents and adults

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This 2017 Italian rodent study found:

“THC [delta9-tetrahydrocannabinol, the psychoactive compound of cannabis] exposure affects histone modifications in the brain of female rats in a region- and age-specific manner. Specifically, THC acts on different targets depending on the considered brain area and, remarkably, the adolescent brain is generally more sensitive to THC than the adult brain.

Adolescent exposure to THC, or to synthetic cannabinoids, induced sex-dependent brain and behavioral alterations at adulthood. In female rats, the phenotype was more complex, as both depressive-like and psychotic-like signs were present.

Development of the depressive/psychotic-like phenotype is restricted to adolescent THC exposure. Not only the behavioral phenotype developed after adolescent, and not adult, exposure, but also changes in both histone modifications and gene expression were more widespread and intense after adolescent treatment, further confirming a specific adolescent susceptibility.

The primary effect in the adolescent brain was represented by changes leading to transcriptional repression, whereas the one observed after adult treatment led to transcriptional activation. Moreover, only in the adolescent brain, the primary effect was followed by a homeostatic response to counterbalance the THC-induced repressive effect, except in the amygdala.”

The authors’ interpretation of the brain area results was:

“The amygdala is more responsive in adult than adolescent animals. Since it has been established that the amygdala is activated during exposure to aversive stimuli, functioning as a “behavioral brake”, different response between adult and adolescent animals could represent the biological bases of the adolescent propensity for risk-taking and novelty-seeking behaviors. Also in adolescent humans, neuroimaging studies have shown a weaker involvement of the amygdala, and a greater contribution of the NAc [nucleus accumbens], in response to negative and positive stimuli compared to adults.”

http://www.mdpi.com/1422-0067/18/10/2094 “Chronic Δ9-THC Exposure Differently Affects Histone Modifications in the Adolescent and Adult Rat Brain”

A study of perinatal malnutrition where the paradigm excluded epigenetic inheritance

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This 2017 New York/Swedish rodent study subject was the epigenetic effects on the F1 children of maternal low protein diet during pregnancy and lactation:

“Male, but not female, offspring of LPD [low protein diet] mothers consistently displayed anxiety– and depression-like behaviors under acute stress.

Our proposed pathway connecting early malnutrition, sex-independent regulatory changes in Egr1 [an Early growth response gene], and sex-specific epigenetic reprogramming of its effector gene, Npy1r [neuropeptide Y receptor Y1 gene], represents the first molecular evidence of how early life risk factors may generate sex-specific epigenetic effects relevant for mental disorders.”

The study was purposely incomplete regarding transgenerational epigenetic effects that may be transmitted from the F1 children to their F2 grandchildren and F3 great-grandchildren. Similar to How one person’s paradigms regarding stress and epigenetics impedes relevant research, the paradigm continued by one of this study’s coauthors restricted inquiry into epigenetic inheritance.

How can the other coauthors respond when a controller of funding publishes the paper referenced in What is epigenetic inheritance? and otherwise makes his narrow views regarding epigenetic inheritance well-known? If the controller’s restricted views won’t allow the funding scope to extend testing to study F2 grandchildren and F3 great-grandchildren, the experiments end, and our understanding of epigenetic inheritance isn’t advanced.

This purposely incomplete study showed that the coauthor only gave lip service to advancing science when he made statements like:

“Further work is needed to understand whether and to what extent true epigenetic inheritance of stress vulnerability adds to the well-established and powerful influence of genetics and environmental exposures.”

The papers of Transgenerational epigenetic inheritance week show the spectrum of opportunities to advance science that were intentionally missed.

https://www.nature.com/articles/s41598-017-10803-2 “Perinatal Malnutrition Leads to Sexually Dimorphic Behavioral Responses with Associated Epigenetic Changes in the Mouse Brain”

A gaping hole in a review of nutritional psychiatry

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This December 2016 Australian review published in September 2017 concerned:

“..the nutritional psychiatry field..the neurobiological mechanisms likely modulated by diet, the use of dietary and nutraceutical interventions in mental disorders, and recommendations for further research.”

The reviewers inexplicably omitted acetyl-L-carnitine, which I first covered in A common dietary supplement that has rapid and lasting antidepressant effects. A PubMed search on “acetyl carnitine” showed over a dozen studies from the past twelve months that were relevant to the review’s subject areas. Here’s a sample, beginning with follow-on research published in June 2016 of the study I linked above:

Reply to Arduini et al.: Acetyl-l-carnitine and the brain: Epigenetics, energetics, and stress

Dietary supplementation with acetyl-l-carnitine counteracts age-related alterations of mitochondrial biogenesis, dynamics and antioxidant defenses in brain of old rats

Neuroprotective effects of acetyl-l-carnitine on lipopolysaccharide-induced neuroinflammation in mice: Involvement of brain-derived neurotrophic factor

ALCAR promote adult hippocampal neurogenesis by regulating cell-survival and cell death-related signals in rat model of Parkinson’s disease like-phenotypes

Analgesia induced by the epigenetic drug, L-acetylcarnitine, outlasts the end of treatment in mouse models of chronic inflammatory and neuropathic pain

The cited references in these recent studies were older, of course, and in the time scope of the review. There’s no excuse for this review’s omission of acetyl-L-carnitine.

https://www.cambridge.org/core/journals/proceedings-of-the-nutrition-society/article/nutritional-psychiatry-the-present-state-of-the-evidence/88924C819D21E3139FBC48D4D9DF0C08 “Nutritional psychiatry: the present state of the evidence” (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”

Epigenetic stress effects in preterm infants

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This 2017 Italian review selected 9 human studies on the epigenetic effects of:

“One of the major adverse events in human development. Preterm infants are hospitalized in the Neonatal Intensive Care Unit where they are exposed to life-saving yet pain-inducing procedures and to protective care.”

Highlights of the referenced studies included:

  • “Early exposure to adverse events during the third trimester of pregnancy is capable to alter the epigenetic status of imprinted and placenta-related genes which have relevant implications for fetal development and preterm infants’ HPA [hypothalamic–pituitary–adrenal] stress reactivity during infancy.”
  • “There was an association between DNAm [DNA methylation] and white matter tract tissue integrity and shape inferred from dMRI [diffusion MRI], suggesting that epigenetic variation may contribute to the cerebral phenotype of preterm birth.”

Limitations of the referenced studies included:

  • “A multiple sampling design that includes parental samples, placental tissue, cord blood and extends across the life-course would be required to investigate the relative contributions of in utero and postnatal exposures to changes in DNAm, and the extent to which preterm birth leaves a legacy on the methylome.”
  • Saliva, blood, and other tissues’ DNA methylation may not produce valid links to brain tissue DNA methylation of the same gene, which may hamper conclusive inferences about behavior, etc.

http://www.sciencedirect.com/science/article/pii/S0149763417302117 “Preterm Behavioral Epigenetics: A systematic review” (not freely available)

http://www.nature.com/tp/journal/v6/n1/full/tp2015210a.html “Epigenomic profiling of preterm infants reveals DNA methylation differences at sites associated with neural function” (one of the studies selected, quoted above)

Epigenetics account for two-thirds of Alzheimer’s disease

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The genetics percentage from a 2017 summary of Alzheimer’s disease research caught my eye:

“Although numerous single nucleotide polymorphisms (SNPs) have now been robustly associated with AD via genome-wide association studies and subsequent meta-analyses, collectively these common SNPs are believed to only account for 33% of attributable risk and the mechanism behind their action remains largely unknown.”

This citation aligned with other studies’ findings per Using twins to estimate the extent of epigenetic effects that on cellular levels, our experiences account for two-thirds of who we are.

The promise of this category of epigenetics research?

“One of the most exciting aspects of identifying disease-associated epigenomic dysfunction is that these mechanisms are potentially reversible.”

Let’s make research on reversing epigenetic changes a priority for funding, and get studies underway here in 2017!

https://www.epigenomicsnet.com/users/27784-katie-lunnon/posts/14634-robust-evidence-for-dna-methylomic-variation-in-alzheimer-s-disease “Robust evidence for DNA methylomic variation in Alzheimer’s disease” (Registration required)

On Primal Therapy with Drs. Art and France Janov

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Experiential feeling therapy addressing the pain of the lack of love.

The hypothalamus couples with the brainstem to cause migraines

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This 2016 German human study with one subject found:

“The hypothalamus to be the primary generator of migraine attacks which, due to specific interactions with specific areas in the higher and lower brainstem, could alter the activity levels of the key regions of migraine pathophysiology.”

The subject underwent daily fMRI scans, and procedures to evoke brain activity. She didn’t take any medications, and suffered three migraine attacks during the 31-day experimental period.

Neuroskeptic commented:

“The dorsal pons has previously been found to be hyperactive during migraine. It’s been dubbed the brain’s ‘migraine generator.’ Schulte and May’s data suggest that this is not entirely true – rather, it looks like the hypothalamus may be the true generator of migraine, while the brainstem could be a downstream mediator of the disorder.

A hypothalamic origin of migraines would help to explain some of the symptoms of the disorder, such as changes in appetite, that often accompany the headaches.”

The above graphic looks to me like the result of feedback mechanisms that either didn’t exist or inadequately handled the triggering event. Other examples of the hypothalamus lacking feedback or being involved in a deviated feedback loop include:

There are many unanswered questions with a one-person study, of course. Addressing the cause of this painful condition would find out when, where, and how a person’s hypothalamus became modified to express migraine tendencies.

I’d guess that migraine tendencies may appear as early as the first trimester of pregnancy, given that a highly functional hypothalamus is needed for survival and development in our earliest lives. Gaining as much familial and historical information as possible from the person would be necessary steps in therapies that address migraine causes.

http://blogs.discovermagazine.com/neuroskeptic/2016/05/22/pinpointing-origins-of-migraine/ “Pinpointing the Origins of Migraine in the Brain”

https://academic.oup.com/brain/article/139/7/1987/2464241 “The migraine generator revisited: continuous scanning of the migraine cycle over 30 days and three spontaneous attacks”

As mentioned in How to cure the ultimate causes of migraines? comments are turned off for this post due to it somehow becoming a magnet for spammers. Readers can comment on that post instead.

Genetic imprinting, sleep, and parent-offspring conflict

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This 2016 Italian review subject was the interplay of genetic imprinting and sleep regulation:

“Sleep results from the synergism between at least two major processes: a homeostatic regulatory mechanism that depends on the accumulation of the sleep drive during wakefulness, and a circadian self-sustained mechanism that sets the time for sleeping and waking throughout the 24-hour daily cycle.

REM sleep apparently contravenes the restorative aspects of sleep; however, the function of this ‘paradoxical’ state remains unknown. Although REM sleep may serve important functions, a lack of REM sleep has no major consequences for survival in humans; however, severe detrimental effects have been observed in rats.

Opposite imprinting defects at chromosome 15q11–13 are responsible for opposite sleep phenotypes as well as opposite neurodevelopmental abnormalities, namely the Prader-Willi syndrome (PWS) and the Angelman syndrome (AS). Whilst the PWS is due to loss of paternal expression of alleles, the AS is due to loss of maternal expression.

Maternal additions or paternal deletions of alleles at chromosome 15q11–13 are characterized by temperature control abnormalities, excessive sleepiness, and specific sleep architecture changes, particularly REM sleep deficits. Conversely, paternal additions or maternal deletions at chromosome 15q11–13 are characterized by reductions in sleep and frequent and prolonged night wakings.

The ‘genomic imprinting hypothesis of sleep’ remains in its infancy, and several aspects require attention and further investigation.”

http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1006004 “Genomic Imprinting: A New Epigenetic Perspective of Sleep Regulation”

A commenter to the review referenced a 2014 study Troubled sleep: night waking, breastfeeding, and parent–offspring conflict that received several reactions, including one by the same commenter. Here are a few quotes from the study author’s consolidated response:

“‘Troubled sleep’ had two major purposes. The first was to draw attention to the oppositely perturbed sleep of infants with PWS and AS and explore its evolutionary implications. The involvement of imprinted genes suggests that infant sleep has been subject to antagonistic selection on genes of maternal and paternal origin with genes of maternal origin favoring less disrupted sleep.

My second major purpose was a critique of the idea that children would be happier, healthier and better-adjusted if we could only return to natural methods of child care. This way of thinking is often accompanied by a belief that modern practices put children at risk of irrevocable harm.

The truth of such claims is ultimately an empirical question, but the claims are sometimes presented as if they had the imprimatur of evolutionary biology. This appeal to scientific authority often seems to misrepresent what 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.

Infant sleep may similarly lack the exquisite organization of systems without evolutionary conflict. Postnatal development, like prenatal development, is subject to difficulties of evolutionarily credible communication between mothers and offspring.”

The author addressed comments related to attachment theory:

“Infants are classified as having insecure-resistant attachment if they maintain close proximity to their mother after a brief separation while expressing negative emotions and exhibiting contradictory behaviors that seem to both encourage and resist interaction. By contrast, infants are classified as having insecure-avoidant attachment if they do not express negative emotion and avoid contact with their mother after reunion.

Insecure-avoidant and insecure-resistant behaviors might be considered antithetic accommodations of infants to less responsive mothers; the former associated with reduced demands on maternal attention, the latter with increased demands. A parallel pattern is seen in effects on maternal sleep. Insecure-avoidant infants wake their mothers less frequently, and insecure-resistant infants more frequently, than securely attached infants.

Parent–child interactions are transformed once children can speak. Infants with more fragmented sleep at 6 months had less language at 18 and 30 months.

Infants with AS have unconsolidated sleep and never learn to speak. The absence of language in the absence of expression of one or more MEGs [maternally expressed imprinted genes] is compatible with a hypothesis in which earlier development of language reduces infant demands on mothers.”

Regarding cultural differences:

“China, Taiwan and Hong Kong have both high rates of bed-sharing and high rates of problematic sleep compared with western countries. Within this grouping, however, more children sleep in their own room but parents report fewer sleep problems in Hong Kong than in either China or Taiwan.

Clearly, cultural differences are significant, and the causes of this variation should be investigated, but the differences cannot be summarized simply as ‘west is worst’.

The fitness [genetic rather than physical fitness] gain to mothers of an extra child and the benefits for infants of longer IBIs [interbirth intervals] are substantial. These selective forces are unlikely to be orders of magnitude weaker than the advantages of lactase persistence, yet the selective forces associated with dairying have been sufficient to result in adaptive genetic differentiation among populations.

The possibility of gene–culture coevolution should not be discounted for behaviors associated with infant-care practices.”

Regarding a mismatch between modern and ancestral environments:

“I remain skeptical of a tendency to ascribe most modern woes to incongruence between our evolved nature and western cultural practices. We did not evolve to be happy or healthy but to leave genetic descendants, and an undue emphasis on mismatch risks conflating health and fitness.

McKenna [a commenter] writes ‘It isn’t really nice nor maybe even possible to fool mother nature.’ Here I disagree. Our genetic adaptations often try to fool us into doing things that enhance fitness at costs to our happiness.

Our genes do not care about us and we should have no compunction about fooling them to deliver benefits without serving their ends. Contraception, to take one obvious example, allows those who choose childlessness to enjoy the pleasures of sexual activity without the fitness-enhancing risk of conception.

Night waking evolved in environments in which there were strong fitness costs from short IBIs and in which parents lacked artificial means of birth-spacing. If night waking evolved because it prolonged IBIs, then it may no longer serve the ends for which it evolved.

Nevertheless, optimal infant development might continue to depend on frequent night feeds as part of our ingrained evolutionary heritage.

It could also be argued that when night waking is not reinforced by feeding, and infants sleep through the night, then conflict within their genomes subsides. Infants would then gain the benefit of unfragmented sleep without the pleiotropic costs of intragenomic conflict. Plausible arguments could be presented for either hypothesis and a choice between them must await discriminating evidence.”

Commenters on the 2014 study also said:

“[Crespi] The profound implications of Haig’s insights into the roles of evolutionary conflicts in fetal, infant and maternal health are matched only by the remarkable absence of understanding, appreciation or application of such evolutionary principles among the research and clinical medical communities, or the general public.

[Wilkins] A mutation may be selected for its effect on the trait that is the basis of the conflict, but that mutation also likely affects other traits. In general, we expect that these pleiotropic effects to be deleterious: conflict over one trait can actually drive other traits to be less adapted. Natural selection does not necessarily guarantee positive health outcomes.

[McNamara] Assuming that AS/REM is differentially influenced by genes of paternal origin then both REM properties and REM-associated awakenings can be better explained by mechanisms of genomic conflict than by traditional claims that REM functions as an anti-predator ‘sentinel’ for the sleeping organism.

[Hinde] Given this context of simultaneous coordination and conflict between mother and infant, distinguishing honest signals of infant need from self-interested, care-extracting signals poses a challenge.“