Brain development

The hypothalamus couples with the brainstem to cause migraines

gettingwell4 4-5 stars Advanced knowledge, Brain development, Brain hemispheres, Brainstem, Cortisol, Epigenetics, Hippocampus, Hypothalamus, Limbic system, Lower brain, Neurochemicals, Oxytocin, Stress

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.“

A limited study of parental transmission of anxiety/stress-reactive traits

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BehavioralTraitsThis 2016 New York rodent study found:

“Parental behavioural traits can be transmitted by non-genetic mechanisms to the offspring.

We show that four anxiety/stress-reactive traits are transmitted via independent iterative-somatic and gametic epigenetic mechanisms across multiple generations.

As the individual traits/pathways each have their own generation-dependent penetrance and gender specificity, the resulting cumulative phenotype is pleiotropic. In the context of genetic diseases, it is typically assumed that this phenomenon arises from individual differences in vulnerability to the various effects of the causative gene. However, the work presented here reveals that pleiotropy can be produced by the variable distribution and segregated transmission of behavioural traits.”

A primary focus was how anxiety was transmitted from parents to offspring:

“The iterative propagation of the male-specific anxiety-like behaviour is most compatible with a model in which proinflammatory state is propagated from H [serotonin1A receptor heterozygote] F0 to F1 [children] females and in which the proinflammatory state is acquired by F1 males from their H mothers, and then by F2 [grandchildren] males from their F1 mothers.

We propose that increased levels of gestational MIP-1β [macrophage inflammatory protein 1β] in H and F1 mothers, together with additional proinflammatory cytokines and bioactive proteins, are required to produce immune system activation in their newborn offspring, which in turn promotes the development of the anxiety-like phenotype in males.

In particular, increase in the number of monocytes and their transmigration to the brain parenchyma in F1 and F2 males could be central to the development of anxiety.”

The researchers studied transmission of behavioral traits and epigenetic changes. Due to my quick take on the study title – “Behavioural traits propagate across generations..” – I had expectations of this study that weren’t born out. What could the researchers have done versus what they did?

The study design removed prenatal and postnatal parental behavioral transmission of behavioral traits and epigenetic changes as each generation’s embryos were implanted into foster wild-type (WT) mothers.

The study design substituted the foster mothers’ prenatal and postnatal parental environments for the biological parents’ environments. So we didn’t find out, for example:

  • To what extents the overly stress-reactive F1 female children’s prenatal environments and postnatal behaviors induced behaviors and/or epigenetic changes in their children; and
  • Whether the F2 grandchildren’s parental behaviors subsequently induced behaviors and/or epigenetic changes in the F3 great-grandchildren.

How did the study meet the overall goal of rodent studies: to help humans?

    1. Only a minority of humans experienced an early-life environment that included primary caregivers other than our biological parents.
    2. Very, very few of us experienced a prenatal environment other than our biological mothers.
    3. The study’s thorough removal of parental behavior was an outstanding methodology to confirm by falsifiability whether parental behavior was both an intergenerational and transgenerational epigenetic inheritance mechanism.
    4. Maybe the researchers filled in some gaps in previous rodent studies, such as determining what is or isn’t a “true transgenerational mechanism.”

As an example of a rodent study that more closely approximated human conditions, the behavior of a mother whose DNA was epigenetically changed by stress induced the same epigenetic changes to her child’s DNA when her child was stressed per One way that mothers cause fear and emotional trauma in their infants:

“Our results provide clues to understanding transmission of specific fears across generations and its dependence upon maternal induction of pups’ stress response paired with the cue to induce amygdala-dependent learning plasticity.”

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.

But when investigating human correlates with behavioral epigenetic changes of rodents in the laboratory, parental behavioral transmission of behavioral traits is often treated the way this study treated it: as a confounder.

I doubt that people who have reached some degree of honesty about their early lives and concomitant empathy for others would agree with this prioritization. The papers of Transgenerational epigenetic inheritance week show the spectrum of opportunities to advance science that were intentionally missed.

http://www.nature.com/ncomms/2016/160513/ncomms11492/full/ncomms11492.html “Behavioural traits propagate across generations via segregated iterative-somatic and gametic epigenetic mechanisms”

A study of genetic imprinting and neurodevelopmental disorders

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This 2016 UK human study assessed the roles of genetic imprinting on diseases that may originate from a certain interval on chromosome 15:

“The 15q11.2-q13.3 region contains a cluster of imprinted genes, which are expressed from one parental allele only as a consequence of germline epigenetic events.

The importance of epigenetic status of duplications at this interval was further underlined by analysis of a number of families. Duplications in two unaffected mothers had a DNA-methylation pattern indicative of being paternally derived, whereas their offspring, who possessed a maternally derived duplication, suffered from psychotic illness.

We clearly implicate 15q11.2-q13.3 interstitial duplications of paternal origin in the aetiology of DD [developmental delay], but do not find them at increased rates in SZ [schizophrenia], which is significantly associated only with duplications of maternal origin.

This study refines the distinct roles of maternal and paternal duplications at 15q11.2-q13.3, underlining the critical importance of maternally active imprinted genes in the contribution to the incidence of psychotic illness.”

The researchers analyzed other studies for better estimates of paternal involvement:

“We show for the first time that paternal duplications are pathogenic. One reason why paternal duplications have been regarded as non-pathogenic in the past is their rare occurrence in patients. Here we demonstrate that they are also rare in the general population as a whole.

Paternal duplications should be less efficiently eliminated from the population by negative selection pressure, due to their lower penetrance for neurodevelopmental disorders. Secondly, some maternal duplications will change to paternal when transmitted from male carriers.

We now suggest one further explanation for their rarity: male patients with SZ and other neurodevelopmental disorders have lower fecundity. Men suffering with SZ have only half the number of offspring compared to women with SZ.”

I would have liked further discussion of the “germline epigenetic events” that apparently contribute to the studied problems. These epigenetic abnormalities may have the potential to be prevented or treated, or at least used as early biomarkers.

The reviewers instead focused on:

“This work will have tangible benefits for patients with 15q11.2-q13.3 duplications by aiding genetic counseling.”

http://journals.plos.org/plosgenetics/article?id=10.1371%2Fjournal.pgen.1005993 “Parental Origin of Interstitial Duplications at 15q11.2-q13.3 in Schizophrenia and Neurodevelopmental Disorders”

Why drugs aren’t ultimately therapeutic

gettingwell4 2-3 stars Required further work, Beliefs, Brain development, Cerebrum, Epigenetics, Glutamate, Hippocampus, Limbic system, Neurochemicals , , ,

This 2016 Oregon review’s concept was the inadequacy of drug-based therapies, explored with the specific subject of epilepsy:

“Currently used antiepileptic drugs:

  • [aren’t] effective in over 30% of patients
  • [don’t] affect the comorbidities of epilepsy
  • [don’t] prevent the development and progression of epilepsy (epileptogenesis).

Prevention of epilepsy and its progression [requires] novel conceptual advances.”

The overall concept that current drug-based therapies poorly address evolutionary biological realities was illustrated by a pyramid, with the comment that:

“If the basis of the pyramid depicted in Figure 1 is overlooked, it becomes obvious that a traditional pharmacological top-down treatment approach has limitations.”

Why drug ultimately aren't therapeutic

I would have liked the reviewer to further address the “therapeutic reconstruction of the epigenome” point he made in the Abstract:

“New findings based on biochemical manipulation of the DNA methylome suggest that:

  1. Epigenetic mechanisms play a functional role in epileptogenesis; and
  2. Therapeutic reconstruction of the epigenome is an effective antiepileptogenic therapy.”

As it was, the reviewer lapsed into the prevalent belief that the causes of and cures for human diseases will always be found on the molecular level – for example, the base of the above pyramid – and never in human experiences. This preconception leads to discounting human elements – notably absent in the above pyramid – that generate epigenetic changes.

A consequence of ignoring experiential causes of diseases is that the potential of experiential therapies to effect “therapeutic reconstruction of the epigenome” isn’t investigated.

http://journal.frontiersin.org/article/10.3389/fnmol.2016.00026/full “The Biochemistry and Epigenetics of Epilepsy: Focus on Adenosine and Glycine”

Lack of oxygen’s epigenetic effects

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This 2016 Finnish review subject was epigenetic effects of hypoxia:

“Ever since the Cambrian period, oxygen availability has been in the center of energy metabolism. Hypoxia stabilizes expression of hypoxia-inducible transcription factor-1α (HIF-1α), which controls expression of hundreds of survival genes related to enhanced energy metabolism and autophagy.

There are several other signals, mostly related to stresses, which can increase expression of HIF factors and thus improve cellular survival. However, a chronic activation of HIF factors can have detrimental effects, e.g. stimulate cellular senescence and tissue fibrosis commonly enhanced in age-related diseases.

Stabilization of HIF-1α increases expression of histone lysine demethylases (KDM). Hypoxia-inducible KDMs support locally the gene transcription induced by HIF-1α, although they can also control genome-wide chromatin landscape, especially KDMs which demethylate H3K9 and H3K27 sites (repressive epigenetic marks).”

Gene areas where HIF-1α is involved include:

  • “angiogenesis
  • autophagy
  • glucose uptake
  • glycolytic enzymes
  • immune responses
  • embryonic development
  • tumorigenesis
  • generation of miRNAs.”

HIF-1a signaling

Figure 1 above was instructive in that the reviewers pointed out the lack of a feedback mechanism in HIF-1α signaling. A natural lack of feedback to the HIF-1α signaling source contributed to diseases such as:

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

The point was similar to a study referenced in The PRice “equation” for individually evolving: Which equation describes your life? that:

“Evolution may preferentially mitigate damage to a biological system than reduce the source of this damage.”

This review subject has many interdependencies and timings within a complex network. Contexts are important:

“Cross-talk between NF-κB [nuclear factor kappa B] and HIF-1α in inflammation might be organized in cell type and context-dependent manner.

It seems that ROS [reactive oxygen species] affect HIF-1α signaling in a context-dependent manner.

Hypoxia stimulated expression of KDM3A and KDM4B genes in different cellular contexts. Given that KDM3A and KDM4B are the major histone demethylases which remove repressive H3K9 sites, their role as transcriptional cofactors seems to be important in activation of HIF-1α signaling. Members of KDM4 subfamily have a crucial role in DNA repair systems, although responses seem to be enzyme-specific and appear in a context-dependent manner.

Acute hypoxia can stimulate cell-cycle arrest but does not provoke cellular senescence in all contexts.”

It wasn’t mentioned that hypoxia evokes cellular Adaptations to stress encourage mutations in a DNA area that causes diseases.

The review was tailored for the publishing journal Aging and Disease, and the subject was best summed up by:

“HIF-1α can control cellular fate in adult animals, either stimulating proliferation or triggering cellular senescence, by regulating the expression of different KDMs in a context-dependent manner.”

This review covered hypoxic conditions during human development that are clearly origins of many immediate and later-life diseases. However, cited remedies only addressed symptoms.

That these distant causes can no longer be addressed is a hidden assumption of research and treatment of effects of health problems. Aren’t such assumptions testable here in the current year?

http://www.aginganddisease.org/article/2016/2152-5250/ad-7-2-180.shtml “Hypoxia-Inducible Histone Lysine Demethylases: Impact on the Aging Process and Age-Related Diseases”

Using salivary microRNA to diagnose autism

gettingwell4 4-5 stars Advanced knowledge, Brain development, Cerebrum, Epigenetics, Hippocampus, Limbic system , , ,

This 2016 New York human study found:

“Measurement of salivary miRNA in this pilot study of subjects with mild ASD [autism spectrum disorder] demonstrated differential expression of 14 miRNAs that are:

  • expressed in the developing brain,
  • impact mRNAs related to brain development, and
  • correlate with neurodevelopmental measures of adaptive behavior.”

Some problems with current diagnostic methods for autism are:

“The first sign of ASD commonly recognized by pediatricians is a deficit in communication and language that does not manifest until 18–24 months of age.

The mean age of diagnosis for children with ASD is 3 years, and approximately half of these are false-positives.

Despite a substantial genetic component, no single gene variant accounts for >1 % of ASD incidence.

Nearly 2000 individual genes have been implicated in ASD, but none are specific to the disorder.”

Study limitations included:

“Aside from the sample size and cross-sectional nature of this pilot study, another limitation is the age of ASD and control subjects it describes (4–14 years) which are not representative of the target population in which ASD biomarkers would ideally be utilized (0–2 years). However, selecting a homogenous group of subjects with mild ASD (as measured by ADOS) that was well-established and diagnosed by a developmental specialist requires subjects with long-standing diagnoses.”

Understanding later-life consequences of disrupted neurodevelopment is critical for tracing symptoms back to their causes, as noted in Grokking an Adverse Childhood Experiences (ACE) score. I wonder how long it will take for researchers in other fields to stop wasting resources and do what this study did: focus on epigenetic biomarkers that have developmental origins.

http://bmcpediatr.biomedcentral.com/articles/10.1186/s12887-016-0586-x “Salivary miRNA profiles identify children with autism spectrum disorder, correlate with adaptive behavior, and implicate ASD candidate genes involved in neurodevelopment”

Contending with epigenetic consequences of violence to women

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This 2016 UK review subject was the interplay of genomic imprinting and intergenerational epigenetic information transfer:

“A range of evolutionary adaptations associated with placentation transfers disproportionate control of this process to the matriline, a period unique in mammalian development in that there are three matrilineal genomes interacting in the same organism at the same time (maternal, foetal, and postmeiotic oocytes).

Genomic imprinting is absent in egg laying mammals and only around 6 imprinted genes have been detected in a range of marsupial species; this is in contrast to eutherian mammals where around 150 imprinted genes have been described.

The interactions between the maternal and developing foetal hypothalamus and placenta can provide a template by which a mother can transmit potentially adaptive information concerning potential future environmental conditions to the developing brain.

In circumstances either where the early environment provides inaccurate cues to the environmental conditions prevailing when adult due to rapid environmental change or when disruptions to normal neural development occur, the mismatch between the environmental predictions made during early development and subsequent reality may mean that an organism may have a poorly adapted phenotype to its adult environment. An appreciation of these underlying evolutionary salient processes may provide a novel perspective on the [causal] mechanisms of a range of health problems.

The concept of a brain that is not pathological in the classical sense but it is simply mismatched to its environment has been most extensively studied in the context of ancestral and early developmental nutrition. However, this concept can be extended to provide insights into the development of a range of alternative neural phenotypes.”

The review’s final sentence was:

“Examination of the adaptive potential of a range of neural and cognitive deficits in the context of evolutionary derived foetocentric brain and placental development, epigenetics and environmental adaptation may provide novel insights into the development and potential treatment of a range of health, neurological, and cognitive disorders.”

One of the reviewers was cited in Epigenetic DNA methylation and demethylation with the developing fetus, which the review cited along with Epigenetic changes in the developing brain change behavior.

Researchers who avoid hypotheses that can’t be proven wrong could certainly test the subject matter of this review if they investigated their subjects’ histories.

For example, let’s say a patient/subject had symptoms where the “150 imprinted genes” were implicated. What are the chances a clinician or researcher would be informed by this review’s material and investigate the mother’s and grandmother’s histories?

For clinicians or researchers who view histories as irrelevant busywork: How many tens of millions of people alive today have mothers who were fetuses when their grandmothers were adversely affected by violence? Wouldn’t it be appropriate to assess possible historical contributions of:

“The mismatch between the environmental predictions made during early development and subsequent reality”

to the patient’s/subject’s current symptoms?

http://www.hindawi.com/journals/np/2016/6827135/ “Placental, Matrilineal, and Epigenetic Mechanisms Promoting Environmentally Adaptive Development of the Mammalian Brain”

A one-sided review of stress

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The subject of this 2016 Italian/New York review was the stress response:

“The stress response, involving the activation of the hypothalamic-pituitary-adrenocortical [HPA] axis and the consequent release of corticosteroid hormones, is indeed aimed at promoting metabolic, functional, and behavioral adaptations. However, behavioral stress is also associated with fast and long-lasting neurochemical, structural, and behavioral changes, leading to long-term remodeling of glutamate transmission, and increased susceptibility to neuropsychiatric disorders.

Of note, early-life events, both in utero and during the early postnatal life, trigger reprogramming of the stress response, which is often associated with loss of stress resilience and ensuing neurobehavioral (mal)adaptations.”

The reviewers’ intentional dismissal of the role of GABA in favor of the role of glutamate was a key point:

“The changes in neuronal excitability and synaptic plasticity induced by stress are the result of an imbalance of excitatory (glutamatergic) and inhibitory (GABAergic) transmission, leading to long-lasting (mal)adaptive functional modifications. Although both glutamate and GABA transmission are critically associated with stress-induced alteration of neuronal excitability, the present review will focus on the modulation of glutamate release and transmission induced by stress and glucocorticoids.”

No particular reason was given for this bias. I inferred from the review’s final sentence that the review’s sponsors and funding prompted this decision:

“In-depth studies of changes in glutamate transmission and dendrite remodeling induced by stress in early and late life will help to elucidate the biological underpinnings of the (mal)adaptive strategies the brain adopts to cope with environmental challenges in one’s life.”

The bias led to ignoring evidence for areas the reviewers posed as needing further research. An example of relevant research the reviewers failed to consider was the 2015 Northwestern University study I curated in A study that provided evidence for basic principles of Primal Therapy that found:

“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.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4812483/ “Stress Response and Perinatal Reprogramming: Unraveling (Mal)adaptive Strategies”

The current paradigm of child abuse limits pre-childhood causal research

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As an adult, what would be your primary concern if you suspected that your early life had something to do with current problems? Would you be interested in effective treatments for causes of your symptoms?

Such information wasn’t available in this 2016 Miami review of the effects of child abuse. The review laid out the current paradigm mentioned in Grokking an Adverse Childhood Experiences (ACE) score, one that limits research into pre-childhood causes for later-life symptoms.

The review’s goal was to describe:

“How numerous clinical and basic studies have contributed to establish the now widely accepted idea that adverse early life experiences can elicit profound effects on the development and function of the nervous system.”

The hidden assumptions of almost all of the cited references were that these distant causes could no longer be addressed. Aren’t such assumptions testable today?

As an example, the Discussion section posed the top nine “most pressing unanswered questions related to the neurobiological effects of early life trauma.” In line with the current paradigm, the reviewer assigned “Are the biological consequences of ELS [early life stress] reversible?” into the sixth position.

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

The review also demonstrated how the current paradigm of child abuse misrepresented items like telomere length and oxytocin. Researchers on the bandwagon tend to forget about the principle Einstein expressed as:

“No amount of experimentation can ever prove me right; a single experiment can prove me wrong.”

That single experiment for telomere length arrived in 2016 with Using an epigenetic clock to distinguish cellular aging from senescence. The review’s seven citations for telomere length that all had findings “associated with” or “linked to” child abuse should now be viewed in a different light.

The same light shone on oxytocin with Testing the null hypothesis of oxytocin’s effects in humans and Oxytocin research null findings come out of the file drawer. See their references, and decide for yourself whether or not:

“Claimed research findings may often be simply accurate measures of the prevailing bias.”

http://www.cell.com/neuron/fulltext/S0896-6273%2816%2900020-9 “Paradise Lost: The Neurobiological and Clinical Consequences of Child Abuse and Neglect”

This post has somehow become a target for spammers, and I’ve disabled comments. Readers can comment on other posts and indicate that they want their comment to apply here, and I’ll re-enable comments.

Beneficial epigenetic effects of mild stress with social support during puberty

gettingwell4 4-5 stars Advanced knowledge, Brain development, Cerebrum, Cortisol, Epigenetics, Hippocampus, Hypothalamus, Limbic system, Memory, Neurochemicals, Serotonin, Stress , , , ,

This 2016 Pennsylvania rodent study found:

“Stress in the context of social support experienced over the pubertal window can promote epigenetic reprogramming in the brain to increase resilience to age-related cognitive decline in females.

These findings are actually consistent with previous studies showing that some amount of adversity, or adversity under more favorable circumstances such as social support or a protective gene polymorphism, provides a measure of ‘grit’ in coping with later life challenges.

Our findings provide a unique perspective on this relationship, as they highlight the important link between experience during the pubertal window and cognitive health during aging.”

These researchers made efforts to further investigate causes of unexpected results, such as:

“Peripubertal stress alone did not significantly alter Barnes maze performance in aging compared to aged Controls. Mice that had experienced stress with concurrent social support (CVS + SI) actually performed better than Control aged mice, specifically in learning the reversal task faster.

Peripubertal stress had no effect on corticosterone levels in response to an acute restraint stress or in sensorimotor gating and baseline startle reactivity.”

Their investigations led to epigenetic findings:

“Consistent with our behavioral findings, stress in the context of social interaction resulted in long-term reprogramming of gene expression in the PFC [prefrontal cortex]. While there were no differentially expressed genes between Control and CVS females, there were 88 genes that were significantly different between Control and CVS + SI groups. Of genes that were downregulated, a large portion (23 genes; 35%) were microRNAs.

We found that the PFC transcriptome of CVS + SI aged females was significantly enriched for predicted targets of the 23 microRNAs that were downregulated in the PFC in these mice. This suggests that microRNAs represent a mode of regulation capable of enacting far-reaching programmatic effects, and are a critical epigenetic gene expression regulatory mechanism.”

Applicability to humans was suggested by associations such as:

“A single microRNA can target more than a hundred different mRNA targets, and more than 45,000 conserved microRNA binding sites have been annotated in the 3′ UTR of 60% of human genes.”

A few limitations were noted:

“Given that mice at this age (1 year) are commonly compared to ‘late middle aged’ humans, later aging time points may yield differences in this group. Alternatively, it is possible that there was an effect of peripubertal stress that was not long-lasting due to the mild nature of our chronic stress model.

To include early neglect as a part of the stressor experience, CVS females were weaned one week earlier (PN21) than Control and CVS + SI mice. Addition of stress of this earlier weaning likely poses a significant contribution to programming of the PFC.”

One of the study coauthors was also a coauthor of:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4870871/ “Peripubertal stress with social support promotes resilience in the face of aging”

Using an epigenetic clock with children

gettingwell4 4-5 stars Advanced knowledge, Brain development, Epigenetics , ,

This 2015 UK human study by many of the coauthors of What’s the origin of the problem of being fat? applied the Horvath epigenetic clock method to the same UK mother-child pairs and a Danish cohort:

“There has been no investigation on prenatal and antenatal factors that affect AA [age acceleration] in children. It is possible that the detrimental consequences of a higher AA may accrue over time, initiating in childhood. Conversely, it could be postulated that having a positive AA during early life and childhood is developmentally advantageous. To reflect this, we could refer to AA as an epigenetic measure of development in children.

We found associations between AA and sex, birth weight, caesarean section delivery and several maternal characteristics, namely smoking in pregnancy, weight, BMI, selenium and cholesterol level.

Offspring of non-drinkers had higher AA on average at birth, but this appeared to resolve during childhood. Offspring of smokers had higher AA on average and this difference became larger during childhood and adolescence.

The lack of correlation between AA and several clinical variables may also indicate that AA reflects an ‘intrinsic’ aging rate that is independent of various aging factors.

The observation that the estimated genetic component of AA increased in older study participants may indicate that the AA measure is more biologically meaningful in adults rather than children, though alternatively it could be a reflection of a decreasing environmental influence on DNA methylation patterns over time.

This accords with our finding of strengthening within subject correlation over time, which suggests the period of rapid early life changes in methylation affects epigenetic age during development to a greater extent than adulthood changes in methylation.”

The heritability of age acceleration was analyzed:

“The heritability estimate from our study (h = 0.37) is lower than that reported Horvath (h = 1.0), which was based on a small number of cord blood samples from twin pairs. Both of these heritability estimates were based on relatively few samples. Future large scale studies will be needed to arrive at precise estimates of the heritability of AA in newborns and minors.

While our heritability estimate may seem low, empirical evidence has suggested that fitness related traits tend to have lower heritability than morphological traits because selection acts to purify deleterious genetic variation, and one might consider age accelerated residuals in the former category.”

Like the coauthors’ follow-on study, causality couldn’t be definitively determined:

“Assessing the causal relationship between exposures and AA (through Mendelian randomization) is underpowered in our current data.”

Epigenetic age acceleration at birth seemed to be overall “developmentally advantageous” for offspring of non-drinking mothers. That age acceleration continued for the offspring of smokers at the second and third measurement times (ages 7 and 15-17) seemed to have “detrimental consequences.” I’d guess that the methylation state of specific CpG sites would be more informative than the overall rate in these cases.

The point about “AA..is independent of various aging factors” was similar to one made in Using an epigenetic clock to distinguish cellular aging from senescence:

“Cellular ageing is distinct from cellular senescence and independent of DNA damage response and telomere length.”

The study was a step toward establishing the Horvath epigenetic clock for widespread usage. The Hannum method was also compared and contrasted.

http://hmg.oxfordjournals.org/content/25/1/191.full “Prenatal and early life influences on epigenetic age in children: a study of mother-offspring pairs from two cohort studies”

What’s the origin of the problem of being fat?

gettingwell4 4-5 stars Advanced knowledge, Brain development, Epigenetics , , ,

This 2016 UK human study attempted to replicate the DNA methylation and adiposity associations found by studies on a long-term longitudinal UK cohort:

“We tested for replication of associations between previously identified CpG sites at HIF3A [the hypoxia inducible factor 3 alpha subunit gene] and adiposity in ∼1,000 mother-offspring pairs from the Avon Longitudinal Study of Parents and Children.”

The researchers had sufficient data to test the unidirectional and causal findings of previous studies:

“Availability of methylation and adiposity measures at multiple time points, as well as genetic data, allowed us to assess the temporal associations between adiposity and methylation and to make inferences regarding causality and directionality.”

The analyses didn’t replicate the previous studies’ findings, and a new finding was indicated:

“Our results were discordant with those expected if HIF3A methylation has a causal effect on BMI [body mass index, derived from height and weight] and provided more evidence for causality in the reverse direction i.e. an effect of BMI on HIF3A methylation.

These results are based on robust evidence from longitudinal analyses and were also partially supported by Mendelian randomization analysis, although this latter analysis was underpowered to detect a causal effect of BMI on HIF3A methylation.

Our results also highlight an apparent long-lasting inter-generational influence of maternal BMI on offspring methylation at this locus, which may confound associations between own [offspring] adiposity and HIF3A methylation.”

A person’s parents contributed all of their genetic material and the prenatal environment, and usually almost all of their postnatal and childhood development environment. If a person has a health problem that may have genetic and developmental origins, this is where to look for causes and preventive actions.

That these distant causes can no longer be addressed is a hidden assumption of research and treatment of effects of health problems. Aren’t such assumptions testable here in the current year?

http://diabetes.diabetesjournals.org/content/early/2016/02/01/db15-0996.long (pdf) “DNA methylation and body mass index: investigating identified methylation sites at HIF3A in a causal framework”

Epigenetic effects of diet, and reversing DNA methylation

gettingwell4 2-3 stars Required further work, Acetylcholine, Brain development, Cerebellum, Cerebrum, Cortisol, Dopamine, Epigenetics, Hippocampus, Limbic system, Lower brain, Neurochemicals, Stress , , , , , ,

This 2015 French review focused on:

“The role of maternal health and nutrition in the initiation and progression of metabolic and other disorders.

The effects of various in utero exposures and maternal nutritional status may have different effects on the epigenome. However, critical windows of exposure that seem to exist during development need to be better defined.

The epigenome can be considered as an interface between the genome and the environment that is central to the generation of phenotypes and their stability throughout the life course.”

The reviewer used the term “transgenerational” to refer to effects that were more appropriately termed parental or intergenerational. Per the definition in A review of epigenetic transgenerational inheritance of reproductive disease, for the term to apply there needed to be evidence in at least the next 2 male and/or 3 female generations of:

“Altered epigenetic information between generations in the absence of continued environmental exposure.”

The review had separate sections for animal and human studies.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4663595/ “Impact of Maternal Diet on the Epigenome during In Utero Life and the Developmental Programming of Diseases in Childhood and Adulthood”

I arrived at the above review as a result of it citing the 2014 Harvard Reversing DNA Methylation: Mechanisms, Genomics, and Biological Functions. I’ll quote a few items from that review’s informative “Role of DNA demethylation in neural development” section:

“Distinct parts of mammalian brains, including frontal cortex, hippocampus, and cerebellum, all exhibit age-dependent acquisition of 5hmC [an oxidized derivative of 5mC [methylation of the fifth position of cytosine]].

In fact, the genome of mature neurons in adult central nervous system contains the highest level of 5hmC of any mammalian cell-type (~40% as abundant as 5mC in Purkinje neurons in cerebellum). These observations indicate that 5mC oxidation and potentially DNA demethylation may be functionally important for neuronal differentiation and maturation processes.

A comprehensive base-resolution analyses of 5mC and 5hmC in mammalian frontal cortex in both fetal and adult stages indicate that non-CpG methylation (mCH) and CpG hydroxymethylation (hCG) drastically build up in cortical neurons after birth, coinciding with the peak of synaptogenesis and synaptic pruning in the cortex. This study demonstrated that mCH could become a dominant form of cytosine modifications in adult brains, accounting for 53% in adult human cortical neuronal genome.

In mature neurons, intragenic mCH is preferentially enriched at inactive non-neuronal lineage-specific genes, indicating a role in negative regulation of the associated transcripts. By contrast, genic hCG is positively correlated with gene expression levels.”

Use it or lose it: the interplay of new brain cells, age, and activity

gettingwell4 2-3 stars Required further work, Brain development, Cortisol, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Limbic system, Memory, Neurochemicals, Serotonin, Stress, Telomeres, Testosterone , , , ,

This 2015 German review was of aging and activity in the context of adult neurogenesis:

“Adult neurogenesis might be of profound functional significance because it occurs at a strategic bottleneck location in the hippocampus.

Age-dependent changes essentially reflect a unidirectional development in that everything builds on what has occurred before. In this sense, aging can also be seen as continued or lifelong development. This idea has limitations but is instructive with regard to adult neurogenesis, because adult neurogenesis is neuronal development under the conditions of the adult brain.

The age-related alterations of adult neurogenesis themselves have quantitative and qualitative components. So far, most research has focused on the quantitative aspects. But there can be little doubt that qualitative changes do not simply follow quantitative changes (e.g., in cell or synapse numbers), but emerge on a systems level and above when an organism ages. With respect to adult neurogenesis, only one multilevel experiment including morphology and behavior has been conducted, and, even in that study, only three time points were investigated.

In old age, adult neurogenesis occurs at only a small fraction of the level in early adulthood. The decline does not seem to be ‘regulated’ but rather the by-product of many age-related changes of other sorts.

From a behavioral level down to a synaptic level, activity increases adult neurogenesis. This regulation does not seem to occur in an all-or-nothing fashion but rather influences different stages of neuronal development differently. Both cell proliferation and survival are influenced by or even depend on activity.

The effects of exercise and environmental enrichment are additive, which indicates that increasing the potential for neurogenesis is sufficient to increase the actual use of the recruitable cells in the case of cognitive stimulation. Physical activity would not by itself provide specific hippocampus-relevant stimuli that induce net neurogenesis but be associated with a greater chance to encounter specific relevant stimuli.

Adult hippocampal neurogenesis might contribute to a structural or neural reserve that if appropriately trained early in life might provide a compensatory buffer of brain plasticity in the face of increasing neurodegeneration or nonpathological age-related functional losses. There is still only limited information on the activity-dependent parameters that help to prevent the age-dependent decrease in adult neurogenesis and maintain cellular plasticity.

The big question is what the functional contribution of so few new neurons over so long periods can be. Any comprehensive concept has to bring together the acute functional contributions of newly generated, highly plastic neurons and the more-or-less lasting changes they introduce to the network.”

I’ve quoted quite a lot, but there are more details that await your reading. A few items from the study referenced in the first paragraph above:

“The hippocampus represents a bottleneck in processing..adult hippocampal neurogenesis occurs at exactly the narrowest spot.

We have derived the theory that the function of adult hippocampal neurogenesis is to enable the brain to accommodate continued bouts of novelty..a mechanism for preparing the hippocampus for processing greater levels of complexity.”

The role of the hippocampus in emotion was ignored as it so often is. The way to address many of the gaps mentioned by the author may be to Advance science by including emotion in research.

For example, from the author’s The mystery of humans’ evolved capability for adults to grow new brain cells:

“Adult neurogenesis is already effective early in life, actually very well before true adulthood, and is at very high levels when sexual maturity has been reached. Behavioral advantages associated with adult neurogenesis must be relevant during the reproductive period.”

When human studies are designed to research how “behavioral advantages associated with adult neurogenesis must be relevant” what purpose does it serve to exclude emotional content?

http://cshperspectives.cshlp.org/content/7/11/a018929.full “Activity Dependency and Aging in the Regulation of Adult Neurogenesis”