Control group

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

gettingwell4 < 0 Detracted from science, Amygdala, Beliefs, Brain development, Brainstem, Cerebrum, Cortisol, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Limbic system, Locus coeruleus, Lower brain, Memory, Neurochemicals, Serotonin, Stress, Testosterone , , , , , , , , ,

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!

Nevermind 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”

The persistence of epigenetic marks in Type 1 diabetes

gettingwell4 2-3 stars Required further work, Epigenetics, Memory, Stress , ,

This 2016 California human study found:

“A persistency of DNA methylation over time at key genomic loci associated with diabetic complications. Two sets of DNAs collected at least 16–17 years apart from the same participants are used to show the persistency of DNA-me over time.

Twelve annotated differentially methylated loci were common in both WB [whole blood] and Monos [blood monocytes], including thioredoxin-interacting protein (TXNIP), known to be associated with hyperglycemia and related complications.

The top 38 hyperacetylated promoters in cases included 15 genes associated with the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inflammatory pathway, which is strongly associated with diabetic complications.”

The researchers built on a series of studies that showed how subjects with early intensive interventions didn’t develop further complications, whereas subjects with later intensive interventions:

“Continued to develop complications, such as nephropathy, retinopathy, and macrovascular diseases, at significantly higher rates.

This persistence of benefit from early application of intensive therapy, called ‘metabolic memory,’ is an enigma.”

These researchers needed to also consider a point of Enduring memories? Or continuous toxic stimulation? that:

“The lasting epigenomic effect would not be due to memory, but continuous stimulation by persistent pathogens or persistent components.”

Other studies that involved specific genes of this study include:

http://www.pnas.org/content/113/21/E3002.full “Epigenomic profiling reveals an association between persistence of DNA methylation and metabolic memory in the DCCT/EDIC type 1 diabetes cohort”

Using epigenetic outliers to diagnose cancer

gettingwell4 2-3 stars Required further work, Epigenetics , ,

This 2016 Chinese/UK human cancer cell study tested five algorithms and found:

“Most of the novel proposed algorithms lack the sensitivity to detect epigenetic field defects at genome-wide significance. In contrast, algorithms which recognise heterogeneous outlier DNA methylation patterns are able to identify many sites in pre-neoplastic lesions, which display progression in invasive cancer.

Many DNA methylation outliers are not technical artefacts, but define epigenetic field defects which are selected for during cancer progression.”

The usual method of epigenetic studies involves:

“Identify genomic sites where the mean level of DNAm [DNA methylation] differs as much as possible between the two phenotypes. As we have seen however, such an approach is seriously underpowered in cancer studies where tissue availability is a major obstacle.

In addition to allelic frequency, we also need to take the magnitude of the alteration into consideration. As shown here, infrequent but bigger changes in DNAm (thus defining outliers) are more likely to define cancer field defects, than more frequent yet smaller DNAm changes.”

A similar point was made in Genetic statistics don’t necessarily predict the effects of an individual’s genes:

“Epigenomic analyses are limited by averaging of population-wide dynamics and do not inform behavior of single cells.”

One of the five tested algorithms was made freely available by the researchers. The limitations on its use were discussed, and included:

“Studies conducted in a surrogate tissue such as blood are scenarios where DNAm outliers are probably not of direct biological relevance to cancer development.”

http://bmcbioinformatics.biomedcentral.com/articles/10.1186/s12859-016-1056-z “Stochastic epigenetic outliers can define field defects in cancer”

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”

Observing pain in others had long-lasting brain effects

gettingwell4 4-5 stars Advanced knowledge, Anterior cingulate cortex, Brain hemispheres, Cerebrum, Limbic system, Memory, Neurochemicals, Oxytocin, Stress , ,

This 2016 Israeli human study used whole-head magnetoencephalography (MEG) to study pain perception in military veterans:

“Our findings demonstrate alterations in pain perception following extreme pain exposure, chart the sequence from automatic to evaluative pain processing, and emphasize the importance of considering past experiences in studying the neural response to others’ states.

Differences in brain activation to ‘pain’ and ‘no pain’ in the PCC [posterior cingulate cortex] emerged only among controls. This suggests that prior exposure to extreme pain alters the typical brain response to pain by blurring the distinction between painful and otherwise identical but nonpainful stimuli, and that this blurring of the ‘pain effect’ stems from increased responses to ‘no pain’ rather than from attenuated response to pain.”

Limitations included:

  • “The pain-exposed participants showed posttraumatic symptoms, which may also be related to the observed alterations in the brain response to pain.
  • We did not include pain threshold measurements. However, the participants’ sensitivity to experienced pain may have had an effect on the processing of observed pain.
  • The regions of interest for the examination of pain processing in the pain-exposed group were defined on the basis of the results identified in the control group.
  • We did not detect pain-related activations in additional regions typically associated with pain perception, such as the anterior insula and ACC. This may be related to differences between the MEG and fMRI neuroimaging approaches.”

The subjects self-administered oxytocin or placebo per the study’s design. However:

“We chose to focus on the placebo condition and to test group differences at baseline only, in light of the recent criticism on underpowered oxytocin administration studies, and thus all following analyses are reported for the placebo condition.”

A few questions:

  1. If observing others’ pain caused “increased responses to ‘no pain’,” wouldn’t the same effect or more be expected from experiencing one’s own pain?
  2. If there’s evidence for item 1, then why aren’t “increased responses to ‘no pain'” of affected people overtly evident in everyday life?
  3. If item 2 is often observed, then what are the neurobiological consequences for affected people’s suppression of “increased responses to ‘no pain’?”
  4. Along with the effects of item 3, what may be behavioral, emotional, and other evidence of this suppressed pain effect?
  5. What would it take for affected people to regain a normal processing of others’ “‘pain’ and ‘no pain’?”

https://www.researchgate.net/publication/299546838_Prior_exposure_to_extreme_pain_alters_neural_response_to_pain_in_others “Prior exposure to extreme pain alters neural response to pain in others” Thanks to one of the authors, Ruth Feldman, for providing the full study

A study of how genetic factors determined diet-induced epigenetic changes

gettingwell4 2-3 stars Required further work, Epigenetics , ,

This 2016 California rodent study found:

“HF [high fat] diet leads to persistent alterations of chromatin accessibility that are partially mediated by transcription factors and histone post-translational modifications. These chromatin alterations are furthermore strain specific, indicating a genetic component to the response.

These results suggest that persistent epigenetic modifications induced by HF diet have the potential to impact the long-term risk for metabolic diseases.”

The experimental procedure was that 7-8 week old subjects of two mice strains “were placed on three diet regimens:

  1. control diet for sixteen weeks,
  2. HF diet for sixteen weeks, or
  3. HF diet for an initial eight weeks followed by control diet for eight weeks (diet reversal).”

On diet regimen 3, one of the mouse strains wasn’t able to reverse the epigenetic changes caused by eight weeks of a high-fat diet. The symptoms included:

  • Elevated lipid accumulation and triglyceride levels
  • 15% of chromatin sites were more accessible, with the HNF4α transcription factor implicated
  • 6% of chromatin sites were less accessible due to H3K9 methylation
  • Persistently up-regulated genes were more likely to be in the vicinity of a persistently accessible site
  • A set of persistently up-regulated genes enriched for mitochondrial genes was present only with diet regimen 3 subjects.

A second mouse strain “known to display differences in metabolic dysfunction under HF diet” compared to the first strain didn’t experience the same symptoms on diet regimen 3:

  • Lipid accumulation and triglyceride levels weren’t elevated
  • The majority of diet-induced chromatin remodeling [was] reversible
  • Little overlap with the first strain in the set of genes that changed expression.

The study didn’t suggest any specific human applicability.

http://www.jbc.org/content/early/2016/03/22/jbc.M115.711028.long (pdf) “Persistent chromatin modifications induced by high fat diet”

 

The epigenetic influence of obese parents at conception

gettingwell4 2-3 stars Required further work, Epigenetics , ,

This 2016 German rodent study found:

“Using in vitro fertilization to ensure exclusive inheritance via the gametes, we show that a parental high-fat diet renders offspring more susceptible to developing obesity and diabetes in a sex- and parent of origin–specific mode.”

It would have benefited the researchers to have made the full study freely available. As it is, an interested reader has to ferret out information such as the basic study design (provided in a graphic) which had in the caption that both the parental and offspring diets were normal until:

  • “Between 9 [young adult] and 15 weeks of age.
  • This experiment was replicated at least three times for each F1 cohort, using sperm and oocytes from independent donors.”

Compare that information with the description provided by the study’s most thorough news coverage:

“Researchers raised genetically similar mice for six weeks [beginning at 9 weeks of age] on one of three diets: standard mouse chow [13.5% fat], a low-fat diet [11% fat], or a high-fat [60% fat], high-calorie diet. The latter became obese and developed severe glucose intolerance (a precursor to type 2 diabetes), while the other mice stayed slim.

Harvesting the eggs and sperm from mice in each of the diet groups, the researchers then used in vitro fertilization to make specific, controlled crosses. All of the embryos were transferred to healthy, skinny [actually, the foster mothers were on the standard mouse chow diet] foster mothers. To see if the diet of their biological parents affected their metabolism, all of the pups [actually, young adults at age 9 weeks] were challenged with a high-fat, high-calorie diet [beginning at 9 weeks of age].

Unsurprisingly, the female pups with two obese parents had a high degree of insulin resistance and gained at least 20 percent more weight than the offspring of parents on standard or low-fat diets. Female pups with only one obese parent, either the mother or the father, also gained more weight than the control groups—but only between 8 and 14 percent. The result suggests that the metabolic influence of each parent may be additive.

But in a puzzling finding, the male pups didn’t have the same pattern. The male pups of obese parents did tend to be a bit heavier than those from the control groups, but the difference wasn’t statistically significant, the authors report. They did, however, also have a high degree of insulin resistance.

Examining the glucose intolerance more closely, the researchers noted that offspring (both male and female) tended to have more severe glucose intolerance if their mothers were obese. This backs up epidemiological data in humans that suggests a stronger maternal influence over type 2 diabetes development.”

The study didn’t determine causal biological mechanisms for the observed epigenetic effects. No measurements of DNA methylation, histone modifications, or microRNAs were taken.

I look forward to further research into epigenetic contributions at conception to adulthood symptoms.

http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.3527.html “Epigenetic germline inheritance of diet-induced obesity and insulin resistance” Thanks to the lead author Peter Huypens for providing a copy of the full study

Problematic research into epigenetic effects of paternal stress on male offspring

gettingwell4 0-1 star Wasted resources, Cortisol, Epigenetics, Neurochemicals, Stress ,

This 2016 Chinese rodent study and its accompanying commentary Don’t stress dad — it’s bad for your kids’ health were caught up in an agenda.

The first problem I noticed was that the hyperglycemic effects found only in the male offspring weren’t consistently labelled as sex-specific. Try to find that fact in the paywalled commentary with its intentionally misleading headline, or in the news coverage with headlines such as “Stressed mouse dads give their offspring high blood sugar.”

That the effects were male-only was briefly noted in the study, yet “male” was absent from the “stress-F1 mice” label used after the initial mention.

2015年12月22日-陆炎模式图单独导出-v2

The researchers provided no mechanisms that plausibly linked the effects to offspring sex. There was plenty of time between the May 3, 2015 submission and the February 18, 2016 publication to clarify this and other items. I wonder what the reviewer noted.

The second problem was that the highest number of male “stress-F1 mice” tested was only six. I didn’t see any disclosures of what led to the scarcity of subjects, or of the likely impact of using so few.

A related limitation was that the male “stress-F1 mice” were killed as young adults. Whether or not the hyperglycemic effects carried through to old age or to another generation wasn’t determined.

I’m leery of studies like this one that didn’t have a Limitations section, and especially so when the news coverage overlooked obvious limitations. It was difficult to place the findings in a context other than promoting that a male’s stress may also adversely affect their offspring.

One of the problems that research caught up in an agenda create is that non-headline findings are overlooked. Other than sex-specific effects, the study found that the putative preconception cause of hyperglycemia didn’t cause other symptoms:

  • “No significant growth defects were observed in male offspring from stress-F0 fathers (stress-F1 mice) during their early lives.
  • Insulin sensitivity was not changed in stress-F1 mice.
  • Serum glucagon, leptin, and pro-inflammatory cytokines (tumor necrosis factor α [TNFα], interleukin-6 [IL-6]) were unaffected.
  • Body weight, food intake, locomotor activity, CO2 production, O2 consumption, and respiratory exchange ratios also remained unchanged.
  • Liver weight, liver weight/body weight ratios, hepatic triglyceride content, and the histological phenotypes were also comparable.
  • The methylation pattern and expression of microRNAs were not affected in the fetal brains of stress-F1 mice.”

The handling of the study reminded me of Transgenerational epigenetic programming with stress and microRNA where most of the news coverage similarly focused on it being a male’s stress, not a female’s, that affected the developing embryo. The important part lost from news coverage of that study was it demonstrated how a damaging influence can begin immediately after conception, but the symptoms didn’t present until adulthood!

http://www.sciencedirect.com/science/article/pii/S1550413116300067 “Paternal Psychological Stress Reprograms Hepatic Gluconeogenesis in Offspring”

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”

A problematic study of oxytocin receptor gene methylation, childhood abuse, and psychiatric symptoms

gettingwell4 < 0 Detracted from science, Brain development, Epigenetics, Neurochemicals, Oxytocin, Stress , , , ,

This 2016 Georgia human study found:

“A role for OXTR [oxytocin receptor gene] in understanding the influence of early environments on adult psychiatric symptoms.

Data on 18 OXTR CpG sites, 44 single nucleotide polymorphisms, childhood abuse, and adult depression and anxiety symptoms were assessed in 393 African American adults. The Childhood Trauma Questionnaire (CTQ), a retrospective self-report inventory, was used to assess physical, sexual, and emotional abuse during childhood.

While OXTR CpG methylation did not serve as a mediator to psychiatric symptoms, we did find that it served as a moderator for abuse and psychiatric symptoms.”

From the Limitations section:

  1. “Additional insight will likely be gained by including a more detailed assessment of abuse timing and type on the development of biological changes and adverse outcomes.
  2. The degree to which methylation remains fixed following sensitive developmental time periods, or continues to change in response to the environment, is still a topic of debate and is not fully known.
  3. Comparability between previous findings and our study is limited given different areas covered.
  4. Our study was limited to utilizing peripheral tissue [blood]. OXTR methylation should ideally be assessed in the tissues that are known to express OXTR and directly involved in psychiatric symptoms. The degree to which methylation of peripheral tissues can be used to study methylation changes in response to the environment or in association with behavioral outcomes is currently a topic of debate.
  5. Our study did not evaluate gene expression and thus cannot explore the role of study CpG sites on regulation and expression.”

Addressing the study’s limitations:

  1. Early-life epigenetic regulation of the oxytocin receptor gene demonstrated – with no hint of abuse – how sensitive an infant’s experience-dependent oxytocin receptor gene DNA methylation was to maternal care. Treating prenatal stress-related disorders with an oxytocin receptor agonist provided evidence for prenatal oxytocin receptor gene epigenetic changes.
  2. No human’s answers to the CTQ, Adverse Childhood Experiences, or other questionnaires will ever be accurate self-reports of their prenatal, infancy, and early childhood experiences. These early development periods were likely when the majority of the subjects’ oxytocin receptor gene DNA methylation took place. The CTQ self-reports were – at best – evidence of experiences at later times and places, distinct from earlier experience-dependent epigenetic changes.
  3. As one example of incomparability, the 2009 Genomic and epigenetic evidence for oxytocin receptor deficiency in autism was cited in the Introduction section and again in the Limitations section item 4. Since that study was sufficiently relevant to be used as a reference twice, the researchers needed to provide a map between its findings and the current study.
  4. Early-life epigenetic regulation of the oxytocin receptor gene answered the question of whether or not an individual’s blood could be used to make inferences about their brain oxytocin receptor gene DNA methylation. The evidence said: NO, it couldn’t.
  5. It’s assumed that oxytocin receptor gene DNA methylation directly impacted gene expression such that increased levels of methylation were associated with decreased gene transcription. The study assumed but didn’t provide evidence that higher levels of methylation indicated decreased ability to use available oxytocin due to decreased receptor expression. The study also had no control group.

To summarize the study’s limitations:

  1. The study zeroed in on childhood abuse, and disregarded evidence for more relevant factors determining an individual’s experience-dependent oxytocin receptor gene DNA methylation. That smelled like an agenda.
  2. The study used CTQ answers as determinants, although what happened during the subjects’ earliest life was likely when the majority of epigenetic changes to the oxytocin receptor gene took place. If links existed between the subjects’ early-life DNA methylation and later-life conditions, they weren’t evidenced by CTQ answers about later life that couldn’t self-report relevant experiences from conception through age three that may have caused DNA methylation.
  3. There was no attempt to make findings comparable with cited studies. That practice and the lack of a control group reminded me of Problematic research with telomere length.
  4. The researchers tortured numbers until they confessed “that CpG methylation may interact with abuse to predict psychiatric symptoms.” But there was no direct evidence that each subject’s blood oxytocin gene receptor DNA methylation interacted as such! Did the “may interact” phrase make the unevidenced inferences more plausible, or permit contrary evidence to be disregarded?
  5. See Testing the null hypothesis of oxytocin’s effects in humans for examples of what happens when researchers compound assumptions and unevidenced inferences.

The study’s institution, Emory University, and one of the study’s authors also conducted Conclusions without evidence regarding emotional memories. That 2015 study similarly disregarded relevant evidence from other research, and made statements that weren’t supported by that study’s evidence.

The current study used “a topic of debate” and other disclaimers to provide cover for unconvincing methods and analyses in pursuit of..what? What overriding goals were achieved? Who did the study really help?

http://onlinelibrary.wiley.com/enhanced/doi/10.1111/cdev.12493/ “Oxytocin Receptor Genetic and Epigenetic Variations: Association With Child Abuse and Adult Psychiatric Symptoms”

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.

The effects of imposing helplessness

gettingwell4 2-3 stars Required further work, Amygdala, Brainstem, Cerebrum, Epigenetics, Hippocampus, Hypothalamus, Limbic system, Locus coeruleus, Lower brain, Memory, Stress , , , , , , ,

This 2016 New York rodent study found:

“By using unbiased and whole-brain imaging techniques, we uncover a number of cortical and subcortical brain structures that have lower activity in the animals showing helplessness than in those showing resilience following the LH [learned helplessness] procedure. We also identified the LC [locus coeruleus] as the sole subcortical area that had enhanced activity in helpless animals compared with resilient ones.

Some of the brain areas identified in this study – such as areas in the mPFC [medial prefrontal cortex], hippocampus, and amygdala – have been previously implicated in clinical depression or depression-like behavior in animal models. We also identified novel brain regions previously not associated with helplessness. For example, the OT [olfactory tubercle], an area involved in odor processing as well as high cognitive functions including reward processing, and the Edinger–Westphal nucleus containing centrally projecting neurons implicated in stress adaptation.

The brains of helpless animals are locked in a highly stereotypic pathological state.”

Concerning the study’s young adult male subjects:

“To achieve a subsequent detection of neuronal activity related to distinct behavioral responses, we used the c-fosGFP transgenic mice expressing c-FosGFP under the control of a c-fos promoter. The expression of the c-fosGFP transgene has been previously validated to faithfully represent endogenous c-fos expression.

Similar to wild-type mice, approximately 22% (32 of 144) of the c-fosGFP mice showed helplessness.”

The final sentence of the Introduction section:

“Our study..supports the view that defining neuronal circuits underlying stress-induced depression-like behavior in animal models can help identify new targets for the treatment of depression.”

Helplessness is both a learned behavior and a cumulative set of experiences during every human’s early life. Therapeutic approaches to detrimental effects of helplessness can be different with humans than with rodents in that we can address causes.

The researchers categorized activity in brain circuits as causal in the Discussion section:

“Future studies aimed at manipulating these identified neural changes are required for determining whether they are causally related to the expression of helplessness or resilience.”

Studying whether or not activity in brain circuits induces helplessness in rodents may not inform us about causes of helplessness in humans. Our experiences are often the ultimate causes of helplessness effects. Many of our experiential “neural changes” are only effects, as demonstrated by this and other studies’ induced phenotypes such as “Learned Helplessness” and “Prenatally Restraint Stressed.”

Weren’t the researchers satisfied that the study confirmed what was known and made new findings? Why attempt to extend animal models that only treat effects to humans, as implied in the Introduction above and in the final sentence of the Discussion section:

“Future studies aimed at elucidating the specific roles of these regions in the pathophysiology of depression as well as serve as neural circuit-based targets for the development of novel therapeutics.”

http://journal.frontiersin.org/article/10.3389/fncir.2016.00003/full “Whole-Brain Mapping of Neuronal Activity in the Learned Helplessness Model of Depression” (Thanks to A Paper a Day Keeps the Scientist Okay)

Treating prenatal stress-related disorders with an oxytocin receptor agonist

gettingwell4 4-5 stars Advanced knowledge, Amygdala, Brain development, Cortisol, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Limbic system, Memory, Neurochemicals, Oxytocin, Stress , , ,

This 2015 French/Italian rodent study found:

“Chronic systemic treatment with carbetocin [unavailable in the US] in PRS [prenatally restraint stressed] rats corrected:

  • the defect in glutamate release,
  • anxiety– and depressive-like behavior,

and abnormalities:

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

These findings disclose a novel function of oxytocin receptors in the hippocampus, and encourage the use of oxytocin receptor agonists in the treatment of stress-related psychiatric disorders in adult life.”

carbetocin

The adult male subjects were:

“PRS rats..the offspring of dams exposed to repeated episodes of restraint stress during pregnancy.

These rats display anxiety- and depressive-like behaviors and show an excessive glucocorticoid response to acute stress, which is indicative of a dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis caused by an impaired hippocampal glucocorticoid negative feedback.

PRS rats show a selective reduction in glutamate release in the ventral hippocampus.”

The researchers cited several other studies they have performed with the PRS phenotype. In the current study:

“Carbetocin treatment had no effect on these behavioral and neuroendocrine parameters in prenatally unstressed (control) rats, with the exception of a reduced expression of the oxytocin receptor gene in the amygdala.

Carbetocin displayed a robust therapeutic activity in PRS rats, but had no effect in unstressed rats, therefore discriminating between physiological and pathological conditions.”

The PRS phenotype showed the ease with which a child can be epigenetically changed – even before they’re born – to be less capable over their entire life. Just stress the pregnant mother-to-be.

https://www.sciencedirect.com/science/article/abs/pii/S0306453015002395 “Activation of presynaptic oxytocin receptors enhances glutamate release in the ventral hippocampus of prenatally restraint stressed rats” (not freely available) Thanks to coauthor Dr. Eleonora Gatta for providing the full study.

Stress consequences on gut bacteria, behavior, immune system, and neurologic function

gettingwell4 4-5 stars Advanced knowledge, Cerebrum, Cortisol, Dopamine, Epigenetics, Hippocampus, Hypothalamus, Immune system, Limbic system, Neurochemicals, Serotonin, Stress , ,

This 2015 Canadian rodent study found:

“Chronic social defeat induced behavioral changes that were associated with reduced richness and diversity of the gut microbial community.

The degree of deficits in social, but not exploratory behavior, was correlated with group differences between the microbial community profile.

Defeated mice also exhibited reduced abundance of pathways involved in biosynthesis and metabolism of tyrosine and tryptophan: molecules that serve as precursors for synthesis of dopamine, norepinephrine, serotonin, and melatonin, respectively.

This study indicates that stress-induced disruptions in neurologic function are associated with altered immunoregulatory responses.”

These researchers had an extensive Discussion section where they placed study findings in contexts with other rodent and human studies. For example:

“Our analyses also predicted reduced frequency of fatty acid biosynthesis and metabolism pathways, including that of propanoate and butanoate – byproducts of dietary carbohydrate fermentation by intestinal microorganisms.

Butyrate is a potent histone deacetylase (HDAC) inhibitor that exerts antidepressant-like effects by increasing histone acetylation in the frontal cortex and hippocampus, and consequentially, raising BDNF transcript levels.

Although it was previously unclear whether systemic levels of these metabolites achieved in vivo were sufficient to produce behavioral changes, progress has been made by discovering their presence in cerebrospinal fluid and the brain, and demonstrating that colon-derived SCFAs [short chain fatty acids] cross the blood–brain barrier and preferentially accumulate in the hypothalamus, where they can affect CNS activity.”

http://www.psyneuen-journal.com/article/S0306-4530%2815%2900934-8/fulltext “Structural & functional consequences of chronic psychosocial stress on the microbiome & host”

A problematic study of beliefs and dopamine

gettingwell4 < 0 Detracted from science, Beliefs, Brainstem, Cerebrum, Dopamine, Limbic system, Lower brain, Neurochemicals, Thalamus , ,

This 2015 Virginia Tech human study found:

“Dopamine fluctuations encode an integration of RPEs [reward prediction errors, the difference between actual and expected outcomes] with counterfactual prediction errors, the latter defined by how much better or worse the experienced outcome could have been.

How dopamine fluctuations combine the actual and counterfactual is unknown.”

From the study’s news coverage:

“The idea that “what could have been” is part of how people evaluate actual outcomes is not new. But no one expected that dopamine would be doing the job of combining this information in the human brain.”

Some caveats applied:

  • Measurements of dopamine were taken only from basal ganglia areas. These may not act the same as dopamine processes in other brain and nervous system areas.
  • The number of subjects was small (17), they all had Parkinson’s disease, and the experiment’s electrodes accompanied deep brain stimulation implantations.
  • Because there was no control group, findings of a study performed on a sample of people who all had dysfunctional brains and who were all being treated for neurodegenerative disease may not apply to a population of people who weren’t similarly afflicted.

The researchers didn’t provide evidence for the Significance section statement:

“The observed compositional encoding of “actual” and “possible” is consistent with how one should “feel” and may be one example of how the human brain translates computations over experience to embodied states of subjective feeling.”

The subjects weren’t asked for corroborating evidence about their feelings. Evidence for “embodied states of subjective feeling” wasn’t otherwise measured in studied brain areas. The primary argument for “embodied states of subjective feeling” was the second paragraph of the Discussion section where the researchers talked about their model and how they thought it incorporated what people should feel.

The study’s experimental evidence didn’t support the researchers’ assertion – allowed by the reviewer – that the study demonstrated something about “states of subjective feeling.” That the model inferred such “findings” along with the researchers’ statement that it “is consistent with how one should “feel” reminded me of a warning in The function of the dorsal ACC is to monitor pain in survival contexts:

“The more general message you should take away from this is that it’s probably a bad idea to infer any particular process on the basis of observed activity.”

The same researcher who hyped An agenda-driven study on beliefs, smoking and addiction that found nothing of substance was back again with statements such as:

“These precise, real-time measurements of dopamine-encoded events in the living human brain will help us understand the mechanisms of decision-making in health and disease.”

It’s likely that repeated hubris is one way researchers respond to their own history and feelings, such as their need to feel important as mentioned on my Welcome page.

The Parkinson’s patients were willing to become lab rats with extra electrodes that accompanied brain implantations to relieve their symptoms. Findings based on their playing a stock market game didn’t inform us about “mechanisms of decision-making in health and disease” in unafflicted humans. As one counter example, what evidence did the study provide that’s relevant to healthy humans’ decisions to remain healthy by taking actions to prevent disease?

The unwarranted extrapolations revealed a belief that the goal of research should be to explain human actions by explaining the actions of molecules. One problem caused by the preconceptions of this widespread belief is that it leads to study designs and models that omit relevant etiologic evidence embedded in each of the subjects’ historical experiences.

This belief may have factored into why the subjects weren’t asked about their feelings. Why didn’t the study’s design consider as relevant subject-provided evidence for feelings? Because the model already contrived explanations for feelings underlying the subjects’ actions.

http://www.pnas.org/content/113/1/200.full “Subsecond dopamine fluctuations in human striatum encode superposed error signals about actual and counterfactual reward”

Fat made rats fat with dysfunctional brains

gettingwell4 2-3 stars Required further work, Anterior cingulate cortex, Cerebrum, Cortisol, Epigenetics, Hippocampus, Limbic system, Neurochemicals, Stress, Testosterone , , ,

This 2015 New York rodent study found:

“Early stage [diet-induced] obesity, before the onset of diabetes or metabolic syndrome, produced deficits on cognitive tasks that require the prefrontal cortex.

These results strongly suggest that obesity must be considered as a contributing factor to brain dysfunction.”

The difference in the diets of the adult male subjects was that the control group ate 10% fat (20% protein, 70% carbohydrates) whereas the obese group ate 45% fat (20% protein, 35% carbohydrates). Significant changes in body weight were present after the first two weeks on the diets, but testing didn’t begin until after eight weeks.

I thought the study design prematurely terminated the experiments. The study didn’t justify the ultimate purpose of conducting rodent experiments, which is to find possible human applicability.

One study design possibility would have been to continue through old age to find how the conditions progressed. Another possibility would have been to reverse the high-fat diet to find whether the conditions reversed.

http://www.pnas.org/content/112/51/15731.full “Obesity diminishes synaptic markers, alters microglial morphology, and impairs cognitive function”