Stress

Epigenetic changes in the developing brain change behavior

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

This 2015 review cited 143 studies to tie together findings in epigenetic chemistry and behavioral neuroscience.

In addition to studies I’ve previously curated, other research included:

  • a 2012 study which completely abolished mouse maternal behavior by silencing a gene encoding an estrogen receptor;
  • a 2012 study which found that stress-induced changes in the rat hippocampus were heritable;
  • a 2014 study that distinguished between transgenerational and intergenerational epigenetic effects such as:

    “in utero exposure to nutritional status, stress, or toxic environmental factors that act on the developing embryo and its germ line”

  • a 2013 study that showed how genomic imprinting coordinated:

    “Genetic coadaptation where beneficially interacting alleles evolve to become coinherited.”

The current status of research incorporating both epigenetic chemistry and behavioral neuroscience was summed up as:

“A large number of behavioral epigenetic studies attempt to correlate epigenetic marker changes at global levels and in mixed populations of cells with phenotypic changes.

Specific changes at specific gene levels and at single cell levels correlating with behavioral changes remain largely unknown.”

http://www.pnas.org/content/112/22/6789.full “Epigenetic changes in the developing brain: Effects on behavior”

Stress in early life can alter physiology and behavior across the entire lifespan

gettingwell4 4-5 stars Advanced knowledge, Amygdala, Brain development, Cerebrum, Cortisol, Epigenetics, Hippocampus, Immune system, Limbic system, Memory, Neurochemicals, Stress, Testosterone , , , , , , , ,

I’ll quote a few sections of this 2014 summary of 111 studies concerning stress, including the authors’ research:

“The brain is the central organ of stress and adaptation to stressors because:

  • It not only perceives what is threatening or potentially threatening and initiates behavioral and physiological responses to those challenges,
  • But also is a target of the stressful experiences and the hormones and other mediators of the stress response.

The stress history of parents is a significant factor in the resilience of their offspring.

Environmental stress transduces its effects into lasting changes on physiology and behavior, which can vary even among genetically identical individuals.

Stress in early life can alter physiology and behavior across the entire lifespan.

Structural stress memory is even more apparent with regard to gene expression in stress-sensitive brain regions like the hippocampus.

Individual history is important and that there is a memory of stress history retained by neurons at the cellular level in regions like the hippocampus.

Stress has a number of known effects on epigenetic marks in the brain, producing alterations in DNA methylation and histone modifications in most of the stress-sensitive brain regions examined, including the hippocampus, amygdala, and prefrontal cortex.”

It seemed to be taboo to note that most of – and the largest of – detrimental effects of stress occurred during womb-life in the mother’s environment. The authors instead opted for a politically correct “the stress history of parents” phrase.

Referenced studies had findings relevant to the earliest periods of life, including Figure 1:

interactions

“Those organs that show the highest levels of retrotransposon [a repeat element (mobile DNA sequences often involved in mutations) type formed by copy-and-paste mechanisms] activity, such as the brain and placenta, also seem to be both steroidogenic and steroid-sensitive.”

However, Figure 1 was given a beneficial context, and other studies’ findings weren’t mentioned in their contexts of detrimental effects on fetuses of mothers who were stressed while pregnant.

http://www.pnas.org/content/112/22/6828.full “Stress and the dynamic genome: Steroids, epigenetics, and the transposome”

Running a marathon, cortisol, depression, causes, effects, and agendas

gettingwell4 < 0 Detracted from science, Cerebrum, Cortisol, Limbic system, Lower brain, Memory, Neurochemicals, Stress , ,

Let’s imagine that you decide you want to run a marathon. You haven’t run in six months, and you know you’ll have to train.

On the first day of training, as you run your first mile a friend pops out of nowhere and says, “You’re sweating! That means you’re going up to Mile 14 today! Good job, you’re on your way!”

You may appreciate the encouragement, but would a friend’s assessment have anything to do with your physical reality? Before you’ve run one mile, can an observer of your sweat say with certainty that you’ll run 14 miles on your first day of training?

Yeah. That’s how I felt when reading this 2014 UK study that found:

“Adolescent boys who have high levels of stress hormone ‘cortisol’ along with some symptoms of depression are at a 14 times higher risk of the condition than their peers.”

The researchers latched onto teenagers (12-16 years old, mean 13.7) to assess a psychiatric condition. They stated that a physical effect as common as visible sweat was a biomarker that predicted where some of the teenagers were going with their lives.

The study’s only physical measurements were cortisol from saliva samples at 8:00 a.m. on four consecutive days, then repeated a year later. For comparison, a standard lab test is to measure cortisol from saliva taken four times in one day at 9:00 a.m., 1:00 p.m., 5:00 p.m., and 9:00 p.m.

Cortisol is an effect of multiple potential causes, including stress, which itself is often an effect of multiple potential causes. One common cause of stress and its cortisol byproduct is diet, for example, when a person consumes caffeine.

“Mean time between waking and morning-cortisol collection was 50 min.”

I found it hard to believe that teenagers who:

  • woke up at 7:10 a.m.,
  • gulped down who knows what for breakfast,
  • got ready for, and then
  • went to school for an 8:00 a.m. cortisol test

wouldn’t have relatively “elevated morning cortisol” from the resultant stress.

Subjects self-reported depressive symptoms via a 33-item questionnaire initially and again every four months. They were interviewed for psychiatric diagnoses.

The largest separator used for stratification within subjects was an autobiographic memory test. Without this test, the study wouldn’t have made its main finding, so let’s look at the test’s details:

“Anxious and depressed adolescent patients report significantly elevated levels of over-general categoric memories compared with well controls. Six positive and six negative words are presented on flashcards in pseudorandom order, and participants are instructed to recall a particular memory of an event in their life after each word. Sixty seconds were allowed for each response.

Responses were categorized as specific if they referred to an event with a specific time and place, lasting no longer than 1 d[ay]. Responses were considered overgeneral if they formed a general class of repeated events.”

We can see that the autobiographical memory test only considered the subjects’ verbal expressions – within a short time period – of their recalls of emotionally triggered memories. As informed by the principles described in Agenda-driven research on emotional memories, the recall of an emotional memory is a product of the cerebrum responding to input from limbic system and lower brain areas. When someone describes their recall of an emotionally triggered memory, it’s yet another level further removed from the brain areas that store emotional memories.

We can also see that test scores of the subjects’ verbal expressions aren’t capable of providing any etiologic evidence for an effect of high cortisol. A correlation is the best that could ever be shown by an autobiographic memory test. Again, the study’s main finding hinged on this third-order observational method of trying to figure out what’s going on inside subjects’ brains.

The researchers developed a control group, and made only a token attempt to trace the control group teenagers’ histories:

“The primary caregiver was interviewed about the quality of the family environment in three epochs (0–5, 6–11, and 12–14 y of age).

Four classes were found: optimal class, aberrant parenting, discordant, and hazardous.”

Were we supposed to believe that any primary caregiver would tell the truth about anything in a teenager’s history that indicated they had damaged their child? Good luck with that.

Anyway, the researchers didn’t act as though teenagers’ histories had any significant relationships with any present or future conditions. Their ahistoric biases showed by subsequently processing the entire history of each of the control group teenagers into a 1 or a 0 for the model.

The researchers then modeled this binary assessment to be relevant to the study’s main subjects!

The researchers’ agenda led to predetermined findings. Was the reviewer onboard with this agenda?

  • By disregarding the main subjects’ histories, it couldn’t provide etiologic evidence for any present or future effects.
  • By measuring only early morning cortisol, are we surprised that model numbers could be processed into some correlation?
  • Comparing this sole measurement to 325 measurements taken of subjects in Assessing a mountain climber’s condition without noticing their empty backpack made me wonder about the study designers’ real intentions.

News coverage of the study jumped on its flimsy finding to demand that something must be done. What did researchers offer teenagers who needed help?

  • After citing research that:

    “Showed null effects for two active treatments [cognitive behavioral therapy (CBT) and attentional training, respectively]”

    they recommended some unspecific:

    “New models of public mental health education and intervention in the youth population.”

  • After citing research that found:

    “Current diagnostic classifications [e.g., the Diagnostic and Statistical Manual for Mental Disorders (DSM) and the International Classification of Diseases (ICD)] have proved to have low diagnostic validity for investigations on the etiology, prevention, or treatment of MD [major depression]“

    the study relied on these diagnoses anyway, and then disclaimed:

    “It may also be the case that current classifications, as used in this study, such as DSM and ICD are simply not optimally specified.”

They didn’t make their case that “elevated morning cortisol” effect was an adequate biomarker for teenagers who needed help. They did a disservice to their subjects by neither investigating nor providing any etiologic evidence for observed effects.

Who really benefited from this underlying agenda? I didn’t see that it was teenagers who may have actually needed assistance.

Did the study’s funders know that these efforts had enormous lacks? And what did:

“New models of public mental health education and intervention in the youth population”

really mean?

http://www.pnas.org/content/111/9/3638.full “Elevated morning cortisol is a stratified population-level biomarker for major depression in boys only with high depressive symptoms”

Changing an individual’s future behavior even before they’re born

gettingwell4 5+ stars Premium, Brain development, Epigenetics, Stress , , , ,

This 2015 Harvard fruit fly research was a companion of the Is what’s true for a population what’s true for an individual? study.

The researchers began with the question:

“If we could rear genetically identical individuals from a variety of genetic backgrounds and rear them in the same environment, how much phenotypic variation between individuals of the same genotype would we see?”

They answered with:

“We show that different genotypes vary dramatically in their propensity for variability, that phenotypic variability itself, as a trait, can be heritable, and that loci affecting variability can be mapped.”

The specific problem that probably prompted this study was that the methodology of genome-wide association studies (GWAS) usually:

“Focuses on the average effect of alternative alleles averaged in a population.”

What this methodology often missed was:

“When phenotypic variation results from alleles that modify phenotypic variance rather than the mean, this link between genotype and phenotype will not be detected.”

The researchers altered the environment during a critical period of fruit flies’ development in order to induce epigenetic changes in the fruit fly pupae brains:

“Disruption of Ten-a [the synaptic target recognition gene Tenascin accessory] expression in midpupa affects behavioral variance [the standard statistical dispersion parameter].

In all cases, disrupting Ten-a increased the variability [the median of the absolute deviation from each observation’s median] in turning bias with no effect on the mean.”

I fully expect researchers to demonstrate that this finding has general applicability for humans, especially during womb-life. Research such as:

are steps in this direction just for one factor in the human fetal environment – stress. The effects of stressing a human fetus should be at least as significant as the effects produced on the study’s subjects with increased temperature during pupation.

http://www.pnas.org/content/112/21/6706.full “Behavioral idiosyncrasy reveals genetic control of phenotypic variability”

Chaos – not balance – and competition for resources are the natural order

gettingwell4 5+ stars Premium, Epigenetics, Immune system, Primal Therapy, Stress , ,

This 2015 Amsterdam/New Zealand/Cornell shore-life study found:

“Species abundances in natural ecosystems may never settle at a stable equilibrium.

Species in one of the world’s oldest marine reserves showed chaotic fluctuations for more than 20 years. The species replaced each other in cyclic order, yet the exact timing and abundances of the species were unpredictable.

Our findings provide a field demonstration of nonequilibrium coexistence of competing species through a cyclic succession at the edge of chaos.

Our findings show that natural ecosystems can sustain continued changes in species abundances.”

chaos

http://www.pnas.org/content/112/20/6389.full “Species fluctuations sustained by a cyclic succession at the edge of chaos”

The University of Amsterdam also participated in a 2013 study Evolution of microbial markets where evolutionary biologists studied microbes. Their related findings included:

“Cooperative interactions between individuals of different species.

Strategies important for microbes to optimize their success in potential biological markets:

  • (i) avoid bad trading partners;
  • (ii) build local business ties;
  • (iii) diversify or specialize;
  • (iv) become indispensable;
  • (v) save for a rainy day; and
  • (vi) eliminate the competition.”

A 2015 study How a well-adapted immune system is organized (the *.pdf file is linked because the html has errors) had a related finding that applied to our body’s immune system. The researchers found that the primary reason why each of our immune systems is unique is due to the effect of:

“Competition between receptor clones..NOT a biologically implausible centralized mechanism distributing resources system-wide.

The repertoire of lymphocyte receptors in the adaptive immune system protects organisms from diverse pathogens. A well-adapted repertoire should be tuned to the pathogenic environment to reduce the cost of infections.

Competitive dynamics can allow the immune repertoire to self-organize into a state that confers high protection against infections.”

Chaos and competition for resources are facts of life observed within ourselves and in nature from ocean life down to the microbe level.

Why are we often presented – as a fact of life – that what’s natural is for all aspects of our lives to be in balance? Emotional, economic, social, intellectual – you name it, we’re told that the natural model is one of “stable equilibrium.”

Two hypotheses of Dr. Arthur Janov’s Primal Therapy are relevant:

Trying for closure, though, becomes an act-out – a temporary fulfillment of a substitute need. But the underlying need remains unsatisfied, and soon drives further act-outs. Balance is never achieved.

With this viewpoint, can you see how behavior like the following shows the internal state of the actor as they attempt to thwart the natural reality of the situation?

  • A person in authority who demands that people cease their competition for a resource and instead, accept what the authority figure determines is fair and balanced. An example is limiting supplies with price controls after a disaster.
  • A person who disrupts cooperative behavior that provides a solution for the cooperators’ needs/wants and instead, interposes themselves in a directed solution. An example is requiring licenses for cooperative childcare.
  • A person who insists that peoples’ responses to chaos to form an optimal adaptation cease, and instead, conform to some other responses. An example is prohibiting free movement after a disaster.

It reveals even more about the internal states of people that the above examples become codified. Children are taught that the natural and solely acceptable way to behave is in accordance with these unnatural solutions.

There are some signs that unnatural solutions in society can be reversed. For example, here is a 2013 article about a UK village that benefited from removing all of its traffic signals and reverting to the natural order of human cooperation and competition.

At the individual level, though, it’s up to each one of us to recognize and reverse our unnatural states. We and the people around us will be pleased when we and they are no longer adversely affected by our unconscious act-outs that are driven by our internal states. There’s enough natural chaos without adding more with act-outs.

Our internal systems will suffer damage, for example, when our unconscious act-out is to be busy, always doing something, and we can’t relax. Stress adversely affects our internal systems until we understand and reverse the driving unnatural states.

A possible link between stress responses and human cancers?

gettingwell4 4-5 stars Advanced knowledge, Brain development, Cortisol, Epigenetics, Neurochemicals, Primal Therapy, Stress ,

This 2015 UK rodent study found:

“An unexpected role for the GR [glucocorticoid receptor] in promoting accurate chromosome segregation during mitosis.

We also identify reduced GR expression in several common human cancers, thereby implicating GR as a novel tumor suppressor gene.”

One of the researchers said:

“Cancer is caused by cell division going wrong, but no one has previously looked at the role GR has to play in this process. It’s now clear that it is vital.”

From the study:

“Our findings now show that GR function regulates accurate mitotic progression, with clear implications for human health.

Add a previously unidentified perspective to GR action in cell division, affecting mitotic spindle function.

It may be that this action can be targeted by specific ligands, potentially opening up new therapeutic approaches to treat common cancers.”

The Translating PTSD research findings from animals to humans study also found reduced expression of glucocorticoid receptor genes, which appeared in some rodents after stress. Unfortunately, those researchers’ priorities weren’t to research the causes of this reduced expression.

One relevant hypothesis of Primal Therapy is that trauma in the earliest parts of human life epigenetically impairs the proper functioning of human development processes. A follow-on hypothesis is that the arrival of diseases in later life may be traceable back to the damage done during early-life development processes.

An example of this would be that a developing fetus adapts to being constantly stressed by an anxious and stressed mother. When the changes persist after birth, they may present as maladaptations of the infant to a non-stressful environment. These enduring changes may be among the causes of symptoms decades later such as over- and/or under-reactions to stress.

It seems possible that further research in these areas may find links among human stress responses and human cancers. The current study suggested that the glucocorticoid receptor may play a part in these links.

http://www.pnas.org/content/112/17/5479.full “Glucocorticoid receptor regulates accurate chromosome segregation and is associated with malignancy”

Translating PTSD research findings from animals to humans

gettingwell4 0-1 star Wasted resources, Amygdala, Cortisol, Hippocampus, Limbic system, Neurochemicals, Stress

This 2014 rodent study stressed the animals, measured their stress responses, then killed them and sampled genes in their amygdala, hippocampus, and blood. The researchers found that glucocorticoid receptor signaling genes were the primary pathway associated with “exposure-related individual differences“ in stress responses for the amygdala and blood. This pathway also placed first for the hippocampus in female rats (glucocorticoid receptor was second in male rats and prostate cancer signaling was first).

I’ll quote one press article’s coverage to show where the researchers wanted to go with the study’s findings:

“We found that most of the genes and pathways that are different in PTSD [post-traumatic stress disorder]-like animals compared to resilient animals are related to the glucocorticoid receptor, which suggests we might have identified a therapeutic target for treatment of PTSD.”

How about this lead sentence:

“There may some day be a blood test to determine whether someone suffers from Post-Traumatic Stress Disorder or is at risk for the psychiatric condition.”

Here’s another article’s paraphrase of a different researcher:

“Those are genes that become activated in the presence of stress. Like a key fitting into a lock, the hormone corticosterone, produced naturally by the body, connects to the receptor and has a calming effect.

In some rodents, and apparently in some people, the pathway appears to be defective, and this puts them at higher risk for PTSD.”

Also, from the study’s abstract:

“Corticosterone treatment 1 h[our] after PSS [predator-scent-stress]-exposure prevented anxiety and hyperarousal 7 d[ays] later in both sexes, confirming the GR [glucocorticoid receptor] involvement in the PSS behavioral response.”

Like other researchers continue to do, they stopped this study short of finding causes for the effects:

  1. What were the causes for genes in the glucocorticoid receptor signaling pathway being differentially expressed? “Exposure-related individual differences” isn’t a causal finding.
  2. If this pathway is “defective,” what exactly happened to make it that way?
  3. Did dampening the effects of stress with a shot of cortisol one hour after the stress treat the cause such that the rats were cured? Since the readers of the study and associated articles were led to infer that this treatment was a cure, why destroy the treated animals afterwards before the proofs of long-term efficacy were thoroughly documented and tested?

When studies like this are carried forward with humans, researchers should try to find the causes for these effects. It isn’t sufficient to pretend that there aren’t early-life causes for these effects. Such a pretense leads to the follow-on pretense that later-life consequences are mysteries such as “exposure-related individual differences” and not effects.

Researchers should act like the subjects are feeling human beings who can participate in treatments of both the causes and effects. They should remember that humans are not lab rats who need to be fixed.

http://www.pnas.org/content/111/37/13529.full “Expression profiling associates blood and brain glucocorticoid receptor signaling with trauma-related individual differences in both sexes”

Can a Romanian orphan give informed consent to be an experimental subject?

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

This 2015 study used Romanian orphans as lab rats for findings of which I failed to see the value. The world didn’t really need any further research to demonstrate that foster care would be better for a child than staying in an orphanage.

The researchers placed the orphans in five separate stressful situations, and measured their cortisol and DHEA-S levels, along with their electrocardiograph and impedance cardiograph activity. The findings were:

“Children who were removed from the Romanian institutions and placed with foster parents before the age of 24 months had stress system responses similar to those of children being raised by families in the community.

The children raised in institutions showed blunted responses in the sympathetic nervous system, associated with the flight or fight response, and in the HPA axis, which regulates cortisol.”

One unsupported assertion from the researchers was:

“We provide evidence for a causal link between the early caregiving environment and stress response system reactivity in humans with effects that differ markedly from those observed in rodent models.”

The researchers stated that rodent studies have converged to find:

“Early-life adversity results in hyperreactivity of the sympathetic nervous system (SNS) and hypothalamic–pituitary–adrenal (HPA) axis.”

It’s baloney that the same results from early life adversity in rodents haven’t also been present in humans. Even the lead researcher herself said in a news article:

“More significantly, McLaughlin said, their [the orphans] stress response systems might have been initially hyperactive at earlier points in development, then adapted to high levels of stress hormones.”

The difference was that the rodents were monitored 24/7 until researchers killed and dissected them. The children’s periods of adversity likely started while in the womb, and their lives had been monitored for research purposes sporadically after their births.

Everybody knows that just because adverse events and effects in these children’s lives weren’t recorded by researchers didn’t mean these effects weren’t present at some point.

Particularly irksome was another unsupported assertion from the lead reviewer:

“The children involved in the study are now about 16 years old, and researchers next plan to investigate whether puberty has an impact on their stress responses. It could have a positive effect, McLaughlin said, since puberty might represent another sensitive period when stress response systems are particularly tuned to environmental inputs. “It’s possible that the environment during that period could reverse the impacts of early adversity on the system,” she said.”

No, this is NOT possible. We may as well expect an apple to fall upward.

The impacts of early adversity persist with enduring physiological changes as shown in experimental studies. Studies have NOT provided evidence that the subjects’ environment can cause the effects of complete reversal of all these changes, no matter the stage of life of the subjects.

This point was addressed in The effects of early-life stress are permanent alterations in the child’s brain circuitry and function rodent study:

“The current study manipulates the type and timing of a stressor and the specific task and age of testing to parallel early-life stress in humans reared in orphanages.

The results provide evidence of both early and persistent alterations in amygdala circuitry and function following early-life stress.

These effects are not reversed when the stressor is removed nor diminished with the development of prefrontal regulation regions.”

That study had the same reviewer as the current study. The current study’s lead researcher knew or should have known of this and other relevant research. She knew or should have known of the irreversibility of critical periods, during which developments either occurred or were forever missed.

Did the lead researcher make assertions not supported by the study or relevant research – assertions made counter to her scientific knowledge – show her unease about treating the orphans as lab rats? Was there was some other agenda in play?

The larger problem was the study’s informed consent with this group of Romanian orphans. If you were in contact with a damaged person, and implicitly gave them hope that you would improve their life, then who are you as a feeling human being when you don’t personally carry through? Does the legal documentation matter?

Also, I’ve noticed problems with several studies that had this particular reviewer:

Add the current study to the list.

http://www.pnas.org/content/112/18/5637.full “Causal effects of the early caregiving environment on development of stress response systems in children”

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.

Assessing a mountain climber’s condition without noticing their empty backpack

gettingwell4 2-3 stars Required further work, Acetylcholine, Cortisol, Neurochemicals, Stress

A metaphor: for a mountain climber, which point has the most influence on their condition during the climb?

  • The path ahead?
  • The current situation?
  • The recent past?
  • The starting point?
  • The preparations?

Hard to say? Once the climb has started and until it’s finished, though, are there any points at which the preparations have no influence?

Let’s imagine that factors beyond the climber’s control ruined their preparations, leaving them with no reserves and a limited capability to adapt to environmental changes.

Let’s imagine further that researchers take initial physical and psychological measurements of the climber’s condition at an arbitrary point of the ascent or descent. Due to the design of their measurement system, however, they don’t discover that this climber has an empty backpack.

When the researchers interpret the results, will they understand how the climber’s measurements were influenced by the ruined preparations?  end metaphor

A 2014 Israeli study primary finding was of:

“Fear of terror-induced annual increases in resting heart rate.”

The researchers took 325 measurements each “of 17,380 apparently healthy volunteers” who had “consistent exposure to terror threats.”

The study was opaque in some areas. For example, what was the content and handling of a 4-item anxiety questionnaire?

The supplementary material showed that the headlined “fear of terror” term involved three disparate factors:

  • feeling unsafe;
  • fear of crowds; and
  • anxiety about future harm.

I’d like to understand the bases of why the researchers and the reviewer felt it was appropriate that:

“The scores on these items were averaged to yield a continuous FOT [fear-of-terror] score.”

The researchers probably had sufficient measurements of the subjects’ current conditions. They didn’t have a frame of reference that incorporated the present data with contextual information from each individual’s history back to the earliest parts of their life.

Lacking the links provided by such a framework, the researchers likely misassessed measurements that were influenced by how the subjects’ backpacks were packed.

http://www.pnas.org/content/112/5/E467.full “Fear and C-reactive protein cosynergize annual pulse increases in healthy adults”

A common dietary supplement that has rapid and lasting antidepressant effects

gettingwell4 4-5 stars Advanced knowledge, Cerebrum, Epigenetics, Glutamate, Hippocampus, Limbic system, Neurochemicals, Stress , , ,

This 2012 Italian rodent study found that a common dietary supplement had rapid and lasting antidepressant effects:

“Remarkably, L-acetylcarnitine displayed a clear-cut antidepressant effect already after 3 and 7 d[ays] of daily dosing. No tolerance was developed to the action of L-acetylcarnitine. The drug was even more effective after 21 d[ays], and the effect persisted for at least 2 w[ee]k[s] after drug withdrawal.”

The researchers studied stressed mice and rats to determine that:

  1. An effect of the stress was to epigenetically change the hippocampus to produce less of an important molecule – type 2 metabotropic glutamate (mGlu2).
  2. A reduction of the mGlu2 molecule decreased the hippocampus’ regulation of the glutamate neurotransmitter.
  3. Under-regulation of glutamate, in turn, caused symptoms of depression.

L-acetylcarnitine reversed the immediate causes of stress-induced symptoms by acetylating histone proteins. These control the transcription of the brain-derived neurotrophic factor (BDNF) and mGlu2 receptors in the hippocampus and prefrontal cortex.

LAC putative action

A commentary on this research, Next generation antidepressants, had the above graphic that showed possible mechanisms for the effects of L-acetylcarnitine. Epigenetic histone modifications seem to be more easily reversible than epigenetic DNA methylation.

“Currently, depression is diagnosed only by its symptoms,” Nasca says. “But these results put us on track to discover molecular signatures in humans that may have the potential to serve as markers for certain types of depression.”

It’s tempting to extrapolate this study to humans and test whether depression symptoms could be effectively treated with some multiple of a normal acetyl-L-carnitine dietary supplement dose of 500 mg at $.25 a day. This dietary supplement is better for depression symptoms than placebo analyzed randomized control trials that tested and demonstrated its efficacy.

To cure stress-induced illnesses in humans, though, ultimate causes of stress should be removed or otherwise addressed.

http://www.pnas.org/content/110/12/4804.full “L-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors”

Adaptations to stress encourage mutations in a DNA area that causes diseases

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Stress

This 2015 Baylor human cell study subject was the underlying mechanisms of cellular responses to environmental stressors of cold, heat, hypoxia, and oxidation:

“Because trinucleotide repeats are overrepresented in gene-regulatory proteins, stress-induced trinucleotide repeat mutagenesis may provide a path for the environment to subtly alter gene regulatory networks – with attendant changes in cell behavior – during development, disease, and evolution.”

The study’s overarching framework was that human cells will adapt to best survive in their environment. The study found that the cells’ responses to stress encouraged the creation of mutations in a DNA area that’s:

“The cause of multiple human diseases. This pathway may impact normal cells as they encounter stresses in their environment or during development or abnormal cells as they evolve metastatic potential.”

It’s a logical inference to likewise understand how stressors in a mother’s environment for a developing fetus will cause the fetus to adapt at the cellular level. If, for example, the fetus is stressed by inadequate oxygen – hypoxia – this study shows how cells will adapt in ways that foster mutations and diseases.

When the stressed fetus arrives in a different environment after birth, the newborn’s cells are maladapted to certain aspects of a normal environment – to adequate oxygen in this example. Many of the cells’ adjustments to the old environment persist in the new environment. Pathways epigenetically adapted to best survive during the fetus’ development in the womb may impact the infant’s development in a normal environment.

Researchers could make significant contributions to science by investigating treatments and therapies that potentially reverse causes of epigenetic changes.

http://www.pnas.org/content/112/12/3764.full “Environmental stress induces trinucleotide repeat mutagenesis in human cells”

Pulling on the chain of causes and effects with insulin resistance

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

This 2015 Harvard rodent study found multiple undesirable symptoms and attributed the cause to insulin resistance, which is itself a symptom.

Humans most often develop the symptom of insulin resistance due to causes other than genetics, such as a result of abnormal eating behaviors, which are symptoms of other causes.

Use of insulin-resistant-due-to-genetics mice may have misdirected the researchers to lose focus that their ultimate task was to find ways that their research can help humans. If helping humans was the researchers’ focus, it may have occurred to them to develop evidence for how “something” caused symptoms such as abnormal eating behaviors, that in turn caused a symptom of insulin resistance.

The study’s unexamined causes included why genetically insulin-resistant mice developed symptoms of anxiety and depressive-like behaviors between early adulthood and late middle age. Examples of undesirable symptoms described in the supplementary material included:

  • Higher body weight in late middle age, especially in females;
  • Depressive-like behavior in both sexes by late middle age;
  • Higher corticosterone levels in both sexes by late middle age, even when unstressed; and
  • Higher corticosterone levels in late middle age when stressed, especially in males.

It’s remarkable how researchers consistently get caught in a loop of studying only symptoms, paying little attention to studying causes, then suggesting various medications and treatments to suppress the studied symptoms.

It’s not surprising then that there’s no explanation of why and how symptoms develop. The study designs seldom include trying to show causes for the effects in the first place!

http://www.pnas.org/content/112/11/3463.full “Insulin resistance in brain alters dopamine turnover and causes behavioral disorders”

Losing track of what are symptoms and what are causes with serotonin and stress

gettingwell4 0-1 star Wasted resources, Limbic system, Neurochemicals, Serotonin, Stress, Thalamus ,

I’m starting to appreciate just how far down the rabbit hole researchers can go when they focus on symptoms and ignore causes.

This 2014 Duke study found that low-serotonin mice were more susceptible to stress than normal mice.

Okay so far, except that the study used transgenic mice that only had 20-40% of normal serotonin.

Humans most often develop low-serotonin symptoms for causes other than genetics, such as a second-order result of being subjected to childhood maltreatment and stress.

Use of the low-serotonin-due-to-genetics mice may have misdirected the researchers to lose focus that their ultimate task was to find ways that their research can help humans. If helping humans was the researchers’ focus, it may have occurred to them to show how stress caused “something” that caused low serotonin.

A second finding was that following exposure to stress, the low-serotonin mice didn’t respond to a standard antidepressant, fluoxetine. SSRI medications usually act to increase serotonin transmission, i.e. treat the symptom of low serotonin.

Stress was again not viewed as a cause of “something” that caused low serotonin. Stress was viewed as the reason that the medication didn’t work.

If helping humans was the researchers’ focus, it may have occurred to them that humans may not need medication to treat the low-serotonin symptom if the “something” that stress caused that keeps the low-serotonin symptom in place was removed.

A third finding was that inhibiting the lateral habenula area (proximal to the thalamus) with a drug relieved some depression-like behavior of the low-serotonin mice.

Okay, but one of the researchers went on to say:

“The next step is to figure out how we can turn off this brain region in a relatively non-invasive way that would have better therapeutic potential.”

Would everything would be fine if the low-serotonin mice just stopped displaying symptoms such as the depression-like behavior? Why no focus on causes, no forward thinking that maybe humans wouldn’t want part of their limbic system that performed many other functions to “turn off” just to suppress a symptom?

The researchers apparently didn’t realize their situation viz-à-viz the rabbit hole, as they circled back to the initial finding to develop a fourth finding – a possible reason that low-serotonin mice were more susceptible to stress was because a signaling molecule, β-catenin, wasn’t produced in a pathway that may be involved in resilience.

The news coverage added one more researcher quote:

“If we can identify what’s both upstream and downstream of β-catenin we might be able to come up with attractive drug targets to activate this pathway and promote resilience.”

If we treat a third-order symptom, the signaling molecule, everything will be alright?

Which leads me to ask:

http://www.pnas.org/content/112/8/2557.full “Brain 5-HT deficiency increases stress vulnerability and impairs antidepressant responses following psychosocial stress”

Is it science, or is it a silly and sad farce when researchers “make up” missing data?

gettingwell4 < 0 Detracted from science, Brain development, Epigenetics, Hippocampus, Limbic system, Stress , , ,

This 2014 French study was a parody of science.

The researchers “made up” missing data on over 50% of the men and over 47% of the women! All to satisfy their model that drove an agenda of the effects of adverse childhood experiences.

As an example of how silly and sad this was:

  • Two of the seven subject ages of interest were 23 and 33 consecutively, and
  • One of the nine factors was education level.

If I was a subject, and wasn’t around to give data at age 33 and later, how would the researchers have extrapolated a measurement of my education level of “high school” at age 23?

I’m pretty sure their imputation method would have “made up” education level data points for me of “high school” for ages 33 and beyond. I doubt that the model would have produced my actual education levels of a Bachelors and two Masters degrees at age 33.

Everything I said about the Problematic research on stress that will never make a contribution toward advancing science study applied to this study, including the “allostatic load” buzzword and the same compliant reviewer.

Studies like this both detract from science and are a misallocation of scarce resources. Their design and data aren’t able to reach levels where they can provide etiologic evidence.

Such studies also have limiting effects on how we “do something” about real problems, because the researchers won’t be permitted to produce findings that aren’t politically correct.

http://www.pnas.org/content/112/7/E738.full “Adverse childhood experiences and physiological wear-and-tear in midlife: Findings from the 1958 British birth cohort”

Dr. Arthur Janov interview on his 2011 book Life Before Birth: The hidden script that rules our lives

gettingwell4 4-5 stars Advanced knowledge, Brain development, Cerebrum, Cortisol, Epigenetics, Limbic system, Lower brain, Neurochemicals, Primal Therapy, Stress, Telomeres , , , , , ,

Dr. Arthur Janov’s 2011 book “Life Before Birth: The hidden script that rules our lives” describes problems that start in the earliest parts of our lives, when epigenetic changes due to trauma in the womb affect our development.

“The science has changed. When I first started out 44 years ago, there was nobody who could understand it, or agree, especially the professionals. Now all, or a great deal of the current research, is backing up everything I say.

I’m saying that this therapy is really a matter of life and death now. I should probably start at the beginning and say that there’s trauma in the womb. We need to set back the clock so that we take account of trauma that occurs while our mother is carrying that has lifelong consequences for how long we live, for example. There’s a current research study that shows that as you get more traumatized in the womb, your life expectancy is much shorter.

When you get rid of the childhood pain that happened way back when – and there are ways to do it – you will live much longer. So truly, a proper therapy now is a matter of life and death. Not only because your life expectancy is shorter when you have trauma, but you get sick earlier, you have diabetes, Alzheimer’s, all kinds of diseases on your way to your death, which makes life very uncomfortable.

But that’s just part of what we do. The idea is that we found a way to take the pain out of the system, going all the way back. And what we’re finding is that pain starts way, way earlier than we thought.

I used to think that the greatest point was the birth trauma. Well that’s no longer true. Way before the birth trauma there are traumas from the smoking mothers, the anxious mothers, the depressed mothers, that have lifelong effects on the baby, the offspring.”

“https://www.youtube.com/watch?v=dbUhjZhpEyct”

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