Stress

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”

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.

If research treats “Preexisting individual differences” as a black box, how can it find causes for stress and depression?

gettingwell4 0-1 star Wasted resources, Epigenetics, Immune system, Stress ,

This 2014 research studied both humans and rodents to provide further evidence on the physiology of defeat. The researchers demonstrated that with mice:

“Bone marrow transplants of stem cells that produce leucocytes lacking IL-6 (the cytokine interleukin 6) or when injected with antibodies that block IL-6 prior to stress exposure, the development of social avoidance was reduced.”

The researchers also showed in humans that standard antidepressants didn’t act to lower IL-6.

So, what were we to make of this finding?

“Preexisting differences in the sensitivity of a key part of each individual’s immune system to stress confer a greater risk of developing stress-related depression or anxiety.”

  • Was it sufficient for the researchers and the news articles covering the research to treat “preexisting differences” as a black box that nobody could enter to find causes for the effects of “developing stress-related depression or anxiety?”
  • Did things happen in each individual’s history to cause the “preexisting differences” or was each individual born that way?
  • Why was the research directed at symptoms with no mention of any underlying causal factors?

It wasn’t sufficient for the researchers to carry on their experiments with assumptions that there weren’t early-life causes for the above symptoms. Such a pretense leads to the follow-on pretense that later-life consequences weren’t effects of causes, but were instead, mysteries due to “preexisting individual differences.”

http://www.pnas.org/content/111/45/16136.full “Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress”

Problematic research on stress that will never make a contribution toward advancing science

gettingwell4 < 0 Detracted from science, Cortisol, Neurochemicals, Stress

This 2014 UK human study found:

“Type 2 diabetes is characterized by disruption of stress-related processes across multiple biological systems and increased exposure to life stress.”

HOWEVER, the stress effects weren’t conclusively shown to be either a cause or consequence of type 2 diabetes. Correlation wasn’t causation.

Looking around for clues as to what went wrong, I found this data sample of cortisol in a small table that comprised the total amount of information in the supplementary material:

“Geometric means, adjusted for education, marital status, BMI, smoking status, use of statins, and time of day.”

It’s hubris for the researchers to state that they improved data measurements by averaging them after adjusting for all of the above six factors.

Maybe the problem was elsewhere, maybe in the study design. Wherever the problems were, they guaranteed that the researchers would NEVER find cause and effect.

But maybe that’s the point?

There appeared to be other agendas that ensured studies like these failed to make a contribution toward advancing science. The researchers inevitably used buzzwords such as “allostatic load” and cited the need for further studies (money). Everybody was okay with that, including the reviewer, and everybody kept their safe jobs.

Such studies also had limiting effects on how we “do something” about real problems because the researchers wouldn’t produce findings that weren’t politically correct.

http://www.pnas.org/content/111/44/15693.full “Disruption of multisystem responses to stress in type 2 diabetes: Investigating the dynamics of allostatic load”

If research provides evidence for the causes of stress-related disorders, why only focus on treating the symptoms?

gettingwell4 0-1 star Wasted resources, Brainstem, Cortisol, Hippocampus, Hypothalamus, Limbic system, Locus coeruleus, Lower brain, Memory, Neurochemicals, Stress , , ,

This 2014 rodent research reliably induced many disorders common to humans. Here are some post-birth problems the researchers caused, primarily by applying different types of stress, as detailed in the study’s supplementary material:

Yet the researchers’ goal was to identify a brain receptor for:

“Novel therapeutic targets for stress-related disorders.”

In other words, develop new drugs to treat the symptoms.

Where are the studies that have goals to prevent these common problems being caused in humans by humans?

Where is the research on treatments to reverse the enduring physiological impacts to stress by treating the causes?

What do you think of this excerpt?

“Accumulating evidence suggests that traumatic events particularly during early life (e.g., parental loss or neglect) coupled with genetic factors are important risk factors for the development of depression and anxiety disorders.

Moreover, the brain is particularly vulnerable to the effects of stress during this period.

Maternal separation in rodents is a useful model of early-life stress that results in enduring physiological and behavioral changes that persist into adulthood, including increased hypothalamic–pituitary–adrenal (HPA)–axis sensitivity, increased anxiety, and visceral hypersensitivity.”

http://www.pnas.org/content/111/42/15232.full “GABAB(1) receptor subunit isoforms differentially regulate stress resilience”

How to make a child less capable even before they are born: stress the pregnant mother-to-be

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

This 2014 rodent study showed how to make a less-capable pup by stressing the mother early in gestation. The study centered on a placental enzyme (OGT) that translates a mother’s stress into neuroprogramming of her developing fetus.

One finding was that this enzyme was less plentiful when the fetus was male compared with female.

Another finding was that the enzyme was less plentiful when the mother was stressed early in gestation, compared with unstressed mothers.

Informed by the first two findings, the researchers studied the placentae of male pups where the mother was stressed early in gestation. They found that these placentae had lower levels of an enzyme (Hsd17b3) that converts the precursor androstenedione into testosterone.

The resultant finding was that the male pups of stressed mothers had lower levels of testosterone than the control group of male pups.

A fourth finding was that offspring of both sexes born with a placenta where the OGT enzyme was less plentiful had 10-20% less body weight, a condition that developed after weaning. The researchers attributed this finding to reduced mitochondrial function in the hypothalamus compared with normal mice.

http://www.pnas.org/content/111/26/9639.full “Targeted placental deletion of OGT recapitulates the prenatal stress phenotype including hypothalamic mitochondrial dysfunction”

Are stress-induced epigenetic changes to DNA inherited across generations?

gettingwell4 0-1 star Wasted resources, Amygdala, Brain development, Cortisol, Epigenetics, Limbic system, Memory, Neurochemicals, Stress , , , , ,

This 2014 Geneva/Cambridge plant study ended by stating:

“The unequivocal demonstration of transgenerational transmission of environmentally-induced epigenetic traits remains a significant challenge.

One of the critical activities erasing stress memories is conserved between plants and mammals.”

However, the researchers didn’t demonstrate that their findings were broadly applicable for mammals or organisms other than the specific plant variety they studied. Possible reasons for these limited findings were given in a 2015 Australian study referenced by Mechanisms of stress memories in plants:

“The majority of DNA methylation analyses performed in plants to date have focused on Arabidopsis, despite being relatively depleted of TEs [transposable elements] (15–20% of the genome) and being poorly methylated compared to other plant genomes.

These studies have lacked the resolution to provide the specific context and genomic location of the changes in DNA methylation.”

There are also significant differences in how epigenetic inheritance across generations may operate among different species per Epigenetic reprogramming in plant and animal development.

Neither the current study nor the above review addressed the behavioral aspect of stress-induced epigenetic inheritance across generations. For example, the behavior of a mother whose DNA was epigenetically changed by stress can induce the same epigenetic changes to her child’s DNA when her child is 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.”

http://www.pnas.org/content/111/23/8547.full “Identification of genes preventing transgenerational transmission of stress-induced epigenetic states”

Hypothalamic oxytocin and vasopressin have sex-specific effects on pair bonding, gregariousness, and aggression

gettingwell4 4-5 stars Advanced knowledge, Hypothalamus, Limbic system, Neurochemicals, Oxytocin, Stress, Vasopressin

This 2014 bird study showed the complementary effects of neurochemicals vasopressin and oxytocin in the hypothalamus.

Oxytocin neurons in the hypothalamus promote pair bonding and gregariousness in females.

Vasopressin neurons in the hypothalamus promote maternal care, social recognition, and gregariousness in both males and females, and aggression in males toward females.

Vasopressin and oxytocin released generally and in other parts of the brain have different effects. For example:

“Central administration of oxytocin also attenuates stress-induced effects on the brain and reverses stress-induced social avoidance.”

http://www.pnas.org/content/111/16/6069.full “Hypothalamic oxytocin and vasopressin neurons exert sex-specific effects on pair bonding, gregariousness, and aggression in finches”

Why do researchers title their study the cortex vs. the limbic system or lower brain?

gettingwell4 2-3 stars Required further work, Brain development, Brainstem, Cerebrum, Limbic system, Lower brain, Stress ,

This 2012 review of 89 studies was ostensibly of the prefrontal cortex. The review title showed how researchers characterize their work as studying the cerebrum, even when they primarily deal with the limbic system and lower brains.

For example, the reviewer discussed rodent studies of the developing pup fetus regarding:

  • Sensory/motor – Paternal complex housing, maternal complex housing
  • Stress – Mild stress, bystander stress, moderate stress
  • Psychoactive drugs – Stimulants
  • Adult stimulants – Ethanol

The active brain areas of the rodent fetus are the brainstem and the limbic system, and those areas were primarily what was studied. The cerebrum of the developing pup is a tiny strip that has little cognitive function.

http://www.pnas.org/content/109/Supplement_2/17186.full “Experience and the developing prefrontal cortex”

Chronic stress changes the architecture of the hippocampus, leading to depression and cognitive impairment

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

This 2014 rodent study gave further details that:

“Chronic stress, which can precipitate depression, induces changes in the architecture and plasticity of apical dendrites that are particularly evident in the CA3 region of the hippocampus.”

Other studies on the hippocampus CA3 region include:

http://www.pnas.org/content/111/45/16130.full “Role for NUP62 depletion and PYK2 redistribution in dendritic retraction resulting from chronic stress”