4-5 stars Advanced knowledge

Advanced knowledge

A walk in the park increases poor research practices and decreases reviewer critical thinking

gettingwell4 4-5 stars Advanced knowledge

“That’s right folks – the key behavioral interaction of the paper – is non-significant. Measly. Minuscule.

Forget about p-values for a second and consider the gall it takes to not only completely skim over this fact (nowhere in the paper is it mentioned) and head right to the delicious t-tests, but to egregiously promote this ‘finding’ in the title, abstract, and discussion as showing evidence for an effect of nature on rumination!

No correlations with the (non-significant) behavior. Just pure and simple reverse inference piled on top of fallacious interpretation of a non-significant interaction.”

http://www.pnas.org/content/112/28/8567.full “Nature experience reduces rumination and subgenual prefrontal cortex activation”

One way our bodies remember our histories

gettingwell4 4-5 stars Advanced knowledge, Immune system, Memory

This 2015 California rodent study found:

“Potentially pathogenic memory cells in lymph nodes and redistribution throughout normal and inflamed skin may help explain the generalized worsening of psoriasis reported in patients undergoing localized skin treatment with imiquimod.”

The opening sentence was:

“An attribute of adaptive immunity is the generation of memory cells that mount enhanced responses after rechallenge.”

Of course an immune system remembers – that’s part of its function.

When the subject is memory, let’s not disregard the multiple ways that our bodies remember our histories.

http://www.pnas.org/content/112/26/8046.full “Inflammation induces dermal Vγ4+ γδT17 memory-like cells that travel to distant skin and accelerate secondary IL-17–driven responses”

The effects of inescapable, uncontrollable, repeated stress on the hippocampus

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

This 2015 MIT rodent study found:

“Behavioral stress impairs cognitive function via activation of a specific direct neural circuit from the basolateral amygdala to the dorsal hippocampus. Moreover, we delineate a molecular mechanism by which behavioral stress is translated to hippocampal dysfunction via a p25/Cdk5 (cyclin-dependent kinase 5)-dependent pathway and epigenetic alterations of neuroplasticity-related gene expression.”

The researchers made several intermediate findings to develop their main finding:

1. “Repeated stress is accompanied by

  • generation of p25,
  • up-regulation and phosphorylation of glucocorticoid receptors,
  • increased HDAC2 [the gene encoding the histone deacetylase 2 enzyme] expression, and
  • reduced expression of memory-related genes [most, but not all that were tested] in the hippocampus.”

2. “BLA [basolateral amygdala] activation is both necessary and sufficient for stress-associated molecular changes and memory impairments.”

3. “This effect [2. above] relies on direct glutamatergic projections from the BLA to the dorsal hippocampus.”

4. “p25 generation is necessary for the stress-induced memory dysfunction.”

From the Results section:

“Control mice showed a significant preference for the novel over the familiar object or location, whereas RFS [repetitive foot shock]-treated mice performed no better than chance.”

The subject adult mice underwent:

“Inescapable, uncontrollable repeated stress.”

Do humans also experience impaired “cognitive function” and “hippocampal dysfunction” and “epigenetic alterations of neuroplasticity-related gene expression” caused by “inescapable, uncontrollable repeated stress”?

And what are the real histories of people who aren’t curious, who don’t show “a significant preference for the novel over the familiar object or location”?

http://www.pnas.org/content/112/23/7291.full “Basolateral amygdala bidirectionally modulates stress-induced hippocampal learning and memory deficits through a p25/Cdk5-dependent pathway”

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”

One way beliefs produce pleasure and reward in the cerebrum

gettingwell4 4-5 stars Advanced knowledge, Beliefs, Cerebrum, Dopamine, Neurochemicals ,

This 2014 Singapore human study found:

“Differences in belief learning – the degree to which players were able to anticipate and respond to the actions of others, or to imagine what their competitor is thinking and respond strategically – was associated with variation in three genes which primarily affect dopamine functioning in the medial prefrontal cortex.

In contrast, differences in trial-and-error reinforcement learning – how quickly they forget past experiences and how quickly they change strategy – was associated with variation in two genes that primarily affect striatal dopamine.”

One of the researchers said:

“The findings correlate well with previous brain studies showing that the prefrontal cortex is involved in belief learning, while the striatum is involved in reinforcement learning.”

The study didn’t demonstrate cause and effect, however, and the researchers cautioned:

“It would be mistaken to interpret our results as suggesting that dopamine genes function as “belief learning genes.”

The study added to the science of how beliefs act on the pleasure and reward parts of the cerebrum.

http://www.pnas.org/content/111/26/9615.full.pdf “Dissociable contribution of prefrontal and striatal dopaminergic genes to learning in economic games” (the pdf file is linked because the html had errors)

The critical period for some aspects of human sight can be extended past childhood

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

This 2013 human study provided further details of critical periods in human development. The study subjects were:

“11 children enrolled in a humanitarian and scientific effort in India that provides corrective surgery to children with treatable cataracts and subsequently studies their visual abilities.”

The researchers found:

“The human visual system can retain plasticity beyond critical periods, even after early and extended blindness.

We define “early-onset” blindness as occurring before 1 y of age. We define “extended” blindness as lasting at least until early childhood, when many visual abilities in normally developing children reach adult levels. Contrast sensitivity in particular develops until approximately age 7 in normally sighted humans.

Of the 11 children, five had no discernible improvement, whereas one child’s vision grew worse, probably because of post-surgical complications. Five of the patients showed remarkable enhancement, however, and of these, an 11-year-old and a 15-year-old showed 30-fold improvement in contrast sensitivity.

“The visual brain can be plastic for longer than we originally thought,” concludes Kalia. “Many of the kids dramatically improve their quality of life.”

http://www.pnas.org/content/111/5/2035.full “Development of pattern vision following early and extended blindness”

The prefrontal cortex develops more repressive function at puberty

gettingwell4 4-5 stars Advanced knowledge, Brain development, Cerebrum, Primal Therapy , ,

This 2014 primate study found:

“The average magnitude of functional connections measured between neurons was lower overall in the prefrontal cortex of peripubertal [age when puberty starts] monkeys compared with adults. The difference resulted because negative functional connections (indicative of inhibitory interactions) were stronger and more prevalent in peripubertal compared with adult monkeys.”

The researchers found more inhibitory functional connections at the onset of puberty than during adulthood. This repressive functionality presumably develops at puberty because that’s when it’s relatively more needed:

“The bias toward increased inhibitory connectivity we report here for young monkeys might also be an intrinsic feature of human prefrontal cortex at a comparable stage of development.”

One hypothesis of Dr. Arthur Janov’s Primal Therapy is that repression is an important function that the prefrontal cortex evolved.

http://www.pnas.org/content/111/10/3853.full “Age-dependent changes in prefrontal intrinsic connectivity”

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”

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”

The hypothalamus’ role in how calorie restriction delays aging

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

This 2015 Portuguese rodent study showed the underlying mechanism to explain why restricting calories delays aging.

A calorie reduction of 20 to 40% increased production of a normally occurring molecule (neuropeptide Y) in the hypothalamus part of the limbic system. The increased amounts of the molecule stimulated autophagy (the breakdown and recycling of cellular components) in hypothalamic neurons.

“Because both hypothalamic autophagy and neuropeptide Y levels decrease with age..modulation of hypothalamic neuropeptide Y levels may be considered a potential strategy to produce protective effects against hypothalamic impairments associated with age and to delay aging.”

http://www.pnas.org/content/112/13/E1642.full “Neuropeptide Y stimulates autophagy in hypothalamic neurons”

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”

Oxytocin blocks alcohol intoxication symptoms

gettingwell4 4-5 stars Advanced knowledge, Neurochemicals, Oxytocin, Vasopressin

This joint 2015 Australian/German rodent study found that oxytocin bound to the brain receptors that cause loss of motor control with alcohol intoxication, and prevented rats from displaying these symptoms:

“While oxytocin might reduce your level of intoxication, it won’t actually change your blood alcohol level,” Dr Bowen said. “This is because the oxytocin is preventing the alcohol from accessing the sites in the brain that make you intoxicated, it is not causing the alcohol to leave your system any faster.”

Vasopressin didn’t have the same effect.

The level of alcohol used to produce this finding was roughly equivalent to a human drinking a bottle of wine over a few hours. Oxytocin didn’t prevent loss of motor control when the equivalent of a bottle of vodka was administered because the excess ethanol found its way into other brain receptors and put the rats to sleep.

The study showed oxytocin acting in its original functionalities such as water regulation rather than with its evolved social functions as described in How oxytocin and vasopressin were repurposed through evolution to serve social functions.

http://www.pnas.org/content/112/10/3104.full “Oxytocin prevents ethanol actions at δ subunit-containing GABA-A receptors and attenuates ethanol-induced motor impairment in rats”

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.

Dr. Arthur Janov Book Expo America 2008 Interview

gettingwell4 4-5 stars Advanced knowledge, Cerebrum, Limbic system, Lower brain, Primal Therapy , ,

“Our therapy is centered on needs.

As we grow up we have different kinds of needs.

The need right after birth is be touched.

The need at birth is to have a good birth with oxygen, etc.

Then it’s to be held, to be listened to, and so on.

For each of the needs that are not fulfilled, there’s pain.

And it’s registered on different levels of the brain.

What we have found a way to do is to go back down into the brain and take those pains out of the system.

So you don’t have to take pills to stuff it back.

What we do is, little by little, take the pain out of the system that is based on not-fulfilled needs.

So that’s basically what Primal Therapy is about.”