Neurochemicals

How brain neurons remain stable when constantly stimulated

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

This 2015 UK rodent study provided details of how neurons in the hippocampus respond to stimuli. The researchers found that hippocampal neurons:

“Remain electrically stable when confronted with chronic increases in neuronal activity.”

Changes in electrical potential changed the initial segment of the neuron’s axon.

Synapses formed along the segment, and stayed in place while this highly-plastic segment moved along the axon. The location mismatch:

“Allows the GABAergic [producing gamma-Aminobutyric acid, an inhibitory neurochemical] synapses to strongly oppose action potential generation, and thus downregulate pyramidal cell excitability.”

The researchers also used the two antioxidants endogenous to humans, superoxide dismutase and glutathione, to supplement the culture medium.

http://www.pnas.org/content/112/31/9757.full “Activity-dependent mismatch between axo-axonic synapses and the axon initial segment controls neuronal output”

Perpetuating the meme that rodent PTSD experiments necessarily apply to humans

gettingwell4 0-1 star Wasted resources, Cerebrum, Limbic system, Lower brain, Memory, Neurochemicals, Stress

This 2015 Texas A&M rodent study found:

“Propranolol administration dampened the stress-induced impairment in extinction observed when extinction training is delivered shortly after fear conditioning.”

The researchers were way off base in extrapolating this study to humans:

“Propranolol may be a helpful adjunct to behavioral therapy for PTSD, particularly in patients who have recently experienced trauma.”

Would National Institutes of Health Grant R01MH065961 money have been available without perpetuating the meme that rodent PTSD experiments necessarily apply to humans? Or are a priori findings necessary in order to get research funded?

In rodent studies such as this one, the origins of both the disease and the “cure” are all exerted externally. But humans aren’t lab rats. We can perform effective therapy that doesn’t involve some outside action being done to us.

Studies such as Fear extinction is the learned inhibition of retrieval of previously acquired responses make clear that extinction is equivalent to suppression. “Behavioral therapy for PTSD” that suppresses symptoms can’t be a “cure” for humans since the original causes for the symptoms aren’t treated.

Even if this study’s recommendation to administer a drug applied to humans, neither drugs nor “behavioral therapy for PTSD” address the underlying causes.

http://www.pnas.org/content/112/28/E3729.full “Noradrenergic blockade stabilizes prefrontal activity and enables fear extinction under stress”

Dopamine may account for differences in cognitive performance

gettingwell4 2-3 stars Required further work, Anterior cingulate cortex, Cerebrum, Dopamine, Hippocampus, Limbic system, Memory, Neurochemicals, Thalamus ,

This 2015 German human study found:

“Dopamine may account for adult age differences in brain signal variability.”

The researchers administered amphetamine to the subjects to boost their dopamine levels, and measured their cognitive performance on several working memory tests under fMRI:

“Older adults expressed lower brain signal variability at placebo, but met or exceeded young adult..”

brain signal variability levels when on speed.

The order of the tests also influenced the results. Older adults who received amphetamine during the initial series of tests performed better on placebo during the second series of tests.

As is often done, the researchers focused on effects and not causes. I didn’t see questionnaires or investigation into possible historical or biological factors for reduced dopamine levels, leaving the researchers with age as the only correlated-but-not-causative explanation.

http://www.pnas.org/content/112/24/7593.full “Amphetamine modulates brain signal variability and working memory in younger and older adults”

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”

An inhibitory gene that affects alcohol binge behavior

gettingwell4 2-3 stars Required further work, Beliefs, Cerebrum, Dopamine, Limbic system, Lower brain, Neurochemicals, Thalamus , , ,

This 2015 La Jolla rodent study found that an inhibitory gene affected alcohol binging behavior:

“Our study reveals the behavioral impact of this cellular effect, whereby the level of GIRK3 [the gene] expression in the VTA [ventral tegmental area] tunes ethanol intake under binge-type conditions: the more GIRK3, the less ethanol drinking.”

GIRK3-silenced mice still binged, though, and got alcohol’s rewarding effects through dopamine’s other neural pathways.

High concentrations of the gene were found in the thalamus part of the limbic system of wild-type mice, the control group. Per the study’s title, this gene presumably contributes to the thalamus’ overall function of gating information from limbic system and lower brain areas to reach the cerebrum and vice versa.

And the potential causes for reduced GIRK3 expression are..?? Hopefully – someday – researchers will be focused on finding causes for abnormal gene expression rather than being content to just study effects of abnormal gene expression. Until then, the usual practice of considering only the effects led these researchers to:

“Believe that a compound selectively targeting GIRK3-containing channels may hold promise for reducing alcohol consumption in heavy binge drinkers.”

http://www.pnas.org/content/112/22/7091.full “GIRK3 gates activation of the mesolimbic dopaminergic pathway by ethanol”

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”

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)

A mixed bag of findings about oxytocin, its receptor, and autism

gettingwell4 0-1 star Wasted resources, Epigenetics, Neurochemicals, Oxytocin ,

This 2014 Stanford human study found:

“No empirical support for the OXT [oxytocin] deficit hypothesis of ASD [autism spectrum disorder], nor did plasma OXT concentrations differ by sex, OXTR [oxytocin receptor] SNPs [single nucleotide polymorphisms], or their interactions.”

Apparently, there was a:

“Prevalent but not well-interrogated OXT deficit hypothesis of ASD.”

The researchers followed up this worthwhile finding with three weak findings. The first, as stated by one of the study’s lead researchers, was:

“It didn’t matter if you were a typically developing child, a sibling or an individual with autism: Your social ability was related to a certain extent to your oxytocin levels.”

The second weak finding was that, regarding OXTR SNPs:

“The minor allele of rs2254298 predicted global social impairments on the SRS [Social Responsiveness Scale] and diagnostic severity on the ADI-R [Autism Diagnostic Interview-Revised]. In contrast, the major allele of rs53576 predicted impaired affect recognition performance on the NEPSY [A Developmental NEuroPSYchological Assessment].”

This was at odds with other relevant research, leading the researchers to state:

“The functional significance of these two intronic variants remains unknown.”

The third weak finding irked me:

“Plasma OXT concentrations were highly heritable.”

because the researchers didn’t attempt to differentiate the contribution of the environment for the observed blood oxytocin levels, as did the similar How epigenetic DNA methylation of the oxytocin receptor gene affects the perception of anger and fear study.

I wonder what the reviewer’s feedback was about these weak findings. Did he make the researchers insert specific language into the lengthy paragraph about the study’s limitations, or did he give them a pass?

http://www.pnas.org/content/111/33/12258.full “Plasma oxytocin concentrations and OXTR polymorphisms predict social impairments in children with and without autism spectrum disorder”

What causes disconnection between the limbic system and the cerebrum?

gettingwell4 0-1 star Wasted resources, Cerebrum, Dopamine, Glutamate, Hippocampus, Limbic system, Memory, Neurochemicals

This 2014 Swedish human study with 339 subjects aged 25-80 years old found that as the subjects’ age increased, their hippocampus became less connected to their cerebrums:

“Age-related cortico–hippocampal functional connectivity disruption leads to a more functionally isolated hippocampus at rest, which translates into aberrant hippocampal decoupling and deficits in active mnemonic processing.”

The lead researcher said:

“What we can now show is that memory problems that come with increased age are most likely due to a process where the interaction among different regions of the hippocampus increases in response to less inhibitory cortical input. This in turn means that the hippocampus risks being more isolated from other important networks in the brain which impacts our ability to actively engage the hippocampus, for example to remember different events.”

Like other researchers commonly do, they excluded emotional content from the study. See another Swedish study Emotional memories and out-of-body–induced hippocampal amnesia as an example of why emotional memories are necessary in order to properly study the hippocampus.

1) As a result of excluding emotional content and other aspects of the study’ design such as using 25 as the beginning age of the subjects, all the researchers could muster as a explanatory factor was age. However, they had to couch their findings as “age-related” because age in and of itself wasn’t a causal explanation for the observed effects.

2) The findings weren’t even truly “age-related”  because, for example, the study didn’t necessarily apply to people below the age of 25. Had the study included 10-18 year old subjects, the researchers may have found that “less inhibitory cortical input” may also be present before puberty, as The prefrontal cortex develops more repressive function at puberty study indicated.

3) Had the study design included neurochemicals, the researchers may have found that “cortico–hippocampal functional connectivity disruption” was due to factors that influenced dopamine and glutamate levels, as A mechanistic study of neurotransmitters in the hippocampus indicated.

4) A finding that “cortico–hippocampal functional connectivity disruption” was influenced by other factors may also have been made had the study design included the subjects’ histories. Per my Welcome page, the findings of much of the recent research I’ve curated on this blog, and the references in those studies show that when basic needs aren’t met, especially early in people’s lives, and the painful conditions persist, enduring physiological changes may occur.

5) What the researchers noted in the study’s limitation paragraph were references to fMRI scans rather than limitations such as those mentioned above regarding the study design. The study provided unconvincing evidence for causes of “cortico–hippocampal functional connectivity disruption” and it wasn’t because of fMRI limitations.

http://www.pnas.org/content/111/49/17654.full “Elevated hippocampal resting-state connectivity underlies deficient neurocognitive function in aging”

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.

A missed opportunity to research the oxytocin receptor gene and autism

gettingwell4 2-3 stars Required further work, Amygdala, Brain development, Epigenetics, Hypothalamus, Limbic system, Neurochemicals, Oxytocin, Vasopressin ,

This 2013 study:

“Examined whether genetic variants of the OXTR [oxytocin receptor] affect face recognition memory in families with an autistic child.

We investigated whether common polymorphisms in the genes encoding the oxytocin and vasopressin 1a receptors influence social memory for faces.”

I feel that the researchers missed an opportunity to improve their assessment of the autism-related genetic contribution to the study’s findings by separating the degree of environmental influence on the oxytocin receptor gene expression, as did the How epigenetic DNA methylation of the oxytocin receptor gene affects the perception of anger and fear study.

An assessment of epigenetic DNA methylation of the oxytocin receptor gene may have been even more compelling because the researchers genetically sampled one non-autistic sibling in each of the autistic children’s families. I hope the study’s samples are still available, because they may offer the possibility of evaluating the contribution of the autistic children’s historical environment with potential confirmation from their siblings.

Both studies gave their subjects similar facial emotion recognition tests, with the current one deriving from findings about autism, and the second from findings about the amygdala. The studies also had common references, such as a 2010 study, A common allele in the oxytocin receptor gene (OXTR) impacts prosocial temperament and human hypothalamic-limbic structure and function.

http://www.pnas.org/content/111/5/1987.full “Common polymorphism in the oxytocin receptor gene (OXTR) is associated with human social recognition skills”

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.