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”

Are a child’s genes the causes for their anxiety?

gettingwell4 0-1 star Wasted resources, Amygdala, Brain development, Brainstem, Cerebrum, Epigenetics, Limbic system, Lower brain, Stress , , ,

This 2015 Wisconsin macaque study was another attempt to justify the school’s continuing captivity of thousands of monkeys. The researchers performed a study that – if its experimental design was truly informative for helping humans – could have been done with humans.

A problem I saw in the news coverage was that the finding of:

“35 percent of variation in anxiety-like tendencies is explained by family history”

was attributed to genetics, with headlines such as “Anxious Brains Are Inherited, Study Finds.” The lead researcher encouraged this misinterpretation with statements such as:

“Over-activity of these three brain regions are inherited brain alterations that are directly linked to the later life risk to develop anxiety and depression.”

However, the researchers produced this finding by running numbers on family trees, not by studying genetic samples to assess the contributions of genetic and epigenetic factors!

The study’s “family history” correlation was different than finding an inherited genetic causation that wasn’t influenced by the subjects’ caged environments!

The study found:

“Metabolism within a tripartite prefrontal-limbic-midbrain circuit mediates some of the inborn risk for developing anxiety and depression.

The brain circuit that was genetically correlated with individual differences in early-life anxiety involved three survival-related brain regions. These regions were located in the brain stem, the most primitive part of the brain; the amygdala, the limbic brain fear center; and the prefrontal cortex, which is responsible for higher-level reasoning and is fully developed only in humans and their primate cousins.”

The 592 subjects were the human-equivalent ages of 3 to 12 years old. Primate brainstems and limbic systems are fully-developed BEFORE these ages.

The researchers skipped over potential evidence for the important contributions of epigenetic factors to “the later life risk to develop anxiety and depression” that change the studied brain areas during womb-life, infancy, and early childhood. Studies such as:

show:

  1. A developing fetus adapts to being constantly stressed by an anxious mother.
  2. When these adaptations persist after birth, they may present as physiological and behavioral maladaptations of the infant and young child to a non-stressful environment.
  3. Later in life, these enduring changes may be among the causes of symptoms such as the anxious overreactions the current study found.

http://www.pnas.org/content/112/29/9118.full “Intergenerational neural mediators of early-life anxious temperament”

Over 500 million people affected but no news coverage

gettingwell4 2-3 stars Required further work ,

Sometimes I wonder how research becomes newsworthy. I couldn’t find any news coverage of this 2015 Chinese rodent study which provided details of the effects of a gene for which:

“Over 500 million people worldwide carry a specific polymorphism.

Is a risk factor for liver cancer.”

1 out of every 15 people alive today has this condition, and can expect:

“Increased sensitivity to acute or chronic alcohol-induced toxicity

Higher risk for gastrointestinal cancers

Enzyme deficiency in the liver, leading to inefficient detoxification of aldehydes and accumulation of cancer-causing mutations.”

Was the lack of news coverage because 40% of East Asians are affected? Would this study become newsworthy if 40% of some other group was affected?

http://www.pnas.org/content/112/29/9088.full “ALDH2(E487K) mutation increases protein turnover and promotes murine hepatocarcinogenesis”

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”

What could cause humans to have a unique sense of smell?

gettingwell4 2-3 stars Required further work, Epigenetics, Immune system, Memory

This 2015 Israeli human study found:

“Each person expresses a nearly unique set of different olfactory receptor genes, and therefore may have unique olfactory perception.”

From news coverage of the study, the researchers thought that their findings may be of use for:

“Smell-based social networks

A diagnostic tool for diseases that affect the sense of smell, such as Parkinson’s

A security biometric.”

The researchers attempted to link the subjects’ olfactory components to components of their immune systems. Since studies such as:

provided details on how our immune systems become unique, it would follow that this study’s subjects’ immune systems may have been the underlying cause for the findings.

However, in the study’s limitations paragraph, the researchers stated that this study didn’t demonstrate such causes:

“We did not directly measure genetic makeup.

Given that HLA [human leukocyte antigen genes that regulate our immune systems] captures self and olfactory fingerprints capture self, then there will be a link between HLA and olfactory fingerprints even if they are not the result of linked genes.”

Perhaps the causes for our “unique olfactory perception” will be researched in future studies.

http://www.pnas.org/content/112/28/8750.full “Individual olfactory perception reveals meaningful nonolfactory genetic information”

What’s an appropriate control group for a schizophrenia study?

gettingwell4 < 0 Detracted from science, Cerebrum ,

The researchers who did Our long-term memory usually selects what we pay closer visual attention to study were back zapping subjects’ brains again in this 2015 human study.

Prior to zapping subjects’ brains:

“In healthy individuals, these theta waves were steady and synchronized, but in people with schizophrenia, the waves were weak and disorganized, suggesting that they were having a harder time processing the mistake. And the subjects’ behavior bore that out—the healthy subjects slowed down by a few milliseconds when they made mistakes and did better in the next round, while the subjects with schizophrenia did not.”

Processing of an appropriate control group wasn’t clear to me from reading supplementary material. Subject patients were diagnosed with schizophrenia and took psychoactive medication which these researchers equated to chlorpromazine (Thorazine) dosages. Control group subjects had neither the condition nor were prescribed medications.

  • How did these researchers differentiate influences of psychoactive medications on experimental results from other influences on subjects’ conditions?
  • Were there numerical calculations not shown in supplementary material that somehow nullified effects of psychoactive medications?
  • To be sure that zapping was effective for subjects’ conditions, wouldn’t control group subjects need to take the same medications so that experimental data reflected only differences attributable to schizophrenia?

These researchers also asserted:

“Causal changes in the low-frequency oscillations improved behavioral responses to errors and long-range connectivity at the single-trial level.”

However, brain waves can’t be termed as base causes of human behavior. Studies such as:

clearly established that brain waves are effects of base causes.

http://www.pnas.org/content/112/30/9448.full “Synchronizing theta oscillations with direct-current stimulation strengthens adaptive control in the human brain”

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.

Using epigenetic DNA methylation markers to estimate biological age

gettingwell4 < 0 Detracted from science, Epigenetics, Stress, Telomeres

I curated this 2015 Georgia human study only for its use of two methods of estimating biological age. The researchers misguidedly used these techniques to help paint a scientific patina on an agenda.

One of the methods was originated by a coauthor of The degree of epigenetic DNA methylation may be used as a proxy to measure biological age study. He compared his epigenetic clock technique with the other technique here:

  • His technique used the same 353 DNA regions (CpGs, cytosine and guanine separated by only one phosphate link) across different tissues to compare tissue/organ ages;

  • “The DNA methylation levels of 193 of these markers increase with age but the remaining 160 markers show the opposite behavior.”

  • His technique had a Pearson correlation coefficient of r=0.96 with chronological age in this 2013 study;
  • The other technique:

    “Works poorly for blood samples from subjects who are younger than 20.”

That such methods were available calls into question why the researchers of A study of biological aging in young adults with limited findings didn’t avail themselves of these techniques. They used techniques that were less informative such as telomere length. As an example of how that study’s methods were known to be limited, this 2009 study found that the correlation between chronological age and telomere length was r = −0.51 in women and r = −0.55 in men.

http://www.pnas.org/content/112/33/10325.full “Self-control forecasts better psychosocial outcomes but faster epigenetic aging in low-SES youth”

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”

A study of biological aging in young adults with limited findings

gettingwell4 0-1 star Wasted resources, Epigenetics, Telomeres ,

This 2015 New Zealand human study used the same subjects of the More from the researchers that found people have the same personalities at age 26 that they had at age 3 study. These researchers used 10 biologic age markers of subjects at age 38 to find that their biological ages ranged from 28 to 61.

F2.large

Researchers assessed subjects’ pace of aging at ages 26, 32, and 38 with 11 more biomarkers, including leukocyte telomere length. Three of the initial 10 biomarkers weren’t used because measurements were taken only at age 38.

These researchers also assessed physical functioning, physical limitations, cognitive testing, retinal imaging, self-rated health, and facial aging. There was a fascinating graph in the supplementary material of the effect on each of these assessments of successively leaving out each of 18 pace-of-aging biomarkers.

There were three areas I expected to see covered that weren’t addressed in this study:

  1. Where were links back to all relevant measurements and predictions made when these subjects were ages 3, 5, 7..? Other studies of these same subjects made such links, but only cognitive testing was linked back in this study. Were these researchers trying to pretend that these dramatic later-life physical measurements weren’t effects of earlier-life causes?
  2. Where were psychological measurements? Are we to believe that subjects’ states of mind had no relationships to their biomarkers?
  3. I didn’t see any effort to use newer measures such as The degree of epigenetic DNA methylation may be used as a proxy to measure biological age study. I’d expect that these subjects’ historical tissue samples were available. The peer reviewer certainly was familiar with newer biomarkers.

http://www.pnas.org/content/112/30/E4104.full “Quantification of biological aging in young adults”

Interruptions to the circadian cycle negatively affect memory consolidation

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

This 2015 German rodent study found:

“The control of sleep and memory consolidation may share common molecular mechanisms.”

Somewhat counter to the “Enhanced memory consolidation” in the study’s title, the researchers also found:

“Elevated IGF2 [insulin-related growth factor 2] signaling in the long term, however, has a negative impact on cognitive processing.”

The IGF2 finding was in genetically altered mice that had their circadian rhythm permanently disturbed, however. The study didn’t clearly determine the contribution of other factors that could have contributed to the cognitive decline.

The study traced fear memories induced by stress through the cerebrum to the anterior cingulate cortex and hippocampus parts of the limbic system.

Researchers have no problems studying emotional memories in these brain areas with rodents. In human memory experiments, however, emotional content is consistently excluded, as if none of our memories had anything to do with our feelings.

http://www.pnas.org/content/112/27/E3582.full “Enhanced memory consolidation in mice lacking the circadian modulators Sharp1 and -2 caused by elevated Igf2 signaling in the cortex”

A study on alpha brain waves and visual processing that had limited findings

gettingwell4 0-1 star Wasted resources, Amygdala, Beliefs, Cerebrum, Hippocampus, Limbic system, Memory

This 2015 Wisconsin human study found:

“Forming predictions about when a stimulus will appear can bias the phase of ongoing alpha-band oscillations toward an optimal phase for visual processing, and may thus serve as a mechanism for the top-down control of visual processing guided by temporal predictions.”

The researchers measured delta (1-4 Hz), theta (4-7 Hz), alpha (9-13 Hz), and low beta (15-20 Hz) brain waves. Their findings applied only to the alpha band in their experimental tasks, which excluded emotional content.

Brain waves studies such as Are hippocampal place cells controlled by theta brain waves from grid cells? and Research that identifies the source of generating gamma brain waves established different experimental conditions that elicited brain waves in non-alpha frequency bands. Such studies may have been relevant to further explain this study’s negative findings.

Visual perception studies such as We are attuned to perceive what our brains predict will be rewarding and Our long-term memory usually selects what we pay closer visual attention to provided insight into possible causes for the observed effects. It may have provided additional findings if the researchers of this study were also interested in causal factors that affected visual processing.

Other studies on visual perception such as The amygdala is where we integrate our perception of human facial emotion provided reasons to not exclude emotional content in brain studies. The current study’s researchers claimed that they provided insights relevant to neurological disorders by stating:

“Because forming the appropriate sensory predictions can have a large impact on our visual experiences and visually guided behaviors, a mechanism thought to be disrupted in certain neurological conditions like autism and schizophrenia, an understanding of the neural basis of these predictions is critical.”

However, I didn’t see that the researchers provided such an understanding since their experimental designs excluded emotional content. I wonder what the reviewer saw that justified this Significance section statement.

http://www.pnas.org/content/112/27/8439.full “Top-down control of the phase of alpha-band oscillations as a mechanism for temporal prediction”

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”

Do scientists have to perpetuate memes in order to keep their jobs?

gettingwell4 < 0 Detracted from science, Amygdala, Anterior cingulate cortex, Beliefs, Cerebrum, Hippocampus, Limbic system, Thalamus , , ,

I was disgusted by this 2015 Korean human study.

Is the current state of science such that researchers won’t be funded unless there’s an implicit guarantee that their studies will produce politically correct findings? It seemed that the primary reason for the study’s main finding of:

“Neural markers reflecting individual differences in human prosociality”

was to perpetuate that non-causal, non-explanatory meme.

Per If research treats “Preexisting individual differences” as a black box, how can it find causes for stress and depression? it wasn’t sufficient in 2015 to pretend that there are no early-life causes for the observed behavior and fMRI scan results of the subjects. Such a pretense leads to the follow-on pretense that later-life consequences are not effects, but are instead, a “mystery” due to “individual differences.”

The researchers asserted:

“Our present findings shed some light on the mystery of human altruism.”

Weren’t the findings of the People who donated a kidney to a stranger have a larger amygdala 2014 study of extraordinary altruists big enough clues for these researchers to feature the amygdala in the fMRI scans?

The main experiment had the female, college student, right-handed subjects try to “reduce the duration of exposure to stressful noise.” Why weren’t brain areas that are especially susceptible to stress like the hippocampus featured in the fMRI scans?

The secondary reason for the study seemed to be to perpetuate the harmful “self-sacrifice = good, individuality = bad” meme.

The main reason this meme is harmful is that it condones a subset of people’s unconscious act outs. People are encouraged to avoid conscious awareness both of who they really are and of what drives their feelings, thoughts, and actions.

Despite not asking the subjects directly about either their motivations or their histories, these researchers asserted that the study demonstrated:

“The automatic and intuitive nature of prosocial motivation.”

What was largely observed were the subjects’ unconscious act outs, not some higher-order functions as the researchers mischaracterized them.

Similar to Who benefits when research promotes a meme of self-sacrifice? I suspect that a major motivation behind scientific justification for memes like the self-sacrifice promoted by this study is to rush people past what really happened in their lives.

I wonder what value we would place on the “social norms internalized within an individual” if we felt and honestly understood our real history.

This study and the Do you know a stranger’s emotional motivations for smiling? study had the same reviewer, and shared several of the burden-of-proof problems. Both studies demonstrated a lack of researcher interest in finding causes for the observed effects.

What was the agenda with these researchers and the reviewer? Why would the researchers glorify factors that cause difficulties when one tries to live a life of one’s own choosing?

http://www.pnas.org/content/112/25/7851.full “Spatial gradient in value representation along the medial prefrontal cortex reflects individual differences in prosociality”

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”

How brains mature during critical periods

gettingwell4 5+ stars Premium, Brain development, Epigenetics, Hippocampus, Limbic system , , , ,

This 2015 German rodent study found:

“Once silent synapses are consolidated in any neural circuit, initial experience-dependent functional optimization and critical periods end.

Silent synapses are thought to be immature, still-developing excitatory synapses.”

The number of silent synapses related to visual processing was measured at ~50% at eye opening. Visual experience reduced this to 5% or less by adulthood in the study’s control group. Removing a protein in the subjects’ hippocampus silenced the synapses back up to ~50%, even in adults.

Critical periods are:

“Characterized by the absolute requirement for experience in a restricted time window for neural network optimization.

Although some functions can be substantially ameliorated after the CP [critical period], they are rarely optimally restored.”

Two human studies were cited on critical periods in second-language and musical skills development, Sensitive periods in human development: Evidence from musical training (not freely available).

The researchers generalized their findings as:

“Experience-dependent unsilencing of silent synapses constitutes an important general maturational process during CPs of cortical development of different functional domains and suggest an interplay with inhibitory circuits in regulating plasticity.”

http://www.pnas.org/content/112/24/E3131.full “Progressive maturation of silent synapses governs the duration of a critical period”