Prefrontal cortex

A mechanistic study of neurotransmitters in the hippocampus

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

This 2015 UK rodent study found:

“A mechanistic understanding of how alterations in dopamine and NMDAR [a type of glutamate receptor that participates in excitatory neurotransmission] function can lead to the disruption of hippocampal–PFC [prefrontal cortex] functional connectivity.

These results show how dopaminergic activation induces long-term hypofunction of NMDARs, which can contribute to disordered functional connectivity, a characteristic that is a hallmark of psychiatric disorders such as schizophrenia.”

One of the experiments applied theta-frequency (5 Hz) waves to the rats’ hippocampi and dampened the electrical activity of the NMDAR type of glutamate receptor.

However, this effect of theta waves was dependent on the activation of D2 dopamine receptors. The study’s findings should inform researchers who treat brain waves as base causes of behavior in studies such as What’s an appropriate control group for a schizophrenia study?

This study’s findings may also inform researchers of studies such as the What causes disconnection between the limbic system and the cerebrum? of a neurochemical basis for “the disruption of hippocampal–PFC functional connectivity.”

http://www.pnas.org/content/112/35/11096.full “Disruption of hippocampal–prefrontal cortex activity by dopamine D2R-dependent LTD of NMDAR transmission”

Words are neither the problem nor the solution

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

“Words are neither the problem nor the solution. They are the last evolutionary step in processing the feeling or sensation. They are the companions of feelings.

We cannot make progress on the third-line cognitive level alone. We can become aware of why we act the way we do but nothing changes biologically; it is like being aware of a virus and expecting the awareness alone to kill it. Our biology has been left out of the therapeutic equation.”

Janov’s Reflections on the Human Condition: On the Difference Between Abreaction and Feeling (Part 6/9).

Emotionless brain research that didn’t deal with human reality

gettingwell4 0-1 star Wasted resources, Amygdala, Anterior cingulate cortex, Brainstem, Cerebrum, Hippocampus, Limbic system, Lower brain, Thalamus

Are tasks you do at work and home never influenced by emotional content or contexts?

Does your ability to focus on a task always have nothing to do with your emotional state?

The researchers who designed this 2015 Boston human study acted as if both of your answers to these questions were “Yes” by stripping out any emotional content from their experiments. As a result, this study which purported to:

“Have the potential to provide additional insights into how inhibitory control may break down in a wide variety of individuals with neurological or psychiatric difficulties”

couldn’t achieve anything near its goal.

This study included fMRI scans of subjects’ entire brains. Limbic system areas were in 3 of the 5 modules, and lower brain areas were in one.

Functional MRI signals depend on changes in blood flow that follow changes in brain activity. Given this study’s goal, did it make sense for researchers to design experiments that didn’t actively engage scanned areas of subjects’ brains?

It wasn’t all that difficult to include emotional content that could potentially contribute to the purported goal. This 1996 review described studies that developed varieties of emotional content with the same test type (Stroop) used. Presumably these approaches had made progress since 1996 incorporating emotional content in Stroop tests given to normal people, who were subjects in this study.

http://www.pnas.org/content/112/32/10020.full “Flexible brain network reconfiguration supporting inhibitory control”

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”

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”

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”

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”

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”

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”

RNA as a proxy signal for context-specific biological activity

gettingwell4 2-3 stars Required further work, Brain development, Cerebrum, Hippocampus, Hypothalamus, Limbic system, Thalamus , ,

This 2015 Harvard/MIT rodent study was of long (more than 200 nucleotides) noncoding (non-protein coding) RNAs (ribonucleic acids). These are of interest because:

“Within the mammalian body, the largest repertoire and diversity of lncRNA genes outside the germ line occurs in the brain, where lncRNAs exhibit regional and cell-specific localization.

The expression patterns of lncRNAs may serve as a proxy signal for important, context-specific biological activity.”

The researchers explained what they could and couldn’t determine with current techniques and technologies:

“The whole-gene ablation method used here is often a first approach to determine the functionality of a locus.

Although each of these loci contains a lncRNA, it is important to consider that any observation resulting from this strategy could reflect the loss of any regulatory element in the deleted region.

The rate of lncRNA gene discovery has significantly outpaced our ability to evaluate both the physiological significance and function of these genes. It is difficult to predict whether the loss of any particular lncRNA locus will present a phenotype, but crucial information on the spatiotemporal dynamics of expression from each locus can provide significant direction and focus to downstream mechanistic studies by highlighting those loci most likely to have a physiological impact.

It is important to stress that no single method exists that can account for all possible mechanisms of action of a noncoding locus. Within these limits, the phenotypes observed after ablation of specific lncRNA loci confirm that expression of this class of noncoding RNAs can serve as a proxy signal to identify functional genomic loci with physiological relevance to disease and development, independent of whether this activity is directly ascribed to a functional lncRNA molecule.”

http://www.pnas.org/content/112/22/6855.full “Spatiotemporal expression and transcriptional perturbations by long noncoding RNAs in the mouse brain”

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)

Limits of dMRI brain studies

gettingwell4 2-3 stars Required further work, Cerebrum

This 2015 macaque study found:

“∼50% of the cortical surface was effectively inaccessible for long-range diffusion tracking.

Current and future high-resolution dMRI [diffusion magnetic resonance imaging] studies of the human brain will need to develop methods to overcome the challenges posed by superficial white matter systems to determine long-range anatomical connections accurately.”

The researchers stated:

“Although in many respects the macaque brain is a good approximation of the human brain, both species have undergone profound evolutionary changes since the time of their most recent common ancestor living more than 20 million years ago, particularly in regard to the massive expansion of the cerebral cortex in the human brain. Thus, it is of great value to assess human anatomical connections directly and comprehensively.”

Sound familiar? That’s also the point I made in Do popular science memes justify researchers’ cruelties to monkeys?

http://www.pnas.org/content/112/21/E2820.full “Superficial white matter fiber systems impede detection of long-range cortical connections in diffusion MR tractography”