Hippocampus

Problematic research that ignored the hippocampus as the seat of emotional memories

gettingwell4 < 0 Detracted from science, Cerebrum, Hippocampus, Limbic system, Memory

If this 2015 human study from the San Diego Veterans Administration developed findings of any note, I didn’t see them.

Like other studies, this study ignored the hippocampus’ position as the seat of emotional memories. The experiments were designed to not contain any emotional content.

The researchers mainly wanted to fight a 60-year old battle on whether or not the hippocampus contributed to spatial processing. They ignored all the research on place cells, such as:

to name three of the hundreds of place cell studies available.

By ignoring these and other studies, the researchers declared:

“We have not found evidence that this is the case.”

The lead researcher continued with speculations that couldn’t be verified with the current experiments’ data:

“We think they can do these spatial tasks because these tasks can be managed within short-term memory functions, supported by the frontal lobe of the neocortex.

The spatial tasks that we can do with our neocortex using short-term memory must be performed by the hippocampus in rats.”

Basically, the rest of the scientific world must supply irrefutable evidence (which will be ignored) but the reader can just take the lead researcher’s words as fact for what’s going on inside human and rodent brains, although:

  • No fMRI scans were performed during the experiments,
  • No hard measurements were taken.

The findings were based on observations of six subjects:

  • With hippocampal lesions of unspecified duration,
  • Drawing pictures, and
  • Narrating what they imagined about a playground.

I wonder what the reviewers saw in this study that factually advanced science. Did the statement:

“These results support the traditional view that the human hippocampus is primarily important for memory.”

convey something new? Make a contribution to science?

Studies like this one not only detract from science. They are also a waste of resources that supposedly the Veterans Administration have in short supply.

The design and data of such studies are not able to reach levels where they can provide evidence of causes and effects of anything within their scope. That’s a good indication of some other agenda in play.

http://www.pnas.org/content/112/15/4767.full “Memory, scene construction, and the human hippocampus”

Are hippocampal place cells controlled by theta brain waves from grid cells?

gettingwell4 2-3 stars Required further work, Hippocampus, Limbic system, Memory

This 2015 Canadian rodent study tried to establish that grid cells in the medial entorhinal cortex generated brain waves in the theta frequency range that controlled place cells in the hippocampus part of the limbic system.

The researchers stated:

“Our results deviate from the prediction.”

but a commentary Do the spatial frequencies of grid cells mold the firing fields of place cells? said the researchers:

“Obtained fascinating results, largely supporting the model.”

What’s fascinating to me is the volume of studies on the hippocampus that ignore its position as the seat of emotional memories. Human experiments involving the hippocampus are usually designed to not contain any emotional content.

Two studies showed functions of hippocampal place cells:

A summary study of 118 other studies What do grid cells contribute to place cell firing? provided additional information on grid cells and hippocampal place cells, head direction cells, boundary cells, and cells that encode object locations.

The summary study related to the current study by stating that the research through early 2014 arguably found:

“Grid and place cell firing patterns are not successive stages of a processing hierarchy, but complementary and interacting representations that work in combination.”

http://www.pnas.org/content/112/13/4116.full “Place field expansion after focal MEC inactivations is consistent with loss of Fourier components and path integrator gain reduction”

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”

Epigenetic DNA methylation of the oxytocin receptor gene affected the perception of anger and fear

gettingwell4 2-3 stars Required further work, Amygdala, Anterior cingulate cortex, Brain development, Brain hemispheres, Cerebrum, Epigenetics, Hippocampus, Limbic system, Neurochemicals, Oxytocin, Thalamus ,

This 2015 Virginia human study:

“Reveals how epigenetic variability in the endogenous oxytocin system impacts brain systems supporting social cognition and is an important step to better characterize relationships between genes, brain, and behavior.”

The researchers did a lot of things right:

  • They studied a priori selected brain areas, followed by whole brain analyses;
  • Their subjects were carefully selected

    “Because methylation levels have been shown to differ as a function of race, we restricted our sample to Caucasians of European descent”

    but they didn’t restrict subjects to the same gender;

  • They acknowledged as a limitation:

    “A lack of behavioral evidence to reveal how these epigenetic and neural markers impact the overt social phenotype.”

One thing on which I disagree with the researchers is their assessment of what needs to be done next. Their news release stated:

“When imagining the future possibilities and implications this DNA methylation and oxytocin receptor research may have, the investigators think a blood test could be developed in order to predict how an individual may behave in social situations.”

Nice idea, but the next step should be to complete the research. The next step is to develop evidence for how the oxytocin receptor gene became methylated.

The subjects had a wide range of DNA methylation at the studied gene site – from 33% to 72% methylated!

Why?

At the same gene site:

“There was a significant effect of sex such that females have a higher level of methylation than males.”

Why?

Given these significant effects, why was there no research into likely causes?

Aren’t early periods in people’s lives the most likely times when the “Epigenetic modification of the oxytocin receptor gene” that “influences the perception of anger and fear in the human brain” takes place?

Wouldn’t findings from research on the subjects’ histories potentially help other people?

http://www.pnas.org/content/112/11/3308.full “Epigenetic modification of the oxytocin receptor gene influences the perception of anger and fear in the human brain”

Neural plasticity trumps genetics in the hippocampus part of the limbic system

gettingwell4 2-3 stars Required further work, Brain development, Epigenetics, Hippocampus, Limbic system, Memory , ,

This 2015 rodent study used a genetic strain of mice that was bred to not express a gene that enabled long-term memory in the hippocampus. The mice were not memory-impaired, however, due to their brains’ neural plasticity.

The researchers found:

“Deletion of genes in organisms does not always give rise to phenotypes because of the existence of compensation.

The current work provides an example of how a complex brain system may adjust to the effects of gene deletion to recover function.”

The Early human brain development can be greatly modified by environmental factors study showed even greater plasticity in another part of the human brain where the people faced much larger obstacles than gene deletion.

I view this finding as a cautionary tale to reference any time a study comes out stating that A and B genes are found to cause X and Y symptoms or behavior. Researchers don’t have enough evidence in 2015 to unequivocally describe what rodent brains are capable of, much less human brains.

The researchers implied how they kept faith in their work with the phrase:

“The compensatory mechanism is imperfect and does not fully restore cGKII-dependent function.”

Is perfection the standard to which their research is also held?

http://www.pnas.org/content/112/10/3122.full “Network compensation of cyclic GMP-dependent protein kinase II knockout in the hippocampus by Ca2+-permeable AMPA receptors”

Is it science, or is it a silly and sad farce when researchers “make up” missing data?

gettingwell4 < 0 Detracted from science, Brain development, Epigenetics, Hippocampus, Limbic system, Stress , , ,

This 2014 French study was a parody of science.

The researchers “made up” missing data on over 50% of the men and over 47% of the women! All to satisfy their model that drove an agenda of the effects of adverse childhood experiences.

As an example of how silly and sad this was:

  • Two of the seven subject ages of interest were 23 and 33 consecutively, and
  • One of the nine factors was education level.

If I was a subject, and wasn’t around to give data at age 33 and later, how would the researchers have extrapolated a measurement of my education level of “high school” at age 23?

I’m pretty sure their imputation method would have “made up” education level data points for me of “high school” for ages 33 and beyond. I doubt that the model would have produced my actual education levels of a Bachelors and two Masters degrees at age 33.

Everything I said about the Problematic research on stress that will never make a contribution toward advancing science study applied to this study, including the “allostatic load” buzzword and the same compliant reviewer.

Studies like this both detract from science and are a misallocation of scarce resources. Their design and data aren’t able to reach levels where they can provide etiologic evidence.

Such studies also have limiting effects on how we “do something” about real problems, because the researchers won’t be permitted to produce findings that aren’t politically correct.

http://www.pnas.org/content/112/7/E738.full “Adverse childhood experiences and physiological wear-and-tear in midlife: Findings from the 1958 British birth cohort”

Research on brain areas involved when we imagine people, places, and pleasantness

gettingwell4 2-3 stars Required further work, Amygdala, Beliefs, Brain hemispheres, Cerebrum, Hippocampus, Limbic system, Thalamus ,

This highly jargoned 2014 Harvard study was on how people imagine that they’ll feel in the future.

One of the researchers was an author of:

I was surprised that this study also didn’t ignore the limbic system to the point to where the researchers wouldn’t even bother to measure important areas.

Limbic system areas that process people were different than those that process places. For example, the data in Table S4 showed that the subjects’ left amygdala and hippocampus were more activated when simulating future familiar people, whereas their right hippocampus was more activated when simulating future familiar places.

The researchers may have improved the study’s findings if they were informed by studies such as the Hippocampus replays memories and preplays to extend memories into future scenarios, which found that “place” cells in the CA1 segment of the hippocampus preplay events that imagine future scenarios of:

“Novel spatial experiences of similar distinctiveness and complexity.”

Such information may have helped to disambiguate one of the study’s findings in Table S5, that both sides of the subjects’ hippocampus were more activated than other brain regions when simulating both familiar people and places.

The researchers got a little carried away in broadly attributing most of the study’s findings to the ventromedial prefrontal cortex. For example, the data in Table S6 showed that the thalamus was more activated when the subjects anticipated positive pleasantness, but not when negative effects were anticipated.

We know from Thalamus gating and control of the limbic system and cerebrum is a form of memory that this is normally how the thalamus part of the limbic system actively controls and gates information to and from the cerebrum. Their data showed thalamic gating in operation:

  • Active when passing along pleasantness to cerebral areas, and
  • Passive when blocking unpleasantness from cerebral areas.

Also, I didn’t see how the researchers differentiated some of their findings from a placebo effect. For example, Using expectations of oxytocin to induce positive placebo effects of touching is a cerebral exercise found:

“Pain reduction dampened sensory processing in the brain, whereas increased touch pleasantness increased sensory processing.”

This was very similar to the above finding involving the thalamus.

http://www.pnas.org/content/111/46/16550.full “Ventromedial prefrontal cortex supports affective future simulation by integrating distributed knowledge”

Are you feeling kinda blue? Think your brain cells are too few? Get your fat cells on that bike and ride!

gettingwell4 2-3 stars Required further work, Hippocampus, Limbic system

This 2014 rodent study found that fat cells released a certain hormone during exercise that produced two beneficial effects:

  • the hormone increased hippocampal neurogenesis;
  • it also reduced depression-like behaviors.

So if you’re feeling kinda blue,

Think your brain cells are too few?

Get your fat cells on that bike and ride!

http://www.pnas.org/content/111/44/15810.full “Physical exercise-induced hippocampal neurogenesis and antidepressant effects are mediated by the adipocyte hormone adiponectin”

Fear extinction is the learned inhibition of retrieval of previously acquired responses

gettingwell4 4-5 stars Advanced knowledge, Amygdala, Cerebrum, Epigenetics, Hippocampus, Limbic system, Memory

This 2014 rodent study showed that fear extinction doesn’t depend on memory retrieval:

“These results show that extinction and retrieval are separate processes and strongly suggest that extinction is triggered or gated by the conditioned stimulus even in the absence of retrieval.”

Key to my understanding this finding came from a definition in another summary study by the authors, The learning of fear extinction, where they stated:

“Extinction is the learned inhibition of retrieval of previously acquired responses.”

These two studies and Hippocampal mechanisms involved in the enhancement of fear extinction caused by exposure to novelty should inform researchers of studies such as If rodent training has beneficial epigenetic effects, how can the next step be human gene therapy? of desirable alternative treatments, rather than proceeding from rodent training directly to human gene therapy.

http://www.pnas.org/content/112/2/E230.full “Extinction learning, which consists of the inhibition of retrieval, can be learned without retrieval”

What is the purpose of music? A review of evolutionary and pleasurable research findings

gettingwell4 2-3 stars Required further work, Amygdala, Anterior cingulate cortex, Cerebrum, Dopamine, Hippocampus, Hypothalamus, Limbic system, Lower brain, Neurochemicals

Ever wonder what happens in your brain and body when you get chills from a musical performance?

This 2013 summary review of 126 studies provided details of brain areas that contribute to our enjoyment of music.

Much of the review addressed Darwin’s observation that music had no readily apparent functional consequence and no clear-cut adaptive function. The researchers noted that:

“There is scant evidence that other species possess the mental machinery to decode music in the way humans do, or to derive enjoyment from it.”

The reasons why different types of music affect us differently are similar to the findings of the Reciprocity behaviors differ as to whether we seek cerebral vs. limbic system rewards study.

Here are the “We seek limbic system rewards” similarities:

“The nucleus accumbens played an important role with both familiar and novel music. In the case of familiar music, hemodynamic activity in the nucleus accumbens was associated with increasing pleasure, and maximally expressed during the experience of chills, which represent the peak emotional response; these were the same regions that showed dopamine release. The nucleus accumbens is tightly connected with subcortical limbic areas of the brain, implicated in processing, detecting, and expressing emotions, including the amygdala and hippocampus. It is also connected to the hypothalamus, insula, and anterior cingulate cortex, all of which are implicated in controlling the autonomic nervous system, and may be responsible for the psychophysiological phenomena associated with listening to music and emotional arousal.”

Here is the “We seek cerebral rewards” part.

“Finally, the nucleus accumbens is tightly integrated with cortical areas implicated in “high-level” processing of emotions that integrate information from various sources, including the orbital and ventromedial frontal lobe. These areas are largely implicated in assigning and maintaining reward value to stimuli and may be critical in evaluating the significance of abstract stimuli that we consider pleasurable.”

http://www.pnas.org/content/110/Supplement_2/10430.full “From perception to pleasure: Music and its neural substrates”

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

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

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

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

“Novel therapeutic targets for stress-related disorders.”

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

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

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

What do you think of this excerpt?

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

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

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

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

The amygdala is where we integrate our perception of human facial emotion

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

We all have specialized brain circuits for recognizing faces.

Each person has their own historical judgment of the emotion in a human face, which may or may not be the emotion objectively displayed by the face.

The amygdala, not the hippocampus, was found to be where we integrate our perception of human facial emotion.

The facial information conveyed by the eyes, not the mouth, was primarily how the amygdala perceived emotion.

This 2014 study was performed on seven neurology patients who had deep-brain electrodes implanted for other purposes of diagnosis or treatment, including epilepsy and autism, and six healthy control subjects. With the electrodes, the researchers were able to measure individual neurons instead of functional MRI aggregate results.

This increased measuring capability enabled the researchers to develop other findings, such as:

“Neuronal selectivity for fear faces in the amygdala comes mainly from a suppression of activity in happy-face trials, whereas selectivity for happy faces is mainly due to an increase in activity for happy-face trials.”

Also:

“The long latency of the amygdala responses we observed already argues for considerable synthesis, consistent with the integration of face input from temporal cortex with signals from other brain regions, as well as substantial processing internal to the amygdala.”

http://www.pnas.org/content/111/30/E3110.full “Neurons in the human amygdala selective for perceived emotion”

Problematic research: If you don’t feel empathy for a patient, is the solution to fake it?

gettingwell4 < 0 Detracted from science, Beliefs, Cerebrum, Hippocampus, Limbic system, Memory, Primal Therapy , , , ,

If you don’t experience empathy for another person, this 2014 Harvard study showed how to use your cerebrum to manipulate your limbic system into displaying a proxy of empathy.

Is this what we want from our human interactions? To have a way to produce an emotion the same way that an actor would as they read their lines?

How to finesse the effect of “no empathy” was the focus. Because these researchers didn’t define a lack of genuine empathy as a symptom of a fundamental problem, they absolved themselves from investigating any underlying causes.

Nice trick in the academic world.

In the real world, in which we are feeling human beings, what may be a cause of no empathy?

Let’s say that someone is in a position that helps people. They have daily encounters where they may be expected to be empathetic, but they seldom have these feelings for others.

One hypothesis of Dr. Arthur Janov’s Primal Therapy is this condition’s origin may be that in the past, a person needed help as a matter of survival, and they weren’t helped. Their unconscious memories of being helpless impel them to act out being helpful in their current life.

This person’s frequent reaction to any hint in the present of the agony of not receiving help back when they desperately needed it is to act out what they needed to have done back then. Helping others also gives them momentary distraction from such painful memories, but any relief is transitory. So they repeat the process.

Let’s say that unconscious needs pressed them into making a career choice of actively helping people. They’re usually too caught up in their own thoughts and feelings and behavior, though, to sense feelings of the people they’re helping.

Something isn’t right, but what’s the problem? They see indicators such as: their actions that should feel fulfilling aren’t fulfilling, they seldom feel empathy, and so on.

Primal Therapy allows patients to therapeutically address origins of such conditions. A symptom such as lack of empathy for others will resolve as historical pains are ameliorated.

Or we can do as this study suggested: produce an inauthentic display – and thereby ignore the lack of empathy as a symptom – and never address causes of no empathy.

http://www.pnas.org/content/111/12/4415.full “Episodic simulation and episodic memory can increase intentions to help others”

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

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

This 2014 rodent study gave further details that:

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

Other studies on the hippocampus CA3 region include:

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

Problematic research: Feigning naivety of the impact of prenatal, infancy and early childhood experiences

gettingwell4 < 0 Detracted from science, Brain development, Epigenetics, Hippocampus, Limbic system, Memory, Stress

What I found curious in this 2012 UK review of 82 studies was the reviewer’s reluctance to highly regard a human’s life before birth, during infancy, and in early childhood.

There was no lack in 2012 of animal studies to draw from to inferentially hypothesize how a human fetal environment causes the fetus to adapt with enduring epigenetic changes.

To take just one study that I won’t curate on this blog because it’s too old:

Weinstock M (2008) The long-term behavioural consequences of prenatal stress. Neurosci Biobehav Rev 32:1073–1086, “Stress, [to the pregnant mother] in rodents as well as nonhuman primates, produces behavioral abnormalities [in the pup], such as

  • an elevated and prolonged stress response,
  • impaired learning and memory,
  • deficits in attention,
  • altered exploratory behavior,
  • altered social and play behavior, and
  • an increased preference for alcohol.”

Yet the reviewer posed the question:

“There is a need to determine just what epigenetic changes do and do not account for. Put succinctly, do they explain individual differences in response to adversity and do they account for variations in health and behavior outcomes?”

I suspect that the cause of this feigned naivety was the political incorrectness of adequately placing importance in the human fetus’ experience of the development environment provided by their mother.

The PC view would have us pretend that there aren’t lasting adverse effects from human prenatal, infancy, and early childhood experiences.

The follow-on pretense to this PC view would be that later-life consequences aren’t effects, but are instead, mysteries due to “individual differences.”

http://www.pnas.org/content/109/Supplement_2/17149.full “Achievements and challenges in the biology of environmental effects”

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