Month: February 2015

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”

The degree of epigenetic DNA methylation may be used as a proxy to measure biological age

gettingwell4 4-5 stars Advanced knowledge, Epigenetics

This fascinating 2014 human study developed the new use of a somewhat intuitive marker of aging. The researchers used the degree of methylation – an epigenetic chemical modification of DNA – as an epigenetic clock to measure biological age.

The researchers found that, on average, the epigenetic age of the liver increased by 3.3 years for every increase in 10 body mass index (BMI) units. Other studied tissue areas weren’t similarly affected.

http://www.pnas.org/content/111/43/15538.full “Obesity accelerates epigenetic aging of human liver”

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”

A biologically relevant event can drive long-term memory in a single training session

gettingwell4 2-3 stars Required further work, Brain development, Dopamine, Epigenetics, Memory, Neurochemicals

This 2014 fruit fly study found:

“A biologically relevant event such as finding food under starvation conditions or being poisoned can drive long-term memory in a single training session.”

I don’t think that we need to discover at these extremes, though, whether or not the finding has human applicability.

We do know from the Dutch hunger winter of 1944 study referenced in the Non-PC alert: Treating the mother’s obesity symptoms positively affects the post-surgery offspring study that prenatal exposure to famine had lifelong ill effects on the children. The exposed children had epigenetic DNA changes – a form of long-term memory – from their mothers’ starvation, which resulted in relative obesity compared with their unexposed siblings.

http://www.pnas.org/content/112/2/578.full “Distinct dopamine neurons mediate reward signals for short- and long-term memories”

Problematic research on stress that will never make a contribution toward advancing science

gettingwell4 < 0 Detracted from science, Cortisol, Neurochemicals, Stress

This 2014 UK human study found:

“Type 2 diabetes is characterized by disruption of stress-related processes across multiple biological systems and increased exposure to life stress.”

HOWEVER, the stress effects weren’t conclusively shown to be either a cause or consequence of type 2 diabetes. Correlation wasn’t causation.

Looking around for clues as to what went wrong, I found this data sample of cortisol in a small table that comprised the total amount of information in the supplementary material:

“Geometric means, adjusted for education, marital status, BMI, smoking status, use of statins, and time of day.”

It’s hubris for the researchers to state that they improved data measurements by averaging them after adjusting for all of the above six factors.

Maybe the problem was elsewhere, maybe in the study design. Wherever the problems were, they guaranteed that the researchers would NEVER find cause and effect.

But maybe that’s the point?

There appeared to be other agendas that ensured studies like these failed to make a contribution toward advancing science. The researchers inevitably used buzzwords such as “allostatic load” and cited the need for further studies (money). Everybody was okay with that, including the reviewer, and everybody kept their safe jobs.

Such studies also had limiting effects on how we “do something” about real problems because the researchers wouldn’t produce findings that weren’t politically correct.

http://www.pnas.org/content/111/44/15693.full “Disruption of multisystem responses to stress in type 2 diabetes: Investigating the dynamics of allostatic load”

We are attuned to perceive what our brains predict will be rewarding

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

What I got from this 2014 human study is that from the beginnings of our lives, we are attuned to perceive what our brains predict will be rewarding.

The subjects’ whole brains were monitored, but only areas of the cerebrum participated in the findings to a significant degree.

“Sounds associated with high rewards increase the sensitivity of vision.

The same neurons that process sensory information are modulated by reward..and thereby influence perception from the earliest stages of cortical processing.

Reward associations modulated responses in regions associated with multisensory processing in which the strength of modulation was a better predictor of the magnitude of the behavioral effect than the modulation in classical reward regions.”

Sounds a little bit like we all might have a mild case of synesthesia.

http://www.pnas.org/content/111/42/15244.full “Cross-modal effects of value on perceptual acuity and stimulus encoding”

If rodent training had beneficial epigenetic effects, how can the next step be human gene therapy?

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

This 2014 rodent study detailed significant and lasting epigenetic DNA methylation in the hippocampus part of the limbic system as a result of fear-extinction training.

The researchers missed the boat when explaining in interviews how their research could apply to humans. What I understood from the interviews was that the researchers were focused on targeting human genes with some outside action.

Recommending human gene therapy smelled like an agenda. If these epigenetic modifications were induced by training in rodents, wouldn’t the next step be research into reversal training or therapeutic activity for humans?

The researchers also found:

“Importantly, these effects were specific to extinction training and did not occur in mice that had been fear conditioned, followed by a single reactivation trial, therefore arguing against the possibility that such epigenetic modifications are nonspecifically induced by the retrieval or reconsolidation of the original fear memory.”

This was fine for rodent studies where the origins of both the disease and the cure were all exerted externally. I didn’t see that it necessarily applied to humans.

After all, we’re not lab rats. We can perform effective therapy that doesn’t involve some outside action being done to us.

http://www.pnas.org/content/111/19/7120.full “Neocortical Tet3-mediated accumulation of 5-hydroxymethylcytosine promotes rapid behavioral adaptation”

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”

Using expectations of oxytocin to induce positive placebo effects of touching

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

This 2013 Scandinavian study detailed which brain structures were involved when fooling oneself about actual sensations in favor of expected sensations.

It was hilarious how the researchers used studies of oxytocin to create expectations in the subjects:

“To induce expectation of intranasal oxytocin’s beneficial effects on painful and pleasant touch experience, participants viewed a 6-min locally developed video documentary about oxytocin’s putative prosocial effects such as involvement in bonding, love, grooming, affective touch, and healing. As all of the material was based on published research, there was no deception. The video concluded that a nasal spray of oxytocin might enhance the pleasantness of:

  • (i) stroking and
  • (ii) warm touch, and
  • (iii) reduce the unpleasantness of pain.”

Other items:

  • Only the placebo effects for the warm and pain-reducing touches were statistically significant, not the stroking touch;
  • The a priori brain areas monitored in the “sensory circuitry” included the thalamus and were all in the right brain hemisphere;
  • The a priori brain areas monitored in the “emotional appraisal circuitry” included the amygdala.

One way the researchers summarized the study was:

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

This finding demonstrated how the thalamus part of the limbic system actively controls and gates information to and from the cerebrum, similar to the Thalamus gating and control of the limbic system and cerebrum is a form of memory study.

There was a terminology problem in the study, evidenced by statements such as:

“We induced placebo improvement of both negative and positive feelings (painful and pleasant touch).”

Touch is a sensation, not a feeling or emotion. This placebo study created expectations of sensations in the subjects’ cerebrums, not expectations of emotions.

Also, including parts of the limbic system such as the amygdala in the “emotional appraisal circuitry” didn’t mean that the researchers studied feelings or emotions. We know from research summarized in the Conscious mental states should not be the first-choice explanation of behavior study that:

“Neither amygdala activity nor amygdala-controlled responses are telltale signatures of fearful feelings.“

The current study cast additional light on the dubious Problematic research on human happiness study. Those researchers were fooled by a positive placebo effect!

http://www.pnas.org/content/110/44/17993.full “Placebo improves pleasure and pain through opposite modulation of sensory processing”

What happens next after a detox program predictably fails?

gettingwell4 0-1 star Wasted resources, Beliefs, Limbic system, Lower brain, Memory, Primal Therapy , ,

This 2014 study was a misguided example of looking solely at the presenting parts of a person’s condition rather than the whole historical person.

What did this study’s researchers decide after finding:

“Alcohol-dependent subjects..remained with high scores of depression, anxiety, and alcohol craving after a short-term detoxification program.”

Was it that the detox program didn’t work because it dealt with suppressing symptoms rather than addressing causes?

NO!

The researchers decided:

“Gut microbiota seems to be a previously unidentified target in the management of alcohol dependence.”

The researchers proceeded on some trendy, in-vogue aspect of their patients with which to tinker.

The researchers ignored that the correlation of the new treatment course didn’t show causation. They also ignored underlying causes for the ineffectiveness of the preceding treatments of symptoms.

Hard to see how the reviewer believed that this study would advance science.

Meanwhile, the researchers continued to ignore the elephants in the room: the relationships of the patients’ histories and their pain.

http://www.pnas.org/content/111/42/E4485.full “Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity”

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”

How to make a child less capable even before they are born: stress the pregnant mother-to-be

gettingwell4 4-5 stars Advanced knowledge, Brain development, Cortisol, Epigenetics, Hypothalamus, Limbic system, Neurochemicals, Primal Therapy, Stress, Testosterone , ,

This 2014 rodent study showed how to make a less-capable pup by stressing the mother early in gestation. The study centered on a placental enzyme (OGT) that translates a mother’s stress into neuroprogramming of her developing fetus.

One finding was that this enzyme was less plentiful when the fetus was male compared with female.

Another finding was that the enzyme was less plentiful when the mother was stressed early in gestation, compared with unstressed mothers.

Informed by the first two findings, the researchers studied the placentae of male pups where the mother was stressed early in gestation. They found that these placentae had lower levels of an enzyme (Hsd17b3) that converts the precursor androstenedione into testosterone.

The resultant finding was that the male pups of stressed mothers had lower levels of testosterone than the control group of male pups.

A fourth finding was that offspring of both sexes born with a placenta where the OGT enzyme was less plentiful had 10-20% less body weight, a condition that developed after weaning. The researchers attributed this finding to reduced mitochondrial function in the hypothalamus compared with normal mice.

http://www.pnas.org/content/111/26/9639.full “Targeted placental deletion of OGT recapitulates the prenatal stress phenotype including hypothalamic mitochondrial dysfunction”

Are stress-induced epigenetic changes to DNA inherited across generations?

gettingwell4 0-1 star Wasted resources, Amygdala, Brain development, Cortisol, Epigenetics, Limbic system, Memory, Neurochemicals, Stress , , , , ,

This 2014 Geneva/Cambridge plant study ended by stating:

“The unequivocal demonstration of transgenerational transmission of environmentally-induced epigenetic traits remains a significant challenge.

One of the critical activities erasing stress memories is conserved between plants and mammals.”

However, the researchers didn’t demonstrate that their findings were broadly applicable for mammals or organisms other than the specific plant variety they studied. Possible reasons for these limited findings were given in a 2015 Australian study referenced by Mechanisms of stress memories in plants:

“The majority of DNA methylation analyses performed in plants to date have focused on Arabidopsis, despite being relatively depleted of TEs [transposable elements] (15–20% of the genome) and being poorly methylated compared to other plant genomes.

These studies have lacked the resolution to provide the specific context and genomic location of the changes in DNA methylation.”

There are also significant differences in how epigenetic inheritance across generations may operate among different species per Epigenetic reprogramming in plant and animal development.

Neither the current study nor the above review addressed the behavioral aspect of stress-induced epigenetic inheritance across generations. For example, the behavior of a mother whose DNA was epigenetically changed by stress can induce the same epigenetic changes to her child’s DNA when her child is stressed per One way that mothers cause fear and emotional trauma in their infants:

“Our results provide clues to understanding transmission of specific fears across generations and its dependence upon maternal induction of pups’ stress response paired with the cue to induce amygdala-dependent learning plasticity.”

http://www.pnas.org/content/111/23/8547.full “Identification of genes preventing transgenerational transmission of stress-induced epigenetic states”

DNA methylation is the most frequent way that duplicate genes are epigenetically silenced

gettingwell4 2-3 stars Required further work, Epigenetics

This 2014 human study showed that DNA methylation was the most frequent way that duplicate genes were epigenetically silenced. Current thinking is that at least half of the genes in the human genome are inactive duplicates.

The study stated:

“Duplicate genes are essential and ongoing sources of genetic material.”

What the researchers didn’t show, however, was that duplicate genes evolve per the study’s title “evolution of duplicate genes.” It was misleading to imply in the study’s headline that duplicate genes evolve.

Evolution occurs as organisms adapt to their environments. Duplicate genes aren’t active in the adaptation process when they are silenced.

http://www.pnas.org/content/111/16/5932.full “DNA methylation and evolution of duplicate genes”

Hypothalamic oxytocin and vasopressin have sex-specific effects on pair bonding, gregariousness, and aggression

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

This 2014 bird study showed the complementary effects of neurochemicals vasopressin and oxytocin in the hypothalamus.

Oxytocin neurons in the hypothalamus promote pair bonding and gregariousness in females.

Vasopressin neurons in the hypothalamus promote maternal care, social recognition, and gregariousness in both males and females, and aggression in males toward females.

Vasopressin and oxytocin released generally and in other parts of the brain have different effects. For example:

“Central administration of oxytocin also attenuates stress-induced effects on the brain and reverses stress-induced social avoidance.”

http://www.pnas.org/content/111/16/6069.full “Hypothalamic oxytocin and vasopressin neurons exert sex-specific effects on pair bonding, gregariousness, and aggression in finches”