A possible link between stress responses and human cancers?

This 2015 UK rodent study found:

“An unexpected role for the GR [glucocorticoid receptor] in promoting accurate chromosome segregation during mitosis.

We also identify reduced GR expression in several common human cancers, thereby implicating GR as a novel tumor suppressor gene.”

One of the researchers said:

“Cancer is caused by cell division going wrong, but no one has previously looked at the role GR has to play in this process. It’s now clear that it is vital.”

From the study:

“Our findings now show that GR function regulates accurate mitotic progression, with clear implications for human health.

Add a previously unidentified perspective to GR action in cell division, affecting mitotic spindle function.

It may be that this action can be targeted by specific ligands, potentially opening up new therapeutic approaches to treat common cancers.”

The Translating PTSD research findings from animals to humans study also found reduced expression of glucocorticoid receptor genes, which appeared in some rodents after stress. Unfortunately, those researchers’ priorities weren’t to research the causes of this reduced expression.

One relevant hypothesis of Primal Therapy is that trauma in the earliest parts of human life epigenetically impairs the proper functioning of human development processes. A follow-on hypothesis is that the arrival of diseases in later life may be traceable back to the damage done during early-life development processes.

An example of this would be that a developing fetus adapts to being constantly stressed by an anxious and stressed mother. When the changes persist after birth, they may present as maladaptations of the infant to a non-stressful environment. These enduring changes may be among the causes of symptoms decades later such as over- and/or under-reactions to stress.

It seems possible that further research in these areas may find links among human stress responses and human cancers. The current study suggested that the glucocorticoid receptor may play a part in these links.

http://www.pnas.org/content/112/17/5479.full “Glucocorticoid receptor regulates accurate chromosome segregation and is associated with malignancy”

Translating PTSD research findings from animals to humans

This 2014 rodent study stressed the animals, measured their stress responses, then killed them and sampled genes in their amygdala, hippocampus, and blood. The researchers found that glucocorticoid receptor signaling genes were the primary pathway associated with “exposure-related individual differences in stress responses for the amygdala and blood. This pathway also placed first for the hippocampus in female rats (glucocorticoid receptor was second in male rats and prostate cancer signaling was first).

I’ll quote one press article’s coverage to show where the researchers wanted to go with the study’s findings:

“We found that most of the genes and pathways that are different in PTSD [post-traumatic stress disorder]-like animals compared to resilient animals are related to the glucocorticoid receptor, which suggests we might have identified a therapeutic target for treatment of PTSD.”

How about this lead sentence:

“There may some day be a blood test to determine whether someone suffers from Post-Traumatic Stress Disorder or is at risk for the psychiatric condition.”

Here’s another article’s paraphrase of a different researcher:

“Those are genes that become activated in the presence of stress. Like a key fitting into a lock, the hormone corticosterone, produced naturally by the body, connects to the receptor and has a calming effect.

In some rodents, and apparently in some people, the pathway appears to be defective, and this puts them at higher risk for PTSD.”

Also, from the study’s abstract:

“Corticosterone treatment 1 h[our] after PSS [predator-scent-stress]-exposure prevented anxiety and hyperarousal 7 d[ays] later in both sexes, confirming the GR [glucocorticoid receptor] involvement in the PSS behavioral response.”

Like other researchers continue to do, they stopped this study short of finding causes for the effects:

  1. What were the causes for genes in the glucocorticoid receptor signaling pathway being differentially expressed? “Exposure-related individual differences” isn’t a causal finding.
  2. If this pathway is “defective,” what exactly happened to make it that way?
  3. Did dampening the effects of stress with a shot of cortisol one hour after the stress treat the cause such that the rats were cured? Since the readers of the study and associated articles were led to infer that this treatment was a cure, why destroy the treated animals afterwards before the proofs of long-term efficacy were thoroughly documented and tested?

When studies like this are carried forward with humans, researchers should try to find the causes for these effects. It isn’t sufficient to pretend that there aren’t early-life causes for these effects. Such a pretense leads to the follow-on pretense that later-life consequences are mysteries such as “exposure-related individual differences” and not effects.

Researchers should act like the subjects are feeling human beings who can participate in treatments of both the causes and effects. They should remember that humans are not lab rats who need to be fixed.

http://www.pnas.org/content/111/37/13529.full “Expression profiling associates blood and brain glucocorticoid receptor signaling with trauma-related individual differences in both sexes”

Do you know a stranger’s emotional motivations for smiling?

The premise of this combination of two studies was:

“Emotional understanding is the central problem of human interaction.”

The researchers reanalyzed a 2008 study’s data, supplemented it with their own 2015 study, and found:

“Social-historical factors..explain cross-cultural variation in emotional expression and smile behavior.

We also report an original study of the underlying states that people believe [my emphasis] are signified by a smile.”

The researchers presented the subjects with a survey that asked them to rate 15 possible reasons for a person to smile at them on a seven-point scale of -3 to +3 for disagreeing/agreeing.

The research methodology didn’t take the additional necessary steps of establishing paired experiments that included presenting a similar survey to a control group of subjects to self-report their emotional motivations for smiling, and then processing the two surveys.

Did the study’s reviewer have anything to say about this lack of validation of the subjects’ beliefs to any factual measurements of a stranger’s corresponding “emotional expression and smile behavior?”

This combination of studies didn’t inform us about the “emotional understanding is the central problem of human interaction” premise. The researchers only provided evidence that the subjects’ cultures were one of many causal factors for the subjects’ beliefs about a hypothetical stranger’s smiling behavior.

The combined studies didn’t contain any emotional content to establish experimental conditions toward the goal of “emotional understanding.” No emotions were involved, for example, when a subject rated “strongly agree” to the “Wants you to like them” reason on a survey for a hypothetical stranger’s smiling behavior.

The studies didn’t show that the subjects rating their beliefs contributed to their real “emotional understanding.” Including emotional content, such as experimentally evoking an actual emotion in response to an actual stranger smiling, possibly could have contributed to real “emotional understanding.

Research that strips out emotional content can’t factually provide evidence for real “emotional expression and smile behavior.” The degrees to which beliefs about and perceptions of a stranger’s smiling actually match their emotional reality remain to be shown.

http://www.pnas.org/content/112/19/E2429.full “Heterogeneity of long-history migration explains cultural differences in reports of emotional expressivity and the functions of smiles”

Can a Romanian orphan give informed consent to be an experimental subject?

This 2015 study used Romanian orphans as lab rats for findings of which I failed to see the value. The world didn’t really need any further research to demonstrate that foster care would be better for a child than staying in an orphanage.

The researchers placed the orphans in five separate stressful situations, and measured their cortisol and DHEA-S levels, along with their electrocardiograph and impedance cardiograph activity. The findings were:

“Children who were removed from the Romanian institutions and placed with foster parents before the age of 24 months had stress system responses similar to those of children being raised by families in the community.

The children raised in institutions showed blunted responses in the sympathetic nervous system, associated with the flight or fight response, and in the HPA axis, which regulates cortisol.”

One unsupported assertion from the researchers was:

“We provide evidence for a causal link between the early caregiving environment and stress response system reactivity in humans with effects that differ markedly from those observed in rodent models.”

The researchers stated that rodent studies have converged to find:

“Early-life adversity results in hyperreactivity of the sympathetic nervous system (SNS) and hypothalamic–pituitary–adrenal (HPA) axis.”

It’s baloney that the same results from early life adversity in rodents haven’t also been present in humans. Even the lead researcher herself said in a news article:

“More significantly, McLaughlin said, their [the orphans] stress response systems might have been initially hyperactive at earlier points in development, then adapted to high levels of stress hormones.”

The difference was that the rodents were monitored 24/7 until researchers killed and dissected them. The children’s periods of adversity likely started while in the womb, and their lives had been monitored for research purposes sporadically after their births.

Everybody knows that just because adverse events and effects in these children’s lives weren’t recorded by researchers didn’t mean these effects weren’t present at some point.

Particularly irksome was another unsupported assertion from the lead reviewer:

“The children involved in the study are now about 16 years old, and researchers next plan to investigate whether puberty has an impact on their stress responses. It could have a positive effect, McLaughlin said, since puberty might represent another sensitive period when stress response systems are particularly tuned to environmental inputs. “It’s possible that the environment during that period could reverse the impacts of early adversity on the system,” she said.”

No, this is NOT possible. We may as well expect an apple to fall upward.

The impacts of early adversity persist with enduring physiological changes as shown in experimental studies. Studies have NOT provided evidence that the subjects’ environment can cause the effects of complete reversal of all these changes, no matter the stage of life of the subjects.

This point was addressed in The effects of early-life stress are permanent alterations in the child’s brain circuitry and function rodent study:

The current study manipulates the type and timing of a stressor and the specific task and age of testing to parallel early-life stress in humans reared in orphanages.

The results provide evidence of both early and persistent alterations in amygdala circuitry and function following early-life stress.

These effects are not reversed when the stressor is removed nor diminished with the development of prefrontal regulation regions.

That study had the same reviewer as the current study. The current study’s lead researcher knew or should have known of this and other relevant research. She knew or should have known of the irreversibility of critical periods, during which developments either occurred or were forever missed.

Did the lead researcher make assertions not supported by the study or relevant research – assertions made counter to her scientific knowledge – show her unease about treating the orphans as lab rats? Was there was some other agenda in play?

The larger problem was the study’s informed consent with this group of Romanian orphans. If you were in contact with a damaged person, and implicitly gave them hope that you would improve their life, then who are you as a feeling human being when you don’t personally carry through? Does the legal documentation matter?

Also, I’ve noticed problems with several studies that had this particular reviewer:

Add the current study to the list.

http://www.pnas.org/content/112/18/5637.full “Causal effects of the early caregiving environment on development of stress response systems in children”

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Emotion inclusion in basic research drives discovery

What happens when a meme influences science? It would seem that researchers’ perceptions start to wheel around its axis.

A meme was the driver of this short 2015 commentary that stated:

“Most preclinical biomedical research, however, has been conducted with inadequate consideration of sex.”

If researchers discovered that gender hadn’t been adequately considered in research, maybe other “evolutionarily fundamental” factors had “inadequate consideration” as well.

Maybe one day soon, researchers will stop the current widespread exclusion of emotional content in studies, especially when the studies already included areas of the brain that are the biological bases of emotions.

To imagine a potentially beneficial future meme, I substituted the word “emotion” for “sex” in the title and part of two paragraphs of this commentary. How well does this fit?

[Emotion] inclusion in basic research drives discovery”

“Why is [emotion] so important?

Although many factors can influence an outcome, [emotion] is evolutionarily fundamental and affects the whole of the population

Across diverse disciplines, researchers risk drawing erroneous conclusions when they extrapolate outcome data from [emotional to non-emotional and vice versa].”

See A missed opportunity to study odor-evoked emotional memories for one deliberate exclusion of emotional content, although including emotions may have been appropriate, informative, and contributed to advancing science.

Click the hippocampus category to see a sample of human studies that may have included the biological seat of emotional memories, but only a scarce few of which included emotional content.

http://www.pnas.org/content/112/17/5257.full “Opinion: Sex inclusion in basic research drives discovery”

Genetic programming of hypothalamic neurons regulates food intake and body weight

These 2015 Michigan/Argentinian fish and rodent studies were of the genetic programming of specific neurons in the hypothalamus. The study linked below found:

“Food intake and body weight regulation depend on proper expression of the gene” in these neurons.

In a second study released at the same time from the same researchers:

“The researchers found that the two enhancers act in ways that complement one another, both encouraging the expression of the Pomc gene at key times. One of the two is found in the same form among all mammals, the other among all placental mammals – suggesting that they’ve been kept intact throughout the evolutionary process.”

Genetic programming of these neurons begins during early brain development. One of the researchers said:

“This work represents the first example of a neuron-specific gene in vertebrates where we have found both the enhancers and a shared transcription factor that control gene expression in the developing brain and then throughout the life span of the adult.”

The first study showed that if the genetic expression of these hypothalamic neurons was disrupted, the individual lost control of their eating (hyperphagia) and the usual result was severe obesity:

“We don’t know, but we think it likely, that it [regulation of these specific hypothalamic neurons in humans] may be similar to the mouse model, where its role is like a dial, with a linear relationship between the amount of Pomc [the gene] expression and the degree of obesity.”

I hope that when extending this research to humans, the researchers don’t exclude emotional content like most studies involving areas of the limbic system have done. Everyone has feelings intermixed with eating and foods. It’s a great disservice to have publicly funded studies not include aspects of emotion that could potentially help people.

http://www.pnas.org/content/112/15/E1861.full “Islet 1 specifies the identity of hypothalamic melanocortin neurons and is critical for normal food intake and adiposity in adulthood”

Is IQ an adequate measure of the quality of a young man’s life?

This 2015 Virginia study used Swedish data to find:

“Adoption into improved socioeconomic circumstances is associated with a significant advantage in IQ.”

The study’s all-male subjects were in 436 sibling relationships:

“..in which at least one member was reared by one or more biological parents and the other by adoptive parents. IQ was measured at age 18–20 as part of the Swedish military service conscription examination.”

One of the researchers said:

“Environmental effects have to be inferred, as in the rare event when pairs of siblings are raised by different parents in different socioeconomic circumstances. The Swedish population data allowed us to find that homes led by better educated parents produce real gains in the cognitive abilities of the children they raise.”

Let’s approach this study from the adopted boys’ perspectives. Their biological families’ situations had to be hellishly tragic in order to separate siblings and put one of them up for adoption. I didn’t find at what age the separations typically took place, but can you imagine what the adopted child felt?

A child is very sensitive to his caregivers’ words, body language, facial expressions, physical touches – to all the things that show him he’s loved. A child learns at an early age from both implicit and overt expressions whether or not he’s accepted for who he is.

It’s extremely traumatic for a child to be rejected for who he is. Consider this passage from Dr. Arthur Janov’s book The Primal Scream:

“Parental need becomes the child’s implicit command.

The child is born into his parents’ needs and begins struggling to fulfill them almost from the moment he is alive.

He may be pushed to smile (to appear happy), to coo, to wave bye-bye, later to sit up and walk, still later to push himself so that his parents can have an advanced child.

As the child develops, the requirements upon him become more complex.

He will have to get A’s, to be helpful and do his chores, to be quiet and undemanding, not to talk too much, to say bright things, to be athletic.

What he will not do is be himself.”

All of the above can happen within a stable family. Can you imagine what a child in an unstable family felt as he learned he wasn’t accepted, and how he tried to adapt?

Everything these adopted children did to be accepted by their original caregivers failed. They were rejected by and ejected from the people who were supposed to love them!

Can you imagine how desperate these adopted children would have been in their new environment?

What wouldn’t they have done to be accepted?

The researchers made a point of cognitive development. But of all of the things that were important to the adopted child, that described his quality of life, does the finding of a higher IQ give even the slightest hint of his reality?

http://www.pnas.org/content/112/15/4612.full “Family environment and the malleability of cognitive ability: A Swedish national home-reared and adopted-away cosibling control study”

Epigenetic production of new brain neurons in the hippocampus

This 2015 La Jolla rodent study provided further details on the production of new neurons in the adult hippocampus:

“We propose that SOX2 sets a permissive epigenetic state in neural progenitor cells, thus enabling proper activation of the neuronal differentiation program under neurogenic cue.”

The researchers stated that the functions of these new brain neurons were:

“Newborn granule neurons generated from neural progenitor cells in the adult hippocampus play a key role in spatial learning and pattern separation.”

http://www.pnas.org/content/112/15/E1936.full “SOX2 primes the epigenetic landscape in neural precursors enabling proper gene activation during hippocampal neurogenesis

How well can catastrophes be predicted?

This 2015 study found a way of modeling catastrophic shifts that smoothed the processes with selectively introduced randomness:

“Most computer models created for the purpose of predicting catastrophes are based on deterministic math—that is, they assume a perfect world where nothing is random. That approach cannot work in the real world of course, because real catastrophes quite often have several contributing factors that are random in nature.

In real life, such events exhibit another common trait of catastrophes, a group of rapid transitions that come about due to a small change in a system.”

If this study’s findings were correct, it would seem that researchers who put together models that used deterministic algorithms to predict catastrophes may have been just expressing their beliefs instead of assessing reality.

There apparently are many researchers whose models incorporate catastrophes. A search on PNAS.org for “catastrophic” shows over 100 studies published since the beginning of last year.

In a related question: Does everything happen for a reason?

  • If randomness is included as a reason, maybe things do.
  • If randomness is excluded, then we’re back to beliefs instead of reality.

In perhaps an unrelated question: Can catastrophes be predictably avoided in our personal lives?

  • Maybe most of them can, if we can eliminate sources of potential harm.
  • Probably not entirely avoided, though, because of the randomness factor.

It’s difficult to have a balanced degree of concern about future harm. Here’s a view from Dr. Arthur Janov in his Primal Healing book p. 70:

“Worrying is not a problem, it is the symptom of something that is occurring physiologically within the brain. What causes the worrying is the problem.

The constant worry is anticipating catastrophe. But what we don’t realize is that the catastrophe already has happened; we simply have no access to it.

We are actually worried about the past, not the future.”

http://www.pnas.org/content/112/15/E1828.full “Eluding catastrophic shifts”

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A missed opportunity to study odor-evoked emotional memories

The researchers of Can a study exclude the limbic system and adequately find how we process value? published another study. In this 2015 human study, subjects were monitored with fMRI scans while making choices on the identity and pleasantness of rewarding food odors.

I feel that the researchers missed quite a few good opportunities to advance science. Instead of making peripheral assessments of limbic system areas and citing numerous other studies, they could have included emotional content in their study and drawn their own conclusions.

Consider these opportunities:

  • Wouldn’t the odors used in the study such as chocolate cake and pizza and strawberry and potato chips – and other “comfort” foods – potentially be associated with emotional responses?
  • Don’t most humans have memories that include pleasant food odors?
  • Wouldn’t it have been informative to ask the subjects during fMRI scans to identify what emotions were evoked by the pleasant food odors?
  • Wouldn’t these resultant fMRI scans be expected to potentially show more strongly activated limbic system areas, given the hippocampus’ position as the seat of emotional memories?
  • Wouldn’t the additional emotional responses and memories and subsequent limbic system area activations potentially influence the subjects’ value judgments?

Instead, the researchers peripherally included limbic system areas in the study. The supplementary material included passages such as:

“Identity-specific value signals were found in not only the OFC, [orbitofrontal cortex] but also the ACC [anterior cingulate cortex] and hippocampus.”

Like the previous study, the current study’s focus was to provide evidence that areas of the cerebrum were in control when people made value judgments. The term “value” in the current study meant:

“the pleasantness of the odor.”

Like the previous study, areas of the limbic system weren’t addressed until the tail end of the supplementary material. The researchers cited other studies in an attempt to dismiss the role of the ACC in making value judgments, then said:

“Although we are unable to distinguish between these alternative explanations, our findings suggest that value-related signals in ACC—whether signed or unsigned—are specific to the identity of the expected outcome.”

Since the current study found that “identity” was encoded by cerebral areas, the above sentence was written to nudge the reader into inferring that the cerebrum dominated value judgments of “the pleasantness of the odor.”

The researchers similarly cited other studies in the last paragraph instead of specifically discussing how they studied the participation of the hippocampus part of the limbic system. They then speculated that the hippocampus’ contributions to value judgments in the current study were explained by the referenced studies:

“We speculate that the hippocampus is involved in retaining sensory-based information about specific rewards, which may be linked to value-based representations in OFC for later consolidation.”

Like the previous study, the researchers were begrudgingly diverted away from their focus on cerebral areas when they were forced to acknowledge the limbic system’s contributions to value judgments of “the pleasantness of the odor.”

http://www.pnas.org/content/112/16/5195.full “Identity-specific coding of future rewards in the human orbitofrontal cortex”