Month: February 2016

The effects of imposing helplessness

gettingwell4 2-3 stars Required further work, Amygdala, Brainstem, Cerebrum, Epigenetics, Hippocampus, Hypothalamus, Limbic system, Locus coeruleus, Lower brain, Memory, Stress , , , , , , ,

This 2016 New York rodent study found:

“By using unbiased and whole-brain imaging techniques, we uncover a number of cortical and subcortical brain structures that have lower activity in the animals showing helplessness than in those showing resilience following the LH [learned helplessness] procedure. We also identified the LC [locus coeruleus] as the sole subcortical area that had enhanced activity in helpless animals compared with resilient ones.

Some of the brain areas identified in this study – such as areas in the mPFC [medial prefrontal cortex], hippocampus, and amygdala – have been previously implicated in clinical depression or depression-like behavior in animal models. We also identified novel brain regions previously not associated with helplessness. For example, the OT [olfactory tubercle], an area involved in odor processing as well as high cognitive functions including reward processing, and the Edinger–Westphal nucleus containing centrally projecting neurons implicated in stress adaptation.

The brains of helpless animals are locked in a highly stereotypic pathological state.”

Concerning the study’s young adult male subjects:

“To achieve a subsequent detection of neuronal activity related to distinct behavioral responses, we used the c-fosGFP transgenic mice expressing c-FosGFP under the control of a c-fos promoter. The expression of the c-fosGFP transgene has been previously validated to faithfully represent endogenous c-fos expression.

Similar to wild-type mice, approximately 22% (32 of 144) of the c-fosGFP mice showed helplessness.”

The final sentence of the Introduction section:

“Our study..supports the view that defining neuronal circuits underlying stress-induced depression-like behavior in animal models can help identify new targets for the treatment of depression.”

Helplessness is both a learned behavior and a cumulative set of experiences during every human’s early life. Therapeutic approaches to detrimental effects of helplessness can be different with humans than with rodents in that we can address causes.

The researchers categorized activity in brain circuits as causal in the Discussion section:

“Future studies aimed at manipulating these identified neural changes are required for determining whether they are causally related to the expression of helplessness or resilience.”

Studying whether or not activity in brain circuits induces helplessness in rodents may not inform us about causes of helplessness in humans. Our experiences are often the ultimate causes of helplessness effects. Many of our experiential “neural changes” are only effects, as demonstrated by this and other studies’ induced phenotypes such as “Learned Helplessness” and “Prenatally Restraint Stressed.”

Weren’t the researchers satisfied that the study confirmed what was known and made new findings? Why attempt to extend animal models that only treat effects to humans, as implied in the Introduction above and in the final sentence of the Discussion section:

“Future studies aimed at elucidating the specific roles of these regions in the pathophysiology of depression as well as serve as neural circuit-based targets for the development of novel therapeutics.”

http://journal.frontiersin.org/article/10.3389/fncir.2016.00003/full “Whole-Brain Mapping of Neuronal Activity in the Learned Helplessness Model of Depression” (Thanks to A Paper a Day Keeps the Scientist Okay)

Does shame keep you up at night?

gettingwell4 2-3 stars Required further work, Stress

This 2016 Netherlands human study found:

“Restless REM [rapid eye movement] sleep reflects a process that interferes with the overnight resolution of distress. Its accumulation may promote the development of chronic hyperarousal.

We use the term “restless REM sleep” here to refer to REM sleep with a high number of phasic events, including arousals and eye movements.

The present study focused on shame, because it may interfere the most with healthy psychological functioning and was shown to be predictive of developing depression and PTSD symptoms, including hyperarousal. By obstructing effective coping mechanisms, shame often hinders therapeutic progress, to the point that it may even lead to a negative therapeutic outcome.

A dedicated assessment of the subjective duration of distress after a shameful experience was complemented by assessments on nocturnal mentation, insomnia severity, hyperarousal, and major life events, as well as an Internet-implemented structured interview on health.”

From the Limitations section:

  1. “Restless REM sleep was not directly quantified but approximated by means of a validated questionnaire rating of thought-like nocturnal mentation.
  2. Non-REM sleep has also been implicated in the resolution of emotional distress.
  3. A third limitation regards the observational nature of the present study..a more definite conclusion will require studies using experimental manipulation of emotions and sleep.
  4. Whereas there was good reason to focus first on distress induced by shame in our innovative approach to the role of sleep in self-conscious emotions rather than the basic emotions usually studied, our findings should not be interpreted as supporting a unique role for shame or self-conscious emotions. Future studies could address whether the duration of distress elicited by other self-conscious and basic emotions has a similar two-factor structure.”

I applaud the inclusion of emotion in research. I’m not convinced that studying shame will lead to etiologic advances in science, though.

How does shame arise in our lives? Is it a biologic human need on the same level as nourishment, protection, and socialization?

Shame is a symptom along with “nocturnal mentation, insomnia severity, hyperarousal.” If a person’s thoughts, feelings, behavior, and sleep are adversely affected by shame, a resolution should be achieved by addressing the underlying causes, not by tamping down the symptoms.

http://www.pnas.org/content/113/9/2538.full “Slow dissolving of emotional distress contributes to hyperarousal”

Telomerase activity outside of telomere maintenance

gettingwell4 2-3 stars Required further work, Immune system, Telomeres

This 2016 Singapore review was on the role of telomerase in cancers. From its background section:

“Telomeres are conserved, repetitive sequences located at the ends of eukaryotic chromosomes which protect the integrity of genomic DNA. DNA polymerase is unable to replicate the 5′ [carbon number] ends of chromosomes, hence, cells require a RNA dependent DNA polymerase called telomerase to synthesize DNA on the lagging strand. Telomerase activity is tightly regulated and seen mainly in germ cells, stem cells and some immune cell types which have high proliferative needs.

In contrast, somatic cells do not display detectable telomerase activity. As a result, the chromosomes of normal somatic cells shorten 50–200 bp [base pair] each replication at the telomeres due to the problem of end replication. Thus, somatic cells are eventually burdened with DNA damage, replication crisis, cellular senescence or apoptosis and can divide only limited number of times, whereas cells that have active telomerase possess unlimited proliferative potential.”

The main section of the review described the details of how:

“Reactivation of telomerase has been considered as a strategy for telomere maintenance and is a major hallmark of cancer. Although the major function of telomerase is thought to be telomere elongation, accumulating evidence has suggested that it can modulate expression of various genes which affect cancer progression and tumorigenesis.”

http://link.springer.com/article/10.1007/s00018-016-2146-9/fulltext.html “Reactivation of telomerase in cancer”

Advance science by including emotion in research

gettingwell4 5+ stars Premium, Amygdala, Anterior cingulate cortex, Beliefs, Brain hemispheres, Brainstem, Cerebellum, Cerebrum, Dopamine, Hippocampus, Hypothalamus, Limbic system, Lower brain, Memory, Neurochemicals, Thalamus , ,

This 2015 analysis of emotion studies found:

“Emotion categories [fear, anger, disgust, sadness, and happiness] are not contained within any one region or system, but are represented as configurations across multiple brain networks.

For example, among other systems, information diagnostic of emotion category was found in both large, multi-functional cortical networks and in the thalamus, a small region composed of functionally dedicated sub-nuclei.

The dataset consists of activation foci from 397 fMRI and PET [positron emission tomography] studies of emotion published between 1990 and 2011.”

From the fascinating Limitations section:

“Our analyses reflect the composition of the studies available in the literature, and are subject to testing and reporting biases on the part of authors. This is particularly true for the amygdala (e.g., the activation intensity for negative emotions may be over-represented in the amygdala given the theoretical focus on fear and related negative states). Other interesting distinctions were encoded in the thalamus and cerebellum, which have not received the theoretical attention that the amygdala has and are likely to be bias-free.

Some regions—particularly the brainstem—are likely to be much more important for understanding and diagnosing emotion than is apparent in our findings, because neuroimaging methods are only now beginning to focus on the brainstem with sufficient spatial resolution and artifact-suppression techniques.

We should not be too quick to dismiss findings in ‘sensory processing’ areas, etc., as methodological artifacts. Emotional responses may be inherently linked to changes in sensory and motor cortical processes that contribute to the emotional response.

The results we present here provide a co-activation based view of emotion representation. Much of the information processing in the brain that creates co-activation may not relate to direct neural connectivity at all, but rather to diffuse modulatory actions (e.g., dopamine and neuropeptide release, much of which is extrasynaptic and results in volume transmission). Thus, the present results do not imply direct neural connectivity, and may be related to diffuse neuromodulatory actions as well as direct neural communication.”

Why did the researchers use only 397 fMRI and PET studies? Why weren’t there tens or hundreds of times more candidate studies from which to select?

The relative paucity of candidate emotion studies demonstrated the prevalence of other researchers’ biases for cortical brain areas. The lead researcher of the current study was a coauthor of the 2016 Empathy, value, pain, control: Psychological functions of the human striatum, whose researchers mentioned that even their analyses of 5,809 human imaging studies was hampered by other imaging-studies researchers’ cortical biases.

Functional MRI signals depend on the changes in blood flow that follow changes in brain activity. Study designers intentionally limit their findings when they scan brain areas and circuits that are possibly activated by human emotions, yet exclude emotional content that may activate these areas and circuits.

Here are a few examples of limited designs that led to limited findings when there was the potential for so much more:

It’s well past time to change these practices now in the current year.

This study provided many methodological tests that should be helpful for research that includes emotion. It showed that there aren’t impenetrable barriers – other than popular memes, beliefs, and ingrained dogmas – to including emotional content in studies.

Including emotional content may often be appropriate and informative, with the resultant findings advancing science. Here are a few recent studies that did so:

http://journals.plos.org/ploscompbiol/article?id=10.1371%2Fjournal.pcbi.1004066 “A Bayesian Model of Category-Specific Emotional Brain Responses”

Publicly-funded researchers need to provide unqualified free access to their studies

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

Starting the second year of this blog with a magazine article New Clues to How the Brain Maps Time reviewed the findings of a 2015 Boston rodent study During Running in Place, Grid Cells Integrate Elapsed Time and Distance Run. The article’s information was mixed such that when the reader arrived at this phrase:

“Moreover, time cells rely on context; they only mark time when the animal is put into a situation in which time is what matters most.”

it wasn’t clear whether the “time cells” referred to grid cells located in the entorhinal cortex (per the referenced study) or some other cells located in the hippocampus.

The hippocampus also has “time cells.” One of the first studies I curated when I started this blog one year ago today was Our memories are formed within a specific context. That 2014 study’s Significance section included:

“A number of recent studies have shown that the hippocampus, a structure known to be essential to form episodic memories, possesses neurons that explicitly mark moments in time.

We add a previously unidentified finding to this work by showing that individual primate hippocampal neurons not only track time, but do so only when specific contextual information (e.g., object identity/location) is cued.”

I attempted to disambiguate the “time cells” location by reading the 2015 study, only to find it was behind a paywall for which the public doesn’t have unqualified free access.

I assert that the study was performed using public funds, and that the researchers’ infrastructure and facilities were paid in part by the US taxpayers. Only US government funding sources were disclosed on the organization Mission Statement page of the study’s lead researcher, whose position is Lab Chief.

I assume that whether or not the study had unqualified free access was the researchers’ decision. Here’s a typical US NIH statement:

“The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”

There are multiple problems with placing publicly-funded studies behind paywalls. One pertinent to this study and article was the accurate presentation of the study’s findings in news coverage.

The article’s author gave her interpretation of the study and the lead researcher’s remarks. She solicited five other researchers’ opinions, and one researcher provided an appraisal in the Comments section.

Was this treatment of the study’s findings sufficient for the public to understand what the US taxpayers paid for?

It was nice to have interpretations and remarks and opinions and appraisals, but these may have diverged from what the study actually found. Without unqualified free access to the study, there was no base on which to compare and contrast the article’s POVs.

Other news coverage of the study provided further examples of why publicly funded research needs to be freely available without qualification:

  • NPR’s coverage also confused the cells’ location: “If grid cells in the hippocampus and entorhinal cortex..”
  • An article carried by multiple sites headlined the cells as “Odometer neurons.” Did the study find that grid cells operated cumulatively like an odometer that began at some stage of the subjects’ development? Or did it find that the grid cells operated more like a trip meter?
  • In the Discover Magazine coverage the lead researcher stated: “..could point to ways to treat memory loss, whether from old age or illness, like Alzheimer’s disease.” Did the study actually find anything about “memory loss?” Was there anything in it about “old age or illness, like Alzheimer’s disease?”

As the study’s news coverage discrepancies and ambiguities demonstrated, there’s every reason for researchers to provide all the details of their work. We’re well past the days when “wise old men” selectively gate information flows.