Our well being influences our mitochondrial biology.

I pass on the abstract from Trumoff et al (open source) below. The bottom line is that our experienced well being correlates with with higher levels of energy transformation machinery in our mitochondria.  

Significance

Psychosocial experiences predict health trajectories, but the underlying mechanism remains unclear. We report that positive psychosocial experiences are linked to greater abundance of the mitochondrial energy transformation machinery, whereas negative experiences are linked to lower abundance. Overall, psychosocial experiences accounted for 18 to 25% of the variance in protein abundance for complex I, the largest and most upstream mitochondrial oxidative phosphorylation (OxPhos) enzyme. At single-cell resolution, positive psychosocial experiences were particularly related to glial cell mitochondrial phenotypes. As a result, opposite associations between glial cells and neurons were naturally masked in bulk transcriptomic analyses. Our results suggest that mitochondrial recalibrations in specific brain cell types may represent a potential psychobiological pathway linking psychosocial experiences to human brain health.

Abstract

Psychosocial experiences affect brain health and aging trajectories, but the molecular pathways underlying these associations remain unclear. Normal brain function relies on energy transformation by mitochondria oxidative phosphorylation (OxPhos). Two main lines of evidence position mitochondria both as targets and drivers of psychosocial experiences. On the one hand, chronic stress exposure and mood states may alter multiple aspects of mitochondrial biology; on the other hand, functional variations in mitochondrial OxPhos capacity may alter social behavior, stress reactivity, and mood. But are psychosocial exposures and subjective experiences linked to mitochondrial biology in the human brain? By combining longitudinal antemortem assessments of psychosocial factors with postmortem brain (dorsolateral prefrontal cortex) proteomics in older adults, we find that higher well-being is linked to greater abundance of the mitochondrial OxPhos machinery, whereas higher negative mood is linked to lower OxPhos protein content. Combined, positive and negative psychosocial factors explained 18 to 25% of the variance in the abundance of OxPhos complex I, the primary biochemical entry point that energizes brain mitochondria. Moreover, interrogating mitochondrial psychobiological associations in specific neuronal and nonneuronal brain cells with single-nucleus RNA sequencing (RNA-seq) revealed strong cell-type-specific associations for positive psychosocial experiences and mitochondria in glia but opposite associations in neurons. As a result, these “mind-mitochondria” associations were masked in bulk RNA-seq, highlighting the likely underestimation of true psychobiological effect sizes in bulk brain tissues. Thus, self-reported psychosocial experiences are linked to human brain mitochondrial phenotypes.

The Neurobiology of Stress: Vulnerability, Resilience, and Major Depression

A valuable trove of open source articles is provided in the Special Feature section of the Dec. 5 issue of PNAS with an introductory article by Akil and Nestler with the title of this post.  The special feature:

...explores the consequences of the broad-scale increase in psychological stress and the evidence that we are facing a second pandemic of depression, anxiety, and other stress-related disorders. The authors of this feature describe challenges faced and scientific advances being made, spanning animal models to human translation, to illustrate new tools and techniques currently being deployed in understanding the biology of stress and resilience and the interplay between genetic and environmental variables.

Three common assumptions about inflammation, aging, and health that are probably wrong

The abstract of a recent PNAS article by Thomas W. McDade (motivated readers can obtain the whole article from me):  

Significance

Inflammation is one of the most important, and potent, physiological systems in the human body. It is widely assumed that levels of inflammation increase with age and that chronic inflammation contributes to cardiovascular diseases. This understanding of inflammation is based on studies of people living in affluent, industrialized settings with low burdens of infectious disease. A broader view, based on research conducted across a wider range of ecological settings globally, indicates that chronic inflammation is not necessarily a “normal” part of aging and that the association between inflammation and age-related diseases is not inevitable. It also suggests that environments early in development have lasting effects on the regulation of inflammation in adulthood, with implications for diseases of aging.

Abstract

Chronic inflammation contributes to the onset and progression of cardiovascular disease and other degenerative diseases of aging. But does it have to? This article considers the associations among inflammation, aging, and health through the lens of human population biology and suggests that chronic inflammation is not a normal nor inevitable component of aging. It is commonly assumed that conclusions drawn from research in affluent, industrialized countries can be applied globally; that aging processes leading to morbidity and mortality begin in middle age; and that inflammation is pathological. These foundational assumptions have shifted focus away from inflammation as a beneficial response to infection or injury and toward an understanding of inflammation as chronic, dysregulated, and dangerous. Findings from community-based studies around the world—many conducted in areas with relatively high burdens of infectious disease—challenge these assumptions by documenting substantial variation in levels of inflammation and patterns of association with disease. They also indicate that nutritional, microbial, and psychosocial environments in infancy and childhood play important roles in shaping inflammatory phenotypes and their contributions to diseases of aging. A comparative, developmental, and ecological approach has the potential to generate novel insights into the regulation of inflammation and how it relates to human health over the life course.

Traumatic Memories Are Processed as Present Experience

Ellen Barry points to work by Perl et al. showing that different patterns of brain activity underlie sad versus traumatic autobiographical memories.  The Perl et al. abstract:

For people with post-traumatic stress disorder (PTSD), recall of traumatic memories often displays as intrusions that differ profoundly from processing of ‘regular’ negative memories. These mnemonic features fueled theories speculating a unique cognitive state linked with traumatic memories. Yet, to date, little empirical evidence supports this view. Here we examined neural activity of patients with PTSD who were listening to narratives depicting their own memories. An intersubject representational similarity analysis of cross-subject semantic content and neural patterns revealed a differentiation in hippocampal representation by narrative type: semantically similar, sad autobiographical memories elicited similar neural representations across participants. By contrast, within the same individuals, semantically similar trauma memories were not represented similarly. Furthermore, we were able to decode memory type from hippocampal multivoxel patterns. Finally, individual symptom severity modulated semantic representation of the traumatic narratives in the posterior cingulate cortex. Taken together, these findings suggest that traumatic memories are an alternative cognitive entity that deviates from memory per se.

Our Baysean Brain and the Placebo Effect

I'm passing on a few clips that give the take home message from a recent NYTimes piece by Haravard Medical School's Ted Kaptchuk, who directs the Harvard-wide program in placebo studies.

...placebos can work even when patients know they are getting a placebo. In 2010 my colleagues and I published a provocative study showing that patients with irritable bowel syndrome who were treated with what we call open-label placebos — as in, we gave them dummy pills and told them so — reported more symptom relief compared with patients who didn’t receive placebos. (These placebos were given with transparency and informed consent.) In another blow to the concept that concealment is required for placebo effects, my team recently published a study comparing open-label placebos and double-blind placebos in irritable bowel syndrome and found no significant difference between the two. A medical myth was overthrown.

Currently, more than a dozen randomized trials demonstrate that open-placebo treatment can reduce symptoms in many illnesses with primarily self-reported symptoms such as chronic low back pain, migraine, knee pain and more. These findings suggest that patients do not have to believe, expect or have faith in placebos to elicit placebo effects. So what’s happening?

To date, the best explanation for the results of open-placebo trials suggests that for certain illnesses in which the brain amplifies symptoms, engaging in a healing drama can nudge the brain to diminish the volume or false alarm of what’s called central sensitization — when the nervous system overemphasizes or amplifies perceptions of discomfort. This mostly involves nonconscious brain processes that scientists call Bayesian brain, which describes how the brain modulates symptoms. The intensification and the relief of symptoms use the same neural pathways. Considerable evidence also shows that placebos, even when patients know they are taking them, trigger the release of neurotransmitters like endorphins and cannabinoids and engage specific regions of the brain to offer relief. Basically, the body has an internal pharmacy that relieves symptoms.

...placebos shouldn’t be a first-line treatment; patients should be given what effective medicines are available. After all, placebos rarely, if ever, change the underlying pathology or objectively measured signs of disease. I like to remind people that they don’t shrink tumors or cure infections.

Crucially, much discussion and reflection is needed among physicians and our health care system as a whole to understand why the act of treatment itself is so powerful to patients even if a pill contains no therapeutic ingredients. Medicine is not only effective drugs and procedures; it’s a human drama of charged engagement. Our team published a study in The BMJ demonstrating that placebo effects can be significantly enhanced in the context of a supportive, respectful and attentive patient-clinician relationship. Acts of human kindness in general are linked to robust placebo effects.

Does a "P-factor" underlie core attributes of mental health maladies?

I want to point to an open source "Core Concepts" article in PNAS by David Adam that presents "the views of some psychiatrists who argue that the same bit of biology—genetics gone awry or some misplaced brain circuitry—could underlie the vast majority of humanity’s mental health problems. Studies have shown, for example, that many of the same genes seem to drive increased risk for autism, attention-deficit hyperactivity disorder (ADHD), bipolar disorder, major depression, and schizophrenia. They call this as-yet-unidentified common cause the “psychopathology factor,” or “p-factor” for short."

Mental problems from early life adversity passed down three generations.

Early life adversity can result in emotional and behavioral problems throughout adulthood in both humans and mice. Battaglia et al. show than in mice this effect can persist through three generations. Exposure to the drug amiloride throughout the three generations can reverse this persistence of anxiety and pain sensitivity by inhidibint the increased activity of membrane ion channels that are its apparent cause. Here is their abstract:

Early-life adversities are associated with altered defensive responses. Here, we demonstrate that the repeated cross-fostering (RCF) paradigm of early maternal separation is associated with enhancements of distinct homeostatic reactions: hyperventilation in response to hypercapnia and nociceptive sensitivity, among the first generation of RCF-exposed animals, as well as among two successive generations of their normally reared offspring, through matrilineal transmission. Parallel enhancements of acid-sensing ion channel 1 (ASIC1), ASIC2, and ASIC3 messenger RNA transcripts were detected transgenerationally in central neurons, in the medulla oblongata, and in periaqueductal gray matter of RCF-lineage animals. A single, nebulized dose of the ASIC-antagonist amiloride renormalized respiratory and nociceptive responsiveness across the entire RCF lineage. These findings reveal how, following an early-life adversity, a biological memory reducible to a molecular sensor unfolds, shaping adaptation mechanisms over three generations. Our findings are entwined with multiple correlates of human anxiety and pain conditions and suggest nebulized amiloride as a therapeutic avenue.

The immaturity of America's therapeutic culture

I  recommend reading the most recent NYTimes David Brook's piece, and pass on here ChatGPT 4's response to my request to summarize the main  its 1,472 words. It produced the following  339 words which nicely cover Brook's core points.  I think I will start using ChatGPT 4 more frequently for this purpose since  I've only recently realized that MindBlog readers who do not subscribe to the NYTimes can not read articles that I point to.  Also, I simply don't have the time to generate summaries myself, because I want to be working on other things.  

Summary of the Essay on the American Therapeutic Culture and Maturity: 

The decline of the American psyche can be linked to cultural shifts that started after World War II, leading to the rise of the therapeutic culture.

Historically, self-worth was derived from one's relationship with God or success in the marketplace. In the therapeutic culture, self-worth is gauged by subjective feelings about oneself.

This culture turned many into fragile narcissists, detached from moral traditions and relying heavily on public affirmation for self-worth.

By 2010, the US faced a mental health crisis, marked by rising rates of depression and suicide. Social media became a platform for seeking validation but often resulted in rejection.

The term “trauma” began to encompass a wider range of upsetting experiences, moving from severe physical harm to milder psychological wounds. Trauma became a dominant theme in culture, with many using it as a primary source of identity.

Safetyism emerged, advocating for protections against emotional harm. This led to concepts like “trigger warnings,” “microaggressions,” and “safe spaces.” 

The approach to trauma became counterproductive, with certain false ideas propagated, such as "what doesn't kill you makes you weaker" and the portrayal of traumatized individuals as passive victims.

An opposing perspective, led by figures like Jordan Peterson, argued for resilience and not viewing oneself as a perpetual victim. Yet, these figures too sometimes portrayed themselves as victims in a different context.

This societal focus on victimhood has led to a public culture that is impulsive and erratic. The loudest voices often dominate discussions, sidelining mature discourse.

The core issue is the therapeutic ethos itself, which disconnects people from a broader moral order and asks individuals to create an identity solely from within. 

True maturity is not self-centered but involves weaving an identity from commitments and relationships with others. It's about seeing situations from multiple perspectives and committing to concrete moral goals.

Maturity allows individuals to be calm and understanding in challenging situations, and this might be the answer to building a more resilient and connected culture in the future.

Mechanisms that link psychological stress to the exacerbation of gut inflammation.

Schneider et al. describe one mechanism by which psychological stress deteriorates our health  -  the enteric nervous system relays psychological stress to intestinal inflammation. Here is their abstract:  

Highlights

• Psychological stress leads to monocyte-mediated exacerbation of gut inflammation

• Chronic glucocorticoid signaling drives the effect of stress on IBD

• Stress induces inflammatory enteric glia that promote monocyte recruitment via CSF1

• Stress provokes transcriptional immaturity in enteric neurons and dysmotility

Summary 

Mental health profoundly impacts inflammatory responses in the body. This is particularlyapparent in inflammatory bowel disease (IBD), in which psychological stress is associated with exacerbated disease flares. Here, we discover a critical role for the enteric nervous system (ENS) in mediating the aggravating effect of chronic stress on intestinal inflammation. We find that chronically elevated levels of glucocorticoids drive the generation of an inflammatory subset of enteric glia that promotes monocyte- and TNF-mediated inflammation via CSF1. Additionally, glucocorticoids cause transcriptional immaturity in enteric neurons, acetylcholine deficiency, and dysmotility via TGF-β2. We verify the connection between the psychological state, intestinal inflammation, and dysmotility in three cohorts of IBD patients. Together, these findings offer a mechanistic explanation for the impact of the brain on peripheral inflammation, define the ENS as a relay between psychological stress and gut inflammation, and suggest that stress management could serve as a valuable component of IBD care.

The vagus nerve, heart rate variability, and subjective wellbeing - a MindBlog self experiment

In this post I pass on to MindBlog readers a NYTimes article by Christina Caron that has been republished several time by the newspaper. It is a sane account of what the vagus nerve is and what it does...The vagus is the main nerve of the parasympathetic nervous system. Unlike the sympathetic nervous system, which is associated with arousal of the body and the “fight or flight” response, the parasympathetic branch helps us rest, digest and calm down. Numerous experiments have shown that increased activity of the nerve correlates with an improvement in mood. from the article (slightly edited):

The activity of the vagus nerve is difficult to measure directly, especially given how complex it is. But because some vagus nerve fibers connect with the heart, experts can indirectly measure cardiac vagal tone — or the way in which your nervous system regulates your heart — by looking at your heart rate variability (HRV), which is the fluctuations in the amount of time between your heartbeats...An abnormal vagal tone — one in which there is very little HRV — has been associated with conditions like diabetes, heart failure and hypertension...A high HRV may signify an ideal vagal tone. The typical range of HRV is between 20 and 200 msec.

I will give my own experience...I have been using an Oura Ring since December 2021, and more recently an Apple watch,  to monitor nighttime resting heart rate, HRV, body temperature, and respiratory rate. By now I have documented numerous instances of a correlation - occurring over a period of several months - between subjective well being, average nighttime HRV, and duration of deep (restorative) sleep. (See the plot below showing HRV and duration of deep sleep over the past several months).  During periods of stress my average nighttime HRV decreases to ~20 msec and remains relatively constant throughout sleep, during periods when I am feeling open, chilled out, and flexible average nighttime HRV has increased to ~100 msec with large variations during the night. I've also played with techniques meant to tweak parasympathetic/sympathetic balance and found that delivering mild shocks to the body by perturbing breathing or using biofeedback to enhance HRV can correlate with increased average nighttime HRV and daytime sense of well being. Even though I take myself to be an unbiased observer and don't think that I am just feeling what I would like to feel - less stressed and more chilled out - it is important note the usual caveat that any human reports might be biased by a placebo effect. [BUT...see added note below]

Screen shot from the Oura Ring web interface:

NOTE ADDED 11/12/23:   The correlation shown has to taken with a grain of salt, because the correlation coefficient dropped to ~0.1 for the next three month period, and remains there as of 11/12/23

Breath - Some basic facts and instructions

I’ve enjoyed reading through James Nestor’s book “Breath - The new science of a lost art,”  and I tried out some of the exercises he points to, such as Tummo, which increases breathing to deliver a brief shock therapy to the sympathetic and parasympathetic systems that regulate breathing, thus temporarily resetting to a more appropriate balance between the two.  He describes numerous useful breathing therapies that have been discovered, forgotten, and then rediscovered over the past 3000 years by different cultural and religious traditions, and in the past 300 years by more modern medical and scientific insights.  Nestor: “Breathing is a key input. From what I’ve learned in the past decade, that 30 pounds of air that passes through our lungs every day and that 1.7 pounds of oxygen our cells consume is as important as what we eat or how much we exercise. Breathing is a missing pillar of health.”

The epilogue to his book provides a very concise list of breathing instructions that can serve as preventative maintenance to assist in maintaining balance in the body so that milder problems don’t blossom into more serious health issues and might restore balance when it is lost.  Here is Nestor’s list, with an assist from ChatGPT 4 condensations of the book’s text that I have tweaked where appropriate.  The condensations are amazing.  They cut through the folksy personal reader-friendly stuff to give the basic facts presented.

In a nutshell, this is what we’ve learned:

SHUT YOUR MOUTH    

A 20-day study found that chronic mouth breathing has significant negative effects on health, including increased stress hormones, risk of sinus infections, high blood pressure, and reduced heart rate variability. Participants experienced persistent nocturnal suffocation, snoring, and sleep apnea, potentially leading to hypertension, metabolic and cognitive problems. Although some measurements remained unchanged, the overall impact was negative, with participants experiencing fatigue, irritation, anxiety, and other discomforts. The human body has evolved to breathe through both the nose and mouth for a reason, and chronic mouth breathing is not a normal or healthy behavior.

BREATHE THROUGH YOUR NOSE

Upon switching back to nasal breathing, participants experienced improved health, with normalized blood pressure, carbon dioxide levels, and heart rates. Snoring reduced dramatically and nasal infections cleared up. Nasal breathing also enhanced physical performance on a stationary bike. The positive outcomes of nasal breathing inspired further research into the effects of sleep tape on snoring and sleep apnea. The experience emphasized the importance of nasal breathing for overall well-being and debunked misconceptions about chronic allergies, congestion, and sleep issues being natural parts of life.

EXHALE

Carl Stough spent a half century reminding his students of how to get all the air out of our bodies so that we could take more in. He emphasized the importance of proper exhalation to improve various aspects of health and performance. By training individuals to exhale longer and more fully, he enabled emphysema patients to recover significantly, opera singers to improve their voices, asthmatics to prevent attacks, and Olympic sprinters to win gold medals. Practicing full exhalations and engaging more of the lung capacity can enhance breathing efficiency, leading to better overall performance and well-being.

CHEW

Ancient skeletons and pre-Industrial Age skulls exhibit large sinus cavities, strong jaws, and straight teeth, attributed to extensive chewing. Unlike other bones, facial bones can continue to grow and remodel throughout life, allowing for improvements in breathing ability at any age. To achieve this, incorporate rougher, raw, and heartier foods into your diet, similar to what our ancestors consumed, which require more chewing effort. Practicing proper mouth posture with lips together, teeth slightly touching, and tongue on the roof of the mouth is also important.

BREATHE MORE, ON OCCASION

While over breathing can be harmful, practicing controlled, heavy breathing for short, intense periods, such as in Tummo, Sudarshan Kriya, and vigorous pranayamas, can be therapeutic. These techniques intentionally stress the body to reset its normal functions and improve overall well-being. Conscious heavy breathing helps us gain control over our autonomic nervous systems and bodies, transforming us from passive passengers to active pilots of our own health.

HOLD YOUR BREATH

Dr. Donald Klein's research on chemoreceptor flexibility, carbon dioxide, and anxieties inspired further investigation into the connections between the amygdalae, breathing, and anxiety. The amygdalae, which govern perceptions of fear and emotions, also control aspects of breathing, and communication between chemoreceptors and the amygdalae is crucial. People with anxiety may suffer from connection issues between these areas, causing them to unintentionally hold their breath and ultimately panic. As a result, their bodies may adapt by over breathing to maintain low carbon dioxide levels. This suggests that anxiety might not be a psychological problem, but rather a natural reaction to an emergency in the body. Further research is needed to test this theory, which could explain why slow and steady breathing therapy is effective for panic, anxiety, and other fear-based conditions.

HOW WE BREATHE MATTERS

The perfect breath, according to the author, involves inhaling for 5.5 seconds and exhaling for 5.5 seconds, resulting in 5.5 breaths per minute and a total of about 5.5 liters of air. Practicing this perfect breathing promotes peak efficiency in the body. Many devices and apps are being developed to help people breathe at this optimal rate. However, the simplest approach requires no technology or equipment and can be practiced anywhere, anytime. This technique has been used by our ancestors for thousands of years, and the author uses it as a way to return to normalcy after periods of stress or inactivity.

 

An appendix to Nestor's book describes several different breathing techniques (such as alternative nostril breathing) and an extended bibliography available at James Nestor's website offers video and audio tutorial for numerous breathing techniques.

Our heartbeat shapes our perception of time (and a comparison of how ChatGPT and Google Bard condense an account of work showing this)...

Ellen Barry has done a review of work by Sadeghi et al, as well as others, on how heart-brain interactions influence our perception of time. I asked ChatGPT to do a 200 word summary of her article of 795 words. It generated 237 words (below), to which I made a small addition. (I feels like I'm using the language generating mental equivalent of a physical prosthesis.) That is followed by Google Bard's response, very impressive. Microsoft's Bing was unable to deal with the task.

A recent study by psychologists at Cornell University has suggested that our heartbeats may play an important role in shaping our perception of time. The study, published in the journal Psychophysiology, found that some distortions in time perception could be driven by variable heartbeat length. The researchers fitted undergraduates with electrocardiograms to measure the length of each heartbeat and asked them to estimate the length of brief audio tones. After longer heartbeat intervals, subjects tended to perceive the tone as longer, while shorter intervals led to shorter perception. Additionally, the subjects’ heartbeat intervals lengthened after each tone, and a lower heart rate appeared to assist with perception. According to Saeedeh Sadeghi, the study’s lead author, “there is no single part of the brain or body that keeps time — it’s all a network. The brain controls the heart, and the heart, in turn, impacts the brain.”

The study addresses the mechanisms behind how we perceive the passage of milliseconds and may help us manage trauma, in which instantaneous experiences are remembered as drawn out. Intense emotional engagement speeds up perception of time, while depression slows it down. Research into perception of time has traditionally focused on different areas of the brain, but there is now greater appreciation that cognitive functions are intimately linked to the control of the body. Time is closely related to metabolic needs, and the body tries to determine how much energy it has available in the moment, which may affect how we perceive the passage of time.

Here is the response from Google Bard, more impressive, I think:

Sure, here is a 200-word summary [note - it's actually 313 words] of the text:

A recent study published in the journal Psychophysiology suggests that our heartbeat may play an important role in our perception of time. The study found that participants who had longer heartbeat intervals tended to perceive brief audio tones as longer, while participants who had shorter heartbeat intervals tended to perceive the tones as shorter. This suggests that our heart rate may influence how we experience the passage of time.

The study's lead author, Saeedeh Sadeghi, said that the findings provide more evidence that "there is no single part of the brain or body that keeps time — it's all a network." She added that the study "could have implications for understanding how people with certain conditions, such as anxiety or depression, experience time differently."

The study's findings are in line with previous research that has shown that our heart rate can affect our cognitive function. For example, one study found that people who were asked to perform a task while listening to their heartbeat performed worse on the task than those who were not listening to their heartbeat. This suggests that our heart rate may distract us and make it more difficult to focus on tasks.

The study's findings also have implications for our understanding of how we experience time in different situations. For example, the study suggests that time may seem to pass more slowly when we are stressed or anxious, as our heart rate tends to increase in these situations. Conversely, time may seem to pass more quickly when we are relaxed or bored, as our heart rate tends to decrease in these situations.

Overall, the study provides new insights into the complex relationship between our heart rate and our perception of time. The findings could have implications for understanding how people with certain conditions experience time differently, as well as for our understanding of how we experience time in different situations.

The fundamentals of empathy

Akinrinade et al. show that the neuropeptide oxytocin is responsible for emotional fear contagion, and involves the same regions of the brain in zebrafish and in mammals, suggesting this most basal form of empathy could have evolved many, many millions of years ago.

Emotional contagion is the most ancestral form of empathy. We tested to what extent the proximate mechanisms of emotional contagion are evolutionarily conserved by assessing the role of oxytocin, known to regulate empathic behaviors in mammals, in social fear contagion in zebrafish. Using oxytocin and oxytocin receptor mutants, we show that oxytocin is both necessary and sufficient for observer zebrafish to imitate the distressed behavior of conspecific demonstrators. The brain regions associated with emotional contagion in zebrafish are homologous to those involved in the same process in rodents (e.g., striatum, lateral septum), receiving direct projections from oxytocinergic neurons located in the pre-optic area. Together, our results support an evolutionary conserved role for oxytocin as a key regulator of basic empathic behaviors across vertebrates.

The pitfalls of defining neural correlates of brain functions

Rust and Le Doux do a useful brief opinion piece from which I pass on two clips, and recommend you read the whole open source text.

...neuroscientists should avoid conflating circuits that control behavior with mental states, especially in the absence of evidence that the two map onto one another. These equivalencies need to be very carefully investigated rather than presumed.

Considerable evidence suggests that circuits involving the amygdala control behavioral and physiological responses to threats. In animal research labs, threats are often recapitulated by pairing a tone with an aversive stimulus such as a weak shock to elicit ‘fear-related behaviors’ such as freezing upon hearing the tone again. The neural circuits that learn the association between the tone and shock and produce freezing behavior are among the best understood in the brain. The problem lies in labeling these circuits with the term ‘fear’, because it presumes that the threat elicits a mental state, a subjective experience, of fear that is caused by activity in the amygdala. However, mounting evidence suggests that the amygdala is not required for the mental state of fear. Instead, the mental state of fear crucially depends, at least in part, on cortical circuits that interpret or conceptualize what is occurring in the social and physical environment and in one’s body. In this framework, amygdala circuits control nonconscious defense behaviors (such as freezing) as opposed to conscious experience. Should this framework be correct, the extensive ongoing efforts devoted to targeting amygdala circuits and rodent behaviors such as freezing and avoidance are unlikely to provide a direct route to treatments for human fear and anxiety disorders. These lines of research can help, but not without recognizing the centrality of subjective experience.

Anxiety - What is it, when is it useful, when is it not?

The title of this post is the discussion topic for the Nov. 6 Austin Rainbow Forum, a monthly discussion group of LGBT seniors that first met in Austin Tx in Jan. 2018. I am using this post to pass on links to some optional background reading:

Martin Seligman and learned helplessness versus helpfulness

Eustress - beneficial stress

Bruce McEwen on good and bad stress

Robert Sapolsky on chronic stress

A deeper look into what our bodies are doing during arousal and calm (click on the arrows at bottom left of presentation frame to expand to full screen)

How nature nurtures

MindBlog has passed on a number of articles on how exposure to nature reduces stress (see a sample list below). Here is a further contribution from Sudimac et al., who show amygdala activity decreases as the result of a one-hour walk in nature:

Since living in cities is associated with an increased risk for mental disorders such as anxiety disorders, depression, and schizophrenia, it is essential to understand how exposure to urban and natural environments affects mental health and the brain. It has been shown that the amygdala is more activated during a stress task in urban compared to rural dwellers. However, no study so far has examined the causal effects of natural and urban environments on stress-related brain mechanisms. To address this question, we conducted an intervention study to investigate changes in stress-related brain regions as an effect of a one-hour walk in an urban (busy street) vs. natural environment (forest). Brain activation was measured in 63 healthy participants, before and after the walk, using a fearful faces task and a social stress task. Our findings reveal that amygdala activation decreases after the walk in nature, whereas it remains stable after the walk in an urban environment. These results suggest that going for a walk in nature can have salutogenic effects on stress-related brain regions, and consequently, it may act as a preventive measure against mental strain and potentially disease. Given rapidly increasing urbanization, the present results may influence urban planning to create more accessible green areas and to adapt urban environments in a way that will be beneficial for citizens’ mental health.

A few previous MindBlog posts on this topic:

Blue Mind - looking at water improves your health and calm 

Pictures of green spaces make you happier. 

More green space in childhood, fewer psychiatric disorders in adulthood.

Emotional contagion and prosocial behavior

Keysers et al. do an open source review of studies on emotional contagion and prosocial behavior in rodents, whose brain regions necessary for emotional contagion closely resemble those associated with human empathy:

Rats and mice show robust emotional contagion by aligning their fear and pain to that of others.

Brain regions necessary for emotional contagion in rodents closely resemble those associated with human empathy; understanding the biology of emotional contagion in rodents can thus shed light on the evolutionary origin and mechanisms of human empathy.

Cingulate area 24 in rats and mice contains emotional mirror neurons that map the emotions of others onto the witnesses’ own emotions.

Emotional contagion prepares animals to deal with threats by using others as sentinels; the fact that rodents approach individuals in distress facilitates such contagion.

In some conditions, rats and mice learn to prefer actions that benefit others, with notable individual differences. This effect depends on structures that overlap with those of emotional contagion.

Stress in older adults accelerates immune system aging.

Seo does a summary article that points to the work of Klopak et al. The Klopak et al. abstract:  

Significance

As the world’s population of older adults increases, understanding disparities in age-related health is essential. Age-related changes in the immune system play a critical role in age-related morbidity and mortality. This study assesses associations between social stress and immunophenotypes as immune age phenotype markers for the first time in a national sample of older US adults. This study helps clarify mechanisms involved in accelerated development of the immune age phenotype, including socioeconomic and lifestyle factors and cytomegalovirus infection and reactivation. This study also identifies important points of intervention that may be useful in addressing inequalities in aging.

Abstract

Exposure to stress is a risk factor for poor health and accelerated aging. Immune aging, including declines in naïve and increases in terminally differentiated T cells, plays a role in immune health and tissue specific aging, and may contribute to elevated risk for poor health among those who experience high psychosocial stress. Past data have been limited in estimating the contribution of life stress to the development of accelerated immune aging and investigating mediators such as lifestyle and cytomegalovirus (CMV) infection. This study utilizes a national sample of 5,744 US adults over age 50 to assess the relationship of social stress (viz., everyday discrimination, stressful life events, lifetime discrimination, life trauma, and chronic stress) with flow cytometric estimates of immune aging, including naïve and terminally differentiated T cell percentages and the ratio of CD4+ to CD8+ cells. Experiencing life trauma and chronic stress was related to a lower percentage of CD4+ naïve cells. Discrimination and chronic stress were each associated with a greater percentage of terminally differentiated CD4+ cells. Stressful life events, high lifetime discrimination, and life trauma were related to a lower percentage of CD8+ naïve cells. Stressful life events, high lifetime discrimination, and chronic stress were associated with a higher percentage of terminally differentiated CD8+ cells. High lifetime discrimination and chronic stress were related to a lower CD4+:CD8+ ratio. Lifestyle factors and CMV seropositivity partially reduced these effects. Results identify psychosocial stress as a contributor to accelerating immune aging by decreasing naïve and increasing terminally differentiated T cells.

How stress focuses brain integration

From Wang et al.(open source, with good graphics):

Despite the prevalence of stress, how brains reconfigure their multilevel, hierarchical functional organization in response to acute stress remains unclear. We examined changes in brain networks after social stress using whole-brain resting-state functional MRI (fMRI) by extending our recently published nested-spectral partition method, which quantified the functional balance between network segregation and integration. Acute stress was found to shift the brain into a more integrated and less segregated state, especially in frontal-temporal regions. Stress also stabilized brain states by reducing the variability of dynamic transition between segregated and integrated states. Transition frequency was associated with the change of cortisol, and transition variability was correlated with cognitive control. Our results show that brain networks tend to be more integrated and less variable after acute stress, possibly to enable efficient coping.

Reduction of stress and inflammatory responses by transcutaneous cervical vagal nerve stimulation

I want to point to an article by Caron that reviews work investigating therapeutic effects of stimulating our vagus nerve, two large nerve fiber bundles that run down both sides of our neck from the brain stem to our internal organs to regulate our parasympathetic 'calming' nervous system (as distinguished from the 'arousing' sympathetic part of our autonomic nervous system.) In the work by Bremmer et al. (open source) cited by Caron I was struck by the simplicity and accessibility of the simple technique used to stimulate the neck vagus nerves and suppress inflammatory and stress responses.

 

Figure 3. Diagram showing placement of tcVNS device on the neck to target the vagus nerve as it travels through the carotid sheath.

For technically inclined readers like myself, I pass on the following details of the vagal stimulation:

Both active tcVNS and sham stimuli were administered using hand-held devices that target the cervical portion of the vagus nerve from the skin (GammaCore, ElectroCore, Basking Ridge, New Jersey). Stimulation was applied using collar, stainless steel electrodes with a conductive electrode gel placed on the left side of the neck over the carotid sheath as determined by palpation of the carotid artery (Figure 3). Active tcVNS devices produced an alternating voltage signal consisting of five 5kHz sine bursts (1 ms of five sine waves with pulse width of 40 ms) repeating at a rate of 25 Hz envelopes. The frequency of 25 Hz was chosen based on prior studies showing optimization of effects on autonomic function and other measures at this frequency...The sham devices produce an alternating biphasic voltage signal consisting of 0.2 Hz square pulses (pulse width of 5 s) eliciting a mild sensation...Both active and sham devices delivered two minutes of stimulation. The stimulation intensity (amplitude of the voltage wavefront) was adjustable using a roll switch that ranged from 0 to 5 a.u. (arbitrary units) with a corresponding peak output ranging from 0 to 30V for active tcVNS, and from 0 to 14 V for the sham device. During each application, the amplitude of the voltage waveform was increased to the maximum the subject could tolerate, without pain. The stimulation continued at the selected intensity...The rationale behind the frequency difference between active (5kHz) and sham (0.2Hz) device waveforms is based on the fact that high frequency voltage signals (such as the active stimulus, 5kHz) pass through the skin with minimal power dissipation due to the low skin-electrode impedance at kHz frequencies. In contrast, lower frequency signals (such as the sham stimulus, 0.2Hz) are mainly attenuated at the skin-electrode interface due to the high impedance (Rosell et al., 1988). Accordingly, the active device operating at higher frequencies can deliver substantial energy to the vagus nerve to facilitate stimulation, while the voltage levels appearing at the vagus would be expected to be orders of magnitude lower for the sham device and thus stimulation is unlikely. Nevertheless, since the sham device does deliver relatively high voltage levels directly to the skin, it activates skin nociceptors, causing a similar feeling to a pinch. This sensation is considered to be necessary for blinding of the participants, particularly longitudinal protocols such as in this manuscript.