Evidence for an influence of meditation on immune-related pathways?

I pass on the abstract, below, and also the entire text of a study by Chaix et al.:

Highlights

• We explored the methylome of trained meditators vs untrained controls in PBMCs. 

• No significant basal difference in methylation profiles was observed between groups. 

• Meditators showed 61 Differentially Methylated Sites after a meditation practice day. 

• These DMS were enriched in genes associated with immune cell processes and ageing. 

• Controls showed no significant DMS after a leisure-based control intervention. 

Abstract

The human methylome is dynamically influenced by psychological stress. However, its responsiveness to stress management remains underexplored. Meditation practice has been shown to significantly reduce stress level, among other beneficial neurophysiological outcomes. Here, we evaluated the impact of a day of intensive meditation practice (t2−t1 = 8 h) on the methylome of peripheral blood mononuclear cells in experienced meditators (n = 17). In parallel, we assessed the influence of a day of leisure activities in the same environment on the methylome of matched control subjects with no meditation experience (n = 17). DNA methylation profiles were analyzed using the Illumina 450 K beadchip array. We fitted for each methylation site a linear model for multi-level experiments which adjusts the variation between t1 and t2 for baseline differences. No significant baseline differences in methylation profiles was detected between groups. In the meditation group, we identified 61 differentially methylated sites (DMS) after the intervention. These DMS were enriched in genes mostly associated with immune cell metabolism and ageing and in binding sites for several transcription factors involved in immune response and inflammation, among other functions. In the control group, no significant change in methylation level was observed after the day of leisure activities. These results suggest that a short meditation intervention in trained subjects may rapidly influence the epigenome at sites of potential relevance for immune function and provide a better understanding of the dynamics of the human methylome over short time windows.

These are clearly very initial findings that need followup to determine the relationship between the fast epigenetic changes caused by the daylong meditative and previously reported long lasting effects of the practice. There need to be randomized controlled studies with larger sample sizes, active control groups, long-term follow-ups, etc.

The paradox of pleasurable fear.

A study by Anderson et al. finds an inverted U-shaped relationship between fear and enjoyment, consistent with the theory that the pursuit of pleasurable fear is a form of play. Fear and enjoyment can coexist in frightening leisure activities that become enjoyable when they offer forms of arousal dynamics that are “just right.”. Here is their abstract:

Haunted attractions are illustrative examples of recreational fear in which people voluntarily seek out frightening experiences in pursuit of enjoyment. We present findings from a field study at a haunted-house attraction where visitors between the ages of 12 and 57 years (N = 110) were equipped with heart rate monitors, video-recorded at peak scare points during the attraction, and asked to report on their experience. Our results show that enjoyment has an inverted-U-shaped relationship with fear across repeated self-reported measures. Moreover, results from physiological data demonstrate that the experience of being frightened is a linear function of large-scale heart rate fluctuations, whereas there is an inverted-U-shaped relationship between participant enjoyment and small-scale heart rate fluctuations. These results suggest that enjoyment is related to forms of arousal dynamics that are “just right.” These findings shed light on how fear and enjoyment can coexist in recreational horror.

How mice feel each other's pain or fear

The abstract from Smith et al, who show the brain basis of empathetic behaviors in mice that mirror those in humans:

Empathy is an essential component of social communication that involves experiencing others’ sensory and emotional states. We observed that a brief social interaction with a mouse experiencing pain or morphine analgesia resulted in the transfer of these experiences to its social partner. Optogenetic manipulations demonstrated that the anterior cingulate cortex (ACC) and its projections to the nucleus accumbens (NAc) were selectively involved in the social transfer of both pain and analgesia. By contrast, the ACC→NAc circuit was not necessary for the social transfer of fear, which instead depended on ACC projections to the basolateral amygdala. These findings reveal that the ACC, a brain area strongly implicated in human empathic responses, mediates distinct forms of empathy in mice by influencing different downstream targets. 

Here is a summary graphic from a perspective by Klein and Gogolla (click to enlarge):

Matriliny reverses gender disparities in inflammation and hypertension.

Fascinating obeervations from Reynolds et al.: 

Significance

Greater autonomy afforded to women in matrilineal societies has been hypothesized to benefit women’s health. Among the Mosuo, a society with both matrilineal and patrilineal subpopulations, we found that gender disparities in chronic disease are not only ameliorated but reversed in matriliny compared with patriliny. Gender disparities in health and chronic disease can thus be tied directly to cultural influences on health, including inequalities in autonomy and resource access between men and women.

Abstract

Women experience higher morbidity than men, despite living longer. This is often attributed to biological differences between the sexes; however, the majority of societies in which these disparities are observed exhibit gender norms that favor men. We tested the hypothesis that female-biased gender norms ameliorate gender disparities in health by comparing gender differences in inflammation and hypertension among the matrilineal and patrilineal Mosuo of China. Widely reported gender disparities in health were reversed among matrilineal Mosuo compared with patrilineal Mosuo, due to substantial improvements in women’s health, with no concomitant detrimental effects on men. These findings offer evidence that gender norms limiting women’s autonomy and biasing inheritance toward men adversely affect the health of women, increasing women’s risk for chronic diseases with tremendous global health impact.

Your brain is not for thinking.

Lisa Feldman Barrett,the author whose book has prompted me to take a mini-sabbitical from MindBlog to do a period of study, has an Op-Ed piece in today's NYTimes that I suggest you read. A few clips to whet your appetite:

Much of your brain’s activity happens outside your awareness. In every moment, your brain must figure out your body’s needs for the next moment and execute a plan to fill those needs in advance...Your brain runs your body using something like a budget... The budget for your body tracks resources like water, salt and glucose as you gain and lose them. Each action that spends resources, such as standing up, running, and learning, is like a withdrawal from your account. Actions that replenish your resources, such as eating and sleeping, are like deposits.

It may seem less natural to view your mental life as a series of deposits and withdrawals. But your own experience is rarely a guide to your brain’s inner workings. Every thought you have, every feeling of happiness or anger or awe you experience, every kindness you extend and every insult you bear or sling is part of your brain’s calculations as it anticipates and budgets your metabolic needs.

There is no such thing as a purely mental cause, because every mental experience has roots in the physical budgeting of your body. This is one reason physical actions like taking a deep breath, or getting more sleep, can be surprisingly helpful in addressing problems we traditionally view as psychological.

We’re all living in challenging times, and we’re all at high risk for disrupted body budgets. If you feel weary from the pandemic and you’re battling a lack of motivation, consider your situation from a body-budgeting perspective. Your burden may feel lighter if you understand your discomfort as something physical. When an unpleasant thought pops into your head, like “I can’t take this craziness anymore,” ask yourself body-budgeting questions. “Did I get enough sleep last night? Am I dehydrated? Should I take a walk? Call a friend? Because I could use a deposit or two in my body budget.”

I’m not saying you can snap your fingers and dissolve deep misery, or sweep away depression with a change of perspective. I’m suggesting that it’s possible to acknowledge what your brain is actually doing and take some comfort from it. Your brain is not for thinking. Everything that it conjures, from thoughts to emotions to dreams, is in the service of body budgeting. This perspective, adopted judiciously, can be a source of resilience in challenging times.

Oxytocin can increase or decrease anxiety-related behaviors.

Duque-Wilckens et al. report experiments in mice showing that oxytocin, usually regarding as reducing anxious behaviors, enables stress-induced social anxiety behaviors if it is produced outside of its normal source in the hypothalmus.  

Significance

The neuropeptide oxytocin is an important regulator of social behavior and is widely considered to reduce anxiety-related behaviors. However, growing evidence suggests that sometimes oxytocin increases anxiety. How can the same molecule have such different effects on behavior? Here we provide evidence that oxytocin produced outside of the hypothalamus is necessary and sufficient for stress-induced social anxiety behaviors. This suggests that the diverse effects of oxytocin on anxiety-related behaviors are mediated by circuit-specific oxytocin action.

Abstract

Oxytocin increases the salience of both positive and negative social contexts and it is thought that these diverse actions on behavior are mediated in part through circuit-specific action. This hypothesis is based primarily on manipulations of oxytocin receptor function, leaving open the question of whether different populations of oxytocin neurons mediate different effects on behavior. Here we inhibited oxytocin synthesis in a stress-sensitive population of oxytocin neurons specifically within the medioventral bed nucleus of the stria terminalis (BNSTmv). Oxytocin knockdown prevented social stress-induced increases in social vigilance and decreases in social approach. Viral tracing of BNSTmv oxytocin neurons revealed fibers in regions controlling defensive behaviors, including lateral hypothalamus, anterior hypothalamus, and anteromedial BNST (BNSTam). Oxytocin infusion into BNSTam in stress naïve mice increased social vigilance and reduced social approach. These results show that a population of extrahypothalamic oxytocin neurons plays a key role in controlling stress-induced social anxiety behaviors.

What to Do When the Future Feels Hopeless

In one of his biweekly 'How to bluild a life' essays Arthur Brooks offers advice on antidotes to feeling of helplessness in the face of the current pandemic. Some clips:

While there’s little we can do to change the harsh realities of the pandemic, we can change the mindset we use to face them. By doing two things, we can improve our ability to cope with this situation, as well as with negativity and feelings of powerlessness in the future.

1. Channel your inner lawyer.

Pessimism generally distorts reality. Seligman and others recommend that pessimists combat their tendency to expect the worst by employing what they call a disputing technique—verbalizing the negative assumptions we are making about the future, and disputing them with realistic facts.

The other day I found myself darkly musing that I would likely never go back in person; that this would be my new normal, forever. This pessimism, fueled by news stories I’ve read with titles like “Will the Coronavirus Forever Alter the College Experience?,” is completely unwarranted in my school’s case. So I disputed it with the facts. We are, in fact, creating hybrid classes, and planning for an in-person future. There’s a good chance I’ll be back in the classroom within the next year. My odd work situation is tedious, but temporary...Most likely, your future is also brighter than what you may think at your darkest moments, so dispute your pessimism not with mindless optimism, but with facts. Build a solid case for something other than the worst-case scenario, and argue it to yourself like a lawyer.

2. Turn constraints into decisions.

...start an examination of every problem by listing the apparent limitations on your freedom, and instead of taking them as given, consider how you can change them...For example, in the case of the coronavirus lockdowns, the complaint about work I most often hear is that with the inability to work in a normal way, productivity is ruined...The answer is to change the definition of productivity...you might use this period to reset your definition of productivity. True, many aspects of many jobs have been made more difficult by the pandemic. But other parts of a truly productive life are begging for your attention. You can set goals for exercise, work on acquiring new skills, spend quality time with loved ones, or learn to tame your monkey mind in meditation. This is the sort of productivity that will reward you in the long run and can help you establish a healthier, happier equilibrium when the pandemic is over...the healthiest way to look at the pandemic—or any difficult period in our lives—is as an opportunity for improvement and personal growth, without pushing away the negative emotions that are a natural by-product of hard times. As we confront pessimism in the context of COVID-19, we will start to see and manage it more generally in our lives.

A brief history of risk

Li, Hills, and Hertwig do an open access review with the title of this post. From their introductory paragraph:

...First, we examined how the frequency of the word risk has changed over historical time. Is the construct of risk playing an ever-increasing role in the public discourse, as the sociological notion of a ‘risk society’ suggests? Second, we investigated how the sentiments for the words co-occurring with risk have changed. Are the connotations of risk becoming increasingly ominous? Third, how has the meaning of risk changed relative to close associates such as danger and hazard? Is risk more subject to semantic change? Finally, we decompose the construct of risk into the specific topics with which it has been associated and track those topics over historical time. This brief history of the semantics of risk reveals new and surprising insights—a fourfold increase in frequency, increasingly negative sentiment, a semantic drift toward forecasting and prevention, and a shift away from war toward chronic disease—reflecting the conceptual evolution of risk in the archeological records of public discourse.

Placebos without deception reduce self-report and neural measures of emotional distress

Interesting work from Guevarra et al. (open source):

Several recent studies suggest that placebos administered without deception (i.e., non-deceptive placebos) can help people manage a variety of highly distressing clinical disorders and nonclinical impairments. However, whether non-deceptive placebos represent genuine psychobiological effects is unknown. Here we address this issue by demonstrating across two experiments that during a highly arousing negative picture viewing task, non-deceptive placebos reduce both a self-report and neural measure of emotional distress, the late positive potential. These results show that non-deceptive placebo effects are not merely a product of response bias. Additionally, they provide insight into the neural time course of non-deceptive placebo effects on emotional distress and the psychological mechanisms that explain how they function.

Here is a description from their text of the EEG signals measured:

The LPP is an electroencephalogram (EEG) derived event-related brain potential (ERP) response that measures millisecond changes in the neural activity involved in emotional processing. The early-time window of the LPP (400–1000 ms) indexes attention allocation34; the sustained time window (1000–6000 ms) indexes conscious appraisals and meaning-making mechanisms involved in emotion processing34,35 and is consistently downregulated by cognitive emotion regulation strategies. Consistent with its role in immediate attentional orienting responses to emotional stimuli and later appraisal processes, neural sources of the LPP include both the amygdala and dorsolateral prefrontal cortex41. Thus, the LPP is ideally suited to help examine the neural mechanisms and time course of non-deceptive placebo effects on emotional distress.

And, conditions presented to participants:

In both experiments, we randomly assigned participants to either a non-deceptive placebo group or a control group. Participants in the non-deceptive placebo group read about placebo effects and were then asked to inhale a nasal spray consisting of saline solution. They were told that the nasal spray was a placebo that contained no active ingredients, but would help reduce their negative emotional reactions to viewing distressing images if they believed it would. Participants in the control group read about the neural processes underlying the experience of pain and were also asked to inhale the same saline solution spray; however, they were told that the purpose of the nasal spray was to improve the clarity of the physiological readings we were recording in the study. The articles were matched for narrative structure, emotional content, and length

Training internal resilience

I want to point to an interesting article by Eva Holland on relieving trauma, which is very relevant to the potential mental0health fallout from living through our current pandemic. Some clips describing a therapy called E.M.D.R., eye movement desensitization and reprocessing:

E.M.D.R. was developed in the late 1980s and greeted with much skepticism at first. “It sounded like yet another of the crazes that have always plagued psychiatry,” Bessel van der Kolk, a trauma expert, wrote in “The Body Keeps The Score.” But clinical trials and peer-reviewed studies that spoke to its efficacy piled up over the three decades since its invention, and Dr. van der Kolk and many others eventually adopted it as part of their therapeutic practice.

It works like this: A therapist prompts the patient to move their eyes back and forth, rhythmically, behind their eyelids. (Devices that beep or buzz help to encourage and regulate the eye movements.) At the same time, the therapist talks the patient through the traumatic event or events at issue, leading them through a series of questions about how their body is reacting to the discussion. It is a strange, and strangely physical, experience. The precise mechanisms at play are not fully understood, but the theory is that something about the eye motion, combined with the focused discussion, can lay the intrusive memories to rest.

E.M.D.R. taught me an important lesson: that internal resilience can be deliberately cultivated...I had never before thought of resilience as a muscle I could train and strengthen. The idea felt empowering.

In a reversal of this therapy, the therapist asks the client to recall four resources from their memories: a places where they have left safest and happiest, a nurturing figure, a protector, and a source of wisdom. The author reports:

As I held a vibrating pod in each hand, and as my eyes rolled back and forth behind my eyelids in time to their pulsing, following the vibrations from left to right and back again, I thought about my grandmother — my nurturing figure, who had died when I was 18. I pictured her at the open kitchen window of her suburban bungalow....The pods pulsed. My eyes moved from side to side. I felt loved and safe. To my surprise, I felt stronger, too. In the time since, I have sometimes called up those sensory memories of my grandmother when I’m upset, or when I feel in need of support. It always helps.

The article proceeds to discuss further techniques for cultivating resilience that do not involve paying a therapist.

Our brain's chemistry of love neutralizes its chemistry of fear.

Arthur Brooks, in his biweekly Atlantic Column, offers some very sane comments on the underlying fear that virtually all of us experience, especially in this time of COVID-19. He notes several surveys that show an increase of 10-20% in fear, anxiety, and stress over the past 10-20 years. There will always be threats to face and things to fear, and his stance is that...

The way to combat fear within ourselves is with its opposite emotion—which is not calmness, or even courage. It’s love...The Chinese philosopher Lao Tzu wrote in the Tao Te Ching, “Through Love, one has no fear.” More than 500 years later, Saint John the Apostle said the same thing: “There is no fear in love. But perfect love drives out fear, because fear has to do with punishment. The one who fears is not made perfect in love.”

Love neutralizes fear. It took about 2,000 years, but contemporary neurobiological evidence has revealed that Lao Tzu and Saint John were absolutely on the money...Fear is a primary emotion processed in the amygdala, a part of the brain that detects threats and signals to the body to produce the stress hormones that make us ready for fight or flight. This is largely involuntary, and, while necessary for survival, is unpleasant..The fear response is also maladapted to modern life. For example, a friend of mine with a large Twitter following once told me that he felt his chest tighten every day as he clicked on the social media app on his phone. His amygdala was alerting him that dangerous threats lay ahead, and he was getting a dose of adrenaline and cortisol in response—even though nothing was likely going to harm him.

However, we have a natural modulator of the hyperactive amygdala: the neuropeptide oxytocin, sometimes called the “love molecule.” Oxytocin is often produced in the brain in response to eye contact and touch, especially between loved ones. The feeling it creates is intensely pleasurable; indeed, life would be unbearable without it. There is evidence that an oxytocin deficit is one reason for the increase in depression during the coronavirus pandemic, with its lockdowns and social distancing.

Oxytocin has also been found to reduce anxiety and stress by inhibiting the response of the amygdala to outside stimuli. If you have loving contact with others, the outside world will seem less scary and threatening to you. What Saint John asserted is literally true: Perfect love drives out fear.

Brooks continues by noting many trends that over the past 20-30 years have decreased the amount of love in our lives, leading to an epidemic of loneliness.He then suggests concrete steps to bring more love into our lives by first sharing our fears with someone we trust, and by expressing you appreciation, affection or love for a friend or family member whom you would not normally address in this way.

Urgent care for our brains.

I gave a Zoom lecture to the Austin Prime Timers group on May 17 titled "Urgent care for our brains" and thought I might as well point to the lecture text and graphics here on MindBlog. The text is informal, casual, and directed to our current situation with COVID-19.

How stress triggers inflammation

Acute stress seems to amplify inflammatory disease despite the fact many stress hormones such as cortisol actually suppress the immune system. Qing et al. show that this is because the rise in adrenaline (epinephrine) and norepinephrine levels during acute stress triggers the release of the pro-inflammatory cytokine interleukin-6 (IL-6) by brown fat cells. IL-6 is the signal for liver release of the glucose needed for the fight or flight response, but this comes at the cost of enhancing mortality to a subsequent inflammatory challenge. Here is their abstract:

Highlights

• IL-6 is the dominant endocrine cytokine induced by acute stress in mice

• Stress-inducible IL-6 is produced in brown adipocytes via ADRB3 signaling

• IL-6 is required for stress hyperglycemia and adaptive “fight or flight” responses

• Stress-induced IL-6 decreases tolerance to a subsequent inflammatory challenge

Summary

Acute psychological stress has long been known to decrease host fitness to inflammation in a wide variety of diseases, but how this occurs is incompletely understood. Using mouse models, we show that interleukin-6 (IL-6) is the dominant cytokine inducible upon acute stress alone. Stress-inducible IL-6 is produced from brown adipocytes in a beta-3-adrenergic-receptor-dependent fashion. During stress, endocrine IL-6 is the required instructive signal for mediating hyperglycemia through hepatic gluconeogenesis, which is necessary for anticipating and fueling “fight or flight” responses. This adaptation comes at the cost of enhancing mortality to a subsequent inflammatory challenge. These findings provide a mechanistic understanding of the ontogeny and adaptive purpose of IL-6 as a bona fide stress hormone coordinating systemic immunometabolic reprogramming. This brain-brown fat-liver axis might provide new insights into brown adipose tissue as a stress-responsive endocrine organ and mechanistic insight into targeting this axis in the treatment of inflammatory and neuropsychiatric diseases.

Feeling bad is not bad.

MindBlog is passing on the link to each of Arthur Brooks' biweekly articles in his series "How to Build a Life". This latest installment deals with negative emotions, using them to grow and develop resilience rather than pushing them away. It is more difficult to summarize in a tidy way as I have some previous installments in the series. I suggest you read the whole piece. I will note the last two paragraphs:

One last thought: In 2019, the comedian Stephen Colbert was asked in an interview by CNN’s Anderson Cooper about a plane crash that killed Colbert’s father and two of his brothers when he was 10 years old. Cooper quoted a previous statement by Colbert that he had learned to “love the thing that I most wish had not happened.” He asked Colbert to clarify this extraordinary remark. “It’s a gift to exist, and with existence comes suffering,” Colbert replied. “I don’t want it to have happened … but if you are grateful for your life … then you have to be grateful for all of it. You can’t pick and choose what you’re grateful for.”

Colbert’s words resonated deeply with me, and perhaps they do with you, too. No normal person skips merrily into a tragic loss, nor usually seeks out even minor discomfort. But those things find us, over and over again in life. This is especially true today, in the era of COVID-19. The meaning from this pain, and the benefits it can bring to our lives and society, comes from how we choose to use it.

Making Us/Them Dichotomies More Benign.

I'm reposting this item from 2016 as particularly relevant to the present.... Interesting thoughts from Robert Sapolsky:

A truly discouraging thing to me is how easily humans see the world as dichotomized between Us and Them. This comes through in all sorts of ways —social anthropology, lord of the flies, prison experiments, linguistics (all those cultures where the word for the members of that culture translates into "People," thus making a contrast with the non-people living in the next valley). 

As a neurobiologist, I'm particularly impressed with and discouraged by one finding relevant to this. There's a part of the brain called the amygdala that has lots to do with fear and anxiety and aggression. Functional brain imaging studies of humans show that the amygdala becomes metabolically active when we look at a scary face (even when the face is flashed up so quickly that we aren't consciously aware of seeing it). And some recent work—solid, done by top people, independently replicated — suggests that the amygdala can become activated when we view the face of someone from another race. The Them as scary, and the Them being someone whose skin color is real different from our own. 

Damn, that's an upsetting finding. 

But right on the heels of those studies are follow-ups showing that the picture is more complicated. The "Other skin color = scared activated amygdala = the Other" can be modified by experience. "Experience," can be how diverse of a world you grew up in. More diversity, and the amygdala is likely to become activated in that circumstance. And also, "experience," can be whether, shortly before your amygdala is put through the brain imaging paces, you are subtly biased to think about people categorically or as individuals. If you're cued towards individuating, your amygdala doesn't light up. 

Thus, it seems quite plausible to me that we are hard-wired towards making Us/Them distinctions and not being all that nice to the Them. But what is anything but hard-wired is who counts as an Us and as a Them —we are so easily manipulated into changing those categories. 

So, I'm optimistic that with the right sort of priorities and human engineering (whatever that phrase means), we can be biased towards making Us/Them dichotomies far more benign than they tend to be now. Say, by making all of us collectively feel like an Us with Them being the space aliens that may attack us some day. Or making the Them to be mean, shitty, intolerant people without compassion. 

But, I'm sure not optimistic that we'll soon be having political, religious or cultural leaders likely to move us effectively in that direction. Just to deflate that optimism.

How Covid-19 stress scrambles our brains

The pandemic is providing an opportunity for a massive, real-time experiment on stress.  Even mild stress can impair the activities of the prefrontal cortex areas 'executive' functions that regulate our attentional focus and emotions. When this area grows more quiet more reactionary brain networks that it normally inhits (centering on the amygdalae) are unleashed. You should read the article by Laura Sanders that describes, with clear illustrations, experiments showing how our thoughtful planning activities are disrupted by stress.

Anxiolytic actions of oxytocin, unlike those of benzodiazepines, involve brain regions outside the amygdala

From Kreuder et al.:

Significance

A potential new target for anxiolytic drug development is the oxytocin (OXT) neuropeptide system. An emerging question is whether OXT has similar effects on the neural microcircuitry of fear compared with clinically established compounds such as benzodiazepines. The present functional MRI study showed that both OXT and its benzodiazepine comparator lorazepam (LZP) reduced centromedial amygdala responses to fear signals. OXT, but not LZP, increased extra-amygdalar connectivity between the centromedial amygdala and frontoparietal regions. Thus, while both compounds inhibited the centromedial amygdala, OXT, but not LZP, elicited large-scale connectivity changes of potential therapeutic relevance.

Abstract

Benzodiazepines (BZDs) represent the gold standard of anxiolytic pharmacotherapy; however, their clinical benefit is limited by side effects and addictive potential. Consequently, there is an urgent need to develop novel and safe anxiolytics. The peptide hormone oxytocin (OXT) exhibits anxiolytic-like properties in animals and humans, but whether OXT and BZDs share similar effects on the neural circuitry of fear is unclear. Therefore, the rationale of this ultra-high-field functional MRI (fMRI) study was to test OXT against the clinical comparator lorazepam (LZP) with regard to their neuromodulatory effects on local and network responses to fear-related stimuli. One hundred twenty-eight healthy male participants volunteered in this randomized double-blind, placebo-controlled, between-group study. Before scanning using an emotional face-matching paradigm, participants were randomly administered a single dose of OXT (24 IU), LZP (1 mg), or placebo. On the behavioral level, LZP, but not OXT, caused mild sedation, as evidenced by a 19% increase in reaction times. On the neural level, both OXT and LZP inhibited responses to fearful faces vs. neutral faces within the centromedial amygdala (cmA). In contrast, they had different effects on intra-amygdalar connectivity; OXT strengthened the coupling between the cmA and basolateral amygdala, whereas LZP increased the interplay between the cmA and superficial amygdala. Furthermore, OXT, but not LZP, enhanced the coupling between the cmA and the precuneus and dorsomedial prefrontal cortex. These data implicate inhibition of the cmA as a common denominator of anxiolytic action, with only OXT inducing large-scale connectivity changes of potential therapeutic relevance.

Social animals need connection for health and survival

Snyder-Mackler et al. have reviewed the relationships between social environment and many aspects of health and well-being across nonhuman mammals and investigated the similarities between these and patterns in humans. They found many of the same threats and responses across social mammals.

From their introduction:

The relationship between the social environment and mortality risk has been known in humans for some time, but studies in other social mammals have only recently been able to test for the same general phenomenon. These studies reveal that measures of social integration, social support, and, to a lesser extent, social status independently predict life span in at least four different mammalian orders. Despite key differences in the factors that structure the social environment in humans and other animals, the effect sizes that relate social status and social integration to natural life span in other mammals align with those estimated for social environmental effects in humans. Also like humans, multiple distinct measures of social integration have predictive value, and in the taxa examined thus far, social adversity in early life is particularly tightly linked to later-life survival.

Animal models have also been key to advancing our understanding of the causal links between social processes and health. Studies in laboratory animals indicate that socially induced stress has direct effects on immune function, disease susceptibility, and life span. Animal models have revealed pervasive changes in the response to social adversity that are detectable at the molecular level. Recent work in mice has also shown that socially induced stress shortens natural life spans owing to multiple causes, including atherosclerosis. This result echoes those in humans, in which social adversity predicts increased mortality risk from almost all major causes of death.

A comparative perspective on the social determinants of health (click to enlarge).

Meet the psychobiome

Elizabeth Pennisi does a piece on the search for new brain drugs in human poop, generated by the ~ 2 kilograms of bacteria, fungi, viruses, and archaea that live in our gut.

..with as many as 20 million genes among them, those microbes pack a genomic punch that our measly 20,000 genes can't match. Gut bacteria can make and use nutrients and other molecules in ways the human body can't — a tantalizing source of new therapies.

Holobiome, a small startup company,...plans to capitalize on growing evidence from epidemiological and animal studies that link gut bacteria to conditions as diverse as autism, anxiety, and Alzheimer's disease. Since its founding a mere 5 years ago, Holobiome has created one of the world's largest collections of human gut microbes...A growing number of researchers see a promising alternative in microbe-based treatments, or “psychobiotics,”... the targeted ailments include depression and insomnia, as well as constipation, and visceral pain like that typical of irritable bowel syndrome—conditions that may have neurological as well as intestinal components.

One interesting approach involves finding bacteria that secrete the inhibitory neurotransmitter GABA.

One growth factor Strandwitz identified turned out to be the key to launching his entrepreneurial dreams. He and colleagues isolated a bacterium that couldn't survive on typical culture media and required an amino acid called gamma-aminobutyric acid (GABA) to thrive. GABA is a neurotransmitter that inhibits neural activity in the brain, and its misregulation has been linked to depression and other mental health problems.

The researchers reasoned that if this gut microbe had to have GABA, some other microbe must be making it. Such GABA producers might be a psychobiotic gold mine. Strandwitz and colleagues began to add gut microbes one at a time to petri dishes containing the GABA eater. If the GABA eater thrived, the scientists would know they'd found a GABA producer. They discovered such producers among three groups of bacteria, including Bactereroides. They quickly filed a patent for packaging those bacteria—or their products—to treat people with depression or other mental disorders.

Before publishing those findings, the group teamed up with researchers at Weill Cornell Medicine who were doing a brain scan study of 23 people diagnosed with depression. They found that people with fewer Bacteroides bacteria had a stronger pattern of hyperactivity in the prefrontal cortex, which some researchers have associated with severe depression. The collaboration reported its findings on 10 December 2018 in Nature Microbiology, along with the discovery of GABA-producing bacteria.

GABA is too big to reach the brain by slipping across the blood-brain barrier, a cellular defense wall that limits the size and types of molecules that can get into the brain from blood vessels. Instead, the molecule may act through the vagus nerve or the enteroendocrine cells. Some researchers might question why bacteria would be any more beneficial than GABA-boosting drugs. But Strandwitz says the bacteria may do more than simply boost GABA. He notes that they produce molecules that may have other effects on the brain and body, thereby addressing other symptoms of depression.

Psychedelic psychiatry's brave new world, and a new rapid-acting antidepressannt

I want to point to this open source article in Cell magazine, that provides an up to date review of resurrection of research into possible clinical uses of psychotropic compounds such as psilocybin.

After a legally mandated, decades-long global arrest of research on psychedelic drugs, investigation of psychedelics in the context of psychiatric disorders is yielding exciting results. Outcomes of neuroscience and clinical research into 5-Hydroxytryptamine 2A (5-HT2A) receptor agonists, such as psilocybin, show promise for addressing a range of serious disorders, including depression and addiction.

Also, a review by Krystal et al. notes FDA approval of the first mechanistically new treatment for depression in over sixty years - a form of ketamine (the party drug Special K, also used as an anesthetic.) Motivated readers can obtain the full text from me.

The discovery of the strikingly rapid and robust antidepressant effects of r/s-ketamine for the treatment of antidepressant-resistant symptoms of depression has led to new insights into the biology of antidepressants and the FDA approval of its s-isomer, Esketamine (Spravato), the first mechanistically new treatment for depression in over 60 years.