Blood proteins are different in people who exercise.

There is abundant documentation of the positive effects of exercise: lengthening life spans, reducing disease risks, improving heart health, bolstering immune system and psychological resilience. Knowledge of how exercise does this is still at a primitive state. Santos-Parker et al. decided to examine the array of proteins that circulate in our bloodstream (the "plasma proteome") many of them known to be involved in health-related processes. Their summary and abstract:

This is the first study to assess the relation between plasma proteomic patterns and aerobic exercise status in healthy adults. Weighted correlation network analysis identified 10 distinct proteomic modules, including 5 patterns specific for exercise status. Additionally, 5 modules differed with aging in men, two of which were preserved in older exercising men. Exercise-associated modules included proteins related to inflammation, stress pathways, and immune function and correlated with clinical and physiological indicators of healthspan.

Habitual aerobic exercise enhances physiological function and reduces risk of morbidity and mortality throughout life, but the underlying molecular mechanisms are largely unknown. The circulating proteome reflects the intricate network of physiological processes maintaining homeostasis and may provide insight into the molecular transducers of the health benefits of physical activity. In this exploratory study, we assessed the plasma proteome (SOMAscan proteomic assay; 1,129 proteins) of healthy sedentary or aerobic exercise-trained young women and young and older men (n = 47). Using weighted correlation network analysis to identify clusters of highly co-expressed proteins, we characterized 10 distinct plasma proteomic modules (patterns). In healthy young (24 ± 1 yr) men and women, 4 modules were associated with aerobic exercise status and 1 with participant sex. In healthy young and older (64 ± 2 yr) men, 5 modules differed with age, but 2 of these were partially preserved at young adult levels in older men who exercised; among all men, 4 modules were associated with exercise status, including 3 of the 4 identified in young adults. Exercise-linked proteomic patterns were related to pathways involved in wound healing, regulation of apoptosis, glucose-insulin and cellular stress signaling, and inflammation/immune responses. Importantly, several of the exercise-related modules were associated with physiological and clinical indicators of healthspan, including diastolic blood pressure, insulin resistance, maximal aerobic capacity, and vascular endothelial function. Overall, these findings provide initial insight into circulating proteomic patterns modulated by habitual aerobic exercise in healthy young and older adults, the biological processes involved, and their relation to indicators of healthspan.

A Seasonal Offering...

The cellist in a piano trio that I am playing with invited me (as a sight reading pianist who is always on the prowl for string players) to attend a gathering last Friday of Austin TX string players. They meet every year to sight read Christmas music. I pulled out my iPhone and recorded a small clip of the group that collected on the local recital hall stage to play the Corelli Christmas concerto.

 

"Meaningful Life" science - a tonic for our times?

I am a rye crisp empathy challenged old fart, but I try sometimes to kind, generous, and nice. And, I sometimes wonder what planet the Greater Good Magazine people at Berkeley are living on. I wish them the best, and as an antidote to these challenging times in which our country is being run by a president with the emotional maturity of a four year old, pass on "The Top 10 Insights from the “Science of a Meaningful Life” in 2018."  The article describes original research articles relevant to 10 propositions:

It takes 120 hours (or more) to make a good friend

You’re not as good at empathy as you think you are

Mindfulness can help you manage your anger

Sleeplessness breeds loneliness

Smartphones can make in-person interactions less enjoyable

Teen emotions really are jumbled

We can’t assume that SEL (social-emotional learning)programs meet the needs of all students

Americans are divided by identity, not issues

More egalitarian cultures are better for everyone

People may be kinder in racially diverse neighborhoods

Brain correlates of successful cognitive aging.

From Wang et al. (open access to text and figures):

Prevention of age-related cognitive decline is an increasingly important topic. Recently, increased attention is being directed at understanding biological models of successful cognitive aging. Here, we examined resting-state brain regional low-frequency oscillations using functional magnetic resonance imaging in 19 older adults with excellent cognitive abilities (Supernormals), 28 older adults with normative cognition, 57 older adults with amnestic mild cognitive impairment, and 26 with Alzheimer’s disease. We identified a “Supernormal map”, a set of regions whose oscillations were resistant to the aging-associated neurodegenerative process, including the right fusiform gyrus, right middle frontal gyrus, right anterior cingulate cortex, left middle temporal gyrus, left precentral gyrus, and left orbitofrontal cortex. The map was unique to the Supernormals, differentiated this group from cognitive average-ager comparisons, and predicted a 1-year change in global cognition (indexed by the Montreal Cognitive Assessment scores, adjusted R2 = 0.68). The map was also correlated to Alzheimer’s pathophysiological features (beta-amyloid/pTau ratio, adjusted R2 = 0.66) in participants with and without cognitive impairment. These findings in phenotypically successful cognitive agers suggest a divergent pattern of brain regions that may either reflect inherent neural integrity that contributes to Supernormals’ cognitive success, or alternatively indicate adaptive reorganization to the demands of aging.

Corruption of online social systems by Bots

From Stella et al.:

Societies are complex systems, which tend to polarize into subgroups of individuals with dramatically opposite perspectives. This phenomenon is reflected—and often amplified—in online social networks, where, however, humans are no longer the only players and coexist alongside with social bots—that is, software-controlled accounts. Analyzing large-scale social data collected during the Catalan referendum for independence on October 1, 2017, consisting of nearly 4 millions Twitter posts generated by almost 1 million users, we identify the two polarized groups of Independentists and Constitutionalists and quantify the structural and emotional roles played by social bots. We show that bots act from peripheral areas of the social system to target influential humans of both groups, bombarding Independentists with violent contents, increasing their exposure to negative and inflammatory narratives, and exacerbating social conflict online. Our findings stress the importance of developing countermeasures to unmask these forms of automated social manipulation.

More on slowing down aging.

Some recent articles:

Gretchen Reynolds points to work showing that vigorous aerobic exercise causes an increase in the length of telomeres, pieces of DNA at the end of chromosomes that protect DNA from damage during cell division. Telomere length is a measure of a cell's functional age They normally shorten with aging, and when they no longer protect our DNA, the cell becomes fragile and dies. Werner et al. show that aerobic exercise causes in increase in telomere length, and also the activity of the telomerase enzyme that makes them.

Sahu et al. find that α-Klotho, a protein that suppresses aging in several tissues, can enhance the regeneration of muscle fiber and function.

Finally, a brief engaging article by Dara Horn describes the efforts of aging silicon valley billionaires to extend their lifespan by funding a variety of longevity laboratories.

Can we really inherit trauma?

MindBlog has mentioned a number of studies that claim that the effects of trauma can be passed through generations. Carey does a review that notes that human studies are much less persuasive than animal research using mice.

The debate centers on genetics and biology. Direct effects are one thing: when a pregnant woman drinks heavily, it can cause fetal alcohol syndrome. This happens because stress on a pregnant mother’s body is shared to some extent with the fetus, in this case interfering directly with the normal developmental program in utero.

But no one can explain exactly how, say, changes in brain cells caused by abuse could be communicated to fully formed sperm or egg cells before conception. And that’s just the first challenge. After conception, when sperm meets egg, a natural process of cleansing, or “rebooting,” occurs, stripping away most chemical marks on the genes. Finally, as the fertilized egg grows and develops, a symphony of genetic reshuffling occurs, as cells specialize into brain cells, skin cells, and the rest. How does a signature of trauma survive all of that?

...for now, and for many scientists, the research in epigenetics falls well short of demonstrating that past human cruelties affect our physiology today, in any predictable or consistent way.

Bad news on human nature - a listicle

I pass on clips from an Aeon piece by Jarrett that notes some of the darker and less impressive aspects of human behavior. Each of the points is accompanied by an explanatory paragraph.

We view minorities and the vulnerable as less than human.

We experience Schadenfreude (pleasure at another person’s distress) by the age of four.

We believe in karma – assuming that the downtrodden of the world deserve their fate.

We are blinkered and dogmatic.

We would rather give ourselves electric shocks than spend time in our own thoughts.

We are vain and overconfident.

We are moral hypocrites.

We are all potential trolls.

We favour ineffective leaders with psychopathic traits.

We are sexually attracted to people with dark personality traits.

Septuagenarians with the bodies of 25-year-olds

This septuagenarian (76 year old) author of this MindBlog always enjoys coming across reports of research, such as the work of Trappe and collaborators, which is pointed to in an article by Gretchen Reynolds. The studies focused on men and women who had taken up exercise as a recreational hobby during the running and exercise booms of the 1970s, on averaging exercising 5 day/wk for 7 h/wk over the past 52 ± 1 yr. From Reynolds:

Using local advertisements and other recruitment methods, they found 28 of them, including seven women, each of whom had been physically active for the past five decades. They also recruited a second group of age-matched older people who had not exercised during adulthood and a third group of active young people in their 20s...when the researchers compared the active older people’s aerobic capacities to those of established data about “normal” capacities at different ages, they calculated that the aged, active group had the cardiovascular health of people 30 years younger than themselves.

The abstract of the research article by Trappe and collaborators notes measurements of levels of muscle capillarization and aerobic enzyme activity 20%-90% greater than in non-exercising controls.

Stop talking about 'male' and 'female' brains.

As a counterpoint to yesterday's post, which invokes the Extreme Male Brain theory of autism, I pass on some clips from a piece by Joel and Fine that contests this categorization...

Consider, for example, Cambridge University psychologist Simon Baron-Cohen’s influential Empathizing-Systemizing theory of brains and the accompanying “extreme male brain” theory of autism. This presupposes there is a particular “systemizing” brain type that we could meaningfully describe as “the male brain,” that drives ways of thinking, feeling, and behaving that distinguish the typical boy and man from the typical “empathizing” girl and woman.

...one of us, Daphna Joel, led an analysis of four large data sets of brain scans, and found that the sex differences you see overall between men’s and women’s brains aren’t neatly and consistently seen in individual brains. In other words, humans generally don’t have brains with mostly or exclusively “female-typical” features or “male-typical” features. Instead, what’s most common in both females and males are brains with “mosaics” of features, some of them more common in males and some more common in females.

...Joel and colleagues then applied the same kind of analysis to large data sets of psychological variables, to ask: Do sex differences in personality characteristics, attitudes, preferences, and behaviors add up in a consistent way to create two types of humans, each with its own set of psychological features? The answer, again, was no: As for brain structure, the differences created mosaics of feminine and masculine personality traits, attitudes, interests, and behaviors...what was typical of both men and women (70 percent of them, to be exact) was a mosaic of feminine and masculine characteristics.

...if autism is indeed more prevalent in males, this may be associated with a difference between the sexes in the odds that a rare combination of brain characteristics makes an appearance, rather than with the typical male brain being a little more “autistic" than the typical female brain. Indeed, a recent study found that males with autism spectrum disorder had an atypical combination of “female-like” and “male-like” brain activity patterns.

The key point here is that although there are sex differences in brain and behavior, when you move away from group-level differences in single features and focus at the level of the individual brain or person, you find that the differences, regardless of their origins, usually “mix up” rather than “add up.” (The reason for this mixing-up of characteristics is that the genetic and hormonal effects of sex on brain and behavior depend on, and interact with, many other factors.) This yields many types of brain and behavior, which neither fall into a “male” and a “female” type, nor line up tidily along a male-female continuum.

The claim that science tells us that the possibility of greater merging of gender roles is unlikely because of “natural” differences between the sexes, focuses on average sex differences in the population — often in combination with the implicit assumption that whatever we think men are “more” of, is what is most valuable for male-dominated roles. (Why else would organizations offer confidence workshops for women, rather than modesty training for men?) But the world is inhabited by individuals whose unique mosaics of characteristics can’t be predicted on the basis of their sex. So let’s keep working on overcoming gender stereotypes, bias, discrimination, and structural barriers before concluding that sex, despite being a poor guide to our brains and psychological characteristics, is a strong determinant of social structure.

Testing theories of sex differences and autism with big data.

From Greenberg et al:

Significance

In the largest study to date of autistic traits, we test 10 predictions from the Empathizing–Systemizing (E-S) theory of sex differences and the Extreme Male Brain (EMB) theory of autism. We confirmed that typical females on average are more empathic, typical males on average are more systems-oriented, and autistic people on average show a “masculinized” profile. The strengths of the study are the inclusion of a replication sample and the use of big data. These two theories can be considered to have strong support. We demonstrate that D-scores (difference between E and S) account for 19 times the variance in autistic traits than do other demographic variables, including sex, underscoring the importance of brain types in autism.

Abstract

The Empathizing–Systemizing (E-S) theory of typical sex differences suggests that individuals may be classified based on empathy and systemizing. An extension of the E-S theory, the Extreme Male Brain (EMB) theory suggests that autistic people on average have a shift towards a more masculinized brain along the E-S dimensions. Both theories have been investigated in small sample sizes, limiting their generalizability. Here we leverage two large datasets (discovery n = 671,606, including 36,648 autistic individuals primarily; and validation n = 14,354, including 226 autistic individuals) to investigate 10 predictions of the E-S and the EMB theories. In the discovery dataset, typical females on average showed higher scores on short forms of the Empathy Quotient (EQ) and Sensory Perception Quotient (SPQ), and typical males on average showed higher scores on short forms of the Autism Spectrum Quotient (AQ) and Systemizing Quotient (SQ). Typical sex differences in these measures were attenuated in autistic individuals. Analysis of “brain types” revealed that typical females on average were more likely to be Type E (EQ > SQ) or Extreme Type E and that typical males on average were more likely to be Type S (SQ > EQ) or Extreme Type S. In both datasets, autistic individuals, regardless of their reported sex, on average were “masculinized.” Finally, we demonstrate that D-scores (difference between EQ and SQ) account for 19 times more of the variance in autistic traits (43%) than do other demographic variables including sex. Our results provide robust evidence in support of both the E-S and EMB theories.

Watching memories change the brain - a challenge to the traditional view

I pass on both the Science Magazine summary of Brodt et al., as well as the summary graphic in a review of their article by Assaf, and finally the Brodt et al. abstract:

How fast do learning-induced anatomical changes occur in the brain? The traditional view postulates that neocortical memory representations reflect reinstatement processes initiated by the hippocampus and that a genuine physical trace develops only through reactivation over extended periods. Brodt et al. combined functional magnetic resonance imaging (MRI) with diffusion-weighted MRI during an associative declarative learning task to examine experience-dependent structural brain plasticity in human subjects (see the Perspective by Assaf). This plasticity was rapidly induced after learning, persisted for more than 12 hours, drove behavior, and was localized in areas displaying memory-related functional brain activity. These plastic changes in the posterior parietal cortex, and their fast temporal dynamics, challenge traditional views of systems memory consolidation.

Models of systems memory consolidation postulate a fast-learning hippocampal store and a slowly developing, stable neocortical store. Accordingly, early neocortical contributions to memory are deemed to reflect a hippocampus-driven online reinstatement of encoding activity. In contrast, we found that learning rapidly engenders an enduring memory engram in the human posterior parietal cortex. We assessed microstructural plasticity via diffusion-weighted magnetic resonance imaging as well as functional brain activity in an object–location learning task. We detected neocortical plasticity as early as 1 hour after learning and found that it was learning specific, enabled correct recall, and overlapped with memory-related functional activity. These microstructural changes persisted over 12 hours. Our results suggest that new traces can be rapidly encoded into the parietal cortex, challenging views of a slow-learning neocortex.

The coding of perception in language is not universal.

From Majid et al.:

Is there a universal hierarchy of the senses, such that some senses (e.g., vision) are more accessible to consciousness and linguistic description than others (e.g., smell)? The long-standing presumption in Western thought has been that vision and audition are more objective than the other senses, serving as the basis of knowledge and understanding, whereas touch, taste, and smell are crude and of little value. This predicts that humans ought to be better at communicating about sight and hearing than the other senses, and decades of work based on English and related languages certainly suggests this is true. However, how well does this reflect the diversity of languages and communities worldwide? To test whether there is a universal hierarchy of the senses, stimuli from the five basic senses were used to elicit descriptions in 20 diverse languages, including 3 unrelated sign languages. We found that languages differ fundamentally in which sensory domains they linguistically code systematically, and how they do so. The tendency for better coding in some domains can be explained in part by cultural preoccupations. Although languages seem free to elaborate specific sensory domains, some general tendencies emerge: for example, with some exceptions, smell is poorly coded. The surprise is that, despite the gradual phylogenetic accumulation of the senses, and the imbalances in the neural tissue dedicated to them, no single hierarchy of the senses imposes itself upon language.

The neuroscience of hugs.

Packheiser et al. observed more than 2,500 hugs at an international airport, hugs with positive emotions at arrival gates and hugs with negative emotions at departure gates. (Hugging causes the release of oxytocin, the human pair-bonding hormone.) They also looked at neutral hugs of people who offered blindfolded hugs to strangers in the street. Most people showed a preference for right-sided hugs in all three situations (leading with the right hand and arm, the right hand being used by most people for skilled activities). Left-sided hugs occurred more frequently in emotional situations, no matter whether they were positive or negative. The left side of the body is controlled by the right side of the brain — which is heavily involved in processing both positive and negative emotions. Thus, this drift to the left side may show an interaction between emotional networks and motor preferences. Their abstract:

Humans are highly social animals that show a wide variety of verbal and non-verbal behaviours to communicate social intent. One of the most frequently used non-verbal social behaviours is embracing, commonly used as an expression of love and affection. However, it can also occur in a large variety of social situations entailing negative (fear or sadness) or neutral emotionality (formal greetings). Embracing is also experienced from birth onwards in mother–infant interactions and is thus accompanying human social interaction across the whole lifespan. Despite the importance of embraces for human social interactions, their underlying neurophysiology is unknown. Here, we demonstrated in a well-powered sample of more than 2500 adults that humans show a significant rightward bias during embracing. Additionally, we showed that this general motor preference is strongly modulated by emotional contexts: the induction of positive or negative affect shifted the rightward bias significantly to the left, indicating a stronger involvement of right-hemispheric neural networks during emotional embraces. In a second laboratory study, we were able to replicate both of these findings and furthermore demonstrated that the motor preferences during embracing correlate with handedness. Our studies therefore not only show that embracing is controlled by an interaction of motor and affective networks, they also demonstrate that emotional factors seem to activate right-hemispheric systems in valence-invariant ways.

Limited prosocial effects of meditation.

Kreplin et al. do a meta-analysis, and Kreplin writes a more general review of studies on the effects of meditation. The Krepline et al. abstract:

Many individuals believe that meditation has the capacity to not only alleviate mental-illness but to improve prosociality. This article systematically reviewed and meta-analysed the effects of meditation interventions on prosociality in randomized controlled trials of healthy adults. Five types of social behaviours were identified: compassion, empathy, aggression, connectedness and prejudice. Although we found a moderate increase in prosociality following meditation, further analysis indicated that this effect was qualified by two factors: type of prosociality and methodological quality. Meditation interventions had an effect on compassion and empathy, but not on aggression, connectedness or prejudice. We further found that compassion levels only increased under two conditions: when the teacher in the meditation intervention was a co-author in the published study; and when the study employed a passive (waiting list) control group but not an active one. Contrary to popular beliefs that meditation will lead to prosocial changes, the results of this meta-analysis showed that the effects of meditation on prosociality were qualified by the type of prosociality and methodological quality of the study. We conclude by highlighting a number of biases and theoretical problems that need addressing to improve quality of research in this area.

How stress changes our brains' blood flow.

From Elbau et al.:

Ample evidence links dysregulation of the stress response to the risk for psychiatric disorders. However, we lack an integrated understanding of mechanisms that are adaptive during the acute stress response but potentially pathogenic when dysregulated. One mechanistic link emerging from rodent studies is the interaction between stress effectors and neurovascular coupling, a process that adjusts cerebral blood flow according to local metabolic demands. Here, using task-related fMRI, we show that acute psychosocial stress rapidly impacts the peak latency of the hemodynamic response function (HRF-PL) in temporal, insular, and prefrontal regions in two independent cohorts of healthy humans. These latency effects occurred in the absence of amplitude effects and were moderated by regulatory genetic variants of KCNJ2, a known mediator of the effect of stress on vascular responsivity. Further, hippocampal HRF-PL correlated with both cortisol response and genetic variants that influence the transcriptional response to stress hormones and are associated with risk for major depression. We conclude that acute stress modulates hemodynamic response properties as part of the physiological stress response and suggest that HRF indices could serve as endophenotype of stress-related disorders.

More on the sociopathy of social media.

Languishing in my queue of potential posts have been two articles that I want to mention and pass on to readers.

Max Fisher writes on the unintended consequences of social media, from Myanmar to Germany:

I first went to Myanmar in early 2014, when the country was opening up, and there was no such thing as personal technology. Not even brick phones.

When I went back in late 2017, I could hardly believe it was the same country. Everybody had his or her nose in a smartphone, often logged in to Facebook. You’d meet with the same sources at the same roadside cafe, but now they’d drop a stack of iPhones on the table next to the tea.

It was like the purest possible experiment in what the same society looks like with or without modern consumer technology. Most people loved it, but it also helped drive genocidal violence against the Rohingya minority, empower military hard-liners and spin up riots.

...we’re starting to understand the risks that come from these platforms working exactly as designed. Facebook, YouTube and others use algorithms to identify and promote content that will keep us engaged, which turns out to amplify some of our worst impulses. (Fisher has done articles on algorithm driven violence in Germany and Sri Lanka)

And, Rich Hardy points to further work linking social media use and feelings of depression and loneliness. Work of Hunt et al. suggests that decreasing one's social media use can lead to significant improvements in personal well-being.

Our brains are prediction machines. Friston's free-energy principle

Further reading on the article noted in the previous post has made me realize that I have been seriously remiss in not paying more attention to a revolution in how we view our brains. From a Karl Friston piece in Nature Neuroscience on predictive coding:

In the 20th century we thought the brain extracted knowledge from sensations. The 21st century witnessed a ‘strange inversion’, in which the brain became an organ of inference, actively constructing explanations for what’s going on ‘out there’, beyond its sensory epithelia.

And, key points from a Friston review, "The free-energy principle: a unified brain theory?:

Adaptive agents must occupy a limited repertoire of states and therefore minimize the long-term average of surprise associated with sensory exchanges with the world. Minimizing surprise enables them to resist a natural tendency to disorder.

Surprise rests on predictions about sensations, which depend on an internal generative model of the world. Although surprise cannot be measured directly, a free-energy bound on surprise can be, suggesting that agents minimize free energy by changing their predictions (perception) or by changing the predicted sensory inputs (action).

Perception optimizes predictions by minimizing free energy with respect to synaptic activity (perceptual inference), efficacy (learning and memory) and gain (attention and salience). This furnishes Bayes-optimal (probabilistic) representations of what caused sensations (providing a link to the Bayesian brain hypothesis).

Bayes-optimal perception is mathematically equivalent to predictive coding and maximizing the mutual information between sensations and the representations of their causes. This is a probabilistic generalization of the principle of efficient coding (the infomax principle) or the minimum-redundancy principle.

Learning under the free-energy principle can be formulated in terms of optimizing the connection strengths in hierarchical models of the sensorium. This rests on associative plasticity to encode causal regularities and appeals to the same synaptic mechanisms as those underlying cell assembly formation.

Action under the free-energy principle reduces to suppressing sensory prediction errors that depend on predicted (expected or desired) movement trajectories. This provides a simple account of motor control, in which action is enslaved by perceptual (proprioceptive) predictions.

Perceptual predictions rest on prior expectations about the trajectory or movement through the agent's state space. These priors can be acquired (as empirical priors during hierarchical inference) or they can be innate (epigenetic) and therefore subject to selective pressure.

Predicted motion or state transitions realized by action correspond to policies in optimal control theory and reinforcement learning. In this context, value is inversely proportional to surprise (and implicitly free energy), and rewards correspond to innate priors that constrain policies.

Being a Beast Machine: The Somatic Basis of Selfhood

Seth and Tsakiris offer a review in Trends in Cognitive Sciences, with the title of this post, that immediately caught my eye. I'm working on a lecture now that incorporates some of its themes. Here I pass on the abstract, motivated readers can obtain a copy of the full article from me.

Highlights

We conceptualise experiences of embodied selfhood in terms of control-oriented predictive regulation (allostasis) of physiological states.

We account for distinctive phenomenological aspects of embodied selfhood, including its (partly) non-object-like nature and its subjective stability over time.

We explain predictive perception as a generalisation from a fundamental biological imperative to maintain physiological integrity: to stay alive.

We bring together several cognitive science traditions, including predictive processing, perceptual control theory, cybernetics, the free energy principle, and sensorimotor contingency theory.

We show how perception of the world around us, and of ourselves within it, happens with, through, and because of our living bodies.

We draw implications for developmental psychology and identify open questions in psychiatry and artificial intelligence.

Abstract

Modern psychology has long focused on the body as the basis of the self. Recently, predictive processing accounts of interoception (perception of the body ‘from within’) have become influential in accounting for experiences of body ownership and emotion. Here, we describe embodied selfhood in terms of ‘instrumental interoceptive inference’ that emphasises allostatic regulation and physiological integrity. We apply this approach to the distinctive phenomenology of embodied selfhood, accounting for its non-object-like character and subjective stability over time. Our perspective has implications for the development of selfhood and illuminates longstanding debates about relations between life and mind, implying, contrary to Descartes, that experiences of embodied selfhood arise because of, and not in spite of, our nature as ‘beast machines’.

A molecular basis for the placebo effect.

Several popular articles point to work I wish I had been more aware off. Gary Greenberg in the NYTimes, and Cari Romm in The Atlantic, point to work of Kathryn Hall and collaborators showing that placebo responses are strongest in patients with a variant of a gene (COMT, which regulates the amount of dopamine in the brain) that causes higher levels of dopamine, which is linked to pain the the good feeling that come with reward. Irritable bowel syndrome patients with the high-dopamine version of the gene were more likely to report that the placebo treatment had relieved their symptoms, an effect that was even stronger in the group that had received their treatment from a caring provider. Variations in the COMT gene locus are unlikely to fully account for a complex behavior like the placebo response, but contribute to the puzzle. Here is the abstract from the Hall et al. paper:

• Predisposition to respond to placebo treatment may be in part a stable heritable trait. 

• Candidate placebo response pathways may interact with drugs to modify outcomes in both the placebo and drug treatment arms of clinical trials. 

• Genomic analysis of randomized placebo and no-treatment controlled trials are needed to fully realize the potential of the placebome.

Placebos are indispensable controls in randomized clinical trials (RCTs), and placebo responses significantly contribute to routine clinical outcomes. Recent neurophysiological studies reveal neurotransmitter pathways that mediate placebo effects. Evidence that genetic variations in these pathways can modify placebo effects raises the possibility of using genetic screening to identify placebo responders and thereby increase RCT efficacy and improve therapeutic care. Furthermore, the possibility of interaction between placebo and drug molecular pathways warrants consideration in RCT design. The study of genomic effects on placebo response, ‘the placebome’, is in its infancy. Here, we review evidence from placebo studies and RCTs to identify putative genes in the placebome, examine evidence for placebo–drug interactions, and discuss implications for RCTs and clinical care.