Possible mechanism of psychedelic therapeutic effects

From the latest issue of Science Magazine:  

The mechanism underlying psychedelic action

Psychedelic compounds promote cortical structural and functional neuroplasticity through the activation of serotonin 2A receptors. However, the mechanisms by which receptor activation leads to changes in neuronal growth are still poorly defined. Vargas et al. found that activation of intracellular serotonin 2A receptors is responsible for the plasticity-promoting and antidepressant-like properties of psychedelic compounds, but serotonin may not be the natural ligand for those intracellular receptors (see the Perspective by Hess and Gould). —PRS

Abstract

Decreased dendritic spine density in the cortex is a hallmark of several neuropsychiatric diseases, and the ability to promote cortical neuron growth has been hypothesized to underlie the rapid and sustained therapeutic effects of psychedelics. Activation of 5-hydroxytryptamine (serotonin) 2A receptors (5-HT2ARs) is essential for psychedelic-induced cortical plasticity, but it is currently unclear why some 5-HT2AR agonists promote neuroplasticity, whereas others do not. We used molecular and genetic tools to demonstrate that intracellular 5-HT2ARs mediate the plasticity-promoting properties of psychedelics; these results explain why serotonin does not engage similar plasticity mechanisms. This work emphasizes the role of location bias in 5-HT2AR signaling, identifies intracellular 5-HT2ARs as a therapeutic target, and raises the intriguing possibility that serotonin might not be the endogenous ligand for intracellular 5-HT2ARs in the cortex.

MindBlog picks some of its favorite posts on defining what a self is…

The following links are from a recent scan of what pops up if I click on items in ‘Selected MindBlog Categories’ in the right column of this page - to remind myself of some of the results of my personal reflections on the topics indicated. The chronological list starts with the most recent posts.

Enlightenment, Habituation, and Renewal - Or, Mindfulness as the opiate of the thinking classes?

The non-duality industry as a panacea for the anxieties of our times? 

I am not my problem

Self, purpose, and tribal mentality as Darwinian adaptations (or…Why why aren’t we all enlightened?) 

MindBlog passes on a note: on the relief of not being yourself.

Some rambling on "Selves" and “Purpose"

Why don’t we do what we know works better?

An "Apostle's Creed" for the humanistic scientific materialist?

A fish passes the mirror self recognition test!

Our human abilities continue to found in more evolutionarily distant species. From Kohda et al.:

Some animals have the remarkable capacity for mirror self-recognition (MSR), yet any implications for self-awareness remain uncertain and controversial. This is largely because explicit tests of the two potential mechanisms underlying MSR are still lacking: mental image of the self and kinesthetic visual matching. Here, we test the hypothesis that MSR ability in cleaner fish, Labroides dimidiatus, is associated with a mental image of the self, in particular the self-face, like in humans. Mirror-naive fish initially attacked photograph models of both themselves and unfamiliar strangers. In contrast, after all fish had passed the mirror mark test, fish did not attack their own (motionless) images, but still frequently attacked those of unfamiliar individuals. When fish were exposed to composite photographs, the self-face/unfamiliar body were not attacked, but photographs of unfamiliar face/self-body were attacked, demonstrating that cleaner fish with MSR capacity recognize their own facial characteristics in photographs. Additionally, when presented with self-photographs with a mark placed on the throat, unmarked mirror-experienced cleaner fish demonstrated throat-scraping behaviors. When combined, our results provide clear evidence that cleaner fish recognize themselves in photographs and that the likely mechanism for MSR is associated with a mental image of the self-face, not a kinesthetic visual-matching model. Humans are also capable of having a mental image of the self-face, which is considered an example of private self-awareness. We demonstrate that combining mirror test experiments with photographs has enormous potential to further our understanding of the evolution of cognitive processes and private self-awareness across nonhuman animals.

Fundamentally rethinking what a mind is and how a brain works.

The February Issue of Trends in Cognitive Science has an open source Opinions article from Lisa Feldman Barrett and collaborators that suggests that new research approaches grounded in different ontological commitments will be required to properly describe brain-behavior relationships. Here is a clip of the introductory text and a graphic clip from the article. Finally, I pass on the concluding remarks on fundamentally rethinking what a mind is and how a brain works.

Most brain imaging studies present stimuli and measure behavioral responses in temporal units (trials) that are ordered randomly. Participants’ brain signals are typically aggregated to model structured variation that allows inferences about the broader population from which people were sampled. These methodological details, when used to study any phenomenon of interest, often give rise to brain-behavior findings that vary unexpectedly (across stimuli, context, and people). Such findings are typically interpreted as replication failures, with the observed variation discounted as error caused by less than rigorous experimentation (Box 1). Methodological rigor is of course important, but replication problems may stem, in part, from a more pernicious source: faulty assumptions (i.e., ontological commitments) that mis-specify the psychological phenomena of interest.

In this paper, we review three questionable assumptions whose reconsideration may offer opportunities for a more robust and replicable science: 

 (1) The localization assumption: the instances that constitute a category of psychological events (e.g., instances of fear) are assumed to be caused by a single, dedicated psychological process implemented in a dedicated neural ensemble (see Glossary). 

 (2) The one-to-one assumption: the dedicated neural ensemble is assumed to map uniquely to that psychological category, such that the mapping generalizes across contexts, people, measurement strategies, and experimental designs. 

 (3) The independence assumption: the dedicated neural ensemble is thought to function independently of contextual factors, such as the rest of the brain, the body, and the surrounding world, so the ensemble can be studied alone without concern for those other factors. Contextual factors might moderate activity in the neural ensemble but should not fundamentally change its mapping to the instances of a psychological category. 

 These three assumptions are rooted in a typological view of the mind, brain, and behavior [1. ] that was modeled on 19th century physics and continues to guide experimental practices in much of brain-behavior research to the present day. In this paper, we have curated examples from studies of human functional magnetic resonance imaging (fMRI) and neuroscience research using non-human animals that call each assumption into question. We then sketch the beginnings of an alternative approach to study brain-behavior relationships, grounded in different ontological commitments: (i) a mental event comprises distributed activity across the whole brain; (ii) brain and behavior are linked by degenerate (i.e., many-to-one) mappings; and (iii) mental events emerge as a complex ensemble of weak, nonlinearly interacting signals from the brain, body, and external world.

 

Concluding remarks

Scientific communities tacitly agree on assumptions about what exists (called ontological commitments), what questions to ask, and what methods to use. All assumptions are firmly rooted in a philosophy of science that need not be acknowledged or discussed but is practiced nonetheless. In this article, we questioned the ontological commitments of a philosophy of science that undergirds much of modern neuroscience research and psychological science in particular. We demonstrated that three common commitments should be reconsidered, along with a corresponding course correction in methods. Our suggestions require more than merely improved methodological rigor for traditional experimental design. Such improvements are important, but may aid robustness and replicability only when the ontological assumptions behind those methods are valid. Accordingly, a productive way forward may be to fundamentally rethink what a mind is and how a brain works. We have suggested that mental events arise from a complex ensemble of signals across the entire brain, as well as the from the sensory surfaces of the body that inform on the states of the inner body and outside world, such that more than one signal ensemble maps to a single instance of a single psychological category (maybe even in the same context. To this end, scientists might find inspiration by mining insights from adjacent fields, such as evolution, anatomy, development, and ecology , as well as cybernetics and systems theory. At stake is nothing less than a viable science of how a brain creates a mind through its constant interactions with its body, its physical environment, and with the other brains-in-bodies that occupy its social world.

The touch sensitive nerve cells that make mice (and probably us) horny.

From Elias et al. (open source) in the journal Cell:  

Highlights

• Activation of Mrgprb4-lineage touch neurons induces lordosis-like posture

• Activation of Mrgprb4-lineage touch neurons is rewarding

• Mrgprb4-lineage touch neurons are required for female sexual receptivity

• Mrgprb4-lineage touch neurons engage dopaminergic neurons during social behavior

Summary

Pleasurable touch is paramount during social behavior, including sexual encounters. However, the identity and precise role of sensory neurons that transduce sexual touch remain unknown. A population of sensory neurons labeled by developmental expression of the G protein-coupled receptor Mrgprb4 detects mechanical stimulation in mice. Here, we study the social relevance of Mrgprb4-lineage neurons and reveal that these neurons are required for sexual receptivity and sufficient to induce dopamine release in the brain. Even in social isolation, optogenetic stimulation of Mrgprb4-lineage neurons through the back skin is sufficient to induce a conditioned place preference and a striking dorsiflexion resembling the lordotic copulatory posture. In the absence of Mrgprb4-lineage neurons, female mice no longer find male mounts rewarding: sexual receptivity is supplanted by aggression and a coincident decline in dopamine release in the nucleus accumbens. Together, these findings establish that Mrgprb4-lineage neurons initiate a skin-to-brain circuit encoding the rewarding quality of social touch.

A.I. as a path towards mass lunacy

MindBlog wants to be part of the passing on of this elegantly stated clip from an article by novelist, literary critic, and essayist Walter Kirn:

What chatbots do is scrape the web, the library of texts already written, and learn from it how to add to the collection, which causes them to start scraping their own work in ever enlarging quantities, along with the texts produced by future humans. Both sets of documents will then degenerate. For as the adoption of A.I. relieves people of their verbal and mental powers and pushes them toward an echoing conformity, much as the mass adoption of map apps have abolished their senses of direction, the human writings from which the A.I. draws will decline in originality and quality along with their derivatives. Enmeshed, dependent, mutually enslaved, machine and man will unite their special weaknesses — lack of feeling and lack of sense — and spawn a thing of perfect lunacy, like the child of a psychopath and an idiot.

I can hear the objections to this dire scenario of a million gung-ho programmers as well as the ambitious A.I. itself, but I, a creative writer, am wed to it. I think dramatically first and scientifically second, such is my art. My ancient and possibly endangered art is imagining worst cases and playing them out to their bitter, tragic ends, as Sophocles did when he posited a king who unwittingly killed his father, married his mother, and then launched an inquiry into the matter after vowing to slay the perpetrator. See? See what writers were capable of then?

Now we have ‘Ant-Man.’ And worse, ‘Ant-Man’ sequels, enhanced by C.G.I.

An fMRI marker of drug and food craving

Koban et al. identify an fMRI-based neural signature of craving that is common to both food and drugs, predicts self-reported craving, distinguishes drug users from non-users, and tracks the efficacy of a cognitive therapy technique to reduce craving:

Craving is a core feature of substance use disorders. It is a strong predictor of substance use and relapse and is linked to overeating, gambling, and other maladaptive behaviors. Craving is measured via self-report, which is limited by introspective access and sociocultural contexts. Neurobiological markers of craving are both needed and lacking, and it remains unclear whether craving for drugs and food involve similar mechanisms. Across three functional magnetic resonance imaging studies (n = 99), we used machine learning to identify a cross-validated neuromarker that predicts self-reported intensity of cue-induced drug and food craving (P < 0.0002). This pattern, which we term the Neurobiological Craving Signature (NCS), includes ventromedial prefrontal and cingulate cortices, ventral striatum, temporal/parietal association areas, mediodorsal thalamus and cerebellum. Importantly, NCS responses to drug versus food cues discriminate drug users versus non-users with 82% accuracy. The NCS is also modulated by a self-regulation strategy. Transfer between separate neuromarkers for drug and food craving suggests shared neurobiological mechanisms. Future studies can assess the discriminant and convergent validity of the NCS and test whether it responds to clinical interventions and predicts long-term clinical outcomes.

Multigenerational Impacts of Childhood Access to the Safety Net.

In an open source article in the January issue of the American Economic Review East et al. show that early life exposure to Medicaid enhances the next generation's health.

We examine multigenerational impacts of positive in utero health interventions using a new research design that exploits sharp increases in prenatal Medicaid eligibility that occurred in some states. Our analyses are based on US Vital Statistics natality files, which enables linkages between individuals' early life Medicaid exposure and the next generation's health at birth. We find evidence that the health benefits associated with treated generations' early life program exposure extend to later offspring. Our results suggest that the returns on early life health investments may be substantively underestimated.

Shifting from foraging to farming, beginning ~12,000 years ago, changed everything.

A special Feature section in the Jan. 17 issue of PNAS offers a series of perspectives on the past 12,000 years of human behavior, adaptation, and evolution that shaped who we are today. An introduction to the special section by Larsen does an overview and brief summary of each of perspectives presented. I pass on the last paragraph (Conclusions) of that summary:

In evolutionary terms, the transition at the Pleistocene–Holocene boundary was extraordinary, especially in consideration of the beginning of a fundamental shift in dietary focus and the downstream effects of diets based on domesticated plants and animals. The transition provided the context for a remarkable increase in population. However, the costs for that success—elevated levels infectious diseases, undernutrition, and conflict—are still with us today. Our species will continue to adapt, to develop strategies for success, and to mitigate challenges. That is what we do. Once we began the shift to and intensification of farming, the remarkable changes seen in humans became critically important developments in recent human evolution. In view of conditions today, including climate change, overpopulation, and the rise in prevalence of infectious diseases, both old and newly emerging, it should come as no surprise that dependence on a few staple crops and shift to sedentary behavior will be with us for the foreseeable future. They are, after all, a legacy of our past, and forming and sharing of the dietary framework, behavioral patterns, and outcomes in health and well-being for all eight billion of us that occupy the world today.

Openness to spiritual experiences...with caution

After a Protestant Christian upbringing (I was a teenage organist in an Austin Lutheran Church, and took a course from theologian Paul Tillich at Harvard), my adult materialistic scientific Deric has never been able to fathom how an intellectual like Ross Douthat could be a devout Catholic. My irrational faith is in a materialism that is open to spiritual experiences and insights, but also strives to explain them in materialistic terms (as I think near-death experiences have been). I think Douthat’s recent opinion piece in the NYTimes very lucid, although I take exception to one of his pronouncements, and I would recommend that you read it. Here are some clips:

...the dissolution of the old order of American religion — the decline of churches and denominations and the rise of deinstitutionalized spirituality — means that more and more religious lives are lived in between worldviews, in experimental territory where it’s a mistake to expect coherence, theological consistency, a definite set of prior assumptions or beliefs...I want to defend the rationality of this kind of spiritual experimentation and then to warn about its dangers.

Douthat then offers three examples experimental style: magical thinking, experimenting with psychedelics, and pantheistic art that blurs spiritual traditions. And he continues:

For the stringent materialist, everything I’ve just described is reasonable as long as it's understood to be playacting, experience hunting, artistic experimentation. Only when it becomes serious does it offend against rationality.

However, stringent materialism is itself a weird late-modern superstition, and the kind of experimentation I’m describing is actually far more rational than a life lived as though the universe is random and indifferent and human beings are gene-transmission machines with an illusion of self-consciousness.

So... put me in the camp of irrational believers in stringent materialism. And... by what authority does Mr. Douthat get to declare spiritual experimentation or superstition is "far more rational than life lived as though the universe is random, etc." Superstition is superstition; irrational is irrational. What criteria are Mr. Douthat using for his "far more rational" judgment. Are they utilitarian?... as in "X diminishes or enhances the well being of humans more than Y"? He should explicitly state them.

Cryptocurrency isn't going away - any more that Gold is...

...as long as cryptocurrency maintains a core of true believers in the block chain concept for guaranteeing trustworthiness. All currencies are useful as tokens for exchange only to the extent that humans believe in them. The point of this brief post is just to pass on links to two recent screeds by Desai and Krugman that make entertaining reading: 

Mihir A. Desai - The Crypto Collapse and the End of the Magical Thinking That Infected Capitalism  

Paul Krugman - Wonking Out: Give Me That Gold Time Religion 

 

 

 

Market exposure and human morality

In the face of resurgent threats to place religion over the rest of civil society, and specious claims that we can't have a moral society without the (varying) moral injunctions of various religions, this recent article by Enke in Nature Human Behavior offers a nice explication of one of several other routes by which moral behaviors have evolved over time. Here is the abstract:

According to evolutionary theories, markets may foster an internalized and universalist prosociality because it supports market-based cooperation. This paper uses the cultural folklore of 943 pre-industrial ethnolinguistic groups to show that a society’s degree of market interactions, proxied by the presence of intercommunity trade and money, is associated with the cultural salience of (1) prosocial behaviour, (2) interpersonal trust, (3) universalist moral values and (4) moral emotions of guilt, shame and anger. To provide tentative evidence that a part of this correlation reflects a causal effect of market interactions, the analysis leverages both fine-grained geographic variation across neighbouring historical societies and plausibly exogenous variation in the presence of markets that arises through proximity to historical trade routes or the local degree of ecological diversity. The results suggest that the coevolutionary process involving markets and morality partly consists of economic markets shaping a moral system of a universalist and internalized prosociality.