Towards mapping neuro-behavioral heterogeneity of psychedelic neurobiology in humans

Precision psychiatry aims to identify markers of inter-individual variability that allow predicting the right treatment for each patient. However, bridging the gap between molecular-level manipulations and neural systems-level functional alterations remains an unsolved problem in psychiatry. After decades of low success rates in pharmaceutical R&D for psychiatric drugs, multiple studies now point to the potential of psychedelics as a promising fast-acting and long-lasting treatment for some psychiatric symptoms. Yet, given the highly psychoactive nature of these substances, a precision medicine approach is essential to map the neural signals related to clinical efficacy in order to identify patients who can maximally benefit from this treatment. Recent studies have shown that bridging the gap between pharmacology, systems-level neural response in humans and individual experience is possible for psychedelic substances, therefore paving the way for a precision neuropsychiatric therapeutic development. Specifically, it has been shown that the integration of brain-wide PET or transcriptomic data, i.e. receptor distribution for the serotonin 2A receptor, with computational neuroimaging methods can simulate the effect of psychedelics on the human brain. These novel 'computational psychiatry' approaches allow for modeling inter-individual differences in neural as well as subjective effects of psychedelic substances. Collectively, this review provides a deep dive into psychedelic pharmaco-neuroimaging studies with a core focus on how recent computational psychiatry advances in biophysically based circuit modeling can be leveraged to predict individual responses. Finally, we emphasize the importance of human pharmacological neuroimaging for the continued precision therapeutic development of psychedelics. Keywords: computational modeling; fMRI; neuroimaging; precision psychiatry; psychedelics; serotonin

Psilocybin-induced changes in cerebral blood flow are associated with acute and baseline inter-individual differences

Research into the use of psilocybin for the treatment of psychiatric disorders is a growing field. Nevertheless, robust brain–behavior relationships linking psilocybin-induced brain changes to subjective drug-induced effects have not been established. Furthermore, it is unclear if the acute neural effects are dependent on individual heterogeneity in baseline characteristics. To address this, we assessed the effects of three oral doses of psilocybin vs. placebo on cerebral blood flow (CBF) using arterial spin labeling in healthy participants (N = 70; n = 31, 0.16 mg/kg; n = 10, 0.2 mg/kg; n = 29, 0.215 mg/kg). First, we quantified psilocybin-induced changes in relative and absolute CBF. Second, in an exploratory analysis, we assessed whether individual baseline characteristics and subjective psychedelic experience are associated with changes in CBF. Psychological and neurobiological baseline characteristics correlated with the psilocybin-induced reduction in relative CBF and the psilocybin-induced subjective experience. Furthermore, the psilocybin-induced subjective experience was associated with acute changes in relative and absolute CBF. The results demonstrated that inter-individual heterogeneity in the neural response to psilocybin is associated with baseline characteristics and shed light on the mechanisms underlying the psychedelic-induced altered state. Overall, these findings help guide the search for biomarkers, paving the way for a personalized medicine approach within the framework of psychedelic-assisted therapy

Psilocybin-induced changes in cerebral blood flow are associated with acute and baseline inter-individual differences

Research into the use of psilocybin for the treatment of psychiatric disorders is a growing field. Nevertheless, robust brain–behavior relationships linking psilocybin-induced brain changes to subjective drug-induced effects have not been established. Furthermore, it is unclear if the acute neural effects are dependent on individual heterogeneity in baseline characteristics. To address this, we assessed the effects of three oral doses of psilocybin vs. placebo on cerebral blood flow (CBF) using arterial spin labeling in healthy participants (N = 70; n = 31, 0.16 mg/kg; n = 10, 0.2 mg/kg; n = 29, 0.215 mg/kg). First, we quantified psilocybin-induced changes in relative and absolute CBF. Second, in an exploratory analysis, we assessed whether individual baseline characteristics and subjective psychedelic experience are associated with changes in CBF. Psychological and neurobiological baseline characteristics correlated with the psilocybin-induced reduction in relative CBF and the psilocybin-induced subjective experience. Furthermore, the psilocybin-induced subjective experience was associated with acute changes in relative and absolute CBF. The results demonstrated that inter-individual heterogeneity in the neural response to psilocybin is associated with baseline characteristics and shed light on the mechanisms underlying the psychedelic-induced altered state. Overall, these findings help guide the search for biomarkers, paving the way for a personalized medicine approach within the framework of psychedelic-assisted therapy.ISSN:2045-232

Reward and loss incentives improve spatial working memory by shaping trial-by-trial posterior frontoparietal signals

Integrating motivational signals with cognition is critical for goal-directed activities. The mechanisms that link neural changes with motivated working memory continue to be understood. Here, we tested how externally cued and non-cued (internally represented) reward and loss impact spatial working memory precision and neural circuits in human subjects using fMRI. We translated the classic delayed-response spatial working memory paradigm from non-human primate studies to take advantage of a continuous numeric measure of working memory precision, and the wealth of translational neuroscience yielded by these studies. Our results demonstrated that both cued and non-cued reward and loss improved spatial working memory precision. Visual association regions of the posterior prefrontal and parietal cortices, specifically the precentral sulcus (PCS) and intraparietal sulcus (IPS), had increased BOLD signal during incentivized spatial working memory. A subset of these regions had trial-by-trial increases in BOLD signal that were associated with better working memory precision, suggesting that these regions may be critical for linking neural signals with motivated working memory. In contrast, regions straddling executive networks, including areas in the dorsolateral prefrontal cortex, anterior parietal cortex and cerebellum displayed decreased BOLD signal during incentivized working memory. While reward and loss sim- ilarly impacted working memory processes, they dissociated during feedback when money won or avoided in loss was given based on working memory performance. During feedback, the trial-by-trial amount and valence of reward/loss received was dissociated amongst regions such as the ventral striatum, habenula and periaqueductal gray. Overall, this work suggests motivated spatial working memory is supported by complex sensory processes, and that the IPS and PCS in the posterior frontoparietal cortices may be key regions for integrating motivational signals with spatial working memory precision

Comparing neural correlates of consciousness: from psychedelics to hypnosis and meditation.

peer reviewedBACKGROUND: Pharmacological and non-pharmacological methods of inducing altered states of consciousness (ASC) are becoming increasingly relevant in the treatment of psychiatric disorders. While comparisons between them are often drawn, to date no study has directly compared their neural correlates. METHODS: To address this knowledge gap we directly compared two pharmacological methods: psilocybin (n=23, dose=0.2mg/kg p.o.) and LSD (n=25, dose=100μg p.o.) and two non-pharmacological methods: hypnosis (n=30) and meditation (n=29) using resting state functional connectivity magnetic resonance imaging (rs-fcMRI), and assessed the predictive value of the data using a machine learning approach. RESULTS: We found that (i) no network reaches significance in all four ASC methods; (ii) pharmacological and non-pharmacological interventions of inducing ASC show distinct connectivity patterns that are predictive at the individual level; (iii) hypnosis and meditation show differences in functional connectivity when compared directly, and also drive distinct differences when jointly compared to the pharmacological ASC interventions; (iv) psilocybin and LSD show no differences in functional connectivity when directly compared to each other, but do show distinct behavioral-neural relationships. CONCLUSION: Overall, these results extend our understanding of the mechanisms of action of ASC and highlight the importance of exploring how these effects can be leveraged in the treatment of psychiatric disorders

Mapping brain-behavior space relationships along the psychosis spectrum

Difficulties in advancing effective patient-specific therapies for psychiatric disorders highlight a need to develop a stable neurobiologically grounded mapping between neural and symptom variation. This gap is particularly acute for psychosis-spectrum disorders (PSD). Here, in a sample of 436 PSD patients spanning several diagnoses, we derived and replicated a dimensionality-reduced symptom space across hallmark psychopathology symptoms and cognitive deficits. In turn, these symptom axes mapped onto distinct, reproducible brain maps. Critically, we found that multivariate brain-behavior mapping techniques (e.g. canonical correlation analysis) do not produce stable results with current sample sizes. However, we show that a univariate brain-behavioral space (BBS) can resolve stable individualized prediction. Finally, we show a proof-of-principle framework for relating personalized BBS metrics with molecular targets via serotonin and glutamate receptor manipulations and neural gene expression maps derived from the Allen Human Brain Atlas. Collectively, these results highlight a stable and data-driven BBS mapping across PSD, which offers an actionable path that can be iteratively optimized for personalized clinical biomarker endpoints

Functional brain networks reflect spatial and temporal autocorrelation

High-throughput experimental methods in neuroscience have led to an explosion of techniques for measuring complex interactions and multi-dimensional patterns. However, whether sophisticated measures of emergent phenomena can be traced back to simpler, low-dimensional statistics is largely unknown. To explore this question, we examined resting-state functional magnetic resonance imaging (rs-fMRI) data using complex topology measures from network neuroscience. Here we show that spatial and temporal autocorrelation are reliable statistics that explain numerous measures of network topology. Surrogate time series with subject-matched spatial and temporal autocorrelation capture nearly all reliable individual and regional variation in these topology measures. Network topology changes during aging are driven by spatial autocorrelation, and multiple serotonergic drugs causally induce the same topographic change in temporal autocorrelation. This reductionistic interpretation of widely used complexity measures may help link them to neurobiology