Brain dynamics predictive of response to psilocybin for treatment-resistant depression

Vohryzek, Jakub; Cabral, Joana; Lord, Louis-David; Fernandes, Henrique M; Roseman, Leor; Nutt, David J; Carhart-Harris, Robin L; Deco, Gustavo; Kringelbach, Morten L

doi:10.1093/braincomms/fcae049

Cited by 5 publications

(2 citation statements)

References 74 publications

(86 reference statements)

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“…In this study, we combined in- vivo single cell calcium imaging of cortical ensembles with behavioral pharmacology to elucidate the neural correlates of psilocybin-enhanced extinction. The existence psilocybin-responsive and non-responsive subpopulations of humans and rats has been the subject of recent investigation 28,75 . Here, we report for the first time that mice are divided into psilocybin responsive and non-responsive groups with respect to post-acute enhancement of TFC extinction.…”

Section: Discussionmentioning

confidence: 99%

Psilocybin-enhanced fear extinction linked to bidirectional modulation of cortical ensembles

Rogers,

Heller,

Corder

2024

Preprint

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The serotonin 2 receptor (5HT2R) agonist psilocybin has demonstrated rapid and long-lasting efficacy across neuropsychiatric disorders characterized by cognitive inflexibility. Psilocybin may accomplish this by inducing rapid and stable dendritic plasticity. However, the impact of psilocybin on patterns of neural activity underlying sustained changes in cognitive and behavioral flexibility has not been characterized. To test the hypothesis that psilocybin enhances behavioral flexibility by rapidly and persistently altering activity in cortical neural ensembles, we performed longitudinal single-cell calcium imaging in the retrosplenial cortex across a five-day trace fear learning and extinction assay. Leveraging tensor component analysis to identify neurons that modulate activity on multiple temporal scales, we found that a single-dose of psilocybin induced cortical ensemble turnover between fear learning and extinction days while oppositely modulating activity in fear- and extinction- active neurons. The extent of suppression of fear-active neurons and recruitment of extinction-active neurons were both predictive of psilocybin-enhanced fear extinction. These results both align with hypotheses that psilocybin enhances behavioral flexibility by recruiting new populations of neurons and introduce a new mechanism involving the suppression of fear-active populations in the retrosplenial cortex.

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Section: Discussionmentioning

confidence: 99%

Psilocybin-enhanced fear extinction linked to bidirectional modulation of cortical ensembles

Rogers,

Heller,

Corder

2024

Preprint

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“…The awakening framework developed by Deco et al (2019) has been robust and helpful in elucidating the underlying mechanisms and brain transitions in different brain states towards control regimes ( Deco et al, 2019 ; Escrichs et al, 2023 ; Mana et al, 2023 ; Vohryzek et al, 2024 ). It consists of a model-free approach, Leading Eigenvector Dynamics Analysis (LEiDA) ( Cabral et al, 2017 ), and a model-based approach, consisting of Hopf whole-brain computational models and off-line in silico perturbations.…”

Section: Introductionmentioning

confidence: 99%

Inducing a meditative state by artificial perturbations: A mechanistic understanding of brain dynamics underlying meditation

Dagnino,

Galadí,

Càmara

et al. 2024

Network Neuroscience

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Contemplative neuroscience has increasingly explored meditation using neuroimaging. However, the brain mechanisms underlying meditation remain elusive. Here, we implemented a mechanistic framework to explore the spatiotemporal dynamics of expert meditators during meditation and rest, and controls during rest. We first applied a model-free approach by defining a probabilistic metastable substate (PMS) space for each condition, consisting of different probabilities of occurrence from a repertoire of dynamic patterns. Moreover, we implemented a model-based approach by adjusting the PMS of each condition to a whole-brain model, which enabled us to explore in silico perturbations to transition from resting-state to meditation and vice versa. Consequently, we assessed the sensitivity of different brain areas regarding their perturbability and their mechanistic local-global effects. Overall, our work reveals distinct whole-brain dynamics in meditation compared to rest, and how transitions can be induced with localized artificial perturbations. It motivates future work regarding meditation as a practice in health and as a potential therapy for brain disorders.

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Different hierarchical reconfigurations in the brain by psilocybin and escitalopram for depression

Deco,

Sanz Perl,

Johnson

et al. 2024

Nat. Mental Health

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Effective interventions for neuropsychiatric disorders may work by rebalancing the brain’s functional hierarchical organization. Here we directly investigated the effects of two different serotonergic pharmacological interventions on functional brain hierarchy in major depressive disorder in a two-arm double-blind phase II randomized controlled trial comparing psilocybin therapy (22 patients) with escitalopram (20 patients). Patients with major depressive disorder received either 2 × 25 mg of oral psilocybin, three weeks apart, plus six weeks of daily placebo (‘psilocybin arm’) or 2 × 1 mg of oral psilocybin, three weeks apart, plus six weeks of daily escitalopram (10–20 mg; ‘escitalopram arm’). Resting-state functional magnetic resonance imaging scans were acquired at baseline and three weeks after the second psilocybin dose (NCT03429075). The brain mechanisms were captured by generative effective connectivity, estimated from whole-brain modeling of resting state for each session and patient. Hierarchy was determined for each of these sessions using measures of directedness and trophic levels on the effective connectivity, which captures cycle structure, stability and percolation. The results showed that the two pharmacological interventions created significantly different hierarchical reconfigurations of whole-brain dynamics with differential, opposite statistical effect responses. Furthermore, the use of machine learning revealed significant differential reorganization of brain hierarchy before and after the two treatments. Machine learning was also able to predict treatment response with an accuracy of 0.85 ± 0.04. Overall, the results demonstrate that psilocybin and escitalopram work in different ways for rebalancing brain dynamics in depression. This suggests the hypothesis that neuropsychiatric disorders could be closely linked to the breakdown in regions orchestrating brain dynamics from the top of the hierarchy.

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Brain dynamics predictive of response to psilocybin for treatment-resistant depression

Cited by 5 publications

References 74 publications

Psilocybin-enhanced fear extinction linked to bidirectional modulation of cortical ensembles

Psilocybin-enhanced fear extinction linked to bidirectional modulation of cortical ensembles

Inducing a meditative state by artificial perturbations: A mechanistic understanding of brain dynamics underlying meditation

Different hierarchical reconfigurations in the brain by psilocybin and escitalopram for depression

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