Brain dynamics predictive of response to psilocybin for treatment-resistant depression
Jakub Vohryzek, Joana Cabral, Louis-David Lord, Henrique M. Fernandes, Leor Roseman, David Nutt et al. · 2024 · 33 citationsRead the paper
Abstract Psilocybin therapy for depression has started to show promise, yet the underlying causal mechanisms are not currently known. Here, we leveraged the differential outcome in responders and non-responders to psilocybin (10 and 25 mg, 7 days apart) therapy for depression—to gain new insights into regions and networks implicated in the restoration of healthy brain dynamics. We used large-scale brain modelling to fit the spatiotemporal brain dynamics at rest in both responders and non-responders before treatment. Dynamic sensitivity analysis of systematic perturbation of these models enabled us to identify specific brain regions implicated in a transition from a depressive brain state to a healthy one. Binarizing the sample into treatment responders (>50% reduction in depressive symptoms) versus non-responders enabled us to identify a subset of regions implicated in this change. Interestingly, these regions correlate with in vivo density maps of serotonin receptors 5-hydroxytryptamine 2a and 5-hydroxytryptamine 1a, which psilocin, the active metabolite of psilocybin, has an appreciable affinity for, and where it acts as a full-to-partial agonist. Serotonergic transmission has long been associated with depression, and our findings provide causal mechanistic evidence for the role of brain regions in the recovery from depression via psilocybin.
What the full text shows
Working prototype- The occurrence of a specific brain substate (substate 3) differed significantly between pre- and post-treatment in responders. — P = 0.0258 (Responders to psilocybin therapy)
- The ability to force a transition toward healthy spatio-temporal dynamics in silico correlates with the density of specific serotonin receptors. — Spearman’s ρ = 0.227 (P = 0.032) for 5-HT 2a; Spearman’s ρ = 0.284 (P = 0.007) for 5-HT 1a (Comparison of responder vs non-responder models at stimulation intensity a = 0.07)
- Functional Connectivity Dynamics (FCD) showed significant differences in temporal similarities of spatial patterns between pre- and post-treatment responders. — P = 0.0163 (Responders to psilocybin therapy)
- Large-scale brain models successfully fit pre-treatment spatio-temporal dynamics for both groups. — KL divergence = 0.0064 (responders), 0.0187 (non-responders) (Using global coupling parameters G = 0.185 and G = 0.165 respectively)
- Setup
- 15 patients with treatment-resistant depression (6 responders, 9 non-responders) receiving two doses of psilocybin (10mg and 25mg); structural connectivity template derived from 16 healthy young adults.
- How
- The researchers used LEiDA to extract probabilistic metastable substates (PMS) from fMRI data and constructed large-scale brain models using Stuart-Landau oscillators coupled via structural connectivity. They performed dynamic sensitivity analysis (in silico perturbations) to identify regions that enable the transition from a depressive to a healthy brain state.
- Limitations
- Small sample size (15 patients) · Reliance on a group-based structural connectivity template rather than individual connectomes · Use of a simplified Stuart-Landau oscillator model to represent complex regional dynamics
Summarized by Gemma 4 from the open-access full text · 8 Oct 2026. Read it