The dynamic response of intrinsic connectivity networks to low-dose psilocybin during face matching in autistic adults

Differences in brain activity involved in emotional-face processing have been reported in autism, but findings are inconsistent. Most studies have focused on characterising time-averaged activation and connectivity of face-processing circuits during emotional face-matching tasks, with little attention to the wider engagement of whole-brain intrinsic connectivity networks (ICNs) supporting fundamental cognitive processes. ICN dynamics (i.e. ICN temporal fluctuations underlying brain reconfigurations supporting cognitive processes) and regulation of this activity by major neurosignalling systems (e.g. the 5-HT system) have also been overlooked. Examining dynamic responsivity to 5-HT modulation, closely related to autistic core symptoms, can advance our understanding of the neurobiology of autistic cognition, potentially providing insights for future targeted interventions.

In this study, we characterised blood-oxygenation-level dependent (BOLD) responses in face-processing circuits, time-averaged whole-brain ICN features, and ICN dynamic features during an emotional face matching task. We also tested the hypothesis that activation of the serotonin system with psilocybin, a partial 5-HT_2A receptor agonist, would differentially affect face-processing circuits and ICNs in autistic and non-autistic adults.

Functional MRI (fMRI) data was acquired during an emotional face matching task in a pseudo-randomised double-blind cross-over study of 33 autistic (50% female) and 28 non-autistic (45.45% female) adults following placebo or 5mg “COMP360” psilocybin (a proprietary synthetic formulation of crystalline psilocybin of Compass Pathways) administered orally on 2 separate visits. We first characterised face-specific circuits as brain regions showing stronger BOLD signal to faces compared to shapes. Then, we identified 14 ICNs with group-level independent component analysis and performed dual regression to obtain subject-specific ICN spatial maps and activity timeseries. We used whole-brain permutation tests to examine group, drug, and their interaction effects on BOLD response and ICNs. Core network strength was calculated as mean contribution of within-network voxels to each ICN. We clustered ICN dynamic activity to 4 recurrent brain states with K-medoid and characterised fractional occupancy (FO), i.e. occurrence probability, of each state. We used linear mixed models to analyse group, drug, stimuli (face/ shape), and their interaction effects on FO.

There was no significant group×drug interaction effects on task performance and the BOLD response of face-processing circuits to emotional faces. However, assessing whole-brain ICNs across the whole task, autistic participants showed less engagement of multiple regions within the salience network (p_{family-wise-error} < 0.025). Also, across the whole task, we observed a significant drug´group interaction effect (p_{false-discovery-rate(FDR)} = 0.044) on core network strength of the salience network: reduced by psilocybin compared to placebo in non-autistic but not in autistic participants. Finally, there were significant drug×stimulus×group interaction effects on salience-attention-network (p_FDR = 0.043) and default-mode-executive-network (p_FDR = 0.043) states: psilocybin decreased the FO of the salience-attention-network state and increased the FO of the default-mode-executive-network state in autistic participants during shape blocks.

In conclusion, activity of face-processing circuits is similar in autistic and non-autistic people, but the salience network was less active in autistic participants. Our findings also suggest that psilocybin disengaged attention ICNs in autism during non-social stimuli, which may support the evaluation of the clinical utility of low dose psilocybin to redirect attention in autism.

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