Neural Mechanisms of Resting-State Networks and the Amygdala underlying the Cognitive and Emotional Effects of Psilocybin

Psilocybin is a serotonergic psychedelic whose primary action at 5-HT2A receptors produces marked alterations of perception, self-experience and emotion, including phenomena described as mystical experiences and ego dissolution. Previous research links such subjective experiences to improvements in depression and anxiety, and several imaging studies report altered amygdala responsivity under psychedelics—most commonly reduced amygdala responses to negative stimuli during the acute drug state, and variable amygdala changes in the post-acute period. Cortical regions, notably prefrontal areas, are known to modulate amygdala activity and are implicated in emotional regulation and disorders of mood and anxiety; however, how psychedelics alter directed (effective) connectivity between large-scale resting-state networks (RSNs) involved in cognition and the amygdala remains incompletely characterised. Stoliker and colleagues set out to examine acute psilocybin-induced changes in directed connectivity between the amygdala and three canonical RSNs: the default mode network (DMN), the salience network (SN) and the central executive network (CEN). Using resting-state fMRI collected during a randomised, double-blind, placebo-controlled crossover trial in healthy adults, the investigators applied spectral dynamic causal modelling (DCM) to estimate effective connectivity and tested whether network–amygdala modulation related to subjective alterations measured after dosing. The authors hypothesised that increased top-down inhibition of the amygdala would contribute to the subjective effects of psilocybin and be relevant to mechanisms underlying therapeutic change.

The study used data from a double-blind, randomised, placebo-controlled crossover trial (Group 2 of a registered study). Twenty-four healthy adults were recruited; the extracted text reports 12 males and 11 females, mean age 26.3 years and one participant who did not complete the study. Resting-state fMRI scans were acquired on two testing days separated by two weeks. On each testing day participants received either psilocybin (0.2 mg/kg orally) or placebo (mannitol and colloidal silicon dioxide). Resting-state data analysed here were collected 70 minutes after administration; scans lasted 10 minutes with participants instructed to close their eyes and avoid repetitive thoughts. MRI data were acquired on a Philips 3T scanner with a 32-channel head coil using a gradient-echo EPI sequence (repetition time 2,430 ms) and 265 volumes per resting-state scan. Preprocessing in SPM12 included slice-timing correction, realignment, spatial normalisation to MNI space and 6 mm FWHM smoothing. Global signal regression (GSR) was included in the pipeline; the authors note supplementary results without GSR. Head motion was inspected and three subjects were excluded for excessive movement, and one participant did not complete the 70-minute scan; the extracted text does not clearly report the final sample size used for the DCM analyses. Subjective effects were measured with the 5-Dimensions Altered States of Consciousness (5D-ASC) questionnaire completed 360 minutes after psilocybin administration. Analyses emphasised two subdimensions: emotional bliss and changed meaning of percepts (a cognitive shift in interpretation and significance of the environment). For neural modelling the investigators used spectral dynamic causal modelling (DCM) to infer directed (effective) connectivity among regions. Region-of-interest coordinates were taken from Neurosynth and networks comprised canonical nodes of the DMN, SN and CEN (the exact ROI list is referenced in a Table in the paper; the extracted text does not provide the full list). Time series for each ROI were summarised as the first principal component of voxels within a 6 mm radius sphere centred on the ROI. Three independent, fully connected spectral DCMs were specified—one for each RSN coupled with the amygdala—focusing on connections between each network and the amygdala rather than inter-network links. Models were inverted per subject and condition; the DCMs achieved high explained variance (mean 90.9% for placebo, 89.8% for psilocybin). Group-level inference used parametric empirical Bayes (PEB) with Bayesian model reduction (BMR). Effective connectivity is reported in Hertz (Hz) and self-connections are log-scaled; the authors applied a posterior probability threshold of >0.99 to identify meaningful associations between connectivity estimates and behavioural scores.

Across the three RSN–amygdala DCMs the principal pattern reported was reduced top-down effective connectivity from cortical RSN regions to the amygdala under psilocybin, accompanied by network-specific within-RSN changes. Specifically, effective connectivity within the DMN and SN decreased under psilocybin, while the CEN showed increased effective connectivity. The DMN model revealed bidirectional inhibitory changes between the posterior cingulate cortex (PCC) and the left amygdala, together with reduced PCC self-inhibition (interpreted as increased synaptic gain). The decrease in bottom-up influence from the left amygdala to PCC was larger than the top-down decrease. Behavioural associations at the authors' threshold indicated the PCC self-connection was associated with reported blissful state, the PCC→left amygdala connection associated with both blissful state and changed meaning of percepts, and the left amygdala→PCC connection associated with changed meaning of percepts. Within the CEN, the investigators observed inhibition from the left dorsolateral prefrontal cortex (DLPFC) and left lateral posterior parietal cortex (PPC) to the amygdala, set against an overall increase in CEN effective connectivity. The authors describe these CEN changes as potentially related to evaluative aspects of thought and note that the pattern is context-dependent; subjects reported nominal anxiety during the study but introspective cognitive set during scanning was not assessed. In the SN model, anterior cingulate cortex (ACC) and anterior insula (AI) regions showed inhibition of the right amygdala. DCM also estimated increased self-inhibition (reduced synaptic gain) in the bilateral amygdala and right AI. The AI→amygdala inhibition was associated with changed meaning of percepts. Several connectivity changes, including the increased self-inhibition of the amygdala and right insula, were not associated with the measured subjective effects. The authors report evidence of hierarchical modulation characterised by decreased cortical-to-amygdala effective connectivity across networks, with complexity in the DMN due to the stronger amygdala→PCC inhibition noted above. Model performance was high (explained variance ~90%); the extracted text reports the use of the 5D-ASC subscales to probe behavioural associations, and statistical conclusions were based on a stringent posterior probability criterion (>0.99). The extracted text does not present full numerical effect sizes, confidence intervals or exact subject counts for the final analysed sample within these results paragraphs.

Stoliker and colleagues interpret their findings as evidence that acute psilocybin produces network-level changes in directed connectivity that coincide with temporary attenuation of amygdala recruitment. Reduced effective connectivity from RSNs to the amygdala, together with within-network modulation, is proposed to underlie aspects of altered cognition and emotion experienced under psilocybin, including shifts in self-referential processing and the altered meaning of percepts. The DMN results are emphasised for their relevance to self-related processing: decreased PCC self-inhibition and altered PCC–amygdala bidirectional inhibition are linked to blissful subjective states and changes in perceptual meaning, consistent with prior reports that PCC dynamics under psychedelics relate to diminished self-boundaries and altered self-awareness. For the CEN, increased intrinsic connectivity alongside inhibitory influences on the amygdala is discussed in relation to evaluative thought, cognitive control and potential contributions to therapeutic revision of beliefs; the authors note that CEN effects are likely task- and context-dependent. SN findings—ACC and AI inhibition of the right amygdala and increased amygdala/AI self-inhibition—are interpreted as reduced salience detection, which might facilitate emotional decentring and reappraisal but could resemble mechanisms implicated in psychotic-like experiences at higher psychedelic doses. The authors situate their results within earlier psychedelic imaging work showing modulation of amygdala–cortical circuits and link the observed connectivity changes to broader claims about increased neural plasticity and network flexibility under psychedelics. They propose that dampened bottom-up amygdala influence combined with altered hierarchical interactions may help bypass conditioned emotional responses and thereby support adaptive reappraisal in therapeutic settings. Acknowledged limitations include the acute and healthy-sample nature of the data (the study examined immediate effects in healthy volunteers rather than clinical outcomes), the lack of an in-scan assessment of participants' introspective set during resting-state acquisition, exclusions for head motion and incomplete scanning (the extracted text does not clearly state the final analysed sample size), and the tentative functional interpretation of effective connectivity changes. The authors also note methodological choices such as global signal regression and modelling assumptions inherent to DCM; supplementary materials report additional analyses (for example, results without GSR). They conclude that while the findings are consistent with psilocybin-induced modulation of emotional and cognitive circuitry and with subjective reports of altered meaning and positive emotion, the functional and clinical significance requires further research, including studies linking these acute mechanistic changes to longer-term therapeutic outcomes.