Changes in music-evoked emotion and ventral striatal functional connectivity after psilocybin therapy for depression

Music listening engages mesolimbic and limbic circuits involved in reward and emotion, with the ventral striatum (VS) and nucleus accumbens (NAc) particularly implicated in musical reward and music-induced physiological responses. Earlier work has linked reduced music-evoked pleasure and altered VS functional connectivity (FC) to trait anhedonia, a core feature of depression. Psychedelic therapy with serotonergic compounds such as psilocybin is often delivered in a setting that uses playlists to promote inward-focused emotional processing; previous studies report that psychedelics can acutely amplify music-evoked emotionality, and that the default mode network (DMN) — a set of cortical regions involved in internally generated thought — is altered during the psychedelic state and after psilocybin treatment for depression. Shukuroglou and colleagues set out to test whether psilocybin therapy for treatment-resistant depression would change subjective music-evoked emotion and NAc (ventral striatal) functional connectivity during music listening. The study examined patients before and after a two-dose psilocybin regimen, combining visual analogue and validated music-emotion scales with fMRI to probe whether changes in music-evoked pleasure related to changes in anhedonia and to alterations in NAc connectivity with regions resembling the DMN.

This work formed part of an open-label feasibility trial approved by relevant institutional and regulatory bodies; all participants provided written informed consent. Nineteen patients with treatment-resistant unipolar depression (13 males, 6 females; mean age 43.1 ± 10.5, range 27–64) met inclusion criteria based on a Hamilton Depression Rating Scale score ≥ 17 and failure to respond to at least two antidepressant trials in the current episode. Key exclusions included current or past psychotic disorders, family history of psychosis, hospitalised suicide attempts, history of mania, pregnancy, needle phobia and current substance or alcohol use disorder. Participants tapered off psychiatric medication under supervision with a minimum 2-week washout prior to study entry. Treatment comprised two supervised psilocybin dosing days separated by 1 week: an initial low oral dose of 10 mg followed one week later by a 25 mg dose. Sessions were conducted in a low-light, reclined setting with eyeshades and a predefined music playlist; patients were encouraged to focus inward. Neuroimaging occurred twice: 1 week before the first dose and 1 day after the second dose. On each scan day two 8-minute functional runs were acquired in eyes-closed conditions: one without music and a second with music. The order of music versus no-music scans was not randomised. Immediately after each run participants rated ‘‘How pleasurable was the previous scan?’’ on a 0–10 visual analogue scale and completed the 21-item Geneva Emotional Music Scale (GEMS-21) to capture multiple music-evoked emotion factors. Hedonic capacity (anhedonia) was measured with the Snaith–Hamilton Pleasure Scale (SHAPS) at each visit. Stimuli were two balanced playlists composed by Carlos Cipa; playlist order was counterbalanced across participants. fMRI data were acquired on a 3T Siemens TrioTim scanner with standard anatomical and T2*-weighted sequences (TR = 2000 ms, TE = 31 ms). Fifteen subjects were included in the fMRI analyses after excluding one participant with a parietal injury and three for excessive head motion (criterion: >20% scrubbed volumes using a framewise displacement [FD] threshold of 0.5). Pre-processing combined FSL, AFNI, Freesurfer and ANTS tools and included despiking, slice-timing, motion correction, brain extraction, registration to MNI space, scrubbing, spatial smoothing (6 mm FWHM), band-pass filtering (0.01–0.08 Hz), detrending and regression of nine nuisance regressors (six motion, three anatomical). Two parallel datasets were prepared: one in MNI space for voxel-wise group analyses and one in native space to extract the NAc time-series. Seed-based FC analyses used individually parcellated NAc seeds derived from Freesurfer in native space. Whole-brain voxel-wise connectivity maps were generated with FSL FEAT (GLM) and mixed-effects group comparisons were run with FLAME 1 + 2. Z maps were thresholded at clusters determined by z > 2.3 and whole-brain p < 0.05. Statistical analyses of behavioural and ROI data were performed in SPSS and GraphPad Prism. A two-way repeated measures ANOVA tested effects of music (music vs no music), treatment (pre vs post) and their interaction on mean Z-statistics extracted from the significant FC cluster. Paired t-tests examined in-scanner pleasure ratings and GEMS factors, with false discovery rate (FDR) correction for multiple comparisons. Pearson correlations explored relationships between changes in pleasure, NAc–DMN FC and SHAPS scores across time points; standard outlier removal (ROUT, Q = 1%) was applied.

Behavioural sample and imaging exclusions: Nineteen participants completed behavioural measures; fMRI analyses were performed on 15 participants after four exclusions (one lesion, three for motion). Motion did not differ significantly between pre- and post-treatment scans (mean FD before 0.180 ± 0.089, after 0.158 ± 0.084, p = 0.23). The mean percentage of scrubbed volumes was low (before 4.6 ± 5.0%, after 3.5 ± 5.2%). Music-evoked pleasure and emotion: A two-way repeated measures ANOVA on in-scanner pleasure ratings showed a significant main effect of music (F = 5.74, df = 18, p = 0.0277) but no main effect of treatment (F = 3.857, df = 18, p = 0.0652) and no interaction (F = 1.846, df = 18, p = 0.191). Follow-up paired t-tests indicated that pleasure ratings during the music scans increased significantly after psilocybin treatment (post-treatment mean 9.00 ± 5.25) relative to pre-treatment (5.84 ± 3.95; t = 2.963, df = 18, p = 0.0083). Additional contrasts showed increased pleasure for music versus no-music scans post-treatment (music 9.00 ± 5.25 vs no music 5.84 ± 5.06; t = 2.565, df = 18, p = 0.0195) and increased pleasure for music post-treatment versus no music pre-treatment (9.00 ± 5.25 vs 4.47 ± 4.36; t = 2.973, df = 18, p = 0.0081). GEMS-21 factor analyses revealed a significant decrease in music-evoked 'Sadness' after treatment (before 2.34 ± 1.13, after 1.47 ± 0.68; t = 2.626, df = 34, p = 0.0123) and a significant increase in 'Peacefulness' (before 1.88 ± 0.80, after 2.54 ± 1.09; t = 2.226, df = 34, p = 0.0328). These tests were FDR-corrected for multiple comparisons with a significance threshold of p = 0.05 after correction. NAc functional connectivity: Seed-based mixed-effects analyses identified decreased FC between the bilateral NAc seed and regions resembling the DMN post-treatment compared to pre-treatment during music listening versus no music. A two-way repeated measures ANOVA on mean Z-statistics within the significant FC mask revealed a significant treatment-by-music interaction (F(1,14) = 115.7, p < 0.0001). Follow-up paired t-tests showed significantly greater NAc–DMN coupling between music and no-music scans before treatment (p < 0.0001, n = 15), whereas after treatment there was significantly less NAc–DMN coupling in both the no-music and music scans (each p < 0.0001, n = 15). Comparisons of after versus before treatment also showed significant differences in both scan types (p < 0.0001). Correlations and anhedonia: Changes in in-scanner pleasure ((music – no music) change pre-to-post) did not correlate with concurrent changes in NAc–DMN FC ((music – no music) change pre-to-post) (r = -0.0135, n = 15, p = 0.9619). SHAPS anhedonia scores decreased significantly across time points (one-way ANOVA F(3,72) = 4.096, p < 0.0001). Paired tests showed reductions from baseline to 1 day (p = 0.0002), 1 week (p < 0.0001) and 3 months (p = 0.0026) post-treatment; all survived Bonferroni correction (adjusted p threshold 0.016). Importantly, increases in music-induced pleasure after treatment correlated negatively with reductions in anhedonia at 1 week (r = -0.52, p = 0.0438), indicating greater post-treatment music pleasure associated with larger decreases in SHAPS scores at that time point. No significant correlations were found between changes in anhedonia and changes in NAc–DMN FC. Reliability: Test–retest reliability for in-scanner pleasure ratings showed fair reliability for the music condition (r = 0.5201, n = 19, p = 0.0112) but not for the no-music condition. NAc–DMN coupling demonstrated good test–retest reliability in the music condition (r = 0.7007, n = 15, p = 0.0018) but not in the no-music condition.

Shukuroglou and colleagues interpret their findings as evidence that psilocybin therapy for treatment-resistant depression increased subjective music-evoked pleasure and altered music-evoked emotional profiles, specifically decreasing reported sadness and increasing peacefulness. The sustained reductions in anhedonia up to 3 months after treatment, and the observed negative correlation at 1 week between increased music pleasure and decreased SHAPS scores, are taken to support a link between improved hedonic responsiveness and reduced anhedonia following psilocybin therapy. On the neural side, the investigators observed a post-treatment reduction in NAc functional connectivity with regions resembling the DMN during music listening. They discuss this pattern cautiously, proposing a tentative model in which a decrease in top-down DMN influence on limbic structures such as the NAc after psilocybin might enable greater music-evoked emotionality. The authors note that this idea aligns with other findings from the broader study showing altered prefrontal–amygdala coupling, and with literature suggesting DMN hyperactivity in depression. However, they emphasise that the present correlational analyses did not support a direct relationship between NAc–DMN FC changes and either music pleasure or anhedonia, making causal inferences premature. Several limitations are acknowledged that constrain interpretation: the small sample size, absence of healthy control comparison, open-label design without placebo, imaging only 1 day after treatment preventing assessment of longitudinal brain changes, lack of control auditory stimuli (e.g. scrambled music), non-randomised order of no-music versus music scans, and the melancholic rather than overtly pleasurable character of the chosen music. The authors recommend future work to include varied music types, preferred-genre stimuli, dynamic time-resolved analyses of musical passages associated with strong emotion, and causal modelling approaches (for example dynamic causal modelling) to test directional hypotheses about DMN–NAc influences.

In summary, the study found increased music-evoked pleasure and changes in specific music-evoked emotions (less sadness, more peacefulness) after psilocybin therapy for treatment-resistant depression, along with sustained reductions in anhedonia up to 3 months. fMRI analyses showed reduced NAc functional connectivity with regions resembling the DMN during music listening post-treatment. The authors tentatively propose that these neural changes could reflect a release of inhibitory DMN influence over NAc-mediated hedonic processing, but note that their correlational results do not confirm this mechanism and further research is required to clarify how recovery of hedonic responsiveness is instantiated in the brain following psilocybin therapy.