In adults with MDD, psilocybin therapy produced larger reductions in anhedonia than escitalopram and preserved subjective affective responses to musical surprises while decreasing ventromedial prefrontal and angular gyrus activation and increasing sensory-region responses. By contrast, escitalopram reduced surprise-related affective responses and increased activation in memory and emotional processing areas, implying divergent mechanisms — psilocybin may lower prediction-error salience or strengthen hedonic priors, whereas escitalopram may diminish them.
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Carhart-Harris, R. L., Giribaldi, B., Watts, R. et al. · New England Journal of Medicine (2021)
Psilocybin therapy (PT) is emerging as an effective intervention for Major Depressive Disorder (MDD), offering comparable efficacy to conventional treatments like selective serotonin reuptake inhibitors (SSRIs). Music, an emotionally evocative stimulus, provides a valuable tool to explore changes in hedonic and predictive processing mechanisms via expectancy violations, or ‘surprises’. This study sought to compare behavioural and functional magnetic resonance imaging (fMRI) responses to musical surprises in MDD patients treated with either PT or the SSRI, escitalopram. In this secondary analysis of a trial, 41 MDD patients (with usable fMRI data) were randomly assigned to either PT (n = 22) or escitalopram (n = 19) treatment groups. Participants listened to music during fMRI and tracked their emotional experience, both before and after a 6-week intervention. Surprise-related valence and arousal indices were calculated. Musical surprises were entered as regressors for whole-brain and region of interest fMRI analyses. PT caused a greater decrease in anhedonia scores compared with escitalopram. While escitalopram led to reductions in surprise-related affective responses, PT showed no significant change. Escitalopram was associated with increased activation in memory and emotional processing areas during musical surprises (versus control events) when compared with PT. Following PT, there was decreased activation in the ventromedial prefrontal cortex and angular gyrus, and greater activation in sensory regions. PT may allow for the subjective response to musical surprises to be maintained through a lasting reduction in the salience of prediction errors, or, alternatively, by increasing hedonic priors. Contrastingly, escitalopram may diminish hedonic priors, highlighting fundamental differences in treatment mechanisms.
Major Depressive Disorder (MDD) is marked by disrupted emotional and hedonic processing, with anhedonia — a reduced capacity to experience pleasure — as a core symptom tied to dysfunction in mesocorticolimbic reward circuitry. Harding and colleagues frame this dysfunction around nodes such as the nucleus accumbens (NAc) and the ventromedial prefrontal cortex (vmPFC), and situate their hypotheses within a Bayesian predictive coding account (the REBUS model) in which psychedelics are proposed to reduce the precision or weighting of top-down priors encoded by deep cortical pyramidal cells. In contrast, selective serotonin reuptake inhibitors (SSRIs) such as escitalopram are widely used but are often associated with limited effects on anhedonia and with reports of emotional blunting. Music is introduced as a naturalistic, hedonic stimulus that evokes reward-related responses and expectancy violations (‘musical surprises’), providing a probe to examine changes in both subjective pleasure and neural responses linked to prediction error and reward. This study aimed to compare the effects of psilocybin therapy (PT) versus escitalopram on behavioural and fMRI responses to musical surprises in patients with MDD. The investigators predicted that PT would produce greater improvement in anhedonia than escitalopram, and that the two treatments would differentially modulate surprise-related pleasantness and neural activation, notably anticipating increased NAc activation to surprising events after PT and distinct surprise-related effects in the vmPFC and superior temporal gyrus (STG). The design used musical surprises together with music-evoked emotion scales to provide a combined behavioural and neurobiological assessment of treatment effects on hedonic and predictive-processing mechanisms.
This report presents a specific fMRI analysis derived from a Phase II, double-blind, randomised, controlled trial in which participants with MDD were allocated to either PT or escitalopram. Of 59 patients enrolled in the parent trial, 50 were included in this analysis; after exclusions for excessive movement or protocol deviation, 22 participants in the PT arm and 19 in the escitalopram arm remained for the present analyses. MRI scanning was performed before any therapeutic intervention (one day prior to first dosing) and again six weeks plus one day after the first dosing day (three weeks after the second psilocybin dose). Scanning-day procedures were identical at both time points and were followed by a continuous music rating task and self-report measures. During fMRI, participants listened with eyes closed to a single piano arrangement (“The Hours” by Philip Glass; 423 s) interleaved with rest blocks (total task 510 s). Data were acquired on a Siemens TIM Trio 3T scanner with high-resolution anatomical MPRAGE and multiband EPI functional sequences (TR = 1250 ms, TE = 30 ms, 3 mm isotropic voxels, 408 volumes). After scanning, participants completed continuous valence and arousal ratings (down-sampled to 1 Hz) and the Geneva Emotional Music Scale (GEMS-25). Anhedonia was assessed using the Snaith–Hamilton Pleasure Scale (SHAPS). Surprising and unsurprising events in the musical stimulus were annotated and ranked by professional musicians in a separate study. For first-level fMRI modelling, the investigators used a general linear model (GLM) with three regressors: surprising events (n = 17), unsurprising events (n = 17), and the remaining music, convolved with a canonical haemodynamic response. Pre-whitening and autocorrelation correction were applied, and contrasts comparing surprising versus unsurprising events were obtained. Mid-level fixed-effects analyses generated within-subject pre-to-post contrasts, and group-level mixed-effects analyses (FLAME 1 + 2) tested a 2 (pre vs post) by 2 (treatment) interaction via unpaired t-tests comparing PT versus escitalopram. Group maps were cluster-corrected (Z = 2.3, p < 0.05). Region-of-interest (ROI) analyses targeted three a priori sites: right NAc (6 mm sphere, MNI 11,9,-1), vmPFC (10 mm sphere, MNI -2,46,-8), and right STG (task-constrained mask). Continuous ratings were processed to derive event-related affective change indices: the first derivative of valence and arousal time series produced valence-increase, valence-decrease, arousal-increase and arousal-decrease traces; mean changes during 1–4 s post-event were extracted and standardised within subjects. Behavioural validation compared surprising with unsurprising events using paired t-tests with alpha adjusted to 0.01 for multiple comparisons. Correlations between surprise-related BOLD in ROIs and subjective measures were also tested.
The final analytic sample comprised 41 participants: 22 in the PT group and 19 in the escitalopram group. On the SHAPS measure of anhedonia both groups improved from pre- to post-treatment, but PT produced a larger mean reduction (PT mean change = -5.273, SEM = 0.7845; escitalopram mean change = -3.211, SEM = 0.5952). A mixed-effects model showed a significant treatment-by-time interaction on SHAPS scores (F(1,39) = 4.170, p = 0.0480). Post hoc paired tests indicated significant pre-to-post decreases in anhedonia within both escitalopram (t(18) = 5.394, p < 0.0001) and PT (t(21) = 6.721, p < 0.0001), consistent with overall efficacy but with a greater effect size for PT. Analysis of music-evoked emotion (GEMS) revealed a treatment-by-time interaction for the vitality factor (F(1,39) = 7.967, p = 0.0075). Escitalopram showed a significant decrease in vitality from pre- to post-treatment (mean = -0.5702, SEM = 0.2292; t(18) = 2.488, p = 0.0229), while PT demonstrated a non-significant numerical increase (mean = 0.333, SEM = 0.222; t(21) = 1.50, p = 0.1482), implying the between-group difference was driven by a decline under escitalopram. No significant treatment or time effects emerged for sublimity or unease. Behavioural validation of the surprise paradigm showed that, at pre-treatment, surprising events produced a transient increase in valence relative to unsurprising events in both groups (escitalopram: t(18) = 3.011, p = 0.0075; PT: t(21) = 4.134, p = 0.0005). Post-treatment, the PT group retained a significant surprise-related valence increase (t(21) = 3.818, p = 0.0010). By contrast, the escitalopram group’s pattern changed after treatment: valence rose for unsurprising events and decreased for surprising ones such that the pre-existing difference between event types was no longer significant (p = 0.2202). No significant surprise-related valence decreases were observed at either time point in either group. Results for arousal were reported in supplementary materials. ROI fMRI analyses identified a significant treatment-by-time interaction in the vmPFC for the surprise>unsurprise contrast (F(1,39) = 7.074, p = 0.0113). Within-group tests showed a significant decrease in surprise-related vmPFC activation post-PT (t(21) = 2.195, p = 0.0395), whereas escitalopram produced a non-significant numerical increase (t(18) = -1.767, p = 0.0941). Baseline (pre-treatment) vmPFC activation did not significantly differ between groups (t(39) = 1.791, p = 0.0810). No significant interaction, main effect of treatment, or time effect was observed in the right NAc (p = 0.7655 for interaction), and STG surprise-related activation was likewise non-significant (p = 0.3575). Surprise-related BOLD in these ROIs did not correlate significantly with SHAPS or music-evoked ratings. Whole-brain group comparisons of pre-to-post changes (escitalopram > PT) showed greater increases under escitalopram (relative to PT) in regions including the right angular gyrus, right posterior supramarginal gyrus, frontal pole, middle frontal gyrus, frontal medial cortex and paracingulate gyrus. There were no significant regions where PT exceeded escitalopram in the between-group contrast. Within-group paired tests revealed no significant within-group effect in escitalopram, but in the PT group widespread post-treatment increases in BOLD to surprising versus unsurprising events were observed in bilateral lateral occipital cortex, occipital fusiform gyrus, occipital pole, right postcentral and precentral gyri, central opercular cortex, and bilateral clusters in the superior temporal gyrus. PT also produced post-treatment reductions in activity in the left lateral occipital cortex extending into the angular gyrus. All group-level maps were cluster-corrected at Z = 2.3, p < 0.05.
Harding and colleagues interpret their findings as evidence of dissociable mechanisms between escitalopram and PT in how musical surprises are processed behaviourally and neurally in MDD. Behaviourally, both treatments reduced anhedonia but PT had a larger effect. Escitalopram reduced music-evoked vitality and attenuated the distinction in valence responses between surprising and unsurprising events post-treatment, consistent with a blunting or redistribution of affective responses. By contrast, PT preserved surprise-related positive valence and produced a modest, non-significant increase in vitality. Neurobiologically, the study found reduced surprise-related vmPFC activation after PT relative to escitalopram, alongside post-PT increases in sensory and occipital regions and decreases in angular gyrus activity. The investigators link decreased vmPFC responses to a possible enduring reduction in the precision weighting of top-down predictions, a mechanism hypothesised in the REBUS account whereby 5-HT2A agonism acutely relaxes priors and could lead to lasting changes in predictive processing. Alternatively, the authors note that PT might increase hedonic priors or positive expectations, which could also explain sustained positive valence to surprises. The increase in sensory-region activation is discussed as a possible shift from internally focused processing to a more externally driven, sensory-dominant mode that might accompany recovery from depression. The absence of any NAc surprise-related effect was unexpected given the literature linking the NAc to musical pleasure; the authors suggest several possible reasons, including diminished NAc responsiveness in depression and individual differences in musical taste and reward. They further highlight that surprise annotation was performed by professional musicians rather than subjectively by participants and that the single-song design, small sample size, repeated exposure to the same piece, lack of physiological arousal measures, and a predominance of positive-valence surprises constrain generalisability. The study team recommends future work using a wider variety of stimuli (including those inducing negative valence), objective arousal measures, stratification by baseline music-evoked pleasantness, and directed connectivity analyses to test hypotheses about increased bottom-up information flow after PT. Overall, the authors conclude that their data provide convergent behavioural and neural evidence for distinct treatment effects of PT versus escitalopram on hedonic and predictive-processing aspects of music-evoked experience in MDD, while acknowledging the exploratory nature and limitations of the findings.
This was a specific fMRI analysis carried out on data from a phase II, double-blind, randomised, controlled trial involving the allocation of participants with MDD to either PT or escitalopram treatment groups; the main study report has been previously published. A total of 59 patients were enrolled but 50 were included in this present analysis, with nine lost due to an incomplete dataset owing to COVID-19 lockdowns. 26 participants were randomised to the PT condition and 24 to the escitalopram condition. Of these participants, five were removed as a result of excessive movement in the fMRI scanner or deviation from the protocol. Overall, a total of 19 patients in the escitalopram group and 22 in the PT group were available for analysis. Further details of participant criteria and trial procedures can be found in Carhart Harris et al.. MRI scanning was performed before any therapeutic intervention (pretreatment, i.e., one-day prior to the first dosing session) and six weeks and one day after the first dosing day (three weeks after the second psilocybin dosing session). Protocols on scanning days were identical, with completion of the fMRI scan, followed by the continuous music rating task and the self-reported subjective measures of music-evoked emotion and anhedonia (see below).
This study sought to evaluate the treatment differences between escitalopram and PT on the affective and neural correlates of musical surprises in patients with MDD. Notably, both treatments were shown to be significantly effective at treating symptoms of anhedonia, with PT demonstrating more robust efficacy. Escitalopram reduced music-evoked feelings of vitality, while PT enhanced them. Surprise-related subjective hedonic response was decreased in the escitalopram condition, whereas there was no change with PT, implying either a blunting effect of escitalopram on hedonic responsiveness or a (relative) enhancement with PT. Meanwhile, regarding brain responses, significantly less surprise-related vmPFC activation was seen with PT versus escitalopram, as seen using a between-condition interaction test. Finally, in a within-condition analysis, increases in activations to surprising musical events in regions associated with visual and sensory processing and decreases in angular gyrus activity were seen post-PT. Contrary to our a priori hypothesis, there was no significant change in surprise-related activation of the NAc in either treatment group. This was unexpected given that the music literature ascribes an intrinsic role to the NAc in surprise-related pleasantness and prediction error coding. One possible explanation may be that there is reduced NAc activation to musical stimuli in depression. Additionally, this lack of effect may be owing to the idiosyncratic nature of musicevoked reward, whereby music taste is influenced by factors including personality traits, intelligence, and musical training. Future studies may attempt to acknowledge the intrinsic variation in music-evoked reward by stratifying treatment groups at baseline by high and low pleasantness ratings. In this study, the PT group showed a significant decrease in the surprise-related activation of the vmPFC relative to the escitalopram condition. Also, in the PT condition only, increased posttreatment activations were seen in sensory regions. From a predictive coding standpoint, the precision weighting or salience of prediction errors, or surprises, is thought to occur in the higher cortical regions such as the vmPFC, where the higher cortex is mandated to process bottom-up information flow. Consequently, a reduction in activation in high level cortex, as seen here in the vmPFC, may reflect a lack of confidence (precision weighting) regarding the incoming prediction error signal. Alterations in salience processing may occur as a lasting consequence of the rapid and dramatic reduction in the precision weighting of top-down predictions hypothesised to occur in the acute psychedelic state. Indeed, 5-HT2A receptors are heavily expressed on deep pyramidal cells in the vmPFCwhere 5-HT 2A R agonism would dysregulate ensemble activity thereand in parallel, decrease precision weighting of top-down predictive processes. It is possible that the post-acute decrease in vmPFC responses to musical surprise observed in the PT condition of this study reflect a lasting decrease in the precision weighting of top-down priors. We acknowledge that this interpretation is speculative, however. Additionally, it has been suggested that increased vmPFC activity in MDD may portray a pathological increase in the executive control of emotion. This may indicate a reduction in the overly enhanced control over affective responses, which may serve as a potential therapeutic mechanism of wherein reduction in top-down control allows for an increase in the bandwidth of emotions experienced. This interpretation is supported by a recent finding from a previous study in treatmentresistant depression that following PT, there is a reduction of music-induced coupling of the NAc to areas in the default mode network (DMN), including the vmPFC. The authors suggested this may enable a recovery of a normal hedonic response, consistent with other findings of increased brain responses to emotional stimuli post-PT. Another interpretation is that a decrease in the responsiveness of the vmPFC to surprise, along with the increase in sensory processing, may reflect a switch from excessively internal processingto a more external, sensory driven mode of processing that may be characteristic of recovery from depression. It is important to note that while there is a significant overlap, there is a distinct difference between perceptual processing, in which future musical events are predicted, and reward processing, which predicts the rewards for future events. Sensory processing is linked to musical aesthetics, whereas reward processing relies on reinforcement learning to maximise reward value that is irrespective of structural specifics. Alterations in the STG functioning was explored due to its role in monitoring auditory possibilitiesand these results demonstrate no treatment difference in the surprise-related activation of the STG and incidental sensory processing of musical surprises. However, reward is a complex psychophysiological construct and the exact interaction between sensory and reward processing of music remains to be adequately studied. Aside from the a priori ROIs which were selected based on their involvement in the processing of musical surprises, results from exploratory whole-brain analyses showed that PT caused an increase in the surprise-related activation of areas that serve visual functions, e.g. the bilateral occipital cortex, and sensory integration functions e.g. the central opercular cortex. Interestingly, symptoms of depression and anhedonia are associated with a decreased ability to discriminate between different sensory stimuli. This increased sensory activation may therefore reveal a potential target of PT with regards to hedonic processing. Furthermore, the post-PT reduction in activation of the angular gyrus is intriguing, particularly owing to its role in the default mode network and as a cross-modal hub where converging multisensory information is combined and integrated. This decrease in activity could suggest a reduction in the cognitive integration of sensory information, allowing for a stronger focus on raw sensory processing during musical surprises. In line with this, our between-group analyses revealed that, compared to escitalopram, the PT condition was associated with decreased activation in areas including the posterior supramarginal gyrus, frontal pole, paracingulate gyrus, and again the angular gyrus. These areas play a role in mediating attention, memory during music listening, and personal familiarity with music. Given that attention is considered to be the cognitive homologue of adding precision weighting or salience to prediction errors, this aligns with our current findings that PT causes a shift in the salience of prediction errors, e.g., deweighting salience processed via the vmPFC and other high level cortical regions. While it is intriguing to consider the role of predictive processing, our behavioural findings related to changes in valence towards surprising events may suggest an alternative hypothesis: PT might enhance the reward response to hedonic stimuli. Instead of reducing priors, PT could increase hedonic priors and positive expectations for surprising events, explaining the sustained positive valence observed. Although clinical research on this is limited, animal have shown that psilocybin can increase optimism bias, with enhanced belief updating after positive outcomes, such as greater reward responses following wins. Consistent with this alternative hypothesis, our data suggest that escitalopram may heighten valence responses to previously neutral stimuli (i.e. unsurprising events), and potentially diminish reward responses to surprising events in the absence of a hedonic prior. This aligns with previous research that escitalopram reduces learning from reward and enhances learning from punishment. However, this interpretation remains speculative and warrants further investigation. To our knowledge, this is the first study to explore the processing of musical surprises in MDD specifically and may offer key insight into alterations in reward processing that can occur post-treatment. Compared with previous studies that have used no music as a control, one of the strengths of this study is that it used other parts of the music as a naturalistic comparator. However, this study had a relatively small sample size and participants listened to only one song inside the scanner, thus the replicability of these findings may be limited. This study would have additionally benefited from objective physiological readings for arousal to further validate these self-reported behavioural measures. Validation via other hedonic stimuli than just music would also have added confidence, if they replicated the main findings presented here with musical surprise. Moreover, participants were required to listen to the same musical piece on multiple occasions throughout the study, thus potentially impacting the response to musical surprises via a familiarity effect. Furthermore, surprising events were annotated separately by professional musicians and subjective level of surprise was not reported by the study group themselves. Additionally, as anticipated, the musical piece used in this study predominantly elicited positive valence in response to surprising elements, which was selected due to its relevance in reward processing in depression. However, musical surprises are more broadly linked to changes in subjective experienceand can also evoke negative valence. To better understand how these interventions influence predictive coding mechanisms, future research should incorporate a broader range of stimuli that includes those capable of inducing negative valence. This approach is especially pertinent given evidence suggesting that PT has lasting effects on affective and neural responses to negative stimuli.. Indeed, given the important and influential role that music plays in PT, future analyses may wish to consider persisting differences in music perception based on an individual's subjective music experience during the acute drug state. PT has been observed to have profound antidepressant effects, with a potentially superior efficacy to SSRIs for MDD, particularly in alleviating anhedonia.. In line with this, we found neurobiological correlates of the hedonic processing of music differed in patients treated with PT e.g. with less activation in the vmPFC activation and increased activation in sensory regions. A follow-up analysis of directed connectivity might test the hypothesis that there is greater bottom-up information flow from the sensory regions post treatment with PT. This has been observed during the acute LSD state, with increased parahippocampal cortex-visual cortex functional connectivity and information flow during music listening. Persisting alteration in functional connectivity has been previously observed, with decreased amygdala-occipital/parietal cortices connectivity during face processing post-PT. Indeed, the present findings could be regarded as suggestive evidence that PT decreases the top-down executive control of emotions in an enduring way, as has been reported qualitatively and quantitatively with PT for depression. The reduction by escitalopram of the affective response to musical surprises, fits with fMRI measured brain responses to other emotional stimuli, thus supporting intrinsic differences in the therapeutic mechanism of SSRIs versus those of PT.
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