BACKGROUND:Exercise therapy reduces depressive and anxiety symptoms, but its neural mechanisms remain unclear. We examined whether running therapy reorganizes dynamic brain functional connectivity in affective disorders (AFFs). METHODS:Resting-state functional magnetic resonance imaging was analyzed at baseline in 66 healthy control participants and 50 individuals with AFFs. Coactivation pattern (CAP) analysis identified recurring whole-brain states and their temporal dynamics. After baseline comparisons, patients received 16 weeks of running therapy or antidepressant treatment. Then, we examined treatment-related CAP changes and their associations with symptom improvement. RESULTS:At baseline, individuals with AFFs showed fewer occurrences and shorter dwell time of the visual-somatosensory-subcortical CAP (VS-SCCAP) than control participants (both ps ≤ .04, ηp2 ≈ 0.04-0.05). Running therapy induced a treatment-specific reorganization of brain dynamics, with decreased default mode CAP (DMCAP) occurrences (F = 8.18, p = .01, ηp2 = 0.13) and dwell time (F = 11.51, p < .001, ηp2 = 0.19) and increased VS-SCCAP occurrences (F = 8.10, p = .01, ηp2 = 0.13) and entries (F = 5.39, p = .03, ηp2 = 0.08). Greater reductions in DMCAP entries and transitions from DMCAP to VS-SCCAP were associated with greater improvement in anxiety- and fear-related symptoms (ρ = -0.54 to -0.45, all q ≤ .03). CONCLUSIONS:Running therapy was associated with treatment-specific reorganization of large-scale brain dynamics in AFFs. Symptom improvement was linked to changes in DM CAP dynamics and transitions between DM and VS states.

Background:Major depressive disorder (MDD) is heterogeneous in clinical presentation and treatment response. The COORDINATE-MDD consortium identified two magnetic resonance imaging (MRI)-derived neuroanatomical profiles: dimension 1 (D1), with relatively preserved gray and white matter, and dimension 2 (D2), showing widespread reductions aligned with immunometabolic profile. Profiles were associated with distinct responses to selective serotonin reuptake inhibitor (SSRI) antidepressant and placebo (PLA). In this study, we examined electrophysiological correlates of the neuroanatomical profiles and their relationship to treatment outcome. Methods:Baseline resting-state, eyes-closed electroencephalography (EEG) was acquired from 237 medication-free participants with MDD who were in a current depressive episode (155 women; mean age [SD] = 37.47 [13.36] years) from CAN-BIND (Canadian Biomarker Integration Network in Depression) (SSRI) and EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care) (SSRI or PLA). EEG features included spectral power, frontal alpha asymmetry (FAA), multiscale sample entropy, and intersite phase clustering. Effects of profile (D1 and D2) and clinical outcome (responder, nonresponder; defined as ≥50% symptom improvement) were examined with age, sex, and site as covariates. Results:No significant electrophysiological differences were observed after covariate adjustment. However, among participants who subsequently responded to treatment, D1 showed greater baseline alpha power in frontal and central regions and lower relative delta posteriorly compared with D2. In PLA-treated responders, D2 showed spectral slowing, elevated low-frequency power, reduced gamma, and coarse-scale entropy compared with D1. Baseline FAA was lower in responders than nonresponders, independent of the neuroanatomical profile. Conclusions:EEG differences between MRI-defined neuroanatomical profiles emerged in relation to clinical outcome. D1 was associated with electrophysiological patterns consistent with flexible, globally regulated cortical dynamics in SSRI responders, whereas D2 showed a distinct pattern in PLA responders, indicating partially separable neural mechanisms underlying pharmacological and PLA treatment effects.

Abstract Background Major depressive disorder (MDD) is clinically heterogeneous, hindering identification of reproducible biomarkers. Using a semi-supervised machine learning approach, HYDRA, we previously identified two neuroanatomical dimensions from structural MRI in medication-free MDD from COORDINATE-MDD consortium. These dimensions (D1, D2) showed differential responses to selective serotonin reuptake inhibitor (SSRI) antidepressants and placebo. External replication in UK Biobank linked D2, characterized by widespread subtle neuroanatomical reductions, to an immuno-metabolic profile. Here, we examined whether these dimensions are detectable early in the course of illness. Methods We applied the pre-trained model to structural MRI data from the multisite PRONIA cohort, comprising individuals with recent-onset depression (ROD; n = 377; mean age 25.8 years, SD 6.0; 51.3% female) and healthy controls (n = 267; mean age 25.5 years, SD 6.4; 61.0% female). Participants were assigned to clusters (C1, C2) corresponding to the previously identified dimensions (D1, D2). Clusters were compared on clinical symptom profiles, peripheral inflammatory markers, and in a subset (n = 107), proteomic ageing indices. Results Two neuroanatomical clusters were identified in PRONIA. C1 (n = 265) showed higher negative symptom severity and elevated interleukin-2 levels. C2 (n = 140) was associated with higher residual proteomic age. Overall depressive symptom severity did not differ significantly between clusters. Conclusions Neuroanatomical dimensions of MDD are reproducible and detectable at illness onset. Associations with negative symptom severity, inflammatory signalling, and proteomic ageing suggest these dimensions capture biologically meaningful heterogeneity early in depression. These findings support a biologically informed framework for stratified treatment approaches in MDD.

Background Working memory deficits are common in mood disorders and severely affect everyday functioning. Serotonin (5-HT) signalling has been implicated in depression and is also involved in cognitive functioning. However, its relevance for working memory remains largely unexplored. Aims Using positron emission tomography (PET) brain imaging, we investigated the link between working memory and multiple 5-HT brain features in both healthy individuals and patients with mood disorders in a cross-sectional analysis of pooled data-sets. Method We used multiple linear regression to test the associations between working memory performance and 5-HT 1B receptor (5-HT1BR) (healthy controls: 28), 5-HT 2A receptor (5-HT2AR) (healthy controls: 116), 5-HT 4 receptor (5-HT4R) (healthy controls: 97, patients: 98) and 5-HT transporter (5-HTT) (healthy controls: 137, patients: 12) PET binding in the frontal cortex. The frontal cortex was chosen as region of interest as it is critical for working memory functions. Results There was no association between working memory and 5-HT1BR (p = 0.14), 5-HT2AR (p = 0.99) or 5-HTT (p = 0.80) frontal cortex binding in healthy controls. For the 5-HT4R, we observed a significant interaction effect of group status (p = 0.01), with patients showing a positive association (β = 6.51, p = 0.02) and healthy individuals showing no significant association (p = 0.16). Conclusions We found no evidence that key 5-HT receptor systems are associated with working memory performance in healthy individuals, but did observe a positive association for 5-HT4R in patients with mood disorder. We speculate that although 5-HT neurotransmission markers may map onto working memory performance in the healthy state, pathologically altered 5-HT signalling may contribute to working memory deficits in mood disorders, possibly through downstream signalling and/or interactions with other neurotransmitter systems.

Abstract A prominent theory of psychedelics is that they increase brain entropy. Thirteen studies have evaluated psychedelic effects on fMRI brain entropy, each applying a distinct measure. Here we evaluated these metrics in an independent 28-participant healthy cohort with 121 pre- and post-psilocybin fMRI scans. We assessed relations between brain entropy and objective and subjective psychedelic drug effects using linear mixed-effects models. All metrics were evaluated using two parcellation strategies and 7 denoising pipelines. We observed consistent significant positive associations for Shannon entropy of the spatial eigendistribution of the time by voxel matrix, path-length, instantaneous correlations, brain-state switching, and sample entropy at short time-scales. We consistently did not observe significant effects for 8 of 14 entropy metrics and observe inconsistent positive effects for Lempel-Ziv complexity of the BOLD signal. Brain entropy quantifications showed limited inter-measure correlations. Our observations support a nuanced acute psychedelic effect on brain entropy, empirically demonstrating that these metrics do not reflect a singular construct.

BACKGROUND:Patients with chronic cluster headache (CCH) suffer from poor sleep, which may impact their brain microstructure and parenchymal clearance of waste products. Psilocybin has shown promise for the treatment of CCH and has been linked to increased neuroplasticity with possible influences on brain microstructure. AIMS:To investigate the effects of psilocybin on sleep, brain water diffusivity, and microstructure in CCH. METHODS:Eleven CCH patients underwent diffusion-weighted MRI and subjective sleep quality assessment with the Pittsburgh Sleep Quality Index (PSQI) before and 1 week after three psilocybin administrations (0.14 mg/kg) spaced 1 week apart. Measures taken prior to intervention were also compared to 24 healthy controls, and subjective sleep quality was related to brain microstructure and diffusivity across groups. RESULTS:We found that sleep was poor in CCH patients, but improved after psilocybin treatment (CCH mean PSQI change (SD) = -2.50 (2.1), pFWER = 0.015). When analyzing brain microstructure and water diffusivity in conjunction, we found differences between CCH patients and controls, which were primarily driven by differences in grey matter. On average, psilocybin intervention in CCH patients was not associated with statistically significant changes in brain microstructure or water diffusivity. However, most patients exhibited lower white matter diffusivity and neurite volume after intervention. Subjective sleep quality showed borderline significant correlations of moderate effect size with brain microstructure and water diffusivity. CONCLUSION:Subjective sleep quality improved in CCH patients after psilocybin and showed some evidence of an association with measures of brain microstructure and water diffusivity. CLINICALTRIALS:gov identifiers:Prophylactic Effects of Psilocybin on Chronic Cluster Headache (EPOCH; NCT04280055) and The Neurobiological Effect of 5-HT2AR Modulation (NeuroPharm2; NCT03289949).

Background:Major depressive disorder (MDD) is associated with altered brain structure and evidence of accelerated brain aging. However, previous studies have been limited by clinical samples with mixed medication status and multiple mood states, modest sample sizes, small percentage of MDD individuals older than 65 years of age, and/or reliance on summary-level data. Methods:Harmonized T1-weighted MRI from MDD (n = 645), all medication-free and in a current depressive episode, and matched healthy controls (n = 645), segmented into 145 regional volumes, from 11 sites in COORDINATE-MDD consortium. Brain age gap (BAG) was estimated using gradient boosting regression with nested cross-validation. Group differences in BAG (and age-corrected BAG [cBAG]) were examined across age strata. Regional contributions were evaluated using Shapley Additive exPlanations. Results:MDD was associated with significantly elevated cBAG compared with healthy controls (mean difference + 2.01 years). Age-stratified analyses showed no differences before mid-30s, with progressively larger gaps thereafter, reaching +6.85 years in MDD aged 55 and older. cBAG differed across neuroanatomical phenotypes associated with differential antidepressant response, cognitive impairment, increased adverse life events, increased self-harm and suicide attempts, and a pro-atherogenic metabolic profile. Key contributing regions included lateral and medial prefrontal regions, middle temporal gyrus, putamen, supplementary motor cortex, central operculum, and cerebellum. Conclusions:Accelerated structural brain aging in MDD is age-dependent and is most pronounced in a neuroanatomical phenotype associated with worse key clinical outcomes. The findings support neuroprogression models of MDD while demonstrating that cBAG is not a uniform feature of MDD and seem to be more strongly expressed in a specifically clinically vulnerable disease phenotype.

Serotonin (5-hydroxytryptamine, 5-HT) is a neuromodulator underpinning various psychological and physiological processes, with dysregulation implicated in numerous psychiatric disorders. Non-invasive measurement of endogenous 5-HT release in the living human brain is essential to advance understanding of the serotonergic system. The combination of Positron Emission Tomography (PET) neuroimaging of serotonergic receptors with pharmacological and behavioural challenges that stimulate endogenous 5-HT release, offers a unique approach to quantify 5-HT dynamics in vivo. In 2010, Paterson and colleagues concluded in a thorough review that measures of 5-HT release were constrained by limitations in the sensitivity of available tracers and potency of pharmacological challenges. Novel tracers combined with optimised pharmacological challenge paradigms have demonstrated sensitivity to changes in endogenous 5-HT, enabling reproducible detection of acute 5-HT release in both preclinical and human studies in the last 15 years of research. These include the use of agonist radioligands with preferential binding to high-affinity receptor states, such as [11C]AZ10419369 and [11C]Cimbi-36, antagonist tracers, such as [18F]Altanserin, refined challenge designs using pharmacological 5-HT releasers, such as fenfluramine and amphetamine, and the integration of hybrid PET/MR imaging to assess neurovascular aspects. These advances have shifted the field from questioning feasibility to addressing optimal strategies for measuring serotonergic dynamics.

IntroductionCognitive impairment in mood disorders and schizophrenia spectrum disorders hampers patients' clinical and functional outcomes. A key challenge in pro-cognitive treatment development is the limited insight into the underlying neurocircuitry correlates of cognitive changes. This longitudinal functional magnetic resonance imaging (fMRI) study aimed to investigate the neural underpinnings of the cognitive benefits of virtual reality-based cognitive remediation therapy (VR-CRT) and their association with treatment-related cognitive improvement.MethodsThis study includes data from a subsample of 31 symptomatically stable, cognitively impaired patients with mood disorder or schizophrenia spectrum disorder (VR-CRT: n = 18; VR control: n = 13) with complete fMRI data. Participants underwent a strategic memory encoding fMRI task and neuropsychological assessment outside the scanner before and after four weeks of bi-weekly VR-CRT vs. VR control treatment and an additional neuropsychological assessment three months after treatment completion. Twenty-eight matched healthy controls (HC) underwent a single fMRI and neuropsychological assessment for baseline comparisons.ResultsVR-CRT vs. VR control treatment increased encoding-related neural activity in the left dorsal prefrontal cortex, bilateral occipital cortex, left inferior temporal gyrus, left frontal pole, and intracalcarine cortex (ps <= 0.03). Moreover, prefrontal and occipital cortex activity increases correlated with treatment-related cognitive improvement at treatment completion and at the three-month follow-up (ps <= 0.02).ConclusionThe encoding-related dorsal prefrontal and occipital activity increase and its association with cognitive benefits of VR-CRT highlights a potential transdiagnostic neurocircuitry biomarker for pro-cognitive interventions. If replicated in larger samples, the findings highlight VR-CRT as a promising pro-cognitive treatment candidate.

Biased neural and behavioral responses to emotional information, specifically threat-related amygdala and fusiform hyperactivity and negative bias in the recognition of facial expressions, have emerged as potential biomarkers of responses to short-term intervention outcomes in major depressive disorder (MDD) and bipolar disorder (BD). However, investigating the influence of these biomarkers on the risk of longer-term adverse outcomes, over at least a year, may provide valuable insights for developing tailored interventions to improve outcomes in these often recurrent and persistent disorders. Thus, we examined whether threat-related amygdala and fusiform responses, and negative biases in facial expression recognition were associated with a one-year risk of psychiatric hospitalizations. The study participants were 112 individuals diagnosed with either BD (n = 62) or MDD (n = 50), who underwent functional magnetic resonance imaging during an emotion face processing task and behavioral assessments of negative emotional biases. Longitudinal data on psychiatric hospitalizations for up to one-year after the participants' study inclusion were obtained using the Danish registers. The analyses were conducted using a Cox regression model, adjusting for demographics, and clinical variables such as prior hospitalizations, diagnoses, illness chronicity, baseline symptoms, and medication. The results showed that left amygdala hyperactivity to fearful vs. happy faces (HR = 14.05, 95% CI: 1.17-168.26, p = 0.037), and increased speed in recognizing negative vs. positive facial expressions (HR = 20.75, 95% CI: 4.13-104.11, p = 0.0002), were significantly associated with subsequent psychiatric hospitalizations. Future studies are needed to explore whether targeting negative threat biases, such as through psychotherapeutic interventions, might help reduce overall disease burden, and potentially decrease societal costs associated with hospitalizations in these conditions.

Abstract Objective To estimate the prevalence of epilepsy-associated malformations of cortical development (MCDs) in Eastern Denmark, and to validate whether epilepsy prevalence in the same population is consistent with national estimates. Methods A retrospective cohort study of people registered with ICD-10 code DG40* and/or DZ033A from 1998 up to 1 July 2023 was conducted. The study population was defined as all living residents in Eastern Denmark with at least one recorded hospital-patient contact within the year preceding 1 July 2023. Magnetic resonance imaging (MRI) availability was required to assess presence of any MCD. MRI radiology reports were manually reviewed or evaluated using a language model to identify MCDs, including encephalocele, focal cortical dysplasia (FCD), hemimegalencephaly, heterotopia, hypothalamic hamartoma, lissencephaly, polymicrogyria and schizencephaly. Prevalence estimates were calculated for each MCD subtype and for epilepsy overall, and compared with the available literature. Results On 1 July 2023, 28,739 people met inclusion criteria, and 14,434 had an available brain MRI, including radiological description of possible MCDs. The prevalence per 100,000 population was 1044.6 (95% CI 1032.6 to 1056.6) for epilepsy and 32.1 (95% CI 30.1 to 34.3) for any MCD associated with seizures. Reported MCD prevalence in the literature, when existent, was derived from pediatric age-ranged selected cohorts, except for FCD. No prevalence estimates for hemimegalencephaly and heterotopia were identified. Significance We presented the first population-based estimates of seizure-associated MCD prevalence in a large all-age cohort. Direct comparison with prior literature was prevented due to differences in study design and population structure, but epilepsy prevalence was consistent with previously reported national estimates. Key points First prevalence estimates of malformation of cortical development presenting with seizures on a large all-age cohort. Epilepsy prevalence estimates align with Denmark’s nationwide estimates previously reported. Language models used on nation-wide registries can contribute to elucidate the epidemiology of rare conditions.

Molecular neuroimaging with positron emission tomography (PET) and single-photon emission computed tomography (SPECT) enables quantification of specific molecular targets in the living brain. Despite its scientific impact, molecular neuroimaging research has historically faced challenges due to high costs, small sample sizes, laboratory-specific analysis pipelines, and limited large-scale data sharing. These factors have hindered reproducibility and the broader reuse of valuable PET datasets. The OpenNeuroPET initiative was established to address these barriers by developing standards, infrastructure, and open-source tools for organizing, sharing, and analyzing molecular neuroimaging data. Through collaborations across Europe and North America, OpenNeuroPET has supported the PET extension of the Brain Imaging Data Structure (PET-BIDS), providing a standardized framework for PET datasets and metadata. Building on PET-BIDS, tools such as PET2BIDS, ezBIDS, and BIDSCoin facilitate data conversion and curation. In parallel, OpenNeuro now hosts PET-BIDS datasets for open sharing, while complementary platforms such as PublicnEUro enable GDPR-compliant controlled access. Emerging open-source workflows and BIDS applications further support automated, reproducible PET preprocessing and quantitative analysis, promoting harmonized processing across centers. Together, these developments mark an important step toward an open molecular neuroimaging ecosystem in which datasets, software, and workflows can be transparently shared, reused, and scaled for collaborative research.

Background Parkinson's disease (PD) and multiple system atrophy (MSA) are considered α-synucleinopathies, characterized by the presence of pathological α-synuclein (α-syn) aggregates. A positron emission tomography (PET) tracer for imaging α-syn aggregates in vivo is highly sought after, as disease progression correlates with the accumulation of aggregated α-syn. We recently reported [ 18 F]asyn-44 as a radiotracer for α-syn, worthy of evaluation in higher species, based on in vitro binding data from human brain tissues and in vivo PET imaging studies in rodents. Objective [ 3 H]ACI-12589 is a promising α-syn PET tracer which recently showed binding in MSA patients but appears to have limited utility in other α-synucleinopathies. Objective 1) compare the in vitro binding properties of our lead, [ 3 H]asyn-44, to [ 3 H]ACI-12589; Objective 2) evaluate [ 18 F]asyn-44 and [ 18 F]ACI-12589 kinetics by in vivo PET imaging in normal rodents; Objective 3) assess pharmacokinetic properties and metabolism of [ 18 F]asyn-44 in normal pig and non-human primate (NHP). Methods In vitro autoradiography with [ 3 H]asyn-44 and [ 3 H]ACI-12589 was performed to compare radiotracer binding in PD, MSA, Alzheimer's disease and healthy control post-mortem brain tissue. Additionally, preclinical PET imaging was performed in rats with [ 18 F]ACI-12589 to compare with our previously reported [ 18 F]asyn-44 data. Further evaluation of [ 18 F]asyn-44 in higher species was carried out by preclinical PET imaging in pig and NHP with metabolite analysis. Liver microsome assays and mass spectrometry were performed to identify the metabolites formed in NHP. Results [ 3 H]Asyn-44 and [ 3 H]ACI-12589 displayed different binding properties in both PD and MSA tissue, suggesting that the tracers target different binding sites and asyn-44 might therefore be more suited for PD imaging. In the pig, [ 18 F]asyn-44 readily entered the brain and no brain penetrant metabolites were observed in arterial blood samples. In the NHP, [ 18 F]asyn-44 readily entered the brain but was rapidly metabolized. Radiolabeled metabolites of asyn-44 were proposed and will be considered in the design of future derivatives. Conclusions Species differences in metabolism of [ 18 F]asyn-44 are observed between pig and NHP, and do not support the further translation of [ 18 F]asyn-44. Additionally, autoradiography with [ 3 H]asyn-44 revealed low signal specificity and high non-displaceable binding. We report evidence for off-target binding of [ 3 H]ACI-12589 to amyloid-β plaques. The limitations of both [ 3 H]asyn-44 and [ 3 H]ACI-12589 reported here support the development of additional derivatives and structural scaffolds of asyn-44 with the potential to improve radiotracer specificity and selectivity towards α-syn.

BackgroundCognitive impairment persists during partial or full remission in 50–70% of individuals with mood disorders and impacts daily functioning and clinical prognosis. Preclinical evidence suggests that extended exposure to moderate hypoxia, combined with motor-cognitive learning, may elevate neuroplasticity and improve cognition. In these individuals with remitted mood disorders, we found that cognitive training under repeated moderate normobaric hypoxia improved executive function, and here investigate neurobiological mechanisms.MethodsParticipants with major depressive disorder (MDD) or bipolar disorder (BD) in partial or full remission were randomized to 3 weeks of 3.5-h daily normobaric hypoxia (12% O2) combined with cognitive training five to 6 days per week or treatment-as-usual (TAU). Participants were assessed with cognitive tests and diffusion-weighted MRI at baseline and 1 month after treatment completion (week 8) as part of the ALTIBRAIN trial (ClinicalTrials.gov: NCT06121206). Prefrontal and hippocampal gray matter microstructure were modelled with Neurite Orientation Dispersion and Density Imaging (NODDI).ResultsFifty-seven participants (mean age 39 years, SD: 13, 70% female) with baseline MRI data were included. No significant effects of hypoxia-cognition training vs. TAU on neurite density index (NDI) or orientation dispersion index (ODI) were observed in either the prefrontal cortex or hippocampus (all p-FDR ≥ 0.832). No significant associations were observed between microstructural changes and changes in cognitive function in either region (all p-FDR ≥ 0.721). At baseline, microstructure in both regions was not associated with executive function or global cognition (all p > 0.40).ConclusionThe absence of detectable microstructural changes, despite selective improvements in executive function, indicates that NODDI-derived metrics did not capture structural correlates of the cognitive response to hypoxia-cognition training. Whether this reflects functional neural mechanisms, measurement insensitivity, or the timing of the single follow-up assessment remains to be determined. Future studies should incorporate multiple imaging time points to capture the dynamic trajectories of putative microstructural brain changes.

The serotonin 1B receptor can be studied in vivo with PET using [11C]AZ10419369, and has been linked to both the pathophysiology and treatment of major depressive disorder (MDD). Ketamine and electroconvulsive therapy (ECT) both exert rapid and potent antidepressive effects, and although these treatments may not act directly on the serotonin system, they both cause dose-dependent increases in serotonin levels, and there is convergent evidence suggesting that the serotonin system may be important for their mechanisms of action. In this study, we re-analysed a multi-centre dataset of 222 [11C]AZ10419369 PET measurements from three centres, including MDD patients examined with PET both before and after treatment with ketamine (n = 19 completers), saline placebo (n = 10), or ECT (n = 13 completers). Using a hierarchical Bayesian approach (SiMBA) that takes advantage of the full dataset to improve parameter estimation and enable data harmonisation across centres, we demonstrate large increases in 5-HT1BR binding following both ketamine (6.4%, 95% CI: 3.1-9.6%) and ECT (9.3%, 95% CI: 4.3-14.2%). Ketamine-induced changes were statistically distinguishable from placebo, and an exploratory cross-centre comparison enabled by the data harmonisation within the combined modelling framework, suggests that ECT-induced changes are also distinguishable from placebo. These changes were not associated with individual symptom improvement. These findings suggest that despite differences in the pri-mary target of these rapid acting treatments for depression, they may converge on similar downstream changes to the serotonin system.

Psychedelics such as psilocybin have been linked to enhanced neuroplasticity and symptom relief in affective disorders, but the neurobiological mechanisms and impact of environmental context remain unclear. Here, we tested whether a single dose of psilocybin (0.3 mg/kg) alters synaptic density in healthy individuals and whether setting-dependent subjective experience shapes this effect. Fifteen healthy participants had a psilocybin-induced psychedelic experience either inside an MRI scanner or in a therapeutic-like room. We assessed synaptic density changes by measuring the Synaptic Vesicle glycoprotein 2A in the frontal cortex and hippocampus with [¹¹C]UCB-J PET at baseline and one-week post-dose, and assessed subjective experiences immediately afterwards and at three months. Overall, we found no statistically significant increase in SV2A density. However, participants treated in the therapeutic-like setting exhibited more intense mystical-type experiences, longer-lasting psychological benefits, and greater increases in synaptic density than those dosed in the MRI scanner. These findings indicate that psilocybin's neuroplastic effects are modulated by environmental context, with important implications for psychedelic-assisted therapies. ClinicalTrial: NCT03289949.