Alec John Jamieson

Background: The transdiagnostic symptom of anhedonia, or the loss of pleasure in previously pleasurable things, is common across several chronic physical and mental illnesses. Music therapy has been effective in treating a range of conditions associated with anhedonia, but only 3 cases have been reported that targeted increasing hedonic capacity and all relied on descriptive data (qualitative and quantitative). Functional magnetic resonance imaging (fMRI) evidence demonstrates that pleasure is associated with increased activity in the limbic system, including the anterior cingulate cortex, as well as the prefrontal cortex. As such, changes within these regions may provide objective evidence to explore how music therapy acts to reduce anhedonia symptomatology. Objective: Our primary aim is to examine the feasibility of a music therapy intervention to increase hedonic capacity among individuals with anhedonia. We also aim to examine congruence across psychometric results and interview data to generate estimates of effect size and explore participants’ qualitative experiences. In addition, we aim to identify any correspondence between these outcomes and changes in brain activity associated with reward processing during targeted fMRI tasks. This study will generate hypotheses for testing in future studies. Methods: This pilot study uses a sequential mixed methods design to first identify whether there are pre-post changes in the primary outcome measures and then to identify correlations between interview data, psychometric data, and objective measures of brain structure and functioning (fMRI). Participants were 13 adults with high cognitive function who scored within the clinical range for anhedonia on the Dimensional Anhedonia Rating Scale (DARS). Participants were engaged in a 4-month music therapy intervention developed through preliminary case studies, which involved daily independent pleasure-focused music activities and regular contact with a therapeutic guide. The fMRI data acquired include resting-state fMRI and task-based functional paradigms designed to probe musical pleasure (music listening task) and reward prediction (reversal reward learning task). Data will be analyzed using individual general linear models to identify associations with symptom improvement, as well as longitudinal changes in functioning. Results: The study received internal funding support from the University of Melbourne in September 2024. Data collection commenced in August 2025 and was concluded by mid-2026. As of September 2026, 13 participants have been recruited, and data will be analyzed by the end of 2026, with results expected to be published in 2027. Conclusions: The results of this pilot study will contribute to knowledge about the effects of this music therapy intervention on reducing anhedonia and introduce a study protocol that could be used in subsequent, more robust studies to explore potential mechanisms.

Background: Cognitive restructuring, the process of identifying and challenging negative thoughts, is a key technique for treating depressive and anxiety disorders. Although neuroimaging studies have characterised the brain systems supporting cognitive restructuring in healthy individuals, it remains unclear how these systems are altered in depression and anxiety, or whether each disorder is associated with distinct neural dysfunction. Methods: Seventy-three clinical participants with depressive or anxiety disorders and 70 healthy controls completed a cognitive restructuring paradigm during 7 Tesla functional magnetic resonance imaging (fMRI). The task required participants to either repeat a series of negative statements or challenge them using Socratic questioning. Group-level fMRI analyses examined the effects of depressive and anxiety symptom severity on brain activation, while dynamic causal modelling characterized the directional neural influences between implicated regions. Results: During challenging compared to repeating statements, greater depressive symptoms were associated with reduced dorsolateral prefrontal cortex (dlPFC) activation. Conversely, greater anxiety symptoms were associated with greater dlPFC activation. Effective connectivity results revealed that depressive symptoms were associated with greater inhibition from the ventrolateral prefrontal cortex (vlPFC) to the ventromedial prefrontal cortex, whereas anxiety symptoms were associated with greater excitation from the dlPFC to amygdala and greater inhibition from the vlPFC to amygdala. Conclusions: While clinical participants modified negative beliefs as effectively as healthy controls, depressive and anxiety symptoms were associated with dissociable neural signatures during restructuring. This suggests that cognitive behavioral therapy may engage partially distinct mechanisms depending on symptom profile, a possibility that warrants longitudinal investigation of treatment response.

Social anxiety disorder (SAD) is among the most prevalent anxiety disorders, and it has been associated with signs of advanced biological ageing. Despite this, brain age research on anxiety disorders remains limited. This mega-analysis investigated brain ageing in adults with SAD within the ENIGMA-Anxiety Working Group. Structural MRI scans from 576 participants with SAD and 1 355 non-affected healthy controls (HCs) across 26 international samples were included. Brain age was estimated from 77 cortical and subcortical regions using a publicly available ENIGMA brain age model. The brain-predicted age difference (brain-PAD) was calculated as the difference between brain age and chronological age. Group and subgroup differences (comorbidity, medication) were assessed using linear mixed-effect models. In the full sample, there was no group difference in brain-PAD ( β diagnosis (SE)=0.70 (0.37) years, p =0.061). In a subgroup of participants with SAD with comorbid anxiety disorders (n=184 SAD, n=1 355 HCs), a brain-PAD of +2.39 (0.93) years (Cohen’s d =0.23, p FDR=0.003) was observed. This brain-PAD became smaller after exclusion of participants with comorbid agoraphobia and specific phobia, suggesting that these disorders may partly drive the advanced brain-PAD. In conclusion, this ENIGMA-Anxiety mega-analysis did not find evidence of advanced brain ageing in the full sample of adult participants with SAD relative to HCs. However, a sub-analysis suggested that SAD with co-occurring phobic disorders, or the phobic disorders themselves, are associated with neurostructural patterns typical of older brains. Future research could utilise transdiagnostic samples with information on age of onset and disorder duration to further clarify this relation.

The clinical and biological heterogeneity of major depressive disorder (MDD) may reflect the aggregation of different conditions with distinct pathologies under a single diagnostic label. Neuroanatomical heterogeneity in MDD was examined using a harmonized, age- and sex-matched sample from the ENIGMA MDD consortium (N = 5146; age range: 9–82 years; 64% female). Analyses of global neurostrucutral variability revealed greater cortical thickness heterogeneity in MDD compared with healthy controls (Cohen’s d = –0.26). Regionally, increased variability in cortical thickness was most prominent in the cingulate (+6.1 to +6.6% more variation in MDD) and insular (+5.8%) cortices, as well as in the frontal (+5.7 to +6.8%) and temporal (+6.1 to +6.8%) lobes. Heterogeneity in cortical thickness was more pronounced among patients using antidepressant medication (Cohen’s d = –0.39). Patient-specific analyses further showed that individuals with markedly increased cortical thickness variability (th percentile relative to the normative range) exhibited greater depressive symptom severity than those within the normative range (5 ^th –95 ^th percentile; Cohen’s d = 0.19–0.36). Overall, the results indicate that neuroanatomical heterogeneity in MDD is primarily expressed in cortical thickness, offering refined insights into the neurobiological complexity of structural alterations associated with depression. These findings could guide future stratification efforts examining whether regionally confined changes in cortical thickness within areas of pronounced variability reflect clinically meaningful patient subgroups.

Background: Interoceptive dysfunction, the impaired sensing and interpretation of internal bodily states, has emerged as a potential transdiagnostic feature across several psychiatric conditions, particularly depressive and anxiety disorders. Despite their high comorbidity, it remains unclear whether these conditions are associated with similar or distinct alterations in brain regions underlying this process. To clarify this, we conducted a systematic review and meta-analysis of functional magnetic resonance imaging studies examining interoceptive processing in depressive and anxiety disorders. Methods: Using a pre-registered protocol (registration number: CRD42024579900), we conducted systematic searches across five databases: PsycINFO, EMBASE, PubMed, Scopus, and Web of Science. Our initial search yielded 315 unique studies. After applying our inclusion criteria, we identified 11 relevant studies with a total of 659 participants (269 healthy controls and 390 clinical participants). Results: Our systematic review and meta-analysis revealed significantly reduced activation in the right dorsal mid-insula and left posterior insula during interoceptive tasks in individuals with major depressive disorder. Interestingly, no significant effects were observed for anxiety disorders or the combined sample compared with healthy controls. Qualitative synthesis suggested potential insula hyperactivation in anxiety, aligning with theories of interoceptive hypervigilance. Conclusion: These findings support models of allostatic dysfunction in depressive and anxiety disorders, highlighting the insula’s role in interpreting bodily signals. Clinically, this underscores the potential of interoception-focused interventions to recalibrate insula processing and alleviate symptoms. Further research in anxiety disorders with reduced methodological heterogeneity would aid in clarifying the effects suggested by the qualitative synthesis.

BACKGROUND The transdiagnostic symptom of anhedonia, or the loss of pleasure in previously pleasurable things, is common across several chronic physical and mental illnesses. Music therapy has been effective in treating a range of conditions associated with anhedonia, but the precise neurobiological mechanisms underpinning music therapy’s efficacy remain unclear. One potential mechanism is musical pleasure, as a re-activator of the pleasure system. Functional Magnetic Resonance Imaging (fMRI) evidence demonstrates that pleasure is associated with increased activity of the limbic system including the anterior cingulate cortex (ACC), as well as the pre-frontal cortex. As such, changes within these regions may be one such mechanism through which music therapy acts to reduce anhedonia symptomatology. OBJECTIVE Our primary objective is to examine indicators of increased pleasure/hedonic capacity in individuals with anhedonia before and after completing a 3 month structured music therapy intervention involving daily music-based activities . We will assess whether musical pleasure mediates the relationship between music therapy and decreased anhedonia symptoms. METHODS We will pilot pre-post testing of a cohort of 9 participants who have scored as symptomatic of anhedonia using the Dimensional Anhedonia Rating Scale (DARS). We will investigate validated psychometrics tools (the DARS and Snaith-Hamilton Pleasure Scale (SHAPS)) and objective measures of brain structure and functioning (fMRI) pre- and post-intervention. fMRI data acquired will include resting-state fMRI and acquisitions during naturalistic listening to music pieces in addition to functional paradigms designed to probe musical pleasure (music listening task) and reward prediction (reversal reward learning task). Data will be analysed using individual general linear models to identify associations with symptom improvement as well as well longitudinal changes in functioning. RESULTS The study received internal funding support from the University of Melbourne in September 2024. Data collection commenced in August 2025 and will conclude by mid-2026. As of December 2025, 9 participants have been recruited, and data will be analysed by the end of 2026 with results to be published in 2027. CONCLUSIONS The results of this study will contribute to knowledge of music therapy and anhedonia and the understanding of musical pleasure as a potential mechanism for improvement. CLINICALTRIAL N/A

The habenula is implicated in signaling negative reward prediction errors (RPE), yet direct causal evidence demonstrating its influence on downstream human brain circuits is limited. Using ultra-high field (7T) fMRI and dynamic causal modelling across two negative RPE-inducing experimental tasks, we characterize habenula-directed connectivity with monoaminergic midbrain and cortical pathways in healthy adults. Negative feedback drove strong habenula inhibition of ventral tegmental area and dorsal raphe nucleus activity, while positive feedback had an excitatory effect. These core effects are replicated across reversal learning and perceptual decision uncertainty tasks, establishing a generalizable mechanism for behavioral adaptation. Task-specific modulatory effects emerged in pathways between the subcortical and cortical regions (ventral tegmental area→dorsal anterior cingulate cortex, dorsal raphe nucleus→medial prefrontal cortex, and dorsal anterior cingulate cortex→habenula), revealing context-dependent cortical elaboration of negative RPE-driven habenula signals. This provides the first evidence in humans for bivalent causal modulation of habenula function on monoaminergic midbrain and cortical pathways, demonstrating how the brain integrates negative and positive signals to guide adaptive behavior.

The understanding of how antidepressant (AD) use is associated with brain structure in individuals with major depressive disorder (MDD) remains incomplete. We aimed to examine the association between AD medication use and brain morphology in relation to age and sex by pooling structural neuroimaging and clinical data from 32 cohorts within the ENIGMA-MDD working group. Interaction effects of group (2076 cases with current AD use (AD), 1495 cases not currently taking AD (nAD) and 5125 healthy controls (HC)) with age and sex, and main effects of group on regional brain structure (cortical surface area and thickness, and subcortical volume) were examined. Additionally, we examined the effect of AD type (SSRI, SNRI or mirtazapine) and duration of use on brain morphology. Younger individuals in the AD group showed lower bilateral middle temporal gyrus thickness compared to nAD and HC, but this was not seen in older individuals (crossover around 50 years). Lower hippocampal volume and thinner inferior temporal gyrus were shown in AD compared to nAD. These effects were independent of group differences in disease-course-related measures, but were driven by depressive symptom severity. Greater bilateral rostral anterior cingulate thickness was found in individuals older than approximately 40 years taking mirtazapine compared to individuals taking SSRIs or SNRIs. Evidence for subtle structural brain differences in temporal and limbic regions in individuals with MDD who currently use AD medication were found compared to those not currently taking AD medication. Future longitudinal studies are needed to determine the causality of these associations.