Centre for Youth Mental Health - Research Publications
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ItemMulti-site benchmark classification of major depressive disorder using machine learning on cortical and subcortical measures.(Springer Science and Business Media LLC, 2024-01-11)Machine learning (ML) techniques have gained popularity in the neuroimaging field due to their potential for classifying neuropsychiatric disorders. However, the diagnostic predictive power of the existing algorithms has been limited by small sample sizes, lack of representativeness, data leakage, and/or overfitting. Here, we overcome these limitations with the largest multi-site sample size to date (N = 5365) to provide a generalizable ML classification benchmark of major depressive disorder (MDD) using shallow linear and non-linear models. Leveraging brain measures from standardized ENIGMA analysis pipelines in FreeSurfer, we were able to classify MDD versus healthy controls (HC) with a balanced accuracy of around 62%. But after harmonizing the data, e.g., using ComBat, the balanced accuracy dropped to approximately 52%. Accuracy results close to random chance levels were also observed in stratified groups according to age of onset, antidepressant use, number of episodes and sex. Future studies incorporating higher dimensional brain imaging/phenotype features, and/or using more advanced machine and deep learning methods may yield more encouraging prospects.
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ItemNo Preview AvailableAcceptability and feasibility of a multidomain harmonized data collection protocol in youth mental health(WILEY, 2023-05)OBJECTIVE: To develop targeted treatment for young people experiencing mental illness, a better understanding of the biological, psychological, and social changes is required, particularly during the early stages of illness. To do this, large datasets need to be collected using standardized methods. A harmonized data collection protocol was tested in a youth mental health research setting to determine its acceptability and feasibility. METHOD: Eighteen participants completed the harmonization protocol, including a clinical interview, self-report measures, neurocognitive measures, and mock assessments of magnetic resonance imaging (MRI) and blood. The feasibility of the protocol was assessed by recording recruitment rates, study withdrawals, missing data, and protocol deviations. Subjective responses from participant surveys and focus groups were used to examine the acceptability of the protocol. RESULTS: Twenty-eight young people were approached, 18 consented, and four did not complete the study. Most participants reported positive subjective impressions of the protocol as a whole and showed interest in participating in the study again, if given the opportunity. Participants generally perceived the MRI and neurocognitive tasks as interesting and suggested that the assessment of clinical presentation could be shortened. CONCLUSION: Overall, the harmonized data collection protocol appeared to be feasible and generally well-accepted by participants. With a majority of participants finding the assessment of clinical presentation too long and repetitive, the authors have made suggestions to shorten the self-reports. The broader implementation of this protocol could allow researchers to create large datasets and better understand how psychopathological and neurobiological changes occur in young people with mental ill-health.
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ItemNo Preview AvailableThe Study of Ketamine for Youth Depression (SKY-D): study protocol for a randomised controlled trial of low-dose ketamine for young people with major depressive disorder(BMC, 2023-10-24)BACKGROUND: Existing treatments for young people with severe depression have limited effectiveness. The aim of the Study of Ketamine for Youth Depression (SKY-D) trial is to determine whether a 4-week course of low-dose subcutaneous ketamine is an effective adjunct to treatment-as-usual in young people with major depressive disorder (MDD). METHODS: SKY-D is a double-masked, randomised controlled trial funded by the Australian Government's National Health and Medical Research Council (NHMRC). Participants aged between 16 and 25 years (inclusive) with moderate-to-severe MDD will be randomised to receive either low-dose ketamine (intervention) or midazolam (active control) via subcutaneous injection once per week for 4 weeks. The primary outcome is change in depressive symptoms on the Montgomery-Åsberg Depression Rating Scale (MADRS) after 4 weeks of treatment. Further follow-up assessment will occur at 8 and 26 weeks from treatment commencement to determine whether treatment effects are sustained and to investigate safety outcomes. DISCUSSION: Results from this trial will be important in determining whether low-dose subcutaneous ketamine is an effective treatment for young people with moderate-to-severe MDD. This will be the largest randomised trial to investigate the effects of ketamine to treat depression in young people. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ID: ACTRN12619000683134. Registered on May 7, 2019. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377513 .
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ItemNo Preview AvailableA brain model of altered self-appraisal in social anxiety disorder.(Springer Science and Business Media LLC, 2023-11-11)The brain's default mode network has a central role in the processing of information concerning oneself. Dysfunction in this self-referential processing represents a key component of multiple mental health conditions, particularly social anxiety disorder (SAD). This case-control study aimed to clarify alterations to network dynamics present during self-appraisal in SAD participants. A total of 38 adolescents and young adults with SAD and 72 healthy control participants underwent a self-referential processing fMRI task. The task involved two primary conditions of interest: direct self-appraisal (thinking about oneself) and reflected self-appraisal (thinking about how others might think about oneself). Dynamic causal modeling and parametric empirical Bayes were then used to explore differences in the effective connectivity of the default mode network between groups. We observed connectivity differences between SAD and healthy control participants in the reflected self-appraisal but not the direct self-appraisal condition. Specifically, SAD participants exhibited greater excitatory connectivity from the posterior cingulate cortex (PCC) to medial prefrontal cortex (MPFC) and greater inhibitory connectivity from the inferior parietal lobule (IPL) to MPFC. In contrast, SAD participants exhibited reduced intrinsic connectivity in the absence of task modulation. This was illustrated by reduced excitatory connectivity from the PCC to MPFC and reduced inhibitory connectivity from the IPL to MPFC. As such, participants with SAD showed changes to afferent connections to the MPFC which occurred during both reflected self-appraisal as well as intrinsically. The presence of connectivity differences in reflected and not direct self-appraisal is consistent with the characteristic fear of negative social evaluation that is experienced by people with SAD.
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ItemNo Preview AvailableInflammatory subgroups of schizophrenia and their association with brain structure: A semi-supervised machine learning examination of heterogeneity(ACADEMIC PRESS INC ELSEVIER SCIENCE, 2023-10)OBJECTIVE: Immune system dysfunction is hypothesised to contribute to structural brain changes through aberrant synaptic pruning in schizophrenia. However, evidence is mixed and there is a lack of evidence of inflammation and its effect on grey matter volume (GMV) in patients. We hypothesised that inflammatory subgroups can be identified and that the subgroups will show distinct neuroanatomical and neurocognitive profiles. METHODS: The total sample consisted of 1067 participants (chronic patients with schizophrenia n = 467 and healthy controls (HCs) n = 600) from the Australia Schizophrenia Research Bank (ASRB) dataset, together with 218 recent-onset patients with schizophrenia from the external Benefit of Minocycline on Negative Symptoms of Psychosis: Extent and Mechanism (BeneMin) dataset. HYDRA (HeterogeneitY through DiscRiminant Analysis) was used to separate schizophrenia from HC and define disease-related subgroups based on inflammatory markers. Voxel-based morphometry and inferential statistics were used to explore GMV alterations and neurocognitive deficits in these subgroups. RESULTS: An optimal clustering solution revealed five main schizophrenia groups separable from HC: Low Inflammation, Elevated CRP, Elevated IL-6/IL-8, Elevated IFN-γ, and Elevated IL-10 with an adjusted Rand index of 0.573. When compared with the healthy controls, the IL-6/IL-8 cluster showed the most widespread, including the anterior cingulate, GMV reduction. The IFN-γ inflammation cluster showed the least GMV reduction and impairment of cognitive performance. The CRP and the Low Inflammation clusters dominated in the younger external dataset. CONCLUSIONS: Inflammation in schizophrenia may not be merely a case of low vs high, but rather there are pluripotent, heterogeneous mechanisms at play which could be reliably identified based on accessible, peripheral measures. This could inform the successful development of targeted interventions.
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ItemNo Preview AvailableComorbidity between major depressive disorder and physical diseases: a comprehensive review of epidemiology, mechanisms and management(Wiley, 2023-10)Populations with common physical diseases - such as cardiovascular diseases, cancer and neurodegenerative disorders - experience substantially higher rates of major depressive disorder (MDD) than the general population. On the other hand, people living with MDD have a greater risk for many physical diseases. This high level of comorbidity is associated with worse outcomes, reduced adherence to treatment, increased mortality, and greater health care utilization and costs. Comorbidity can also result in a range of clinical challenges, such as a more complicated therapeutic alliance, issues pertaining to adaptive health behaviors, drug-drug interactions and adverse events induced by medications used for physical and mental disorders. Potential explanations for the high prevalence of the above comorbidity involve shared genetic and biological pathways. These latter include inflammation, the gut microbiome, mitochondrial function and energy metabolism, hypothalamic-pituitary-adrenal axis dysregulation, and brain structure and function. Furthermore, MDD and physical diseases have in common several antecedents related to social factors (e.g., socioeconomic status), lifestyle variables (e.g., physical activity, diet, sleep), and stressful live events (e.g., childhood trauma). Pharmacotherapies and psychotherapies are effective treatments for comorbid MDD, and the introduction of lifestyle interventions as well as collaborative care models and digital technologies provide promising strategies for improving management. This paper aims to provide a detailed overview of the epidemiology of the comorbidity of MDD and specific physical diseases, including prevalence and bidirectional risk; of shared biological pathways potentially implicated in the pathogenesis of MDD and common physical diseases; of socio-environmental factors that serve as both shared risk and protective factors; and of management of MDD and physical diseases, including prevention and treatment. We conclude with future directions and emerging research related to optimal care of people with comorbid MDD and physical diseases.
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ItemCross disorder comparisons of brain structure in schizophrenia, bipolar disorder, major depressive disorder, and 22q11.2 deletion syndrome: A review of ENIGMA findings(WILEY, 2022-05)This review compares the main brain abnormalities in schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and 22q11.2 Deletion Syndrome (22q11DS) determined by ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) consortium investigations. We obtained ranked effect sizes for subcortical volumes, regional cortical thickness, cortical surface area, and diffusion tensor imaging abnormalities, comparing each of these disorders relative to healthy controls. In addition, the studies report on significant associations between brain imaging metrics and disorder-related factors such as symptom severity and treatments. Visual comparison of effect size profiles shows that effect sizes are generally in the same direction and scale in severity with the disorders (in the order SZ > BD > MDD). The effect sizes for 22q11DS, a rare genetic syndrome that increases the risk for psychiatric disorders, appear to be much larger than for either of the complex psychiatric disorders. This is consistent with the idea of generally larger effects on the brain of rare compared to common genetic variants. Cortical thickness and surface area effect sizes for 22q11DS with psychosis compared to 22q11DS without psychosis are more similar to those of SZ and BD than those of MDD; a pattern not observed for subcortical brain structures and fractional anisotropy effect sizes. The observed similarities in effect size profiles for cortical measures across the psychiatric disorders mimic those observed for shared genetic variance between these disorders reported based on family and genetic studies and are consistent with shared genetic risk for SZ and BD and structural brain phenotypes.
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ItemNo Preview AvailableUnderstanding What Drives Long-term Engagement in Digital Mental Health Interventions: Secondary Causal Analysis of the Relationship Between Social Networking and Therapy Engagement(JMIR PUBLICATIONS, INC, 2023)BACKGROUND: Low engagement rates with digital mental health interventions are a major challenge in the field. Multicomponent digital interventions aim to improve engagement by adding components such as social networks. Although social networks may be engaging, they may not be sufficient to improve clinical outcomes or lead users to engage with key therapeutic components. Therefore, we need to understand what components drive engagement with digital mental health interventions overall and what drives engagement with key therapeutic components. OBJECTIVE: Horyzons was an 18-month digital mental health intervention for young people recovering from first-episode psychosis, incorporating therapeutic content and a private social network. However, it is unclear whether use of the social network leads to subsequent use of therapeutic content or vice versa. This study aimed to determine the causal relationship between the social networking and therapeutic components of Horyzons. METHODS: Participants comprised 82 young people (16-27 years) recovering from first-episode psychosis. Multiple convergent cross mapping was used to test causality, as a secondary analysis of the Horyzons intervention. Multiple convergent cross mapping tested the direction of the relationship between each pair of social and therapeutic system usage variables on Horyzons, using longitudinal usage data. RESULTS: Results indicated that the social networking aspects of Horyzons were most engaging. Posting on the social network drove engagement with all therapeutic components (r=0.06-0.36). Reacting to social network posts drove engagement with all therapeutic components (r=0.39-0.65). Commenting on social network posts drove engagement with most therapeutic components (r=0.11-0.18). Liking social network posts drove engagement with most therapeutic components (r=0.09-0.17). However, starting a therapy pathway led to commenting on social network posts (r=0.05) and liking social network posts (r=0.06), and completing a therapy action led to commenting on social network posts (r=0.14) and liking social network posts (r=0.15). CONCLUSIONS: The online social network was a key driver of long-term engagement with the Horyzons intervention and fostered engagement with key therapeutic components and ingredients of the intervention. Online social networks can be further leveraged to engage young people with therapeutic content to ensure treatment effects are maintained and to create virtuous cycles between all intervention components to maintain engagement. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12614000009617; https://www.australianclinicaltrials.gov.au/anzctr/trial/ACTRN12614000009617.
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ItemBrain structural covariance network differences in adults with alcohol dependence and heavy-drinking adolescents(WILEY, 2022-05)BACKGROUND AND AIMS: Graph theoretic analysis of structural covariance networks (SCN) provides an assessment of brain organization that has not yet been applied to alcohol dependence (AD). We estimated whether SCN differences are present in adults with AD and heavy-drinking adolescents at age 19 and age 14, prior to substantial exposure to alcohol. DESIGN: Cross-sectional sample of adults and a cohort of adolescents. Correlation matrices for cortical thicknesses across 68 regions were summarized with graph theoretic metrics. SETTING AND PARTICIPANTS: A total of 745 adults with AD and 979 non-dependent controls from 24 sites curated by the Enhancing NeuroImaging Genetics through Meta Analysis (ENIGMA)-Addiction consortium, and 297 hazardous drinking adolescents and 594 controls at ages 19 and 14 from the IMAGEN study, all from Europe. MEASUREMENTS: Metrics of network segregation (modularity, clustering coefficient and local efficiency) and integration (average shortest path length and global efficiency). FINDINGS: The younger AD adults had lower network segregation and higher integration relative to non-dependent controls. Compared with controls, the hazardous drinkers at age 19 showed lower modularity [area-under-the-curve (AUC) difference = -0.0142, 95% confidence interval (CI) = -0.1333, 0.0092; P-value = 0.017], clustering coefficient (AUC difference = -0.0164, 95% CI = -0.1456, 0.0043; P-value = 0.008) and local efficiency (AUC difference = -0.0141, 95% CI = -0.0097, 0.0034; P-value = 0.010), as well as lower average shortest path length (AUC difference = -0.0405, 95% CI = -0.0392, 0.0096; P-value = 0.021) and higher global efficiency (AUC difference = 0.0044, 95% CI = -0.0011, 0.0043; P-value = 0.023). The same pattern was present at age 14 with lower clustering coefficient (AUC difference = -0.0131, 95% CI = -0.1304, 0.0033; P-value = 0.024), lower average shortest path length (AUC difference = -0.0362, 95% CI = -0.0334, 0.0118; P-value = 0.019) and higher global efficiency (AUC difference = 0.0035, 95% CI = -0.0011, 0.0038; P-value = 0.048). CONCLUSIONS: Cross-sectional analyses indicate that a specific structural covariance network profile is an early marker of alcohol dependence in adults. Similar effects in a cohort of heavy-drinking adolescents, observed at age 19 and prior to substantial alcohol exposure at age 14, suggest that this pattern may be a pre-existing risk factor for problematic drinking.
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ItemCoordinated cortical thickness alterations across six neurodevelopmental and psychiatric disorders(NATURE PORTFOLIO, 2022-11-11)Neuropsychiatric disorders are increasingly conceptualized as overlapping spectra sharing multi-level neurobiological alterations. However, whether transdiagnostic cortical alterations covary in a biologically meaningful way is currently unknown. Here, we studied co-alteration networks across six neurodevelopmental and psychiatric disorders, reflecting pathological structural covariance. In 12,024 patients and 18,969 controls from the ENIGMA consortium, we observed that co-alteration patterns followed normative connectome organization and were anchored to prefrontal and temporal disease epicenters. Manifold learning revealed frontal-to-temporal and sensory/limbic-to-occipitoparietal transdiagnostic gradients, differentiating shared illness effects on cortical thickness along these axes. The principal gradient aligned with a normative cortical thickness covariance gradient and established a transcriptomic link to cortico-cerebello-thalamic circuits. Moreover, transdiagnostic gradients segregated functional networks involved in basic sensory, attentional/perceptual, and domain-general cognitive processes, and distinguished between regional cytoarchitectonic profiles. Together, our findings indicate that shared illness effects occur in a synchronized fashion and along multiple levels of hierarchical cortical organization.