Psychiatry - Research Publications
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ItemNeuroimaging Insights: Kava's (Piper methysticum) Effect on Dorsal Anterior Cingulate Cortex GABA in Generalized Anxiety Disorder.(MDPI AG, 2023-10-28)Generalised Anxiety Disorder (GAD) is a prevalent, chronic mental health disorder. The measurement of regional brain gamma-aminobutyric acid (GABA) offers insight into its role in anxiety and is a potential biomarker for treatment response. Research literature suggests Piper methysticum (Kava) is efficacious as an anxiety treatment, but no study has assessed its effects on central GABA levels. This study investigated dorsal anterior cingulate (dACC) GABA levels in 37 adult participants with GAD. GABA was measured using proton magnetic resonance spectroscopy (1H-MRS) at baseline and following an eight-week administration of Kava (standardised to 120 mg kavalactones twice daily) (n = 20) or placebo (n = 17). This study was part of the Kava for the Treatment of GAD (KGAD; ClinicalTrials.gov: NCT02219880), a 16-week intervention study. Compared with the placebo group, the Kava group had a significant reduction in dACC GABA (p = 0.049) at eight weeks. Baseline anxiety scores on the HAM-A were positively correlated with GABA levels but were not significantly related to treatment. Central GABA reductions following Kava treatment may signal an inhibitory effect, which, if considered efficacious, suggests that GABA levels are modulated by Kava, independent of reported anxiety symptoms. dACC GABA patterns suggest a functional role of higher levels in clinical anxiety but warrants further research for symptom benefit. Findings suggest that dACC GABA levels previously un-examined in GAD could serve as a biomarker for diagnosis and treatment response.
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ItemCumulative trauma load and timing of trauma prior to military deployment differentially influences inhibitory control processing across deployment(NATURE PORTFOLIO, 2023-12-05)Military personnel experience high trauma load that can change brain circuitry leading to impaired inhibitory control and posttraumatic stress disorder (PTSD). Inhibitory control processing may be particularly vulnerable to developmental and interpersonal trauma. This study examines the differential role of cumulative pre-deployment trauma and timing of trauma on inhibitory control using the Go/NoGo paradigm in a military population. The Go/NoGo paradigm was administered to 166 predominately male army combat personnel at pre- and post-deployment. Linear mixed models analyze cumulative trauma, trauma onset, and post-deployment PTSD symptoms on NoGo-N2 and NoGo-P3 amplitude and latency across deployment. Here we report, NoGo-N2 amplitude increases and NoGo-P3 amplitude and latency decreases in those with high prior interpersonal trauma across deployment. Increases in NoGo-P3 amplitude following adolescent-onset trauma and NoGo-P3 latency following childhood-onset and adolescent-onset trauma are seen across deployment. Arousal symptoms positively correlated with conflict monitoring. Our findings support the cumulative trauma load and sensitive period of trauma exposure models for inhibitory control processing in a military population. High cumulative interpersonal trauma impacts conflict monitoring and response suppression and increases PTSD symptoms whereas developmental trauma differentially impacts response suppression. This research highlights the need for tailored strategies for strengthening inhibitory control, and that consider timing and type of trauma in military personnel.
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ItemExtreme deviations from the normative model reveal cortical heterogeneity and associations with negative symptom severity in first-episode psychosis from the OPTiMiSE and GAP studies(SPRINGERNATURE, 2023-12-02)There is currently no quantifiable method to predict long-term clinical outcomes in patients presenting with a first episode of psychosis. A major barrier to developing useful markers for this is biological heterogeneity, where many different pathological mechanisms may underly the same set of symptoms in different individuals. Normative modelling has been used to quantify this heterogeneity in established psychotic disorders by identifying regions of the cortex which are thinner than expected based on a normative healthy population range. These brain atypicalities are measured at the individual level and therefore potentially useful in a clinical setting. However, it is still unclear whether alterations in individual brain structure can be detected at the time of the first psychotic episode, and whether they are associated with subsequent clinical outcomes. We applied normative modelling of cortical thickness to a sample of first-episode psychosis patients, with the aim of quantifying heterogeneity and to use any pattern of cortical atypicality to predict symptoms and response to antipsychotic medication at timepoints from baseline up to 95 weeks (median follow-ups = 4). T1-weighted brain magnetic resonance images from the GAP and OPTiMiSE samples were processed with Freesurfer V6.0.0 yielding 148 cortical thickness features. An existing normative model of cortical thickness (n = 37,126) was adapted to integrate data from each clinical site and account for effects of gender and site. Our test sample consisted of control participants (n = 149, mean age = 26, SD = 6.7) and patient data (n = 295, mean age = 26, SD = 6.7), this sample was used for estimating deviations from the normative model and subsequent statistical analysis. For each individual, the 148 cortical thickness features were mapped to centiles of the normative distribution and converted to z-scores reflecting the distance from the population mean. Individual cortical thickness metrics of +/- 2.6 standard deviations from the mean were considered extreme deviations from the norm. We found that no more than 6.4% of psychosis patients had extreme deviations in a single brain region (regional overlap) demonstrating a high degree of heterogeneity. Mann-Whitney U tests were run on z-scores for each region and significantly lower z-scores were observed in FEP patients in the frontal, temporal, parietal and occipital lobes. Finally, linear mixed-effects modelling showed that negative deviations in cortical thickness in parietal and temporal regions at baseline are related to more severe negative symptoms over the medium-term. This study shows that even at the early stage of symptom onset normative modelling provides a framework to identify individualised cortical markers which can be used for early personalised intervention and stratification.
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ItemMetergoline Shares Properties with Atypical Antipsychotic Drugs Identified by Gene Expression Signature Screen(SPRINGER, 2023-12)Novel approaches are required to find new treatments for schizophrenia and other neuropsychiatric disorders. This study utilised a combination of in vitro transcriptomics and in silico analysis with the BROAD Institute's Connectivity Map to identify drugs that can be repurposed to treat psychiatric disorders. Human neuronal (NT2-N) cells were treated with a combination of atypical antipsychotic drugs commonly used to treat psychiatric disorders (such as schizophrenia, bipolar disorder, and major depressive disorder), and differential gene expression was analysed. Biological pathways with an increased gene expression included circadian rhythm and vascular endothelial growth factor signalling, while the adherens junction and cell cycle pathways were transcriptionally downregulated. The Connectivity Map (CMap) analysis screen highlighted drugs that affect global gene expression in a similar manner to these psychiatric disorder treatments, including several other antipsychotic drugs, confirming the utility of this approach. The CMap screen specifically identified metergoline, an ergot alkaloid currently used to treat seasonal affective disorder, as a drug of interest. In mice, metergoline dose-dependently reduced MK-801- or methamphetamine-induced locomotor hyperactivity confirming the potential of metergoline to treat positive symptoms of schizophrenia in an animal model. Metergoline had no effects on prepulse inhibition deficits induced by MK-801 or methamphetamine. Taken together, metergoline appears a promising drug for further studies to be repurposed as a treatment for schizophrenia and possibly other psychiatric disorders.
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ItemSmartphone-delivered multicomponent lifestyle medicine intervention for improving mental health in a nonclinical population: a randomized controlled trial.(Frontiers Media SA, 2023)OBJECTIVE: To prevent the exacerbation of mental health burdens, a growing body of research has recommended a balanced approach that emphasizes both the delivery of mental health treatments to individuals with common mental disorders (CMDs) and the strengthening of protective factors for CMDs among nonclinical populations. This randomized controlled trial (RCT) evaluated the efficacy of a smartphone-delivered multicomponent lifestyle medicine (LM) intervention, Lifestyle Hub, for improving mental health among a nonclinical population of Chinese adults. METHODS: A total of 106 participants with Patient Health Questionnaire-9 total score < 10 and Generalized Anxiety Disorder 7-Item Scale <8 were randomly assigned to either the Lifestyle Hub intervention group (LH, n = 53) or the waitlist control group (WL, n = 53). Lifestyle Hub is an 8-week smartphone-delivered multicomponent LM intervention developed based on the transtheoretical model. The intervention components included lifestyle psychoeducation, physical activity, diet and nutrition, stress management, sleep management, and motivation and goal-setting techniques. Assessments were conducted at baseline, immediate post-intervention, and 1-month follow-up (LH only). RESULTS: The linear mixed effect model based on the intention-to-treat principle indicated that Lifestyle Hub significantly improved overall mental health, depressive symptoms, anxiety symptoms, stress, insomnia severity, overall health-promoting behaviors, dietary quality, and stress management compared to the WL group at immediate post-intervention (d = 0.13-0.56). No significant between-group differences were observed in terms of functional impairment, health-related quality of life, health responsibility, physical activity level, spiritual growth, and interpersonal relations. The intervention gains in the LH group were maintained at 1-month follow-up. The LH participants indicated that Lifestyle Hub was an acceptable intervention for improving mental health, although a significantly higher level of study attrition was observed in the LH group (20.8%) relative to the WL group (5.7%). CONCLUSION: Lifestyle Hub may serve as an efficacious and acceptable intervention for improving mental health in nonclinical adult populations. To extend the benefits of LM interventions at the population level, future studies are warranted to examine a stepped-care approach to delivering LM interventions.Trial registration: This randomized controlled trial was pre-registered with ClinicalTrials.gov (NCT04295369).
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ItemExploring individual fixel-based white matter abnormalities in epilepsy(OXFORD UNIV PRESS, 2023-12-28)Diffusion MRI has provided insight into the widespread structural connectivity changes that characterize epilepsies. Although syndrome-specific white matter abnormalities have been demonstrated, studies to date have predominantly relied on statistical comparisons between patient and control groups. For diffusion MRI techniques to be of clinical value, they should be able to detect white matter microstructural changes in individual patients. In this study, we apply an individualized approach to a technique known as fixel-based analysis, to examine fibre-tract-specific abnormalities in individuals with epilepsy. We explore the potential clinical value of this individualized fixel-based approach in epilepsy patients with differing syndromic diagnoses. Diffusion MRI data from 90 neurologically healthy control participants and 10 patients with epilepsy (temporal lobe epilepsy, progressive myoclonus epilepsy, and Dravet Syndrome, malformations of cortical development) were included in this study. Measures of fibre density and cross-section were extracted for all participants across brain white matter fixels, and mean values were computed within select tracts-of-interest. Scanner harmonized and normalized data were then used to compute Z-scores for individual patients with epilepsy. White matter abnormalities were observed in distinct patterns in individual patients with epilepsy, both at the tract and fixel level. For patients with specific epilepsy syndromes, the detected white matter abnormalities were in line with expected syndrome-specific clinical phenotypes. In patients with lesional epilepsies (e.g. hippocampal sclerosis, periventricular nodular heterotopia, and bottom-of-sulcus dysplasia), white matter abnormalities were spatially concordant with lesion location. This proof-of-principle study demonstrates the clinical potential of translating advanced diffusion MRI methodology to individual-patient-level use in epilepsy. This technique could be useful both in aiding diagnosis of specific epilepsy syndromes, and in localizing structural abnormalities, and is readily amenable to other neurological disorders. We have included code and data for this study so that individualized white matter changes can be explored robustly in larger cohorts in future work.
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ItemNo Preview AvailableA longitudinal study of childhood maltreatment, subcortical development, and subcortico-cortical structural maturational coupling from early to late adolescence.(Cambridge University Press (CUP), 2023-12)BACKGROUND: Examining neurobiological mechanisms that may transmit the effects of childhood maltreatment on mental health in youth is crucial for understanding vulnerability to psychopathology. This study investigated associations between childhood maltreatment, adolescent structural brain development, and mental health trajectories into young-adulthood. METHODS: Structural magnetic resonance imaging data was acquired from 144 youth at three time points (age 12, 16, and 18 years). Childhood maltreatment was reported to occur prior to the first scan. Linear mixed models were utilized to examine the association between total childhood maltreatment, neglect, abuse and (i) amygdala and hippocampal volume development, and (ii) maturational coupling between amygdala/hippocampus volume and the thickness of prefrontal regions. We also examined whether brain development mediated the association between maltreatment and depressive and anxiety symptoms trajectories from age 12 to 28. RESULTS: Total maltreatment, and neglect, were associated with positive maturational coupling between the amygdala and caudal anterior cingulate cortex (cACC), whereby at higher and lower levels of amygdala growth, maltreatment was associated with lower and higher PFC thinning, respectively. Neglect was also associated with maturational coupling of the hippocampus with prefrontal regions. While positive amygdala-cACC maturational coupling was associated with greater increases in anxiety symptoms, it did not significantly mediate the association between maltreatment and anxiety symptom trajectories. CONCLUSION: We found maltreatment to be associated with altered patterns of coupling between subcortical and prefrontal regions during adolescence, suggesting that maltreatment is associated with the development of socio-emotional neural circuitry. The implications of these findings for mental health require further investigation.
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ItemNo Preview AvailableEmotion regulation strategy use in PTSD: A daily life study(ELSEVIER, 2023-10-01)BACKGROUND: Posttraumatic Stress Disorder is associated with emotion regulation difficulties. However, our understanding of these difficulties has been limited by the reliance of previous work on retrospective trait self-reports, which are unable to capture dynamic, ecologically-valid use of emotion regulation strategies. METHODS: To address this issue, this study used an ecological momentary assessment (EMA) design to understand the impact of PTSD on emotion regulation in daily life. We conducted an EMA study in a trauma exposed sample with varying levels of PTSD severity (N = 70; 7 days; 423 observations). RESULTS: We found that PTSD severity was linked to greater use of disengagement and perseverative-based strategies to manage negative emotions, regardless of emotional intensity. LIMITATIONS: Study design did not allow investigation into the temporal use of emotion regulation strategies and small sample size. CONCLUSIONS: This pattern of responding to emotions may interfere with engaging with the fear structure and thus impair emotion processing in current frontline treatments; clinical implications are discussed.
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ItemThe Early Mid-Career Committee (EMCC) of the International Society for Bipolar Disorders: Aspirations and goals(Wiley, 2022-12)In 2021, the International Society for Bipolar Disorders (ISBD) launched a new global initiative to support researchers and clinicians specializing in bipolar disorder who are still in the process of establishing their careers. To capture the needs of this group, an Early and Mid-Career Committee (EMCC) was formed and tasked with the development of activities and initiatives to address this objective. To this end, the committee conducted a needs assessment survey in early 2022 that was distributed and completed worldwide. This paper, authored by members of the committee, outlines the rationale, process, goals, and aspirations of the EMCC and summarizes the development of the needs survey.
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ItemNo Preview AvailableDevelopment of harmonized and co‐calibrated scores for memory, executive functioning, language, and visuospatial in the AIBL Study, ADNI, and NACC datasets(Wiley, 2022-12)Background The Australian Imaging, Biomarkers and Lifestyle (AIBL) Study is a prospective study collecting extensive cognitive, clinical, fluid, and imaging biomarkers data from older adults living in Australia. Integration of outcomes between large prospective studies of AD will provide greater precision in models of AD brain‐behavior relationships, so it is important to align composite scores for cognitive domains between such studies. Methods Detailed methods for AIBL, the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the National Alzheimer’s Coordinating Center (NACC) have been published. Briefly, AIBL participants had cognition assessed with an extensive neuropsychological test battery alongside health and biomarker assessments at entry and each 18‐months thereafter. Granular‐level cognitive data were obtained and an expert panel of two neuropsychologists and a behavioral neurologist categorized each element as assessing memory, executive functioning, language, visuospatial, or none of these, exactly as we have done previously. We also identified elements we had previously calibrated from other studies; after careful quality control and confirmation these served as anchors enabling co‐calibration. We used confirmatory factor analysis bi‐factor models to calibrate the AIBL battery with other studies. We used those calibrations to obtain co‐calibrated scores for all AIBL participants at every study visit. Here we show descriptive statistics for baseline visits, separately by diagnosis (normal cognition, mild cognitive impairment (MCI), dementia) for two enrollment waves for AIBL as well as for each phase of ADNI and across the Uniform Data Set (UDS) 1 & 2 (UDS1/2) and UDS3 time periods for NACC. Results Box plots for memory, executive functioning, language, and visuospatial for people with normal cognition are in Figure 1, MCI in Figure 2, and dementia in Figure 3. These figures show there is substantial cognitive variation across waves within these disease stage groups and across studies. Conclusion Co‐calibrated neuropsychological domain scores provide a common metric for integrating cognitive data across studies. Co‐calibrated scores aggregated across large prospective AD studies such as AIBL, ADNI, and NACC provide a foundation for large‐scale models of the development of AD and can serve as phenotypes for genetics studies. Co‐calibrated scores are available from AIBL, ADNI, and from NACC.