Psychiatry - Research Publications
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ItemNo Preview AvailableDisruptions in white matter microstructure associated with impaired visual associative memory in schizophrenia-spectrum illness(SPRINGER HEIDELBERG, 2022-09-01)Episodic memory ability relies on hippocampal-prefrontal connectivity. However, few studies have examined relationships between memory performance and white matter (WM) microstructure in hippocampal-prefrontal pathways in schizophrenia-spectrum disorder (SSDs). Here, we investigated these relationships in individuals with first-episode psychosis (FEP) and chronic schizophrenia-spectrum disorders (SSDs) using tractography analysis designed to interrogate the microstructure of WM tracts in the hippocampal-prefrontal pathway. Measures of WM microstructure (fractional anisotropy [FA], radial diffusivity [RD], and axial diffusivity [AD]) were obtained for 47 individuals with chronic SSDs, 28 FEP individuals, 52 older healthy controls, and 27 younger healthy controls. Tractography analysis was performed between the hippocampus and three targets involved in hippocampal-prefrontal connectivity (thalamus, amygdala, nucleus accumbens). Measures of WM microstructure were then examined in relation to episodic memory performance separately across each group. Both those with FEP and chronic SSDs demonstrated impaired episodic memory performance. However, abnormal WM microstructure was only observed in individuals with chronic SSDs. Abnormal WM microstructure in the hippocampal-thalamic pathway in the right hemisphere was associated with poorer memory performance in individuals with chronic SSDs. These findings suggest that disruptions in WM microstructure in the hippocampal-prefrontal pathway may contribute to memory impairments in individuals with chronic SSDs but not FEP.
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ItemIn Vivo 7-Tesla MRI Investigation of Brain Iron and Its Metabolic Correlates in Chronic Schizophrenia(NATURE PORTFOLIO, 2022-10-26)Brain iron is central to dopaminergic neurotransmission, a key component in schizophrenia pathology. Iron can also generate oxidative stress, which is one proposed mechanism for gray matter volume reduction in schizophrenia. The role of brain iron in schizophrenia and its potential link to oxidative stress has not been previously examined. In this study, we used 7-Tesla MRI quantitative susceptibility mapping (QSM), magnetic resonance spectroscopy (MRS), and structural T1 imaging in 12 individuals with chronic schizophrenia and 14 healthy age-matched controls. In schizophrenia, there were higher QSM values in bilateral putamen and higher concentrations of phosphocreatine and lactate in caudal anterior cingulate cortex (caCC). Network-based correlation analysis of QSM across corticostriatal pathways as well as the correlation between QSM, MRS, and volume, showed distinct patterns between groups. This study introduces increased iron in the putamen in schizophrenia in addition to network-wide disturbances of iron and metabolic status.
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ItemBrain charts for the human lifespan (vol 604, pg 525, 2022)(NATURE PORTFOLIO, 2022-10-13)
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ItemNeuroanatomical heterogeneity and homogeneity in individuals at clinical high risk for psychosis(SPRINGERNATURE, 2022-07-26)Individuals at Clinical High Risk for Psychosis (CHR-P) demonstrate heterogeneity in clinical profiles and outcome features. However, the extent of neuroanatomical heterogeneity in the CHR-P state is largely undetermined. We aimed to quantify the neuroanatomical heterogeneity in structural magnetic resonance imaging measures of cortical surface area (SA), cortical thickness (CT), subcortical volume (SV), and intracranial volume (ICV) in CHR-P individuals compared with healthy controls (HC), and in relation to subsequent transition to a first episode of psychosis. The ENIGMA CHR-P consortium applied a harmonised analysis to neuroimaging data across 29 international sites, including 1579 CHR-P individuals and 1243 HC, offering the largest pooled CHR-P neuroimaging dataset to date. Regional heterogeneity was indexed with the Variability Ratio (VR) and Coefficient of Variation (CV) ratio applied at the group level. Personalised estimates of heterogeneity of SA, CT and SV brain profiles were indexed with the novel Person-Based Similarity Index (PBSI), with two complementary applications. First, to assess the extent of within-diagnosis similarity or divergence of neuroanatomical profiles between individuals. Second, using a normative modelling approach, to assess the 'normativeness' of neuroanatomical profiles in individuals at CHR-P. CHR-P individuals demonstrated no greater regional heterogeneity after applying FDR corrections. However, PBSI scores indicated significantly greater neuroanatomical divergence in global SA, CT and SV profiles in CHR-P individuals compared with HC. Normative PBSI analysis identified 11 CHR-P individuals (0.70%) with marked deviation (>1.5 SD) in SA, 118 (7.47%) in CT and 161 (10.20%) in SV. Psychosis transition was not significantly associated with any measure of heterogeneity. Overall, our examination of neuroanatomical heterogeneity within the CHR-P state indicated greater divergence in neuroanatomical profiles at an individual level, irrespective of psychosis conversion. Further large-scale investigations are required of those who demonstrate marked deviation.
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ItemNo Preview AvailableAssociation of Structural Magnetic Resonance Imaging Measures With Psychosis Onset in Individuals at Clinical High Risk for Developing Psychosis An ENIGMA Working Group Mega-analysis(AMER MEDICAL ASSOC, 2021-07)IMPORTANCE: The ENIGMA clinical high risk (CHR) for psychosis initiative, the largest pooled neuroimaging sample of individuals at CHR to date, aims to discover robust neurobiological markers of psychosis risk. OBJECTIVE: To investigate baseline structural neuroimaging differences between individuals at CHR and healthy controls as well as between participants at CHR who later developed a psychotic disorder (CHR-PS+) and those who did not (CHR-PS-). DESIGN, SETTING, AND PARTICIPANTS: In this case-control study, baseline T1-weighted magnetic resonance imaging (MRI) data were pooled from 31 international sites participating in the ENIGMA Clinical High Risk for Psychosis Working Group. CHR status was assessed using the Comprehensive Assessment of At-Risk Mental States or Structured Interview for Prodromal Syndromes. MRI scans were processed using harmonized protocols and analyzed within a mega-analysis and meta-analysis framework from January to October 2020. MAIN OUTCOMES AND MEASURES: Measures of regional cortical thickness (CT), surface area, and subcortical volumes were extracted from T1-weighted MRI scans. Independent variables were group (CHR group vs control group) and conversion status (CHR-PS+ group vs CHR-PS- group vs control group). RESULTS: Of the 3169 included participants, 1428 (45.1%) were female, and the mean (SD; range) age was 21.1 (4.9; 9.5-39.9) years. This study included 1792 individuals at CHR and 1377 healthy controls. Using longitudinal clinical information, 253 in the CHR-PS+ group, 1234 in the CHR-PS- group, and 305 at CHR without follow-up data were identified. Compared with healthy controls, individuals at CHR exhibited widespread lower CT measures (mean [range] Cohen d = -0.13 [-0.17 to -0.09]), but not surface area or subcortical volume. Lower CT measures in the fusiform, superior temporal, and paracentral regions were associated with psychosis conversion (mean Cohen d = -0.22; 95% CI, -0.35 to 0.10). Among healthy controls, compared with those in the CHR-PS+ group, age showed a stronger negative association with left fusiform CT measures (F = 9.8; P < .001; q < .001) and left paracentral CT measures (F = 5.9; P = .005; q = .02). Effect sizes representing lower CT associated with psychosis conversion resembled patterns of CT differences observed in ENIGMA studies of schizophrenia (ρ = 0.35; 95% CI, 0.12 to 0.55; P = .004) and individuals with 22q11.2 microdeletion syndrome and a psychotic disorder diagnosis (ρ = 0.43; 95% CI, 0.20 to 0.61; P = .001). CONCLUSIONS AND RELEVANCE: This study provides evidence for widespread subtle, lower CT measures in individuals at CHR. The pattern of CT measure differences in those in the CHR-PS+ group was similar to those reported in other large-scale investigations of psychosis. Additionally, a subset of these regions displayed abnormal age associations. Widespread disruptions in CT coupled with abnormal age associations in those at CHR may point to disruptions in postnatal brain developmental processes.
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ItemBrain charts for the human lifespan(NATURE PORTFOLIO, 2022-04-21)Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight1. Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data ( http://www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones3, showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes.
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ItemNo Preview AvailableImpaired olfactory ability associated with larger left hippocampus and rectus volumes at earliest stages of schizophrenia: A sign of neuroinflammation?(ELSEVIER IRELAND LTD, 2020-07)Impaired olfactory identification has been reported as a first sign of schizophrenia during the earliest stages of illness, including before illness onset. The aim of this study was to examine the relationship between volumes of these regions (amygdala, hippocampus, gyrus rectus and orbitofrontal cortex) and olfactory ability in three groups of participants: healthy control participants (Ctls), patients with first-episode schizophrenia (FE-Scz) and chronic schizophrenia patients (Scz). Exploratory analyses were performed in a sample of individuals at ultra-high risk (UHR) for psychosis in a co-submission paper (Masaoka et al., 2020). The relationship to brain structural measures was not apparent prior to psychosis onset, but was only evident following illness onset, with a different pattern of relationships apparent across illness stages (FE-Scz vs Scz). Path analysis found that lower olfactory ability was related to larger volumes of the left hippocampus and gyrus rectus in the FE-Scz group. We speculate that larger hippocampus and rectus in early schizophrenia are indicative of swelling, potentially caused by an active neurochemical or immunological process, such as inflammation or neurotoxicity, which is associated with impaired olfactory ability. The volumetric decreases in the chronic stage of Scz may be due to degeneration resulting from an active immune process and its resolution.
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ItemWhite Matter Alterations Between Brain Network Hubs Underlie Processing Speed Impairment in Patients With Schizophrenia.(Oxford University Press (OUP), 2021-01)Processing speed (PS) impairment is one of the most severe and common cognitive deficits in schizophrenia. Previous studies have reported correlations between PS and white matter diffusion properties, including fractional anisotropy (FA), in several fiber bundles in schizophrenia, suggesting that white matter alterations could underpin decreased PS. In schizophrenia, white matter alterations are most prevalent within inter-hub connections of the rich club. However, the spatial and topological characteristics of this association between PS and FA have not been investigated in patients. In this context, we tested whether structural connections comprising the rich club network would underlie PS impairment in 298 patients with schizophrenia or schizoaffective disorder and 190 healthy controls from the Australian Schizophrenia Research Bank. PS, measured using the digit symbol coding task, was largely (Cohen's d = 1.33) and significantly (P < .001) reduced in the patient group when compared with healthy controls. Significant associations between PS and FA were widespread in the patient group, involving all cerebral lobes. FA was not associated with other cognitive measures of phonological fluency and verbal working memory in patients, suggesting specificity to PS. A topological analysis revealed that despite being spatially widespread, associations between PS and FA were over-represented among connections forming the rich club network. These findings highlight the need to consider brain network topology when investigating high-order cognitive functions that may be spatially distributed among several brain regions. They also reinforce the evidence that brain hubs and their interconnections may be particularly vulnerable parts of the brain in schizophrenia.
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ItemFunctional Connectivity in Antipsychotic-Treated and Antipsychotic-Naive Patients With First-Episode Psychosis and Low Risk of Self-harm or Aggression A Secondary Analysis of a Randomized Clinical Trial(AMER MEDICAL ASSOC, 2021-09)IMPORTANCE: Altered functional connectivity (FC) is a common finding in resting-state functional magnetic resonance imaging (rs-fMRI) studies of people with psychosis, yet how FC disturbances evolve in the early stages of illness, and how antipsychotic treatment influences these disturbances, remains unknown. OBJECTIVE: To investigate longitudinal FC changes in antipsychotic-naive and antipsychotic-treated patients with first-episode psychosis (FEP). DESIGN, SETTING, AND PARTICIPANTS: This secondary analysis of a triple-blind, randomized clinical trial was conducted over a 5-year recruitment period between April 2008 and December 2016 with 59 antipsychotic-naive patients with FEP receiving either a second-generation antipsychotic or a placebo pill over a treatment period of 6 months. Participants were required to have low suicidality and aggression, to have a duration of untreated psychosis of less than 6 months, and to be living in stable accommodations with social support. Both FEP groups received intensive psychosocial therapy. A healthy control group was also recruited. Participants completed rs-fMRI scans at baseline, 3 months, and 12 months. Data were analyzed from May 2019 to August 2020. INTERVENTIONS: Resting-state functional MRI was used to probe brain FC. Patients received either a second-generation antipsychotic or a matched placebo tablet. Both patient groups received a manualized psychosocial intervention. MAIN OUTCOMES AND MEASURES: The primary outcomes of this analysis were to investigate (1) FC differences between patients and controls at baseline; (2) FC changes in medicated and unmedicated patients between baseline and 3 months; and (3) associations between longitudinal FC changes and clinical outcomes. An additional aim was to investigate long-term FC changes at 12 months after baseline. These outcomes were not preregistered. RESULTS: Data were analyzed for 59 patients (antipsychotic medication plus psychosocial treatment: 28 [47.5%]; mean [SD] age, 19.5 [3.0] years; 15 men [53.6%]; placebo plus psychosocial treatment: 31 [52.5%]; mean [SD] age, 18.8 [2.7]; 16 men [51.6%]) and 27 control individuals (mean [SD] age, 21.9 [1.9] years). At baseline, patients showed widespread functional dysconnectivity compared with controls, with reductions predominantly affecting interactions between the default mode network, limbic systems, and the rest of the brain. From baseline to 3 months, patients receiving placebo showed increased FC principally within the same systems; some of these changes correlated with improved clinical outcomes (canonical correlation analysis R = 0.901; familywise error-corrected P = .005). Antipsychotic exposure was associated with increased FC primarily between the thalamus and the rest of the brain. CONCLUSIONS AND RELEVANCE: In this secondary analysis of a clinical trial, antipsychotic-naive patients with FEP showed widespread functional dysconnectivity at baseline, followed by an early normalization of default mode network and cortical limbic dysfunction in patients receiving placebo and psychosocial intervention. Antipsychotic exposure was associated with FC changes concentrated on thalamocortical networks. TRIAL REGISTRATION: ACTRN12607000608460.
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ItemDifferentiating the effect of antipsychotic medication and illness on brain volume reductions in first-episode psychosis: A Longitudinal, Randomised, Triple-blind, Placebo-controlled MRI Study(SPRINGERNATURE, 2021-07)Changes in brain volume are a common finding in Magnetic Resonance Imaging (MRI) studies of people with psychosis and numerous longitudinal studies suggest that volume deficits progress with illness duration. However, a major unresolved question concerns whether these changes are driven by the underlying illness or represent iatrogenic effects of antipsychotic medication. In this study, 62 antipsychotic-naïve patients with first-episode psychosis (FEP) received either a second-generation antipsychotic (risperidone or paliperidone) or a placebo pill over a treatment period of 6 months. Both FEP groups received intensive psychosocial therapy. A healthy control group (n = 27) was also recruited. Structural MRI scans were obtained at baseline, 3 months and 12 months. Our primary aim was to differentiate illness-related brain volume changes from medication-related changes within the first 3 months of treatment. We secondarily investigated long-term effects at the 12-month timepoint. From baseline to 3 months, we observed a significant group x time interaction in the pallidum (p < 0.05 FWE-corrected), such that patients receiving antipsychotic medication showed increased volume, patients on placebo showed decreased volume, and healthy controls showed no change. Across the entire patient sample, a greater increase in pallidal grey matter volume over 3 months was associated with a greater reduction in symptom severity. Our findings indicate that psychotic illness and antipsychotic exposure exert distinct and spatially distributed effects on brain volume. Our results align with prior work in suggesting that the therapeutic efficacy of antipsychotic medications may be primarily mediated through their effects on the basal ganglia.