Psychiatry - Research Publications
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ItemGenetic Influences on Cost-Efficient Organization of Human Cortical Functional Networks(SOC NEUROSCIENCE, 2011-03-02)The human cerebral cortex is a complex network of functionally specialized regions interconnected by axonal fibers, but the organizational principles underlying cortical connectivity remain unknown. Here, we report evidence that one such principle for functional cortical networks involves finding a balance between maximizing communication efficiency and minimizing connection cost, referred to as optimization of network cost-efficiency. We measured spontaneous fluctuations of the blood oxygenation level-dependent signal using functional magnetic resonance imaging in healthy monozygotic (16 pairs) and dizygotic (13 pairs) twins and characterized cost-efficient properties of brain network functional connectivity between 1041 distinct cortical regions. At the global network level, 60% of the interindividual variance in cost-efficiency of cortical functional networks was attributable to additive genetic effects. Regionally, significant genetic effects were observed throughout the cortex in a largely bilateral pattern, including bilateral posterior cingulate and medial prefrontal cortices, dorsolateral prefrontal and superior parietal cortices, and lateral temporal and inferomedial occipital regions. Genetic effects were stronger for cost-efficiency than for other metrics considered, and were more clearly significant in functional networks operating in the 0.09-0.18 Hz frequency interval than at higher or lower frequencies. These findings are consistent with the hypothesis that brain networks evolved to satisfy competitive selection criteria of maximizing efficiency and minimizing cost, and that optimization of network cost-efficiency represents an important principle for the brain's functional organization.
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ItemDisruption of structure-function coupling in the schizophrenia connectome(ELSEVIER SCI LTD, 2014)Neuroimaging studies have demonstrated that the phenomenology of schizophrenia maps onto diffuse alterations in large-scale functional and structural brain networks. However, the relationship between structural and functional deficits remains unclear. To answer this question, patients with established schizophrenia and matched healthy controls underwent resting-state functional and diffusion weighted imaging. The network-based statistic was used to characterize between-group differences in whole-brain functional connectivity. Indices of white matter integrity were then estimated to assess the structural correlates of the functional alterations observed in patients. Finally, group differences in the relationship between indices of functional and structural brain connectivity were determined. Compared to controls, patients with schizophrenia showed decreased functional connectivity and impaired white matter integrity in a distributed network encompassing frontal, temporal, thalamic, and striatal regions. In controls, strong interregional coupling in neural activity was associated with well-myelinated white matter pathways in this network. This correspondence between structure and function appeared to be absent in patients with schizophrenia. In two additional disrupted functional networks, encompassing parietal, occipital, and temporal cortices, the relationship between function and structure was not affected. Overall, results from this study highlight the importance of considering not only the separable impact of functional and structural connectivity deficits on the pathoaetiology of schizophrenia, but also the implications of the complex nature of their interaction. More specifically, our findings support the core nature of fronto-striatal, fronto-thalamic, and fronto-temporal abnormalities in the schizophrenia connectome.
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ItemNeuroprotection after a first episode of mania: a randomized controlled maintenance trial comparing the effects of lithium and quetiapine on grey and white matter volume(NATURE PUBLISHING GROUP, 2017-01-24)Lithium and quetiapine are effective treatments for bipolar disorder, but their potential neuroprotective effects in humans remain unclear. A single blinded equivalence randomized controlled maintenance trial was conducted in a prospective cohort of first-episode mania (FEM) patients (n=26) to longitudinally compare the putative protective effects of lithium and quetapine on grey and white matter volume. A healthy control sample was also collected (n=20). Using structural MRI scans, voxel-wise grey and white matter volumes at baseline and changes over time in response to treatment were investigated. Patients were assessed at three time points (baseline, 3 and 12-month follow-up), whereas healthy controls were assessed at two time points (baseline and 12-month follow-up). Patients were randomized to lithium (serum level 0.6 mmol l-1, n=20) or quetiapine (flexibly dosed up to 800 mg per day, n=19) monotherapy. At baseline, compared with healthy control subjects, patients with FEM showed reduced grey matter in the orbitofrontal cortex, anterior cingulate, inferior frontal gyrus and cerebellum. In addition, patients had reduced internal capsule white matter volume bilaterally (t1,66>3.20, P<0.01). Longitudinally, there was a significant treatment × time effect only in the white matter of the left internal capsule (F2,112=8.54, P<0.01). Post hoc testing showed that, compared with baseline, lithium was more effective than quetiapine in slowing the progression of white matter volume reduction after 12 months (t1,24=3.76, P<0.01). Our data support the role of lithium but not quetiapine therapy in limiting white matter reduction early in the illness course after FEM.
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ItemDifferential effect of quetiapine and lithium on functional connectivity of the striatum in first episode mania(NATURE PUBLISHING GROUP, 2018-03-06)Mood disturbances seen in first-episode mania (FEM) are linked to disturbed functional connectivity of the striatum. Lithium and quetiapine are effective treatments for mania but their neurobiological effects remain largely unknown. We conducted a single-blinded randomized controlled maintenance trial in 61 FEM patients and 30 healthy controls. Patients were stabilized for a minimum of 2 weeks on lithium plus quetiapine then randomly assigned to either lithium (serum level 0.6 mmol/L) or quetiapine (dosed up to 800 mg/day) treatment for 12 months. Resting-state fMRI was acquired at baseline, 3 months (patient only) and 12 months. The effects of treatment group, time and their interaction, on striatal functional connectivity were assessed using voxel-wise general linear modelling. At baseline, FEM patients showed reduced connectivity in the dorsal (p = 0.05) and caudal (p = 0.008) cortico-striatal systems when compared to healthy controls at baseline. FEM patients also showed increased connectivity in a circuit linking the ventral striatum with the medial orbitofrontal cortex, cerebellum and thalamus (p = 0.02). Longitudinally, we found a significant interaction between time and treatment group, such that lithium was more rapid, compared to quetiapine, in normalizing abnormally increased functional connectivity, as assessed at 3-month and 12-month follow-ups. The results suggest that FEM is associated with reduced connectivity in dorsal and caudal corticostriatal systems, as well as increased functional connectivity of ventral striatal systems. Lithium appears to act more rapidly than quetiapine in normalizing hyperconnectivity of the ventral striatum with the cerebellum. The study was registered on the Australian and New Zealand Clinical Trials Registry (ACTRN12607000639426). http://www.anzctr.org.au.
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ItemPineal Gland Volume in Major Depressive and Bipolar Disorders(FRONTIERS MEDIA SA, 2020-05-20)Abnormal melatonin secretion has been demonstrated in patients with affective disorders such as major depressive disorder (MDD) and bipolar disorder (BD). However, magnetic resonance imaging (MRI) studies that previously investigated the volume of the pineal gland, which regulates circadian rhythms by secreting melatonin, in these patients reported inconsistent findings. The present study employed MRI to examine pineal gland volumes and pineal cyst prevalence in 56 MDD patients (29 currently depressed and 27 remitted patients), 26 BD patients, and matched controls (33 for MDD and 24 for BD). Pineal volumes and cyst prevalence in the current MDD, remitted MDD, and BD groups did not significantly differ from those of the healthy controls. However, pineal gland volumes were significantly smaller in the current MDD subgroup of non-melancholic depression than in the melancholic MDD subgroup. Interestingly, pineal volumes correlated negatively with the severity of loss of interest in the current MDD group. Medication and the number of affective episodes were not associated with pineal volumes in the MDD or BD group. While these results do not suggest that pineal volumes reflect abnormal melatonin secretion in affective disorders, they do point to the possibility that pineal abnormalities are associated with clinical subtypes of MDD and its symptomatology.
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ItemModulation of Brain Resting-State Networks by Sad Mood Induction(PUBLIC LIBRARY SCIENCE, 2008-03-19)BACKGROUND: There is growing interest in the nature of slow variations of the blood oxygen level-dependent (BOLD) signal observed in functional MRI resting-state studies. In humans, these slow BOLD variations are thought to reflect an underlying or intrinsic form of brain functional connectivity in discrete neuroanatomical systems. While these 'resting-state networks' may be relatively enduring phenomena, other evidence suggest that dynamic changes in their functional connectivity may also emerge depending on the brain state of subjects during scanning. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we examined healthy subjects (n = 24) with a mood induction paradigm during two continuous fMRI recordings to assess the effects of a change in self-generated mood state (neutral to sad) on the functional connectivity of these resting-state networks (n = 24). Using independent component analysis, we identified five networks that were common to both experimental states, each showing dominant signal fluctuations in the very low frequency domain (approximately 0.04 Hz). Between the two states, we observed apparent increases and decreases in the overall functional connectivity of these networks. Primary findings included increased connectivity strength of a paralimbic network involving the dorsal anterior cingulate and anterior insula cortices with subjects' increasing sadness and decreased functional connectivity of the 'default mode network'. CONCLUSIONS/SIGNIFICANCE: These findings support recent studies that suggest the functional connectivity of certain resting-state networks may, in part, reflect a dynamic image of the current brain state. In our study, this was linked to changes in subjective mood.
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ItemNo Preview AvailableThe Impact of Cannabis Use on Cognitive Functioning in Patients With Schizophrenia: A Meta-analysis of Existing Findings and New Data in a First-Episode Sample(OXFORD UNIV PRESS, 2012-03)Cannabis use is highly prevalent among people with schizophrenia, and coupled with impaired cognition, is thought to heighten the risk of illness onset. However, while heavy cannabis use has been associated with cognitive deficits in long-term users, studies among patients with schizophrenia have been contradictory. This article consists of 2 studies. In Study I, a meta-analysis of 10 studies comprising 572 patients with established schizophrenia (with and without comorbid cannabis use) was conducted. Patients with a history of cannabis use were found to have superior neuropsychological functioning. This finding was largely driven by studies that included patients with a lifetime history of cannabis use rather than current or recent use. In Study II, we examined the neuropsychological performance of 85 patients with first-episode psychosis (FEP) and 43 healthy nonusing controls. Relative to controls, FEP patients with a history of cannabis use (FEP + CANN; n = 59) displayed only selective neuropsychological impairments while those without a history (FEP - CANN; n = 26) displayed generalized deficits. When directly compared, FEP + CANN patients performed better on tests of visual memory, working memory, and executive functioning. Patients with early onset cannabis use had less neuropsychological impairment than patients with later onset use. Together, these findings suggest that patients with schizophrenia or FEP with a history of cannabis use have superior neuropsychological functioning compared with nonusing patients. This association between better cognitive performance and cannabis use in schizophrenia may be driven by a subgroup of "neurocognitively less impaired" patients, who only developed psychosis after a relatively early initiation into cannabis use.
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ItemNo Preview AvailableGross morphological brain changes with chronic, heavy cannabis use(ROYAL COLLEGE OF PSYCHIATRISTS, 2015-01)We investigated the morphology of multiple brain regions in a rare sample of 15 very heavy cannabis users with minimal psychiatric comorbidity or significant exposure to other substances (compared with 15 age- and IQ-matched non-cannabis-using controls) using manual techniques. Heavy cannabis users demonstrated smaller hippocampus and amygdala volumes, but no alterations of the orbitofrontal and anterior- and paracingulate cortices, or the pituitary gland. These findings indicate that chronic cannabis use has a selective and detrimental impact on the morphology of the mediotemporal lobe.
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ItemNo Preview AvailableAetiological overlap between obsessive-compulsive related and anxiety disorder symptoms: multivariate twin study(CAMBRIDGE UNIV PRESS, 2016-01)BACKGROUND: The aetiological boundary between obsessive-compulsive related disorders (OCRDs) including obsessive-compulsive disorder (OCD) and anxiety disorders is unclear and continues to generate debate. AIMS: To determine the genetic overlap and the pattern of causal relationships among OCRDs and anxiety disorders. METHOD: Multivariate twin modelling methods and a new regression analysis to infer causation were used, involving 2495 male and female twins. RESULTS: The amount of common genetic liability observed for OCD symptoms was higher when considering anxiety disorders and OCRDs in the model v. modelling OCRD symptoms alone. OCD symptoms emerged as risk factors for the presence of generalised anxiety, panic and hoarding symptoms, whereas social phobia appeared as a risk factor for OCD symptoms. CONCLUSIONS: OCD represents a complex phenotype that includes important shared features with anxiety disorders and OCRDs. The novel patterns of risk identified between OCD and anxiety disorder may help to explain their frequent co-occurrence.
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ItemCognitive impairment in euthymic major depressive disorder: a meta-analysis(CAMBRIDGE UNIV PRESS, 2013-10)BACKGROUND: There is evidence to suggest that cognitive deficits might persist beyond the acute stages of illness in major depressive disorder (MDD). However, the findings are somewhat inconsistent across the individual studies conducted to date. Our aim was to conduct a systematic review and meta-analysis of existing studies that have examined cognition in euthymic MDD patients. METHOD: Following a systematic search across several publication databases, meta-analyses were conducted for 27 empirical studies that compared euthymic adult MDD patients (895 participants) and healthy controls (997 participants) across a range of cognitive domains. The influence of demographic variables and confounding factors, including age of onset and recurrent episodes, was examined. RESULTS: Compared with healthy controls, euthymic MDD patients were characterized by significantly poorer cognitive functions. However, the magnitude of observed deficits, with the exception of inhibitory control, were generally modest when late-onset cases were excuded. Late-onset cases demonstrated significantly more pronounced deficits in verbal memory, speed of information processing and some executive functions. CONCLUSIONS: Cognitive deficits, especially poor response inhibition, are likely to be persistent features, at least of some forms, of adult-onset MDD. More studies are necessary to examine cognitive dysfunction in remitted psychotic, melancholic and bipolar spectrum MDD. Cognitive deficits overall appear to be more common among patients with late-onset depression, supporting the theories suggesting that possible vascular and neurodegenerative factors play a role in a substantial number of these patients.