ORCID Profile
0000-0002-8569-7139
Current Organisations
UNSW Sydney
,
Neuroscience Research Australia
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Publisher: Elsevier BV
Date: 05-2018
Publisher: No publisher found
Date: 2018
DOI: 10.1016/J.NEUBIOREV.2018.08.017
Abstract: The glucocorticoid receptor gene (NR3C1) is a critical component of the stress response system. Cytosine methylation of NR3C1 has been repeatedly associated with trauma and mental disorders, including major depression, post-traumatic stress disorder, anxiety, and personality disorders, suggesting that NR3C1 methylation may play a role in stress-related psychopathology. We systematically reviewed 55 studies examining NR3C1 DNA methylation in association with trauma exposure, psychopathology, gene expression, and/or common genetic variants. Overall, a number of NR3C1 CpG sites were significantly associated with trauma or psychopathology, but significant findings were often inconsistent across studies. This lack of consistency is likely influenced by significant methodological variability - experimentally and analytically - across studies. Selected common genetic variants show no significant effect on NR3C1 CpG methylation. In contrast, there was le evidence linking increased methylation of NR3C1 to reduced expression of this gene. The inverse association between methylation and gene expression shown across eight out of ten studies supports the notion that methylation in the promoter region of NR3C1 is associated with transcriptional silencing.
Publisher: Elsevier BV
Date: 10-2019
Publisher: Proceedings of the National Academy of Sciences
Date: 28-03-2023
Abstract: Left–right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small s les and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case–control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected in iduals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected in iduals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case–control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case–control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case–control status. Subtle case–control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.
Publisher: Wiley
Date: 20-10-2023
DOI: 10.1002/BRB3.3292
Publisher: Oxford University Press (OUP)
Date: 04-2018
Publisher: Springer Science and Business Media LLC
Date: 13-04-2017
DOI: 10.1007/S11682-017-9712-0
Abstract: GRM5 (coding for metabotropic glutamate receptor 5, mGluR5) is a promising target for the treatment of cognitive deficits in schizophrenia, but there has been little investigation of its association with cognitive and brain phenotypes within this disorder. We examined the effects of common genetic variation in GRM5 with cognitive function, hippoc al volume, and hippoc al mGluR5 protein levels in schizophrenia patients relative to healthy controls. Two independent GRM5 variants rs60954128 [C>T] and rs3824927 [G>T] were genotyped in a schizophrenia case/control cohort (n=249/261). High-resolution anatomical brain scans were available for a subset of the cohort (n=103 schizophrenia /78 control). All participants completed a standard set of neuropsychological tests. In a separate postmortem cohort (n=19 schizophrenia/20 controls), hippoc al mGluR5 protein levels were examined among in iduals of different GRM5 genotypes. Schizophrenia minor allele carriers of rs60954128 had reduced right hippoc al volume relative to healthy controls of the same genotype (-12.3%) this effect was exaggerated in males with schizophrenia (-15.6%). For rs3824927, compared to major allele homozygotes, minor allele carriers with schizophrenia had lower Intelligence Quotients (IQ). Examination in hippoc al postmortem tissue showed no difference in mGluR5 protein expression according to genotype for either rs60954128 or rs3824927. While these genetic variants in GRM5 were associated with cognitive impairments and right hippoc al volume reduction in schizophrenia, they did not affect protein expression. Further study of these mechanisms may help to delineate new targets for the treatment of cognitive deficits in schizophrenia, and may be relevant to other disorders.
Publisher: Cold Spring Harbor Laboratory
Date: 28-09-2023
Publisher: American Psychological Association (APA)
Date: 06-2018
DOI: 10.1037/PNE0000108
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.PNPBP.2017.12.007
Abstract: The single nucleotide polymorphism (SNP) rs1344706 [A>C] within intron 2 of the zinc finger protein 804A gene (ZNF804A) is associated with schizophrenia at the genome-wide level, but its function in relation to the development of psychotic disorders, including its influence on brain morphology remains unclear. Using both univariate (voxel-based morphometry, VBM cortical thickness) and multivariate (source-based morphometry, SBM) approaches, we examined the effects of variation of the rs1344706 polymorphism on grey matter integrity in 214 Caucasian schizophrenia cases and 94 Caucasian healthy in iduals selected from the Australian Schizophrenia Research Bank. Neither univariate nor multivariate analyses showed any associations between indices of grey matter and rs1344706 variation in schizophrenia or healthy participants. This was revealed in the context of the typical pattern of decreased grey matter integrity in schizophrenia compared to healthy in iduals, including: (1) large grey matter volume reductions in the orbitofrontal and anterior cingulate cortices and the left fusiform/inferior temporal gyri (2) decreased cortical thickness in the left inferior temporal and fusiform gyri, the left orbitofrontal gyrus, as well as in the right pars opercularis recentral gyrus and (3) decreased covariation of grey matter concentration in frontal and limbic brain regions emerging from the SBM analyses. Contrary to some - but not all - previous findings, this study of a large s le of schizophrenia cases and healthy controls reveals no evidence for association between grey matter alterations and variation in rs1344706 (ZNF804A). Differences in s le sizes and ethnicities may account for discrepant findings between the present and previous studies.
Publisher: Elsevier BV
Date: 05-2020
Publisher: Springer Science and Business Media LLC
Date: 10-02-2022
DOI: 10.1038/S41380-022-01460-7
Abstract: Brain morphology differs markedly between in iduals with schizophrenia, but the cellular and genetic basis of this heterogeneity is poorly understood. Here, we sought to determine whether cortical thickness (CTh) heterogeneity in schizophrenia relates to interregional variation in distinct neural cell types, as inferred from established gene expression data and person-specific genomic variation. This study comprised 1849 participants in total, including a discovery (140 cases and 1267 controls) and a validation cohort (335 cases and 185 controls). To characterize CTh heterogeneity, normative ranges were established for 34 cortical regions and the extent of deviation from these ranges was measured for each in idual with schizophrenia. CTh deviations were explained by interregional gene expression levels of five out of seven neural cell types examined: (1) astrocytes (2) endothelial cells (3) oligodendrocyte progenitor cells (OPCs) (4) excitatory neurons and (5) inhibitory neurons. Regional alignment between CTh alterations with cell type transcriptional maps distinguished broad patient subtypes, which were validated against genomic data drawn from the same in iduals. In a predominantly neuronal/endothelial subtype (22% of patients), CTh deviations covaried with polygenic risk for schizophrenia (sczPRS) calculated specifically from genes marking neuronal and endothelial cells ( r = −0.40, p = 0.010). Whereas, in a predominantly glia/OPC subtype (43% of patients), CTh deviations covaried with sczPRS calculated from glia and OPC-linked genes ( r = −0.30, p = 0.028). This multi-scale analysis of genomic, transcriptomic, and brain phenotypic data may indicate that CTh heterogeneity in schizophrenia relates to inter-in idual variation in cell-type specific functions. Decomposing heterogeneity in relation to cortical cell types enables prioritization of schizophrenia subsets for future disease modeling efforts.
Publisher: Wiley
Date: 27-06-2018
DOI: 10.1111/ACPS.12920
Abstract: Exposure to sexual assault is a significant risk factor to develop post-traumatic stress disorder (PTSD) in females. The early neurobiological changes leading to the development of PTSD remain understudied and unclear in this population. Participants were 27 adult females recruited within a month following exposure to sexual assault (T1) and 20 age-matched non-exposed controls. Among the victims, 10 participants met (PTSD+) and 15 did not meet (PTSD-) DSM-IV criteria for PTSD 6 months post-trauma (T2). At both visits, hippoc al and amygdala volumes were extracted from magnetic resonance imaging scans, and indices of total diurnal cortisol changes were derived from in idual areas under the curve relative to the ground (AUCg). Measures at T1 were compared between groups at T1, measures at T2 between groups at T2, and measures at T1 between groups at T2. At T1, victims had significantly smaller bilateral hippoc al volumes, but not AUCg, than controls. At T2, neither hippoc al volume nor AUCg significantly differed among the groups. However, the PTSD+ group had significantly smaller hippoc al volumes at T1 than the control group, but not compared to the PTSD- group. This study indicates that having smaller hippoc al volumes is a risk factor to develop PTSD in females exposed to sexual assault.
Publisher: Cold Spring Harbor Laboratory
Date: 03-09-2018
DOI: 10.1101/399402
Abstract: The cerebral cortex underlies our complex cognitive capabilities, yet we know little about the specific genetic loci influencing human cortical structure. To identify genetic variants, including structural variants, impacting cortical structure, we conducted a genome-wide association meta-analysis of brain MRI data from 51,662 in iduals. We analysed the surface area and average thickness of the whole cortex and 34 regions with known functional specialisations. We identified 255 nominally significant loci ( P ≤ 5 × 10 −8 ) 199 survived multiple testing correction ( P ≤ 8.3 × 10 −10 187 surface area 12 thickness). We found significant enrichment for loci influencing total surface area within regulatory elements active during prenatal cortical development, supporting the radial unit hypothesis. Loci impacting regional surface area cluster near genes in Wnt signalling pathways, known to influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson’s disease, insomnia, depression and ADHD. Common genetic variation is associated with inter-in idual variation in the structure of the human cortex, both globally and within specific regions, and is shared with genetic risk factors for some neuropsychiatric disorders.
Publisher: Elsevier BV
Date: 07-2020
Publisher: CMA Joule Inc.
Date: 09-2018
DOI: 10.1503/JPN.170116
Abstract: Survivors of sexual assault are vulnerable to long-term negative psychological and physical health outcomes, but few studies have investigated changes in cognition, emotional processing and brain function in the early stages after sexual assault. We used a multimodal approach to identify the cognitive and emotional correlates associated with sexual assault in women. Twenty-seven female survivors of sexual assault were included within 4 weeks of the traumatic event, and they were compared with 20 age-matched controls. Participants underwent functional MRI while performing cognitive/emotional tasks (n-back, emotional go/no-go, mental imagery). We also measured diurnal salivary cortisol and conducted neuropsychological assessments of attention and memory abilities. Relative to the control group, the survivors group had lower levels of morning cortisol and showed attentional deficits. We observed no between-group differences in brain activation during the n-back or mental imagery tasks. During the emotional go/no-go task, however, the survivors group showed a lack of deactivation in the dorsal anterior cingulate cortex when processing emotional material, relative to neutral material. Exploratory analyses in the survivors group indicated that symptom severity was negatively associated with cerebellar activation when positive emotional (happy) content interfered with response inhibition, and positively associated with cerebellar activation when thinking of positive (happy) memories. The small s le size was the main limitation of this study. Dysfunctions in the dorsal anterior cingulate cortex and the cerebellum may represent early functional brain modifications that alter higher cognitive processes when emotional material is involved.
Publisher: Cold Spring Harbor Laboratory
Date: 15-02-2022
DOI: 10.1101/2022.02.11.22270877
Abstract: Depressive symptoms are often comorbid to chronic pain. These conditions share aberrant emotion processing and regulation, as well as common brain networks. However, the relationship between depressive symptoms and chronic pain on emotional brain function is unclear. Participants were 26 in iduals with chronic pain (referred to as the Pain group) and 32 healthy controls (HC), who underwent resting-state functional magnetic resonance imaging and completed the Beck Depressive Inventory. Main effects of group, depressive symptom severity (total score), and their interaction were evaluated on functional connectivity from three seed regions (separately, the left and right amygdalae, the medial prefrontal cortex, mPFC) and the rest of the brain. In case of significant interaction, moderation analyses were conducted. The group-by-depressive symptoms interaction was significantly associated with changes in connectivity between the right amygdala and the mPFC ( pFWEc .001). Moderation analysis indicated that, compared to the HC group, the Pain group showed weaker connectivity between these regions at lower levels of depressive symptoms ( p =0.018), and stronger connectivity at higher levels of depressive symptoms ( p =0.001). In addition, the strength of connectivity decreased in the HC ( p =0.004) and increased in the Pain group ( p =0.011) as the severity of depressive symptoms increased. Finally, the Pain group showed significant weaker connectivity between the mPFC seed and the left parahippoc al gyrus compared to the HC group ( pFWEc =0.015). These results indicate that depressive symptoms moderate the impact of chronic pain on the emotional brain function and highlight potential implications for the choice of treatment for chronic pain.
Publisher: Cold Spring Harbor Laboratory
Date: 12-04-2019
DOI: 10.1101/607309
Abstract: Schizophrenia (SZ) and bipolar disorder (BD) share numerous clinical and biological features as well as environmental risk factors that may be associated with altered DNA methylation. In this study we sought to construct a Poly-Methylomic Profile Score (PMPS) for SZ, representing the degree of epigenome-wide methylation according to previously published findings we then examined its association with SZ and BD in an independent s le. DNA methylation for 57 SZ, 59 BD cases and 55 healthy controls (HCs) was quantified using the Illumina 450K methylation beadchip. We constructed five PMPSs for different p-value thresholds using summary statistics reported in a large epigenome-wide schizophrenia case-control association study, weighted by in idual CpG effect sizes. All SZ PMPSs were significantly elevated in SZ cases relative to HCs, with the score calculated at the most stringent threshold accounting for the greatest amount of variance in SZ (compared to other PMPSs derived at more inclusive p -value thresholds). However, none of the PMPSs were associated with BD, or a combined cohort of BD and SZ cases relative to HCs. Results demonstrating elevated PMPSs in SZ relative to BD did not survive correction for multiple testing. PMPSs were also not associated with positive or negative symptom severity. That this SZ-derived PMPSs was elevated among SZ, but not BD participants, suggests that epigenome-wide methylation patterns associated with schizophrenia may represent distinct pathophysiology that is yet to be elucidated. Whether this PMPS may be associated with neuroanatomical or other biological endophenotypes relevant to SZ and/or BD remains to be determined.
Publisher: Elsevier BV
Date: 10-2019
Publisher: Elsevier BV
Date: 03-2021
Publisher: Cold Spring Harbor Laboratory
Date: 23-09-2023
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-05-2020
DOI: 10.1212/NXI.0000000000000739
Abstract: To determine whether virally suppressed HIV neuropathogenesis, a chronic neuroinflammatory state, promotes abnormal brain amyloid deposition. A total of 10 men with virally suppressed HIV-associated neurocognitive disorder (HAND), aged 46–68 years, underwent 11 C-labeled Pittsburgh compound B PET. Data from the Australian Imaging, Biomarkers and Lifestyle (AIBL), including 39 cognitively normal in iduals (aged 60–74 years), 7 in iduals with mild cognitive impairment (MCI) (aged 64–71 years), and 11 in iduals with Alzheimer disease (AD) (aged 55–74 years), were used as reference. Apart from more women, the AIBL cohort was demographically comparable with the HIV s le. Also, the AIBL PET data did not differ by sex. Cerebellum standardized uptake value ratio amyloid values within 22 regions of interest were estimated. In the HIV s le, apolipoprotein E (APOE) was available in 80%, CSF biomarkers in 60%, and 8–10 years of long-term health outcomes in 100%. HAND and the AIBL group with no cognitive deficits had similar amyloid deposition, which was lower than that in both the MCI and AD groups. At the in idual level, one HAND case showed high amyloid deposition consistent with AD. This case also had a CSF-AD–like profile and an E4/E4 for APOE. Clinically, this case declined over 18 years with mild HAND symptoms first, followed by progressive memory decline 8–9 years after the study PET, then progression to severe dementia within 2–3 years, and lived a further 6 years. Another HAND case showed increased amyloid deposition restricted to the hippoc i. Two other HAND cases showed abnormally decreased amyloid in subcortical areas. Relative to cognitively normal older controls, brain amyloid burden does not differ in virally suppressed HAND at the group level. However, in idual analyses show that abnormally high and low amyloid burden occur.
Publisher: Wiley
Date: 03-2018
DOI: 10.1111/INR.12436
Abstract: This paper will review progress towards the identified targets within the Australian government policy document commonly known as 'Closing the Gap' and examine the role of nurses in supporting its implementation. Australia is not alone in seeking to address the health inequity between Indigenous and non-Indigenous people. Globally such health inequities are similar and require interventions supported by governments in conjunction with health and education systems to affect desired change. For this reason, it is timely to undertake a review of progress on the impact of the Closing the Gap initiative. The Australian national partnership agreement and subsequent annual performance reports issued between 2010 and 2017. Targets set within the Australian government national partnership agreement have had a range of success. Those targets not on track require significant long-term investment to ensure their success. Nurses as a large professional group are powerful advocates to speak up and support policy change that affects disempowered social groups. Long-term social change takes time, yet without the commitment of Australian Governments through effective policy and economic support, the inequity in the health of Indigenous people will continue both now and in the future. Nurses, as the largest health professional group, are uniquely placed to support and implement social change at all levels of health care (primary, secondary and tertiary) and to lobby government to amend policy alongside those who are disempowered. Health promotion and education programmes that are led by nurses can make an impact to health disparities within groups who are most at risk.
Publisher: Springer Science and Business Media LLC
Date: 18-04-2016
DOI: 10.1007/S11682-016-9548-Z
Abstract: Childhood trauma is a significant risk factor for the development of psychotic disorders, and may influence executive brain functions. We thus set out to investigate the long-term effects of childhood trauma exposure on brain function of adult chronic patients diagnosed with schizophrenia, schizoaffective disorder and (psychotic) bipolar-I disorder while performing a standard 2/0-back working memory task. Participants were 50 cases diagnosed with schizophrenia/schizoaffective disorder (SCZ), 42 cases with bipolar-I disorder (BD), and 47 healthy controls (HC). Among this s le, 56 clinical cases (SCZ = 32 BD = 24) and 17 HC reported significant levels of childhood trauma, while 36 clinical cases (SCZ = 18 BD = 18) and 30 HC did not. Effects of childhood trauma on working memory-related brain activation were examined in combined s les of clinical cases (independently of diagnosis) relative to HCs, as well as within each diagnostic category. Case-control analyses revealed increased activation of the left inferior parietal lobule as a main effect of trauma exposure. In addition, trauma exposure interacted with a diagnosis of SCZ or BD to reveal trauma-related increased activation in the cuneus in clinical cases and decreased activation in this region in controls. Disorder-specific functional alterations were also evident in the SCZ s le, but not BD. Childhood trauma exposure elicits aberrant function of parietal regions involved in working memory performance regardless of clinical status, as well as task-relevant visual regions that participates to attentional processes. Childhood trauma may therefore contribute to alterations in attention in SCZ and BD while performing an n-back working memory task.
Publisher: Oxford University Press (OUP)
Date: 03-2017
Publisher: Elsevier BV
Date: 11-2017
DOI: 10.1016/J.SCHRES.2017.02.012
Abstract: Childhood trauma is a risk factor for schizophrenia that affects brain functions associated with higher cognitive processes, including social cognition. Alterations in Theory-of-Mind (ToM), or mentalizing skills, are a hallmark feature of schizophrenia, and are also evident in in iduals exposed to childhood trauma. However, the impact of childhood trauma exposure on brain function during social cognition in schizophrenia remains unclear. We thus examined the association between childhood trauma and brain function during the performance of a ToM task in 47 patients diagnosed with schizophrenia or schizoaffective disorder. All participants completed the Childhood Trauma Questionnaire (CTQ) and underwent functional magnetic resonance imaging while performing an established visual-cartoon affective ToM task. Whole-brain multiple regression analysis was performed on ToM-related brain activation, with CTQ total score as regressor of interest, while accounting for the effects of age, sex, diagnosis, symptom severity, behavioural performance, intelligence and medications levels. First, using a small-volume correction approach within a mask made of key regions for ToM [including bilateral temporo-parietal junctions (TPJ), medial prefrontal cortex (mPFC) and posterior cingulate cortex (PCC) recuneus], total CTQ scores were positively associated with activation of the PCC recuneus. Second, exploratory analyses for the rest of the brain (i.e., ROIs masked-out), revealed a positive association between trauma exposure and activation of the dorsomedial prefrontal cortex (dmPFC), and a negative association with activation of the anterior section of the TPJ. These results suggest that childhood trauma exposure may, at least partially, contribute to functional alterations of brain regions essential for effective mental state inference in schizophrenia.
Publisher: Elsevier BV
Date: 2019
Publisher: Wiley
Date: 29-07-2020
DOI: 10.1002/HBM.25098
Abstract: MRI‐derived brain measures offer a link between genes, the environment and behavior and have been widely studied in bipolar disorder (BD). However, many neuroimaging studies of BD have been underpowered, leading to varied results and uncertainty regarding effects. The Enhancing Neuro Imaging Genetics through Meta‐Analysis (ENIGMA) Bipolar Disorder Working Group was formed in 2012 to empower discoveries, generate consensus findings and inform future hypothesis‐driven studies of BD. Through this effort, over 150 researchers from 20 countries and 55 institutions pool data and resources to produce the largest neuroimaging studies of BD ever conducted. The ENIGMA Bipolar Disorder Working Group applies standardized processing and analysis techniques to empower large‐scale meta‐ and mega‐analyses of multimodal brain MRI and improve the replicability of studies relating brain variation to clinical and genetic data. Initial BD Working Group studies reveal widespread patterns of lower cortical thickness, subcortical volume and disrupted white matter integrity associated with BD. Findings also include mapping brain alterations of common medications like lithium, symptom patterns and clinical risk profiles and have provided further insights into the pathophysiological mechanisms of BD. Here we discuss key findings from the BD working group, its ongoing projects and future directions for large‐scale, collaborative studies of mental illness.
Publisher: Royal College of Psychiatrists
Date: 05-2023
DOI: 10.1192/BJO.2023.61
Abstract: Depressive symptoms are often comorbid with chronic pain. These conditions share aberrant emotion processing and regulation, as well as having common brain networks. However, the relationship between depressive symptoms and chronic pain and the effects on emotional brain function are unclear. The present study aimed to disentangle the effects of chronic pain and depressive symptoms on functional connectivity between regions implicated in both these conditions. Twenty-six in iduals with chronic pain (referred to as the pain group) and 32 healthy controls underwent resting-state functional magnetic resonance imaging and completed the Beck Depression Inventory. Main effects of group, depressive symptoms (total severity score) and their interaction on the functional connectivity of three seed regions (the left and right amygdalae and the medial prefrontal cortex mPFC) with the rest of the brain were evaluated. In cases of significant interaction, moderation analyses were conducted. The group × depressive symptoms interaction was significantly associated with changes in connectivity between the right amygdala and the mPFC (family-wise error-corrected P -threshold (pFWEc = 0.008). In the moderation analysis, the pain group showed weaker connectivity between these regions at lower levels of depressive symptoms ( P = 0.020), and stronger connectivity at higher levels of depressive symptoms ( P = 0.003), compared with the healthy controls. In addition, the strength of connectivity decreased in the healthy controls ( P = 0.005) and increased in the pain group ( P = 0.014) as the severity of depressive symptoms increased. Depressive symptoms moderate the impact of chronic pain on emotional brain function, with potential implications for the choice of treatment for chronic pain.
Publisher: Cold Spring Harbor Laboratory
Date: 12-10-2023
Publisher: Wiley
Date: 20-06-2018
DOI: 10.1111/BJC.12187
Abstract: Childhood trauma is a common risk factor for adult psychiatric disorders, such as schizophrenia (SZ) and bipolar-I disorder (BD). However, its association with schizotypal personality traits, as well as cognitive and social cognitive abilities, is less well studied in these populations. In a cohort of 79 SZ cases, 84 BD cases, and 75 healthy controls (HCs), clinically significant levels of childhood trauma exposure (according to scores on the Childhood Trauma Questionnaire CTQ) were evident in 54 SZ, 55 BD, and 26 HC in iduals. Trauma-exposed and non-exposed groups were compared on schizotypal personality features (schizotypy) measured with the Schizotypal Personality Questionnaire (SPQ). Cognitive assessments included executive function, working memory, attention, and immediate and delayed memory. Social cognitive measures assessed facial emotion processing and theory-of-mind abilities. Trauma-exposed participants showed higher levels of schizotypy, especially suspiciousness, relative to non-exposed in iduals, regardless of clinical or HC status. Furthermore, trauma-exposed in iduals showed deficits specifically in social cognitive, but not general cognitive abilities, regardless of clinical or HC status. These trauma-related results were found in the context of higher schizotypy levels in both SZ and BD relative to HC, and lower cognitive and social cognitive performance in SZ, relative to BD and HC groups. These findings suggest that childhood trauma exposure impacts long-term schizotypy outcomes, especially paranoid ideation (suspiciousness), as well as complex social cognitive abilities in both healthy and psychotic populations. However, cognitive deficits associated with psychotic illness may not be distinguishable from those related to trauma exposure in previous studies. Findings Childhood trauma exposure is associated with increased schizotypal features (in particular paranoid ideation) and complex social cognitive abilities, independently of the diagnosis of psychotic disorder. Cognitive and social cognitive deficits were larger in schizophrenia compared to bipolar-I cases and healthy controls, but increased schizotypal features were observed in both schizophrenia and bipolar-I disorder relative to healthy controls. Limitations We were unable to distinguish the specific effects of particular childhood trauma exposures due to the high rate of exposure to more than one type of maltreatment. Retrospective assessment of childhood trauma in adulthood cannot be externally validated, and associations with behavioural traits in later life may be confounded by other factors not studied here.
Publisher: Elsevier BV
Date: 11-2022
Publisher: Springer Science and Business Media LLC
Date: 09-12-2022
DOI: 10.1038/S41380-022-01897-W
Abstract: Schizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years range 18–72 years 67% male) and 2598 healthy controls (mean age 33.8 years, range 18–73 years, 55% male). Brain-predicted age was in idually estimated using a model trained on independent data based on 68 measures of cortical thickness and surface area, 7 subcortical volumes, lateral ventricular volumes and total intracranial volume, all derived from T1-weighted brain magnetic resonance imaging (MRI) scans. Deviations from a healthy brain ageing trajectory were assessed by the difference between brain-predicted age and chronological age (brain-predicted age difference [brain-PAD]). On average, SZ patients showed a higher brain-PAD of +3.55 years (95% CI: 2.91, 4.19 I 2 = 57.53%) compared to controls, after adjusting for age, sex and site (Cohen’s d = 0.48). Among SZ patients, brain-PAD was not associated with specific clinical characteristics (age of onset, duration of illness, symptom severity, or antipsychotic use and dose). This large-scale collaborative study suggests advanced structural brain ageing in SZ. Longitudinal studies of SZ and a range of mental and somatic health outcomes will help to further evaluate the clinical implications of increased brain-PAD and its ability to be influenced by interventions.
Publisher: Springer Science and Business Media LLC
Date: 14-12-2017
DOI: 10.1007/S11682-017-9804-X
Abstract: Virtual reality (VR)-based paradigms use visual stimuli that can modulate visuo-motor networks leading to the stimulation of brain circuits. The aims of this study were to compare the changes in blood-oxygenation level dependent (BOLD) signal when watching and imitating moving real (RH) and virtual hands (VH) in 11 healthy participants (HP). No differences were found between the observation of RH or VH making this VR-based experiment a promising tool for rehabilitation protocols. VH-imitation involved more the ventral premotor cortex (vPMC) as part of the mirror neuron system (MNS) compared to execution and VH-observation conditions. The dorsal-anterior Precuneus (da-Pcu) as part of the Precuneus osterior Cingulate Cortex (Pcu CC) complex, a key node of the Default Mode Network (DMN), was also less deactivated and therefore more involved. These results may reflect the dual visuo-motor roles for the vPMC and the implication of the da-Pcu in the reallocation of attentional and neural resources for bimodal task management. The ventral Pcu CC was deactivated regardless of the condition confirming its role in self-reference processes. Imitation of VH stimuli can then modulate the activation of specific areas including those belonging to the MNS and the DMN.
Publisher: Informa UK Limited
Date: 12-2020
DOI: 10.2147/NDT.S285540
Publisher: Cold Spring Harbor Laboratory
Date: 17-10-2022
DOI: 10.1101/2022.10.13.512111
Abstract: The cerebellum critically contributes to higher-order cognitive and emotional functions such fear learning and memory. Prior research on cerebellar volume in PTSD is scant and has neglected neuroanatomical sub isions of the cerebellum that differentially map on to motor, cognitive, and affective functions. We quantified cerebellar lobule volumes using structural magnetic resonance imaging in 4,215 adults (PTSD n= 1640 Control n=2575) across 40 sites from the from the ENIGMA-PGC PTSD working group. Using a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation, we obtained volumetric estimates for the total cerebellum and 28 subregions. Linear mixed effects models controlling for age, gender, intracranial volume, and site were used to compare cerebellum total and subregional volume in PTSD compared to healthy controls. The Benjamini-Hochberg procedure was used to control the false discovery rate ( p -FDR .05). PTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with PTSD demonstrated smaller total cerebellum volume. In addition, people with PTSD showed reduced volume in subregions primarily within the posterior lobe (lobule VIIB, crus II), but also the vermis (VI, VIII), flocculonodular lobe (lobule X), and cerebellar white matter (all p -FDR 0.05). Effects of PTSD on volume were consistent, and generally more robust, when examining symptom severity rather than diagnostic status. These findings implicate regionally specific cerebellar volumetric differences in the pathophysiology of PTSD. The cerebellum appears to play an important role in high-order cognitive and emotional processes, far beyond its historical association with vestibulomotor function. Further examination of the cerebellum in trauma-related psychopathology will help to clarify how cerebellar structure and function may disrupt cognitive and affective processes at the center of translational models for PTSD.
Publisher: Elsevier BV
Date: 05-2022
Publisher: Springer Science and Business Media LLC
Date: 19-01-2021
Publisher: Wiley
Date: 26-11-2020
DOI: 10.1002/PCHJ.322
Abstract: Schizophrenia (SZ) and bipolar I disorder (BD) share common functional and structural brain abnormalities, as well as various degrees of social cognitive deficits, suggesting shared brain mechanisms. This study examined the relationship between social cognitive skills and structural brain integrity in 60 cases with SZ, 65 cases with psychotic BD, and 61 healthy controls (HCs). All participants underwent structural MRI and completed The Awareness of Social Inference Test (TASIT). Associations between social cognitive performance on each task of the TASIT (Emotion Recognition, Theory of Mind [ToM], and Complex ToM) and indices of gray matter volume and cortical thickness were investigated within three separate groups comprising (a) all cases with a history of psychosis (independently of their diagnostic status), (b) each diagnostic category separately, and (c) an HC group. Cases with psychosis showed worse social cognitive performance compared to the HC group, and SZ cases performed worse than BD on all ToM tasks, but not the Emotion Recognition subtest. Poor ToM performance was associated with thinner anterior temporal lobe in the combined group of cases with psychosis, and with decreased volume of the left fusiform gyrus/cerebellum in the HC group. In the BD group alone, poor ToM performance was associated with similar pattern of thinner anterior temporal lobe, as well as with increased volume in the mid- and posterior cingulate cortex recuneus. However, there were no associations between brain morphometry and social cognition in the SZ group when considered alone. Taken together, ToM behavioral deficits were associated with thinner right anterior temporal lobe, a critical region from a larger affective ToM network among all cases with psychosis, but aberrant morphology of brain regions key for self-processing were specific to the BD group. These findings may have important implications for targeted interventions for the affective social brain network in BD.
Publisher: Elsevier BV
Date: 05-2021
Publisher: Cold Spring Harbor Laboratory
Date: 16-07-2020
DOI: 10.1101/2020.07.15.191114
Abstract: The size of the human head is determined by growth in the first years of life, while the rest of the body typically grows until early adulthood 1 . Such complex developmental processes are regulated by various genes and growth pathways 2 . Rare genetic syndromes have revealed genes that affect head size 3 , but the genetic drivers of variation in head size within the general population remain largely unknown. To elucidate biological pathways underlying the growth of the human head, we performed the largest genome-wide association study on human head size to date (N = 79,107). We identified 67 genetic loci, 50 of which are novel, and found that these loci are preferentially associated with head size and mostly independent from height. In subsequent neuroimaging analyses, the majority of genetic variants demonstrated widespread effects on the brain, whereas the effects of 17 variants could be localized to one or two specific brain regions. Through hypothesis-free approaches, we find a strong overlap of head size variants with both cancer pathways and cancer genes. Gene set analyses showed enrichment for different types of cancer and the p53, Wnt and ErbB signalling pathway. Genes overlapping or close to lead variants – such as TP53 , PTEN and APC – were enriched for genes involved in macrocephaly syndromes (up to 37-fold) and high-fidelity cancer genes (up to 9-fold), whereas this enrichment was not seen for human height variants. This indicates that genes regulating early brain and cranial growth are associated with a propensity to neoplasia later in life, irrespective of height. Our results warrant further investigations of the link between head size and cancer, as well as its clinical implications in the general population.
Publisher: JMIR Publications Inc.
Date: 07-06-2023
DOI: 10.2196/41890
Abstract: Emotion dysregulation is key to the development and maintenance of chronic pain, feeding into a cycle of worsening pain and disability. Dialectical behavioral therapy (DBT), an evidence-based treatment for complex transdiagnostic conditions presenting with high emotion dysregulation, may be beneficial to manage and mitigate the emotional and sensory aspects of chronic pain. Increasingly, DBT skills training as a key component of standard DBT is being delivered as a stand-alone intervention without concurrent therapy to help develop skills for effective emotion regulation. A previous repeated-measure single-case trial investigating a novel technologically driven DBT skills training, internet-delivered DBT skills training for chronic pain (iDBT-Pain), revealed promising findings to improve both emotion dysregulation and pain intensity. This randomized controlled trial aims to examine the efficacy of iDBT-Pain in comparison with treatment as usual to reduce emotion dysregulation (primary outcome) for in iduals with chronic pain after 9 weeks and at the 21-week follow-up. The secondary outcomes include pain intensity, pain interference, anxiety symptoms, depressive symptoms, perceived stress, posttraumatic stress, harm avoidance, social cognition, sleep quality, life satisfaction, and well-being. The trial also examines the acceptability of the iDBT-Pain intervention for future development and testing. A total of 48 people with chronic pain will be randomly assigned to 1 of 2 conditions: treatment and treatment as usual. Participants in the treatment condition will receive iDBT-Pain, consisting of 6 live web-based group sessions led by a DBT skills trainer and supervised by a registered psychologist and the iDBT-Pain app. Participants in the treatment-as-usual condition will not receive iDBT-Pain but will still access their usual medication and health interventions. We predict that iDBT-Pain will improve the primary outcome of emotion dysregulation and the secondary outcomes of pain intensity, pain interference, anxiety symptoms, depressive symptoms, perceived stress, harm avoidance, social cognition, sleep quality, life satisfaction, and well-being. A linear mixed model with random effects of in iduals will be conducted to investigate the differences between the baseline, 9-week (primary end point), and 21-week (follow-up) assessments as a function of experimental condition. Recruitment started in February 2023, and the clinical trial started in March 2023. Data collection for the final assessment is planned to be completed by July 2024. If our hypothesis is confirmed, our findings will contribute to the evidence for the efficacy and acceptability of a viable intervention that may be used by health care professionals for people with chronic pain. The results will add to the chronic pain literature to inform about the potential benefits of DBT skills training for chronic pain and will contribute evidence about technologically driven interventions. Australian New Zealand Clinical Trials Registry ACTRN12622000113752 www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=383208& isReview=true PRR1-10.2196/41890
Publisher: Cold Spring Harbor Laboratory
Date: 26-06-2021
DOI: 10.1101/2021.06.24.21259102
Abstract: Posttraumatic stress disorder (PTSD) is a complex psychiatric condition that has generated much attention in the neuroimaging literature. A neurocircuitry model supporting fronto-limbic dysfunction as a major player in facilitating clinical symptoms of PTSD is well-characterized however, recent literature suggests that network-based approaches may provide additional insight into neural dysfunction in PTSD. Our analysis uses resting-state neuroimaging scans of 1063 adults from the PGC-ENIGMA PTSD Consortium to investigate a network-based model of functional connectivity in PTSD. With a novel, resolution limit-free community detection approach, 16 communities corresponding to functionally meaningful networks were detected with high quality. After group-level community detection, participants were classified into three groups (PTSD, n =418, trauma-exposed controls without PTSD, n =434, and non-trauma exposed healthy controls, n =211). In idual network connectivity metrics were calculated, including whole-brain, default mode network, and central executive network participation coefficient and connectivity strength. Linear mixed effects models revealed group differences in the whole-brain, default mode, and central executive network participation coefficient and connectivity strength such that in iduals with PTSD demonstrated overall greater values. We also described sex differences such that males demonstrate greater whole-brain participation coefficient vs. females and females demonstrate greater default mode network connectivity strength vs. males. Our results suggest that PTSD in adults is associated with reduced specialization and enhanced inter-module communication throughout the brain network, which may contribute to inefficient information processing and poor emotional regulation. This study presents a novel use of resolution limit-free community detection in a large PTSD s le, revealing robust differences in resting-state network topology.
Publisher: CMA Joule Inc.
Date: 2015
DOI: 10.1503/JPN.130283
Publisher: Elsevier BV
Date: 06-2023
Publisher: Elsevier BV
Date: 2019
Publisher: Elsevier BV
Date: 2022
Publisher: Elsevier BV
Date: 11-2013
DOI: 10.1016/J.SCHRES.2013.08.009
Abstract: Working memory (WM) deficits and associated brain dysfunction are among the most well replicated candidate endophenotypic processes in schizophrenia. However, previous studies demonstrate inconsistent over- and under-activation of dorsolateral and ventrolateral prefrontal cortices (DLPFC VLPFC), inferior parietal lobule (IPL) during WM performance, as well as subcortical structures including the striatum, and dysfunctional connectivity among fronto-striatal regions in schizophrenia. However, no previous study has investigated task-related functional connectivity (FC) of DLPFC and striatal regions using a seed-based method here we employed this method to assess patterns of cortical and subcortical functional connectivity among WM structures during a standard 2-back WM task performed by 28 schizophrenia (SZ) and 28 healthy controls (HC). Initial group comparisons of blood oxygenation level dependent (BOLD) responses during the WM task revealed significantly greater bilateral activity in the striatum in SZ relative to HC, but there was no significant group difference in WM cortical activity (right DLPFC, VLPFC or IPL). Analyses of FC within the cortico-subcortical WM network in the HC group revealed positive performance-related FC between the right DLPFC and the right caudate, and between the right VLPFC and the right IPL this pattern was absent in SZ. In contrast, SZ patients showed negative performance-related functional connectivity between the left putamen and the right VLPFC. Direct group comparisons in functional connectivity showed significantly greater performance-related FC between the VLPFC and bilateral putamen, as well as unilaterally between the VLPFC and the right IPL, in HC. Results suggest a critical dysfunction of cortico-striatal connectivity underpinning information retrieval for SZ patients during WM performance.
Publisher: Elsevier BV
Date: 08-2019
Publisher: Elsevier BV
Date: 09-2020
Publisher: Royal College of Psychiatrists
Date: 2023
DOI: 10.1192/BJO.2023.3
Abstract: Dissociative behaviours and hallucinations are often reported in trauma-exposed people with schizophrenia spectrum disorders and post-traumatic stress disorder (PTSD). Auditory hallucinations are the most commonly reported type of hallucination, but often co-occur with experiences in other sensory modalities. The phenomenology and the neurobiological systems involved in visual experiences are not well characterised. Are these experiences similar in nature, content or severity among people with schizophrenia and/or PTSD? What are the neurobiological bases of these visual experiences and what is the role of dissociative behaviours in the formation of these experiences? A study by Wearne and colleagues in BJPsych Open aimed to characterise these phenomenological systems in groups of people with PTSD, schizophrenia or both (schizophrenia + PTSD).
Publisher: Research Square Platform LLC
Date: 28-09-2023
Publisher: Elsevier BV
Date: 04-2014
Publisher: Oxford University Press (OUP)
Date: 04-2020
DOI: 10.1093/SCHBUL/SBAA030.468
Abstract: Cortical neuroanatomical abnormalities have been reported along a continuum between in iduals with chronic schizophrenia, first-episode psychosis, clinical high risk for psychosis, and healthy in iduals self-reporting subclinical psychotic-like experiences (or schizotypy). Recently, the Schizophrenia Working Group within the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) consortium provided meta-analytic evidence for robust cortical thickness abnormalities in schizophrenia, while also indicating that these abnormalities are influenced by illness severity and treatment with antipsychotic medications. In this context, schizotypy research allows the investigation of cortical neuroanatomy associated with the expression of subclinical psychotic-like symptoms without the potential influence of a psychotic illness, its severity, or the use of antipsychotics. This study presents the first large-scale imaging meta-analysis of cortical thickness in schizotypy using standardized methods from 23 datasets worldwide. Cortical thickness and surface area were assessed in MRI scans of 2,695 healthy in iduals (mean [range] age of 29.1 [17–55.8], 46.3% male) who had also completed validated self-report schizotypy questionnaires. Each site processed their local T1-weighted MRI scans using FreeSurfer and, following the protocol outlined in the ENIGMA Schizophrenia Working Group study, extracted cortical thickness for 70 Desikan-Killiany (DK) atlas regions (34 regions per hemisphere + left and right hemisphere mean thickness). At each site, partial correlation analyses were performed between regional cortical thickness by ROI and total schizotypy scores in R, predicting the left, right and mean cortical thickness, adjusting for sex, age and site. Random-effects meta-analyses of partial correlation effect sizes for each of the DK atlas regions were performed using R’s metafor package. False discovery rate (pFDR & .05) was used to control for multiple comparisons. We found significant positive associations between subclinical psychotic-like experiences and mean cortical thickness of the medial orbitofrontal cortex (r = .077 pFDR = .006) and the frontal pole (r = .073 pFDR = .006). When assessed separately by hemisphere, meta-analysis revealed a significant positive association between subclinical psychotic-like experiences and cortical thickness of the left medial orbitofrontal cortex (r = .066 pFDR = .044), and at trend-level with the right medial orbitofrontal cortex (r = .062 pFDR = .053) and the left frontal pole (r = .062 pFDR = .053). No significant associations were observed for surface area. Worldwide cooperative analyses of large-scale brain imaging data support a profile of cortical thickness abnormalities involving prefrontal cortical regions positively related to schizotypy in healthy in iduals. These findings are not secondary to potential influences of disease chronicity or antipsychotic medication on the neuroanatomical correlates of psychotic-like experiences. The directionality of the observed meta-analytical effects in schizotypy is opposite to those previously reported in patients with schizophrenia (i.e., thinner cortex). The present findings of increased thickness may indicate early microstructural deficits (e.g. in myelination) that contribute to vulnerability for psychosis. Alternatively, these may reflect mechanisms of resilience associated with the expression of subclinical manifestations of psychotic symptoms in otherwise healthy in iduals.
Publisher: Elsevier BV
Date: 05-2021
Publisher: Springer Berlin Heidelberg
Date: 2014
Abstract: The role of stress in precipitating psychotic episodes in schizophrenia and bipolar disorder has long been acknowledged. However, the neurobiological mechanism/s of this association have remained elusive. Current neurodevelopmental models of psychosis implicate early dysfunction in biological systems regulating hypothalamic-pituitary-adrenal axis and immune function, with long-term effects on the development of the brain networks responsible for higher order cognitive processes and stress reactivity in later life. There is also increasing evidence of childhood trauma in psychosis, and its impact on the development of brain systems regulating stress. These findings are emerging in the context of a new era of epigenetic methods facilitating the study of environmental effects on gene expression. The evidence is thus converging: exposure to stress at critical periods in life may be an important factor in the development of the brain dysfunction that represents psychosis vulnerability, rather than merely interacting with an independent 'biological vulnerability' to manifest in psychosis.
Publisher: Cold Spring Harbor Laboratory
Date: 28-11-2022
DOI: 10.1101/2022.11.22.22282598
Abstract: Schizotypy represents an index of psychosis-proneness in the general population often associated with childhood trauma exposure. Both schizotypy and childhood trauma are linked to structural brain alterations, and it is possible that trauma exposure moderates the extent of brain morphological differences associated with schizotypy. We addressed this question using data from a total of 1,182 healthy adults (age range: 18-65 years old, 647 females/535 males), pooled from nine sites worldwide, contributing to the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Schizotypy working group. All participants completed both the Schizotypal Personality Questionnaire Brief version (SPQ-B), and the Childhood Trauma Questionnaire (CTQ), and underwent a 3D T1-weighted brain MRI scan from which regional indices of subcortical grey matter volume and cortical thickness were determined. A series of multiple linear regressions revealed that differences in cortical thickness in four regions-of-interest were significantly associated with interactions between schizotypy and trauma subsequent moderation analyses indicated that increasing levels of schizotypy were associated with thicker left caudal anterior cingulate gyrus, right middle temporal gyrus and insula, and thinner left caudal middle frontal gyrus, in people exposed to higher (but not low or average) levels of childhood trauma. This was found in the context of thicker bilateral medial orbitofrontal gyri, right rostral anterior cingulate gyrus, left temporal pole, left insula, and thinner left paracentral lobule directly associated with increasing levels of schizotypy. In addition, thinner left postcentral, superior parietal and lingual gyri, as well as thicker left caudal middle frontal gyrus and smaller left thalamus and right caudate were associated with increasing levels of childhood trauma exposure. These results suggest that alterations in brain regions critical for higher cognitive and integrative processes that are associated with schizotypy may be enhanced in in iduals exposed to high levels of trauma.
Publisher: Elsevier BV
Date: 2019
Publisher: Springer Science and Business Media LLC
Date: 26-02-2022
DOI: 10.1038/S41398-022-01849-6
Abstract: Resilience is a process of adaptive recovery crucial in maintaining mental wellbeing after stress exposure. A psychological factor known to buffer stress and promote positive wellbeing outcomes is the ability to regulate emotions. However, the neural networks underlying resilience, and the possible mediating role of emotion regulation, remain largely unknown. Here, we examined the association between resilience and grey matter covariation (GMC) in healthy adults with and without early life stress (ELS) exposure, and whether emotion regulation mediated this brain-resilience association. Source-based morphometry was used to identify spatial patterns of common GMC in 242 healthy participants. Wellbeing was measured using the COMPAS-W Wellbeing Scale. Linear mixed models were run to establish associations between GMC and wellbeing scores. Moderated mediation models were used to examine a conditional mediating effect of emotion regulation on the brain-wellbeing relationship, moderated by ELS exposure. Distinct ELS-related morphometric patterns were found in association with resilience. In participants without ELS exposure, decreased GMC in the temporo-parietal regions was associated with wellbeing. In participants with ELS exposure, we observed increased patterns of covariation in regions related to the salience and executive control networks, and decreased GMC in temporo-parietal areas, which were associated with resilience. Cognitive reappraisal mediated the brain-wellbeing relationship in ELS-exposed participants only. Patterns of stronger GMC in regions associated with emotional and cognitive functioning in ELS-exposed participants with high levels of wellbeing may indicate possible neural signatures of resilience. This may be further heightened by utilising an adaptive form of emotion regulation.
Publisher: American Medical Association (AMA)
Date: 2021
Publisher: Cold Spring Harbor Laboratory
Date: 02-03-2023
DOI: 10.1101/2023.02.28.23286608
Abstract: Posttraumatic stress disorder (PTSD) is a complex and heterogeneous mental health condition that can develop after exposure to a traumatic event. Clinical trials have used new pharmacological agents to treat PTSD, but their associated neural correlates remain unclear. The present systematic review aims to summarise the changes in brain function associated with the use these pharmacological agents in PTSD. Clinical trials using functional magnetic resonance imaging (fMRI), either at rest or during the performance of tasks, were included if they compared the effects of pharmacological agents in patients with PTSD to either trauma-exposed controls or never exposed to trauma healthy controls. Twelve studies were included, of which eight used intranasal oxytocin, two used hydrocortisone, and one used Tolcapone. Oxytocin administration was associated with normalisation of functional connectivity between the ventromedial prefrontal cortex and amygdala, as well as enhanced the function of brain regions specifically involved in emotion processing (e.g., amygdala), working memory (e.g., dorsolateral prefrontal cortex), reward (putamen). Hydrocortisone did not influence brain function at rest or during the performance of an autobiographical memory task, while tolcapone was associated with increased function in frontal, parietal and striatal regions during the performance of an emotional working memory task. This systematic review identified preliminary evidence for normalizing brain function after use of alternative pharmacological agents to first-line pharmacological treatments.
Publisher: Springer Science and Business Media LLC
Date: 07-12-2018
DOI: 10.1038/S41380-018-0305-0
Abstract: Retinoid metabolites of vitamin A are intrinsically linked to neural development, connectivity and plasticity, and have been implicated in the pathophysiology of schizophrenia. We hypothesised that a greater burden of common and rare genomic variation in genes involved with retinoid biogenesis and signalling could be associated with schizophrenia and its cognitive symptoms. Common variants associated with schizophrenia in the largest genome-wide association study were aggregated in retinoid genes and used to formulate a polygenic risk score (PRS Ret ) for each participant in the Australian Schizophrenia Research Bank. In support of our hypothesis, we found PRS Ret to be significantly associated with the disorder. Cases with severe cognitive deficits, while not further differentiated by PRS Ret , were enriched with rare variation in the retinoic acid receptor beta gene RARB , detected through whole-genome sequencing. RARB rare variant burden was also associated with reduced cerebellar volume in the cases with marked cognitive deficit, and with covariation in grey matter throughout the brain. An excess of rare variation was further observed in schizophrenia in retinoic acid response elements proximal to target genes, which we show are differentially expressed in the disorder in two RNA sequencing datasets. Our results suggest that genomic variation may disrupt retinoid signalling in schizophrenia, with particular significance for cases with severe cognitive impairment.
Publisher: Elsevier BV
Date: 04-2023
Publisher: Oxford University Press (OUP)
Date: 04-2019
Publisher: Cold Spring Harbor Laboratory
Date: 07-06-2023
DOI: 10.1101/2023.06.06.23291034
Abstract: Formal thought disorder (FTD) is a key clinical factor in schizophrenia, but the neurobiological underpinnings remain unclear. In particular, relationship between FTD symptom dimensions and patterns of regional brain volume deficiencies in schizophrenia remain to be established in large cohorts. Even less is known about the cellular basis of FTD. Our study addresses these major obstacles based on a large multi-site cohort through the ENIGMA Schizophrenia Working Group (752 in iduals with schizophrenia and 1256 controls), to unravel the neuroanatomy of positive, negative and total FTD in schizophrenia and their cellular bases. We used virtual histology tools to relate brain structural changes associated with FTD to cellular distributions in cortical regions. We identified distinct neural networks for positive and negative FTD. Both networks encompassed fronto-occipito-amygdalar brain regions, but negative FTD showed a relative sparing of orbitofrontal cortical thickness, while positive FTD also affected lateral temporal cortices. Virtual histology identified distinct transcriptomic fingerprints associated for both symptom dimensions. Negative FTD was linked to neuronal and astrocyte fingerprints, while positive FTD was also linked to microglial cell types. These findings relate different dimensions of FTD to distinct brain structural changes and their cellular underpinnings, improve our mechanistic understanding of these key psychotic symptoms.
Publisher: Cold Spring Harbor Laboratory
Date: 02-03-2022
DOI: 10.1101/2022.03.01.22271652
Abstract: Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small s les and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, using MRI data from 5,080 affected in iduals and 6,015 controls across 46 datasets in the ENIGMA consortium, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected in iduals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macro-structural asymmetry may reflect differences at the molecular, cytoarchitectonic or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.
Publisher: Springer Science and Business Media LLC
Date: 14-09-2021
DOI: 10.1007/S00406-020-01190-3
Abstract: Childhood trauma is a risk factor for psychotic and mood disorders that is associated with abnormal hypothalamic-pituitary-adrenal (HPA) axis function in response to stress and abnormal social brain function. Here, we aimed to determine whether childhood trauma exposure would differently moderate associations between cortisol reactivity and social brain function, among cases with schizophrenia (SZ), bipolar disorder (BD) and in healthy in iduals (HC). Forty cases with SZ, 35 with BD and 34 HCs underwent functional magnetic resonance imaging while performing an emotional face-matching task. Participants completed the Childhood Trauma Questionnaire and cortisol reactivity (i.e. the slope indexing the within-subject difference between pre- and post-imaging salivary cortisol levels) was determined. The severity of childhood trauma moderated the relationship between cortisol reactivity and brain activation in the bilateral temporo-parieto-insular junctions, right middle cingulum, right pre ostcentral gyri, left cerebellum and right lingual gyrus, differently depending on the clinical group. When exposed to high levels of trauma, the cortisol slope was negatively associated with activation in these regions in HC, while the cortisol slope was positively associated with activation in these regions in SZ cases. Similarly, there were differences between the groups in how trauma severity moderated the relationship between cortisol reactivity and functional connectivity between the amygdala and dorsolateral prefrontal cortex. In addition to reflecting typical associations between cortisol reactivity and emotional brain function when not exposed to childhood trauma, these findings provide new evidence that trauma exposure disrupts these relationships in both healthy in iduals and in cases with SZ or BD.
Publisher: Elsevier BV
Date: 05-2021
Publisher: Elsevier BV
Date: 2012
DOI: 10.1016/J.NEUBIOREV.2011.09.004
Abstract: The most prevalent mental disorders, anxiety and mood disorders, are associated with both functional and morphological brain changes that commonly involve the 'fear network' including the (medial) prefrontal cortex, hippoc us and amygdala. Patients suffering from anxiety disorders and major depressive disorder often show excessive amygdala and reduced prefrontal cortex functioning. It is, however, still unclear whether these brain abnormalities disappear or diminish following effective treatment. This review aims to compare the effects of psychotherapy and pharmacotherapy on functional and morphological brain measures in these disorders. Sixty-three studies were included, 30 investigating psychotherapy effects and 33 investigating pharmacotherapy effects. Despite methodological differences, results suggest a functional normalization of the 'fear network'. Pharmacotherapy particularly decreases over-activity of limbic structures (bottom-up effect) while psychotherapy tends to increase activity and recruitment of frontal areas (top-down effect), especially the anterior cingulate cortex. Additionally, pharmacotherapy, but not psychotherapy, has been associated with morphological changes, depending on the disorder. These findings suggest that both types of treatments normalize (functional) brain abnormalities each in specific ways.
Publisher: Elsevier BV
Date: 05-2016
DOI: 10.1016/J.PSYNEUEN.2016.01.021
Abstract: Markers of HPA axis function, including diurnal cortisol rhythm and cortisol responses to stress or pharmacological manipulation, are increasingly reported as disrupted in schizophrenia (SZ) and bipolar disorder (BD). However, there has been no direct comparison of cortisol responses to stress in SZ and BD in the same study, and associations between cortisol dysfunction and illness characteristics remain unclear. In this study we used spline embedded linear mixed models to examine cortisol levels of SZ and BD participants at waking, during the first 45min after waking (representing the cortisol awakening response CAR), during the period of rapid cortisol decline post the awakening response, and in reaction to a stressor (MRI scan), relative to healthy controls (HC). Contrary to expectations, neither SZ nor BD showed differences in waking cortisol levels, CAR, or immediate post-CAR decline compared to HC however, waking cortisol levels were greater in BD relative to SZ. In response to the MRI stressor, the SZ group showed a significant absence of the expected increase in cortisol responsivity to stress, which was seen in both the BD and HC groups. Clinical factors affecting the CAR differed between SZ and BD. In SZ, higher antipsychotic medication dosage was associated with a steeper incline of the CAR, while greater positive symptom severity was associated with a more blunted CAR, and greater levels of anxiety were associated with the blunted cortisol response to stress. In BD, longer illness duration was associated with a steeper incline in CAR and lower levels of waking cortisol. These results suggest that cortisol responses may normalize with medication (in SZ) and longer illness duration (in BD), in line with findings of aberrant cortisol levels in the early stages of psychotic disorders.
Publisher: Frontiers Media SA
Date: 04-01-2023
DOI: 10.3389/FNEUR.2022.1045678
Abstract: Magnetic resonance spectroscopy is a powerful, non-invasive, quantitative imaging technique that allows for the measurement of brain metabolites that has demonstrated utility in diagnosing and characterizing a broad range of neurological diseases. Its impact, however, has been limited due to small s le sizes and methodological variability in addition to intrinsic limitations of the method itself such as its sensitivity to motion. The lack of standardization from a data acquisition and data processing perspective makes it difficult to pool multiple studies and/or conduct multisite studies that are necessary for supporting clinically relevant findings. Based on the experience of the ENIGMA MRS work group and a review of the literature, this manuscript provides an overview of the current state of MRS data harmonization. Key factors that need to be taken into consideration when conducting both retrospective and prospective studies are described. These include (1) MRS acquisition issues such as pulse sequence, RF and B0 calibrations, echo time, and SNR (2) data processing issues such as pre-processing steps, modeling, and quantitation and (3) biological factors such as voxel location, age, sex, and pathology. Various approaches to MRS data harmonization are then described including meta-analysis, mega-analysis, linear modeling, ComBat and artificial intelligence approaches. The goal is to provide both novice and experienced readers with the necessary knowledge for conducting MRS data harmonization studies.
Publisher: Oxford University Press (OUP)
Date: 03-2017
Publisher: BMJ
Date: 11-2022
DOI: 10.1136/BMJOPEN-2022-063102
Abstract: Chronic pain, defined as pain persisting longer than 3 months, is more than an unpleasant sensory experience. Persistent negative emotions and emotional comorbidities, such as depression and anxiety, plague people with chronic pain leading to worsening pain intensity and increasing disability. While cognitive–behavioural therapy (CBT) is the gold standard psychological treatment, recent evidence highlights that CBT lacks efficacy for the physical and emotional aspects of chronic pain. Increasingly, researchers are investigating emotion-centric psychological therapies. While treatment modalities vary, these interventions frequently target understanding emotions, and train in iduals for an emotionally adaptive response. The aim of this systematic review and meta-analysis is to quantify the efficacy of emotion-centric interventions for the physical and emotional characteristics of chronic pain. Electronic databases (EMBASE, PubMed, PsychINFO, Cochrane Central Register of Controlled Trials, CINAHL and Web of Science) will be systematically searched from inception to 28 April 2022 for randomised controlled trials. Studies that compare an emotion-centric intervention with another form of treatment or placebo/control for adults (≥18 years old) with chronic pain will be included. All treatment modes (eg, online or in-person), any duration and group-based or in idual treatments will be included. Studies that do not investigate at least one emotion-centric treatment will be excluded. The primary outcome is pain intensity. Secondary outcomes include emotion dysregulation, depression, anxiety, affect, safety and intervention compliance. A quantitative synthesis using a random effects meta-analysis will be adopted. Risk of bias will be evaluated using Cochrane Risk of Bias V.2.0 with the certainty of evidence assessed according to Recommendation, Assessment, Development and Evaluation. Data permitting, subgroup analysis will be conducted for intervention type and pain condition. Ethical approval is not required for this systematic review. Results may inform an efficacy study examining a new emotion-centric intervention for chronic pain. Dissemination will be through peer-reviewed publications and in conference presentations. CRD42021266815.
Publisher: Springer Science and Business Media LLC
Date: 18-12-2019
DOI: 10.1007/S11065-019-09422-7
Abstract: The delineation of cognitive subtypes of schizophrenia and bipolar disorder may offer a means of determining shared genetic markers and neuropathology among in iduals with these conditions. We systematically reviewed the evidence from published studies reporting the use of data-driven (i.e., unsupervised) clustering methods to delineate cognitive subtypes among adults diagnosed with schizophrenia, schizoaffective disorder, or bipolar disorder. We reviewed 24 studies in total, contributing data to 13 analyses of schizophrenia spectrum patients, 8 analyses of bipolar disorder, and 5 analyses of mixed s les of schizophrenia and bipolar disorder participants. Studies of bipolar disorder most consistently revealed a 3-cluster solution, comprising a subgroup with 'near-normal' (cognitively spared) cognition and two other subgroups demonstrating graded deficits across cognitive domains. In contrast, there was no clear consensus regarding the number of cognitive subtypes among studies of cognitive subtypes in schizophrenia, while four of the five studies of mixed diagnostic groups reported a 4-cluster solution. Common to all cluster solutions was a severe cognitive deficit subtype with cognitive impairments of moderate to large effect size relative to healthy controls. Our review highlights several key factors (e.g., symptom profile, s le size, statistical procedures, and cognitive domains examined) that may influence the results of data-driven clustering methods, and which were largely inconsistent across the studies reviewed. This synthesis of findings suggests caution should be exercised when interpreting the utility of particular cognitive subtypes for biological investigation, and demonstrates much heterogeneity among studies using unsupervised clustering approaches to cognitive subtyping within and across the psychosis spectrum.
Publisher: Cold Spring Harbor Laboratory
Date: 13-12-2022
DOI: 10.1101/2022.12.12.519838
Abstract: Current clinical assessments of Posttraumatic stress disorder (PTSD) rely solely on subjective symptoms and experiences reported by the patient, rather than objective biomarkers of the illness. Recent advances in data-driven computational approaches have been helpful in devising tools to objectively diagnose psychiatric disorders. Here we aimed to classify in iduals with PTSD versus controls using heterogeneous brain datasets from the ENIGMA-PGC PTSD Working group. We analyzed brain MRI data from 3,527 structural-MRI 2,502 resting state-fMRI and 1,953 diffusion-MRI. First, we identified the brain features that best distinguish in iduals with PTSD from controls (TEHC and HC) using traditional machine learning methods. Second, we assessed the utility of the denoising variational autoencoder (DVAE) and evaluated its classification performance. Third, we assessed the generalizability and reproducibility of both models using leave-one-site-out cross-validation procedure for each modality. We found lower performance in classifying PTSD vs. controls with data from over 20 sites (60% test AUC for s-MRI, 59% for rs-fMRI and 56% for d-MRI), as compared to other studies run on single-site data. The performance increased when classifying PTSD from HC without trauma history across all three modalities (75% AUC). The classification performance remained intact when applying the DVAE framework, which reduced the number of features. Finally, we found that the DVAE framework achieved better generalization to unseen datasets compared with the traditional machine learning frameworks, albeit performance was slightly above chance. Our findings highlight the promise offered by machine learning methods for the diagnosis of patients with PTSD. The utility of brain biomarkers across three MRI modalities and the contribution of DVAE models for improving generalizability offers new insights into neural mechanisms involved in PTSD. ⍰ Classifying PTSD from trauma-unexposed healthy controls (HC) using three imaging modalities performed well (∼75% AUC), but performance suffered markedly when classifying PTSD from trauma-exposed healthy controls (TEHC) using three imaging modalities (∼60% AUC). ⍰ Using deep learning for feature reduction (denoising variational auto-encoder DVAE) dramatically reduced the number of features with no concomitant performance degradation. ⍰ Utilizing denoising variational autoencoder (DVAE) models improves generalizability across heterogeneous multi-site data compared with the traditional machine learning frameworks
Publisher: Elsevier BV
Date: 12-2022
DOI: 10.1016/J.PNPBP.2022.110612
Abstract: Recent evidence shows that genetic and environmental risk factors for psychotic disorders are associated with higher levels of schizotypy (or psychosis proneness) in the general population. However, little is known about how these risk factors interact. We specifically examined whether genetic loading for schizophrenia moderates the association between childhood trauma severity and schizotypy. Schizotypy was measured using the Schizotypal Personality Questionnaire (SPQ), and childhood trauma severity was measured with the Childhood Trauma Questionnaire (CTQ) among a total of 168 participants (comprising 51 healthy in iduals, 56 diagnosed with schizophrenia, and 61 with bipolar disorder). Polygenic risk scores (PRS) for schizophrenia were calculated for all participants and examined as a potential moderator of associations between total scores on the CTQ and schizotypy total scores and dimensions (i.e., cognitive-perceptual, interpersonal, disorganised). Multiple linear regression models revealed associations between childhood trauma and all dimensions of schizotypy, but no associations between PRS and schizotypy. A significant interaction between PRS and childhood trauma was evident for the interpersonal and disorganised dimensions of schizotypy, as well as the total score, reflecting positive associations between childhood trauma severity and these two schizotypal dimensions, only for in iduals with low or average PRS for schizophrenia. This suggests that trauma may be able to increase risk for psychosis independently of any genetic vulnerability. The present findings are consistent with the idea of several risk pathways for the development of psychotic disorders.
Publisher: Cold Spring Harbor Laboratory
Date: 11-01-2022
DOI: 10.1101/2022.01.10.21267840
Abstract: Schizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years range 18-72 years 67% male) and 2598 healthy controls (mean age 33.8 years, range 18-73 years, 55% male). Brain-predicted age was in idually estimated using a model trained on independent data based on 68 measures of cortical thickness and surface area, 7 subcortical volumes, lateral ventricular volumes and total intracranial volume, all derived from T1-weighted brain magnetic resonance imaging (MRI) scans. Deviations from a healthy brain ageing trajectory were assessed by the difference between brain-predicted age and chronological age (brain-predicted age difference [brain-PAD]). On average, SZ patients showed a higher brain-PAD of +3.64 years (95% CI: 3.01, 4.26 I 2 = 55.28%) compared to controls, after adjusting for age and sex (Cohen’s d = 0.50). Among SZ patients, brain-PAD was not associated with specific clinical characteristics (age of onset, duration of illness, symptom severity, or antipsychotic use and dose). This large-scale collaborative study suggests advanced structural brain ageing in SZ. Longitudinal studies of SZ and a range of mental and somatic health outcomes will help to further evaluate the clinical implications of increased brain-PAD and its ability to be influenced by interventions.
Publisher: Royal College of Psychiatrists
Date: 22-02-2023
DOI: 10.1192/BJO.2023.25
Abstract: Symptom provocation paradigms have been successfully developed to identify the neural correlates associated with post-traumatic stress disorder (PTSD) symptoms, especially dissociative behaviours, but have critical limitations. Transiently stimulating the sympathetic nervous system and/or the hypothalamic–pituitary–adrenal (HPA) axis can enhance the stress response to symptom provocation and would help identify targets for personalised interventions.
Publisher: Cold Spring Harbor Laboratory
Date: 13-02-2023
DOI: 10.1101/2023.02.12.527904
Abstract: Schizophrenia is associated with widespread brain-morphological alterations, believed to be shaped by the underlying connectome architecture. This study tests whether large-scale structural reorganization in schizophrenia relates to normative network architecture, in particular regional centrality/hubness and connectivity patterns. We examine network effects in schizophrenia across different disease stages, and transdiagnostically explore consistency of such relationships in patients with bipolar and major depressive disorder. We studied anatomical MRI scans from 2,439 adults with schizophrenia and 2,867 healthy controls from 26 ENIGMA sites. Case-control patterns of structural alterations were evaluated against two network susceptibility models: 1) hub vulnerability, which examines associations between regional network centrality and magnitude of disease-related alterations 2) epicenter models, which identify regions whose typical connectivity profile most closely resembles the disease-related morphological alteration patterns. Both susceptibility models were tested across schizophrenia disease stages and compared to meta-analytic bipolar and major depressive disorder case-control maps. In schizophrenia, regional gray matter reductions co-localized with interconnected hubs, in both the functional (r=0.58, p spin .0001) and structural connectome (r=0.32, p spin =0.01). Epicenters were identified in temporo-paralimbic regions, extending to frontal areas. We found unique epicenters for first-episode and early stages, and a shift from occipital to temporal-frontal epicenters in chronic stages. Transdiagnostic comparisons revealed shared epicenters in schizophrenia and bipolar, but not major depressive disorders. Cortical reorganization over the course of schizophrenia closely reflects brain network architecture, emphasizing marked hub susceptibility and temporo-frontal epicenters. The observed overlapping epicenters for schizophrenia and bipolar disorder furthermore suggest shared pathophysiological processes within the schizophrenia-bipolar-spectrum.
Publisher: Elsevier BV
Date: 08-2022
DOI: 10.1016/J.BIOPSYCH.2022.02.959
Abstract: Morphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre erinatal periods may be reflected in in idual variations in cortical surface area later in life. Interregional profiles of group differences in surface area between cases and controls were generated using T1-weighted magnetic resonance imaging from 27,359 in iduals including those with attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and high general psychopathology (through the Child Behavior Checklist). Similarity of interregional profiles of group differences in surface area and prenatal cell-specific gene expression was assessed. Across the 11 cortical regions, group differences in cortical area for attention-deficit/hyperactivity disorder, schizophrenia, and Child Behavior Checklist were dominant in multimodal association cortices. The same interregional profiles were also associated with interregional profiles of (prenatal) gene expression specific to proliferative cells, namely radial glia and intermediate progenitor cells (greater expression, larger difference), as well as differentiated cells, namely excitatory neurons and endothelial and mural cells (greater expression, smaller difference). Finally, these cell types were implicated in known pre erinatal risk factors for psychosis. Genes coexpressed with radial glia were enriched with genes implicated in congenital abnormalities, birth weight, hypoxia, and starvation. Genes coexpressed with endothelial and mural genes were enriched with genes associated with maternal hypertension and preterm birth. Our findings support a neurodevelopmental model of vulnerability to mental illness whereby prenatal risk factors acting through cell-specific processes lead to deviations from typical brain development during pregnancy.
Publisher: Springer Science and Business Media LLC
Date: 06-07-2022
DOI: 10.1007/S00406-022-01450-4
Abstract: Grey matter volume (GMV) may be associated with polygenic risk for schizophrenia (PRS-SZ) and severe cognitive deficits in people with schizophrenia, schizoaffective disorder (collectively SSD), and bipolar disorder (BD). This study examined the interactive effects of PRS-SZ and cognitive subtypes of SSD and BD in relation to GMV. Two-step cluster analysis was performed on 146 clinical cases (69 SSD and 77 BD) assessed on eight cognitive domains (verbal and visual memory, executive function, processing speed, visual processing, language ability, working memory, and planning). Among them, 55 BD, 51 SSD, and 58 healthy controls (HC), contributed to focal analyses of the relationships between cognitive subtypes, PRS-SZ and their interaction on GMV. Two distinct cognitive subtypes were evident among the combined s le of cases: a ‘cognitive deficit’ group (CD N = 31, 20SSD/11BD) showed severe impairment across all cognitive indices, and a ‘cognitively spared’ (CS N = 75 31SSD/44BD) group showed intermediate cognitive performance that was significantly worse than the HC group but better than the CD subgroup. A cognitive subgroup-by-PRS-SZ interaction was significantly associated with GMV in the left precentral gyrus. Moderation analyses revealed a significant negative relationship between PRS-SZ and GMV in the CD group only. At low and average (but not high) PRS-SZ, larger precentral GMV was evident in the CD group compared to both CS and HC groups, and in the CS group compared to HCs. This study provides evidence for a relationship between regional GMV changes and PRS-SZ in psychosis spectrum cases with cognitive deficits, but not in cases cognitively spared.
Publisher: Elsevier BV
Date: 11-2018
Publisher: Elsevier BV
Date: 04-2022
DOI: 10.1016/J.JPAIN.2021.10.003
Abstract: Emotion dysregulation frequently co-occurs with chronic pain, which in turn leads to heightened emotional and physical suffering. This cycle of association has prompted a recommendation for psychological treatment of chronic pain to target mechanisms for emotion regulation. The current trial addressed this need by investigating a new internet-delivered treatment incorporating emotional skills training from dialectical behavioral therapy (DBT). Using a single-case experimental design that is suited to heterogeneous populations and can demonstrate efficacy with a small s le, three participants with chronic pain were recruited. Participants received four weeks of online DBT skills training (iDBT-Pain intervention) which incorporated one-on-one sessions over Zoom and a web app. Results revealed compelling evidence for the intervention on the primary outcome of emotion dysregulation and were promising for the secondary outcome of pain intensity. Improvement was also identified on pre-and post-measures of depression, coping behaviors, sleep problems, wellbeing, and harm avoidance, indicating that the intervention may positively influence other factors related to chronic pain. Overall, the trial provides preliminary efficacy for the intervention to improve chronic pain. However, we recommend further investigation of the iDBT-Pain intervention, either in single case trials, which when conducted with scientific rigor may be aggregated to derive nomothetic conclusions, or in a group-comparison trial to compare with usual modes of treatment. PERSPECTIVE: This trial advances understanding of emotion-focused treatment for chronic pain and provides evidence for a viable new technological treatment. Importantly, as an internet-delivered approach, the iDBT-Pain intervention is accessible to those with restricted mobility and remote communities where there are often limited psychological services for people with chronic pain.
Publisher: Cambridge University Press (CUP)
Date: 18-12-2018
DOI: 10.1017/S0033291718003690
Abstract: Elevated levels of pro-inflammatory cytokines are consistently reported in schizophrenia (SZ) and bipolar-I disorder (BD), as well as among in iduals who have been exposed to childhood trauma. However, higher levels of inflammatory markers in these disorders are yet to be investigated with respect to levels of exposure to different types of childhood trauma. Participants were 68 cases with a diagnosis of schizophrenia/schizoaffective disorder (SZ), 69 cases with a diagnosis of psychotic BD and 72 healthy controls (HC). Serum levels of interleukin 6 (IL-6), tumour necrosis factor- α (TNF- α ) and C-reactive protein (CRP) were quantified, and childhood trauma exposure was assessed with the Childhood Trauma Questionnaire. The SZ group had significantly higher levels of IL-6, TNF- α and CRP when compared with the HC group (all p 0.05, d = 0.41–0.63), as well as higher levels of TNF- α when compared with the BD group ( p = 0.014, d = 0.50) there were no differences between the BD and HC groups for any markers. Exposure to sexual abuse was positively associated (standardised β = 0.326, t = 2.459, p = 0.018) with levels of CRP in the SZ group, but there were no significant associations between any form of trauma exposure and cytokine levels in the HC or BD groups. These results contribute to the evidence for a chronic state of inflammation in SZ but not BD cases. Differential associations between trauma exposure and levels of pro-inflammatory cytokines across the diagnostic categories suggest that trauma may impact biological (stress and immune) systems differently in these patient groups.
Publisher: Elsevier BV
Date: 12-2023
Publisher: Springer Science and Business Media LLC
Date: 27-10-2021
DOI: 10.1038/S41380-021-01359-9
Abstract: Neuroanatomical abnormalities have been reported along a continuum from at-risk stages, including high schizotypy, to early and chronic psychosis. However, a comprehensive neuroanatomical mapping of schizotypy remains to be established. The authors conducted the first large-scale meta-analyses of cortical and subcortical morphometric patterns of schizotypy in healthy in iduals, and compared these patterns with neuroanatomical abnormalities observed in major psychiatric disorders. The s le comprised 3004 unmedicated healthy in iduals (12–68 years, 46.5% male) from 29 cohorts of the worldwide ENIGMA Schizotypy working group. Cortical and subcortical effect size maps with schizotypy scores were generated using standardized methods. Pattern similarities were assessed between the schizotypy-related cortical and subcortical maps and effect size maps from comparisons of schizophrenia (SZ), bipolar disorder (BD) and major depression (MDD) patients with controls. Thicker right medial orbitofrontal/ventromedial prefrontal cortex (mOFC/vmPFC) was associated with higher schizotypy scores ( r = 0.067, p FDR = 0.02). The cortical thickness profile in schizotypy was positively correlated with cortical abnormalities in SZ ( r = 0.285, p spin = 0.024), but not BD ( r = 0.166, p spin = 0.205) or MDD ( r = −0.274, p spin = 0.073). The schizotypy-related subcortical volume pattern was negatively correlated with subcortical abnormalities in SZ (rho = −0.690, p spin = 0.006), BD (rho = −0.672, p spin = 0.009), and MDD (rho = −0.692, p spin = 0.004). Comprehensive mapping of schizotypy-related brain morphometry in the general population revealed a significant relationship between higher schizotypy and thicker mOFC/vmPFC, in the absence of confounding effects due to antipsychotic medication or disease chronicity. The cortical pattern similarity between schizotypy and schizophrenia yields new insights into a dimensional neurobiological continuity across the extended psychosis phenotype.
Publisher: American Psychological Association (APA)
Date: 08-2021
DOI: 10.1037/BUL0000260
Abstract: Schizotypy refers to a multidimensional construct that spans a range of cognitive, behavioral, and personality features, representing liability to psychosis on a continuum between health and illness. Schizotypy has been associated with functional and structural brain alterations as potential intermediate phenotypes on the developmental path to psychosis. We scanned the literature between February 2019 and August 1, 2020 using PubMed, Medline, APA PsycINFO, and ProQuest. We identified eligible articles conducted on participants assessed with psychometric schizotypy across the health-illness spectrum and reporting a direct statistic between schizotypy and a structural, task-related, or functional magnetic resonance imaging brain measure. Articles not peer-reviewed and not written in English were excluded. We systematically reviewed 84 studies that determined the changes in gray matter, brain activation, and connectivity associated with schizotypy in both healthy and clinical cohorts. Morphological and functional changes in the default and the frontoparietal networks, specifically frontal and temporal cortices, were most frequently associated with schizotypy. Yet, we were unable to identify consistent patterns of morphological or functional brain aberration associated with schizotypy, due to methodological differences between studies in the conceptualization and measurement of schizotypy. Efforts toward greater methodological concordance in future neuroimaging research of schizotypy are needed to improve the identification of brain-based endophenotypes for schizophrenia. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
Publisher: Elsevier BV
Date: 09-2023
Publisher: Cold Spring Harbor Laboratory
Date: 30-04-2021
DOI: 10.1101/2021.04.29.21255609
Abstract: Neuroanatomical abnormalities have been reported along a continuum from at-risk stages, including high schizotypy, to early and chronic psychosis. However, a comprehensive neuroanatomical mapping of schizotypy remains to be established. The authors conducted the first large-scale meta-analyses of cortical and subcortical morphometric patterns of schizotypy in healthy in iduals, and compared these patterns with neuroanatomical abnormalities observed in major psychiatric disorders. The s le comprised 3,004 unmedicated healthy in iduals (12-68 years, 46.5% male) from 29 cohorts of the worldwide ENIGMA Schizotypy working group. Cortical and subcortical effect size maps with schizotypy scores were generated using standardized methods. Pattern similarities were assessed between the schizotypy-related cortical and subcortical maps and effect size maps from comparisons of schizophrenia (SZ), bipolar disorder (BD) and major depression (MDD) patients with controls. Thicker right medial orbitofrontal/ventromedial prefrontal cortex (mOFC/vmPFC) was associated with higher schizotypy scores (r=.07, p FDR =.02). The cortical thickness profile in schizotypy was positively correlated with cortical abnormalities in SZ (r=.33, p spin =.01), but not BD (r=.19, p spin =.16) or MDD (r=-.22, p spin =.10). The schizotypy-related subcortical volume pattern was negatively correlated with subcortical abnormalities in SZ (rho=-.65, p spin =.01), BD (rho=-.63, p spin =.01), and MDD (rho=-.69, p spin =.004). Comprehensive mapping of schizotypy-related brain morphometry in the general population revealed a significant relationship between higher schizotypy and thicker mOFC/vmPFC, in the absence of confounding effects due to antipsychotic medication or disease chronicity. The cortical pattern similarity between schizotypy and schizophrenia yields new insights into a dimensional neurobiological continuity across the extended psychosis phenotype.
Publisher: Oxford University Press (OUP)
Date: 10-09-2020
Abstract: Genome-wide association studies (GWAS) of schizophrenia have strongly implicated a risk locus in close proximity to the gene for miR-137. While there are candidate single-nucleotide polymorphisms (SNPs) with functional implications for the microRNA’s expression encompassed by the common haplotype tagged by rs1625579, there are likely to be others, such as the variable number tandem repeat (VNTR) variant rs58335419, that have no proxy on the SNP genotyping platforms used in GWAS to date. Using whole-genome sequencing data from schizophrenia patients (n = 299) and healthy controls (n = 131), we observed that the MIR137 4-repeats VNTR (VNTR4) variant was enriched in a cognitive deficit subtype of schizophrenia and associated with altered brain morphology, including thicker left inferior temporal gyrus and deeper right postcentral sulcus. These findings suggest that the MIR137 VNTR4 may impact neuroanatomical development that may, in turn, influence the expression of more severe cognitive symptoms in patients with schizophrenia.
Publisher: CMA Joule Inc.
Date: 03-2012
DOI: 10.1503/JPN.100167
Publisher: Oxford University Press (OUP)
Date: 04-2020
DOI: 10.1093/SCHBUL/SBAA029.722
Abstract: Negative symptoms can be seen to represent a continuum from subclinical manifestations in the general population to severe symptoms in schizophrenia. Neuroanatomical studies show evidence of fronto-striatal structural abnormalities linked to negative symptoms in patients with schizophrenia (Walton et al. 2018). However, it remains an open question whether these structural associations are also observed in ostensibly healthy in iduals reporting subclinical negative symptoms. The present study used structural T1-weighted brain imaging data from the ENIGMA Schizotypy Working Group to investigate the relationship between subclinical negative symptoms and fronto-striatal structural measures. We included 2,235 healthy unmedicated in iduals with varying levels of schizotypy from 17 centers around the world. The complete s le had a weighted mean (range) age of 29.2 (15.9–39.6) and 59.4% (51–100) were male. Subclinical negative symptoms were assessed at each site separately using factor scores from self-report schizotypy questionnaires (i.e., the Community Assessment of Psychic Experiences, the Oxford-Liverpool Inventory of Feelings and Experiences, or the Schizotypal Personality Questionnaire). Based on prior studies in schizophrenia, we obtained cortical thickness from 22 frontal regions-of-interest (ROIs) and subcortical volumes from 6 striatal ROIs using FreeSurfer. We performed meta-analyses of effect sizes (standardized regression coefficients) from a model predicting mean cortical thickness by subclinical negative symptom scores, adjusting for age, sex, and site. The same analysis was repeated for subcortical volumes including intracranial volume as additional covariate. Meta-analyses revealed significant positive associations between subclinical negative symptoms and cortical thickness of the left frontal pole (βstd=0.091 pFDR=0.009), right medial orbitofrontal cortex (βstd=0.083 pFDR=0.009) and right anterior cingulate cortex (βstd=0.07 pFDR=0.011). Using a large s le of healthy unmedicated in iduals with varying levels of schizotypal personality traits, this ENIGMA meta-analysis showed that subclinical negative symptoms are associated with thicker prefrontal cortex. The present data are contrary to previous findings in schizophrenia, which demonstrates a relationship between negative symptoms and lower prefrontal cortical thickness (Walton et al. 2018). These ergent neural correlates suggest that thicker cortex could be a potential compensatory mechanism preventing in iduals with schizotypy from the clinical manifestation of severe negative symptoms. Alternatively, greater prefrontal cortical thickness could also be associated with pathological processes along the negative symptom continuum prior to clinical manifestation.
Publisher: Elsevier BV
Date: 04-2019
Publisher: Elsevier BV
Date: 12-2021
DOI: 10.1016/J.SCHRES.2021.09.021
Abstract: Childhood trauma confers risk for psychosis and is associated with increased 'schizotypy' (a multi-dimensional construct reflecting risk for psychosis in the general population). Structural brain alterations are associated with both childhood trauma and schizotypy, but the potential role of trauma exposure in moderating associations between schizotypy and brain morphology has yet to be determined. Participants were 160 healthy in iduals (mean age: 40.08 years, SD = 13.64, range 18-64 52.5% female). Childhood trauma exposure was assessed using the Childhood Adversity Questionnaire, and schizotypy was assessed using the Schizotypal Personality Questionnaire. Univariate voxel-based morphometry and multivariate analyses of grey matter volume covariation (GMC derived from independent component analysis) were performed to determine the main effects of schizotypy, trauma exposure and their interaction on these indices of grey matter volume. Moderation analyses were performed following significant interaction. Levels of schizotypy, in particular the Cognitive-Perceptual and Interpersonal dimensions, were negatively associated with GMC in the striatum, the hippoc us arahippoc al gyrus, thalamus and insulae. Trauma exposure was negatively associated with GMC of the middle frontal gyrus and parietal lobule, while negatively associated with GMC in the cerebellum. Levels of schizotypy (total scores, and the cognitive-perceptual dimension) were negatively associated with striatal GMC in in iduals not exposed to trauma, but not in those exposed to trauma. Schizotypy and childhood trauma were independently associated with changes of grey matter in brain regions critical for cognition and social cognition. In in iduals not exposed to trauma, increased schizotypy was associated with decreased striatal and limbic grey matter.
Publisher: Cambridge University Press (CUP)
Date: 20-10-2023
Publisher: Cambridge University Press (CUP)
Date: 10-10-2018
DOI: 10.1017/S0033291717002884
Abstract: Childhood trauma is a risk factor for psychosis. Deficits in response inhibition are common to psychosis and trauma-exposed populations, and associated brain functions may be affected by trauma exposure in psychotic disorders. We aimed to identify the influence of trauma-exposure on brain activation and functional connectivity during a response inhibition task. We used functional magnetic resonance imaging to examine brain function within regions-of-interest [left and right inferior frontal gyrus (IFG), right dorsolateral prefrontal cortex, right supplementary motor area, right inferior parietal lobule and dorsal anterior cingulate cortex], during the performance of a Go/No-Go Flanker task, in 112 clinical cases with psychotic disorders and 53 healthy controls (HCs). Among the participants, 71 clinical cases and 21 HCs reported significant levels of childhood trauma exposure, while 41 clinical cases and 32 HCs did not. In the absence of effects on response inhibition performance, childhood trauma exposure was associated with increased activation in the left IFG, and increased connectivity between the left IFG seed region and the cerebellum and calcarine sulcus, in both cases and healthy in iduals. There was no main effect of psychosis, and no trauma-by-psychosis interaction for any other region-of-interest. Within the clinical s le, the effects of trauma-exposure on the left IFG activation were mediated by symptom severity. Trauma-related increases in activation of the left IFG were not associated with performance differences, or dependent on clinical diagnostic status increased IFG functionality may represent a compensatory (overactivation) mechanism required to exert adequate inhibitory control of the motor response.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 20-03-2020
Abstract: The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 in iduals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. We identified 369 nominally genome-wide significant loci ( P 5 × 10 −8 ) associated with cortical structure in a discovery s le of 33,992 participants of European ancestry. Of the 360 loci for which replication data were available, 241 loci influencing surface area and 66 influencing thickness remained significant after replication, with 237 loci passing multiple testing correction ( P 8.3 × 10 −10 187 influencing surface area and 50 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness surface area and thickness showed a negative genetic correlation ( r G = −0.32, SE = 0.05, P = 6.5 × 10 −12 ), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain s les, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on in idual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 46 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function. ( A ) Measurement of cortical surface area and thickness from MRI. ( B ) Genomic locations of common genetic variants that influence global and regional cortical structure. ( C ) Our results support the radial unit hypothesis that the expansion of cortical surface area is driven by proliferating neural progenitor cells. ( D ) Cortical surface area shows genetic correlation with psychiatric and cognitive traits. Error bars indicate SE. IMAGE CREDITS: (A) K. COURTNEY (C) M. R. GLASS
Publisher: JMIR Publications Inc.
Date: 16-08-2022
Abstract: motion dysregulation is key to the development and maintenance of chronic pain, feeding into a cycle of worsening pain and disability. Dialectical behavioral therapy (DBT), an evidence-based treatment for complex transdiagnostic conditions presenting with high emotion dysregulation, may be beneficial to manage and mitigate the emotional and sensory aspects of chronic pain. Increasingly, DBT skills training as a key component of standard DBT is being delivered as a stand-alone intervention without concurrent therapy to help develop skills for effective emotion regulation. A previous repeated-measure single-case trial investigating a novel technologically driven DBT skills training, internet-delivered DBT skills training for chronic pain (iDBT-Pain), revealed promising findings to improve both emotion dysregulation and pain intensity. his randomized controlled trial aims to examine the efficacy of iDBT-Pain in comparison with treatment as usual to reduce emotion dysregulation (primary outcome) for in iduals with chronic pain after 9 weeks and at the 21-week follow-up. The secondary outcomes include pain intensity, pain interference, anxiety symptoms, depressive symptoms, perceived stress, posttraumatic stress, harm avoidance, social cognition, sleep quality, life satisfaction, and well-being. The trial also examines the acceptability of the iDBT-Pain intervention for future development and testing. total of 48 people with chronic pain will be randomly assigned to 1 of 2 conditions: treatment and treatment as usual. Participants in the treatment condition will receive iDBT-Pain, consisting of 6 live web-based group sessions led by a DBT skills trainer and supervised by a registered psychologist and the iDBT-Pain app. Participants in the treatment-as-usual condition will not receive iDBT-Pain but will still access their usual medication and health interventions. We predict that iDBT-Pain will improve the primary outcome of emotion dysregulation and the secondary outcomes of pain intensity, pain interference, anxiety symptoms, depressive symptoms, perceived stress, harm avoidance, social cognition, sleep quality, life satisfaction, and well-being. A linear mixed model with random effects of in iduals will be conducted to investigate the differences between the baseline, 9-week (primary end point), and 21-week (follow-up) assessments as a function of experimental condition. ecruitment started in February 2023, and the clinical trial started in March 2023. Data collection for the final assessment is planned to be completed by July 2024. f our hypothesis is confirmed, our findings will contribute to the evidence for the efficacy and acceptability of a viable intervention that may be used by health care professionals for people with chronic pain. The results will add to the chronic pain literature to inform about the potential benefits of DBT skills training for chronic pain and will contribute evidence about technologically driven interventions. ustralian New Zealand Clinical Trials Registry ACTRN12622000113752 www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=383208& isReview=true RR1-10.2196/41890
No related grants have been discovered for Yann Quidé.