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    ABSTRACT: Background: Impairments in social cognition have been described in schizophrenia and relate to core symptoms of the disorder. Social cognition is subserved by a network of brain regions, many of which have been implicated in schizophrenia. We hypothesized that deficits in connectivity between components of this social brain network may underlie the social cognition impairments seen in the disorder. Methods: We investigated brain activation and connectivity in a group of individuals with schizophrenia making social judgments of approachability from faces (n = 20), compared with a group of matched healthy volunteers (n = 24), using functional magnetic resonance imaging. Effective connectivity from the amygdala was estimated using the psychophysiological interaction approach. Results: While making approachability judgments, healthy participants recruited a network of social brain regions including amygdala, fusiform gyrus, cerebellum, and inferior frontal gyrus bilaterally and left medial prefrontal cortex. During the approachability task, healthy participants showed increased connectivity from the amygdala to the fusiform gyri, cerebellum, and left superior frontal cortex. In comparison to controls, individuals with schizophrenia overactivated the right middle frontal gyrus, superior frontal gyrus, and precuneus and had reduced connectivity between the amygdala and the insula cortex. Discussion: We report increased activation of frontal and medial parietal regions during social judgment in patients with schizophrenia, accompanied by decreased connectivity between the amygdala and insula. We suggest that the increased activation of frontal control systems and association cortex may reflect a compensatory mechanism for impaired connectivity of the amygdala with other parts of the social brain networks in schizophrenia.
    Schizophrenia Bulletin 07/2013;
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    ABSTRACT: Aims: Alcohol-dependent people who are middle-aged or older have a widespread loss of cortical grey and white matter, particularly in the prefrontal cortex (PFC). We examine if brain abnormalities are detectable in alcohol use disorders before the fifth decade (i.e. <40), and the brain structural differences associated with alcohol abuse/dependence in adolescence. Methods: Case-control studies comparing brain structure in alcohol-abusing/-dependent individuals with normal controls in which the mean age of participants was <40 were identified using Medline, EMBASE and PsychInfo. Studies in which mean age was over and under 21 were considered separately. Results: Twelve papers fulfilled inclusion criteria, five in the adolescent (14-21) and seven in the young adult age range. Two independent groups reported hippocampal and prefrontal volume reductions in adolescents, although this was consistently observed only in females. In young adults (aged 21-40), there were grey matter deficits in the PFC in both sexes. Adult women appeared to, particularly, exhibit white matter differences, evident as reduced area of the corpus callosum. Hippocampal volume reduction was observed in one study of young adults study but not another. Conclusion: The available data suggest that quantitative structural abnormalities of the brain are detectable in young alcohol abusers. There is overlap between the abnormalities seen in adolescents and young adults, although hippocampal volume loss is most consistently seen in the former group. The adolescent hippocampus may be particularly susceptible to alcohol, potentially because of an interaction between adolescent brain development and alcohol exposure.
    Alcohol and Alcoholism 04/2013;
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    Biological psychiatry 03/2013; 73(6):495-6.
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    ABSTRACT: BACKGROUND: Bipolar disorder (BD) and major depressive disorder (MDD) are highly heritable and genetically overlapping conditions characterized by episodic elevation and/or depression of mood. Both demonstrate abnormalities in white matter integrity, measured with diffusion tensor magnetic resonance imaging, that are also heritable. However, it is unclear how these abnormalities relate to the underlying genetic architecture of each disorder. Genome-wide association studies have demonstrated a significant polygenic contribution to BD and MDD, where risk is attributed to the summation of many alleles of small effect. Determining the effects of an overall polygenic risk profile score on neuroimaging abnormalities might help to identify proxy measures of genetic susceptibility and thereby inform models of risk prediction. METHODS: In the current study, we determined the extent to which common genetic variation underlying risk to mood disorders (BD and MDD) was related to fractional anisotropy, an index of white matter integrity. This was conducted in unaffected individuals at familial risk of mood disorder (n = 70) and comparison subjects (n = 62). Polygenic risk scores were calculated separately for BD and MDD on the basis of genome-wide association study data from the Psychiatric GWAS Consortia. RESULTS: We report that a higher polygenic risk allele load for MDD was significantly associated with decreased white matter integrity across both groups in a large cluster, with a peak in the right-sided superior longitudinal fasciculus. CONCLUSIONS: These findings suggest that the polygenic approach to examining brain imaging data might be a useful means of identifying traits linked to the genetic risk of mood disorders.
    Biological psychiatry 02/2013;
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    ABSTRACT: Nonlinear Dynamic Causal Modelling (DCM) for fMRI provides computational modelling of gating mechanisms at the neuronal population level. It allows for estimations of connection strengths with nonlinear modulation within task-dependent networks. This paper presents an application of nonlinear DCM in subjects at high familial risk of schizophrenia performing the Hayling Sentence Completion Task (HSCT). We analysed scans of 19 healthy controls and 46 subjects at high familial risk of schizophrenia, which included 26 high risk subjects without psychotic symptoms and 20 subjects with psychotic symptoms. The activity-dependent network consists of the intra parietal cortex (IPS), inferior frontal gyrus (IFG), middle temporal gyrus (MTG), anterior cingulate cortex (ACC) and the mediodorsal (MD) thalamus. The connections between the MD thalamus and the IFG were gated by the MD thalamus. We used DCM to investigate altered connection strength of these connections. Bayesian Model Selection (BMS) at the group and family level was used to compare the optimal bilinear and nonlinear models. Bayesian Model Averaging (BMA) was used to assess the connection strengths with the gating from the MD thalamus and the IFG. The nonlinear models provided the better explanation of the data. Furthermore, the BMA analysis showed significantly lower connection strength of the thalamocortical connection with nonlinear modulation from the MD thalamus in high risk subjects with psychotic symptoms and those who subsequently developed schizophrenia. These findings demonstrate that nonlinear DCM provides a method to investigate altered connectivity at the level of neural circuits. The reduced connection strength with thalamic gating may be a neurobiomarker implicated in the development of psychotic symptoms. This study suggests that nonlinear DCM could lead to new insights into functional and effective dysconnection at the network level in subjects at high familial risk.
    NeuroImage 02/2013;
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    ABSTRACT: BACKGROUND: Existing studies of brain structural changes before the onset of schizophrenia have considered individuals with either familial risk factors or prodromal symptomatology. We aimed to determine whether findings from these studies are also applicable to those at enhanced risk of developing schizophrenia for another reason-intellectual impairment. METHODS: Participants with intellectual impairment (mean IQ: 78.2) received magnetic resonance imaging of the brain at baseline (mean age: 16 years old) and again 6 years later. The Positive and Negative Syndrome Scale was used to assess psychotic symptoms. Participants were dichotomized using their Positive and Negative Syndrome Scale scores at follow-up and gray matter changes were compared between the groups using tensor based morphometry and semiautomated region of interest analysis. RESULTS: Forty-six individuals had scans of sufficient quality to be included in the study. The tensor based morphometry analyses revealed that those with psychotic symptoms at follow-up showed significantly greater gray matter reductions over 6 years in the medial temporal lobes bilaterally. Region of interest analyses revealed that those individuals with psychotic symptoms at follow-up showed a reduced right hippocampal volume at age 16 and reduced bilateral hippocampal volumes at follow-up. CONCLUSIONS: This unique study of individuals vulnerable to schizophrenia due to intellectual impairment highlights aberrant development in the medial temporal lobe associated with the occurrence of psychotic symptoms. These developmental changes are also evident in populations at enhanced risk of schizophrenia for familial and symptomatic reasons, suggesting they are central to the development of the disorder regardless of the nature of the vulnerability state.
    Biological psychiatry 01/2013;
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    ABSTRACT: Drysdale E, Knight HM, McIntosh AM, Blackwood DHR. Cognitive endophenotypes in a family with bipolar disorder with a risk locus on chromosome 4. Bipolar Disord 2013: 00: 000-000. © 2013 John Wiley & Sons A/S.Published by Blackwell Publishing Ltd. Objectives:  We studied cognitive function in high-risk relatives belonging to a single extended family showing linkage of bipolar disorder to a locus on chromosome 4. High-risk relatives were defined as those that carried the risk haplotype of polymorphic markers, identified in a previous linkage study. This family provided a rare opportunity to characterize a neuropsychological endophenotype in a homogeneous sample of relatives with a common genetic risk factor. Methods:  Fifteen family members carrying the risk haplotype (eight diagnosed with bipolar disorder or depression and seven with no psychiatric diagnosis), unrelated patients with bipolar disorder (n = 36) and major depressive disorder (n = 40), and healthy control subjects (n = 33) were administered the California Verbal Learning Test, Verbal Fluency Test, Hayling Sentence Completion Test, and Brixton Spatial Anticipation Test to assess verbal memory, verbal fluency, and executive function. Results:  Compared with healthy controls, family members carrying the risk haplotype were impaired in indices of memory and executive function. There were no significant differences between unaffected and affected haplotype-carrying family members in any cognitive measure. Pronounced deficits in the encoding stage of verbal memory and category verbal fluency were evident in individuals with the risk haplotype. Conclusions:  Verbal learning and semantic verbal fluency impairments may represent a cognitive endophenotype for both bipolar disorder and major depression in relatives of bipolar disorder patients, as impairment was also present in high-risk relatives who had not developed any affective disorder symptoms. These findings suggest that impairment in semantic organization may be linked to the genetic aetiology of bipolar disorder.
    Bipolar Disorders 01/2013;
  • Biological psychiatry 01/2013; 73(2):107-8.
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    ABSTRACT: Bipolar disorder is a highly heritable condition. First-degree relatives of affected individuals have a more than a ten-fold increased risk of developing bipolar disorder (BD), and a three-fold risk of developing major depressive disorder (MDD) than the general population. It is unclear however whether differences in brain activation reported in BD and MDD are present before the onset of illness. We studied 98 young unaffected individuals at high familial risk of BD and 58 healthy controls using functional Magnetic Resonance Imaging (fMRI) scans and a task involving executive and language processing. Twenty of the high-risk subjects subsequently developed MDD after the baseline fMRI scan. At baseline the high-risk subjects who later developed MDD demonstrated relatively increased activation in the insula cortex, compared to controls and high risk subjects who remained well. In the healthy controls and high-risk group who remained well, this region demonstrated reduced engagement with increasing task difficulty. The high risk subjects who subsequently developed MDD did not demonstrate this normal disengagement. Activation in this region correlated positively with measures of cyclothymia and neuroticism at baseline, but not with measures of depression. These results suggest that increased activation of the insula can differentiate individuals at high-risk of bipolar disorder who later develop MDD from healthy controls and those at familial risk who remain well. These findings offer the potential of future risk stratification in individuals at risk of mood disorder for familial reasons.
    PLoS ONE 01/2013; 8(3):e57357.
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    ABSTRACT: Borderline personality disorder (BPD) is a common and serious mental illness, associated with a high risk of suicide and self harm. Those with a diagnosis of BPD often display difficulties with social interaction and struggle to form and maintain interpersonal relationships. Here we investigated the ability of participants with BPD to make social inferences from faces. 20 participants with BPD and 21 healthy controls were shown a series of faces and asked to judge these according to one of six characteristics (age, distinctiveness, attractiveness, intelligence, approachability, trustworthiness). The number and direction of errors made (compared to population norms) were recorded for analysis. Participants with a diagnosis of BPD displayed significant impairments in making judgements from faces. In particular, the BPD Group judged faces as less approachable and less trustworthy than controls. Furthermore, within the BPD Group there was a correlation between scores on the Childhood Trauma Questionnaire (CTQ) and bias towards judging faces as unapproachable. Individuals with a diagnosis of BPD have difficulty making appropriate social judgements about others from their faces. Judging more faces as unapproachable and untrustworthy indicates that this group may have a heightened sensitivity to perceiving potential threat, and this should be considered in clinical management and treatment.
    PLoS ONE 01/2013; 8(11):e73440.
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