Cortical Surface Area Differentiates Familial High Risk Individuals Who Go on to Develop Schizophrenia

BACKGROUND: Schizophrenia is associated with structural brain abnormalities that may be present before disease onset. It remains unclear whether these represent general vulnerability indicators or are associated with the clinical state itself. METHODS: To investigate this, structural brain scans were acquired at two time points (mean scan interval 1.87 years) in a cohort of individuals at high familial risk of schizophrenia (n 5 142) and control subjects (n 5 36). Cortical reconstructions were generated using FreeSurfer. The high-risk cohort was subdivided into individuals that remained well during the study, individuals that had transient psychotic symptoms, and individuals that subsequently became ill. Baseline measures and longitudinal change in global estimates of thickness and surface area and lobar values were compared, focusing on overall differences between high-risk individuals and control subjects and then on group differences within the high-risk cohort. RESULTS: Longitudinally, control subjects showed a significantly greater reduction in cortical surface area compared with the high-risk group. Within the high-risk group, differences in surface area at baseline predicted clinical course, with individuals that subsequently became ill having significantly larger surface area than individuals that remained well during the study. For thickness, longitudinal reductions were most prominent in the frontal, cingulate, and occipital lobes in all high-risk individuals compared with control subjects. CONCLUSIONS: Our results suggest that larger surface areas at baseline may be associated with mechanisms that go above and beyond a general familial disposition. A relative preservation over time of surface area, coupled with a thinning of the cortex compared with control subjects, may serve as vulnerability markers of schizophrenia

Effects of a balanced translocation between chromosomes 1 and 11 disrupting the DISC1 locus on white matter integrity

Objective Individuals carrying rare, but biologically informative genetic variants provide a unique opportunity to model major mental illness and inform understanding of disease mechanisms. The rarity of such variations means that their study involves small group numbers, however they are amongst the strongest known genetic risk factors for major mental illness and are likely to have large neural effects. DISC1 (Disrupted in Schizophrenia 1) is a gene containing one such risk variant, identified in a single Scottish family through its disruption by a balanced translocation of chromosomes 1 and 11; t(1;11) (q42.1;q14.3). Method Within the original pedigree, we examined the effects of the t(1;11) translocation on white matter integrity, measured by fractional anisotropy (FA). This included family members with (n = 7) and without (n = 13) the translocation, along with a clinical control sample of patients with psychosis (n = 34), and a group of healthy controls (n = 33). Results We report decreased white matter integrity in five clusters in the genu of the corpus callosum, the right inferior fronto-occipital fasciculus, acoustic radiation and fornix. Analysis of the mixed psychosis group also demonstrated decreased white matter integrity in the above regions. FA values within the corpus callosum correlated significantly with positive psychotic symptom severity. Conclusions We demonstrate that the t(1;11) translocation is associated with reduced white matter integrity in frontal commissural and association fibre tracts. These findings overlap with those shown in affected patients with psychosis and in DISC1 animal models and highlight the value of rare but biologically informative mutations in modeling psychosis

Brain structural abnormalities in obesity: relation to age, genetic risk, and common psychiatric disorders: evidence through univariate and multivariate mega-analysis including 6420 participants from the ENIGMA MDD working group

Published online: 28 May 2020Emerging evidence suggests that obesity impacts brain physiology at multiple levels. Here we aimed to clarify the relationship between obesity and brain structure using structural MRI (n = 6420) and genetic data (n = 3907) from the ENIGMA Major Depressive Disorder (MDD) working group. Obesity (BMI > 30) was significantly associated with cortical and subcortical abnormalities in both mass-univariate and multivariate pattern recognition analyses independent of MDD diagnosis. The most pronounced effects were found for associations between obesity and lower temporo-frontal cortical thickness (maximum Cohen´s d (left fusiform gyrus) = −0.33). The observed regional distribution and effect size of cortical thickness reductions in obesity revealed considerable similarities with corresponding patterns of lower cortical thickness in previously published studies of neuropsychiatric disorders. A higher polygenic risk score for obesity significantly correlated with lower occipital surface area. In addition, a significant age-by-obesity interaction on cortical thickness emerged driven by lower thickness in older participants. Our findings suggest a neurobiological interaction between obesity and brain structure under physiological and pathological brain conditions.Nils Opel ... Bernhard T. Baune ... et al

A simplified (modified) Duke Activity Status Index (M-DASI) to characterise functional capacity: A secondary analysis of the Measurement of Exercise Tolerance before Surgery (METS) study

Background Accurate assessment of functional capacity, a predictor of postoperative morbidity and mortality, is essential to improving surgical planning and outcomes. We assessed if all 12 items of the Duke Activity Status Index (DASI) were equally important in reflecting exercise capacity. Methods In this secondary cross-sectional analysis of the international, multicentre Measurement of Exercise Tolerance before Surgery (METS) study, we assessed cardiopulmonary exercise testing and DASI data from 1455 participants. Multivariable regression analyses were used to revise the DASI model in predicting an anaerobic threshold (AT) >11 ml kg −1 min −1 and peak oxygen consumption (VO 2 peak) >16 ml kg −1 min −1, cut-points that represent a reduced risk of postoperative complications. Results Five questions were identified to have dominance in predicting AT>11 ml kg −1 min −1 and VO 2 peak>16 ml.kg −1min −1. These items were included in the M-DASI-5Q and retained utility in predicting AT>11 ml.kg −1.min −1 (area under the receiver-operating-characteristic [AUROC]-AT: M-DASI-5Q=0.67 vs original 12-question DASI=0.66) and VO 2 peak (AUROC-VO2 peak: M-DASI-5Q 0.73 vs original 12-question DASI 0.71). Conversely, in a sensitivity analysis we removed one potentially sensitive question related to the ability to have sexual relations, and the ability of the remaining four questions (M-DASI-4Q) to predict an adequate functional threshold remained no worse than the original 12-question DASI model. Adding a dynamic component to the M-DASI-4Q by assessing the chronotropic response to exercise improved its ability to discriminate between those with VO 2 peak>16 ml.kg −1.min −1 and VO 2 peak<16 ml.kg −1.min −1. Conclusions The M-DASI provides a simple screening tool for further preoperative evaluation, including with cardiopulmonary exercise testing, to guide perioperative management

Longitudinal changes in hippocampal volume in the Edinburgh High Risk Study of Schizophrenia.

Schizophrenia is associated with structural brain abnormalities that are likely to be present before disease onset. It remains unclear to what extent these represent general vulnerability indicators or are associated with the developing clinical state itself. It also remains unclear whether such state or trait alterations may be evident at any given time-point, or whether they progress over time. To investigate this, structural brain scans were acquired at two time-points (mean scan-interval 1.87years) in a cohort of young unaffected individuals at high familial risk of schizophrenia (baseline, n=142; follow-up, n=64) and healthy controls (baseline, n=36; follow-up, n=18). Sub-cortical reconstructions of the hippocampus and amygdala were generated using the longitudinal pipeline available with Freesurfer. The high risk cohort was subdivided into individuals that remained well during the study (HR[well], baseline, n=68; follow-up, n=30), transient and/or partial symptoms that were insufficient to support a formal diagnosis (HR[symp], baseline, n=57; follow-up, n=26) and individuals that subsequently developed schizophrenia according to ICD-10 criteria (HR[ill], baseline, n=17; follow-up, n=8). Longitudinal change in the hippocampus and amygdala was compared, focusing first on overall differences between high-risk individuals and controls and then on sub-group differences within the high-risk cohort. We found a significantly altered developmental trajectory for all high risk individuals compared to controls, with controls showing a significant increase in hippocampal volume over time compared to those at high risk. We did not find evidence of altered longitudinal trajectories based on clinical outcome within the high risk cohort. These results suggest that an altered developmental trajectory of hippocampal volume is associated with a general familial predisposition to develop schizophrenia, as this alteration was not related to subsequent clinical outcome

Hypofrontality in subjects at high genetic risk of schizophrenia with depressive symptoms

BACKGROUND: Subjects at high risk of schizophrenia for genetic reasons were found to demonstrate increased levels of depressive symptoms compared to controls. The current study sought to investigate the neural correlates of depression in these subjects. We hypothesised abnormal activation of dorsolateral prefrontal regions in those at high risk with depression. METHODS: Depression was rated according to DSM-IV criteria. FMRI data was available from 90 high risk subjects, comprising 78 not depressed (HRD-) and 12 depressed (HRD+) subjects. Activation during the Hayling Sentence Completion Task was compared to 25 healthy control subjects without depression. RESULTS: The HRD+ group demonstrated reduced activation of the right middle/superior frontal gyrus compared to both healthy controls and the HRD- group. Increased left superior temporal gyrus activation was also found in the HRD+ group versus the HRD- group. These results survived controlling for the presence of positive psychotic symptoms at the time of the scan. CONCLUSION: Reduced activation of dorsolateral prefrontal regions, widely reported in established schizophrenia and seen here in people at high familial risk with depressive features, may be related to the presence of affective symptoms of the disorder rather than to the presence of positive psychotic symptoms. Since studies have indicated that depressive symptoms antecede illness, these findings may be relevant to the early features of developing psychosis

Deficits in facial, body movement and vocal emotional processing in autism spectrum disorders

Background: Previous behavioural and neuroimaging studies of emotion processing in Autistic Spectrum Disorder (ASD) have focussed on the use of facial stimuli. To date, however, no studies have examined emotion processing in autism across a broad range of social signals. Methods: This study addressed this issue by investigating emotion processing in a group of 23 adults with ASD and 23 age and gender matched controls. Recognition of basic emotions (‘happiness’, ‘sadness’, ‘anger’, disgust’ and ‘fear’) was assessed from facial, body movement and vocal stimuli. The ability to make social judgements (such as approachability) from facial stimuli was also investigated. Results: Significant deficits in emotion recognition were found in the ASD group relative to the control group across all stimulus domains (faces, body movements and voices). These deficits were seen across a range of emotions. The ASD group were also impaired in making social judgements compared to the control group and this correlated with impairments in basic emotion recognition. Conclusion: This study demonstrates that there are significant and broad ranging deficits in emotion processing in ASD present across a range of stimulus domains and in the auditory and visual modality; they cannot therefore be accounted for simply in terms of impairments in face processing or in the visual modality alone. These results identify a core deficit affecting the processing of a wide range of emotional information in ASD which contributes to the impairments in social function seen in people with this condition