Altered brain activation during emotional face processing in relation to both diagnosis and polygenic risk of bipolar disorder

Objectives Bipolar disorder (BD) is a highly heritable disorder with polygenic inheritance. Among the most consistent findings from functional magnetic imaging (fMRI) studies are limbic hyperactivation and dorsal hypoactivation. However, the relation between reported brain functional abnormalities and underlying genetic risk remains elusive. This is the first cross-sectional study applying a whole-brain explorative approach to investigate potential influence of BD case-control status and polygenic risk on brain activation. Methods A BD polygenic risk score (PGRS) was estimated from the Psychiatric Genomics Consortium BD case-control study, and assigned to each individual in our independent sample (N=85 BD cases and 121 healthy controls (HC)), all of whom participated in an fMRI emotional faces matching paradigm. Potential differences in BOLD response across diagnostic groups were explored at whole-brain level in addition to amygdala as a region of interest. Putative effects of BD PGRS on brain activation were also investigated. Results At whole-brain level, BD cases presented with significantly lower cuneus/precuneus activation than HC during negative face processing (Z-threshold=2.3 as cluster-level correction). The PGRS was associated positively with increased right inferior frontal gyrus (rIFG) activation during negative face processing. For amygdala activation, there were no correlations with diagnostic status or PGRS. Conclusions These findings are in line with previous reports of reduced precuneus and altered rIFG activation in BD. While these results demonstrate the ability of PGRS to reveal underlying genetic risk of altered brain activation in BD, the lack of convergence of effects at diagnostic and PGRS level suggests that this relation is a complex one

Assessing brain structural associations with working-memory related brain patterns in schizophrenia and healthy controls using linked independent component analysis

Schizophrenia (SZ) is a psychotic disorder with significant cognitive dysfunction. Abnormal brain activation during cognitive processing has been reported, both in task-positive and task-negative networks. Further, structural cortical and subcortical brain abnormalities have been documented, but little is known about how task-related brain activation is associated with brain anatomy in SZ compared to healthy controls (HC). Utilizing linked independent component analysis (LICA), a data-driven multimodal analysis approach, we investigated structure–function associations in a large sample of SZ (n = 96) and HC (n = 142). We tested for associations between task-positive (fronto-parietal) and task-negative (default-mode) brain networks derived from fMRI activation during an n-back working memory task, and brain structural measures of surface area, cortical thickness, and gray matter volume, and to what extent these associations differed in SZ compared to HC. A significant association (p < .05, corrected for multiple comparisons) was found between a component reflecting the task-positive fronto-parietal network and another component reflecting cortical thickness in fronto-temporal brain regions in SZ, indicating increased activation with increased thickness. Other structure–function associations across, between and within groups were generally moderate and significant at a nominal p-level only, with more numerous and stronger associations in SZ compared to HC. These results indicate a complex pattern of moderate associations between brain activation during cognitive processing and brain morphometry, and extend previous findings of fronto-temporal brain abnormalities in SZ by suggesting a coupling between cortical thickness of these brain regions and working memory-related brain activation

Resting-state heart rate variability is related to respiratory frequency in individuals with severe mental illness but not healthy controls

Heart rate variability (HRV) has become central to biobehavioral models of self-regulation and interpersonal interaction. While research on healthy populations suggests changes in respiratory frequency do not affect short-term HRV, thus negating the need to include respiratory frequency as a HRV covariate, the nature of the relationship between these two variables in psychiatric illness is poorly understood. Therefore, the aim of this study was to investigate the association between HRV and respiratory frequency in a sample of individuals with severe psychiatric illness (n = 55) and a healthy control comparison group (n = 149). While there was no significant correlation between HF-HRV and respiration in the control group, we observed a significant negative correlation in the psychiatric illness group, with a 94.1% probability that these two relationships are different. Thus, we provide preliminary evidence suggesting that HF-HRV is related to respiratory frequency in severe mental illness, but not in healthy controls, suggesting that HRV research in this population may need to account for respiratory frequency. Future work is required to better understand the complex relationship between respiration and HRV in other clinical samples with psychiatric diseases

Contribution of oxytocin receptor polymorphisms to amygdala activation in schizophrenia spectrum disorders

Background Oxytocin has been proposed to mediate amygdala dysfunction associated with altered emotion processing in schizophrenia, but the contribution of oxytocin pathway genes is yet to be investigated. Aims To identify potential different contributions of three oxytocin receptor polymorphisms (rs53576, rs237902 and rs2254298) between patients with schizophrenia spectrum disorders (SCZ), affective spectrum disorders (AD) and healthy controls (HC). Method In a total of 346 participants (104 with SCZ, 100 with AD, and 142 HC) underwent genotyping and functional magnetic resonance imaging (fMRI) during an emotional faces matching paradigm. Genetic association analyses were performed to test the possible effects on task-induced BOLD amygdala response to fearful/angry faces. Results In participants with SCZ, the rs237902 G allele was associated with low amygdala activation (left hemisphere: b=−4.99, Bonferroni corrected P=0.04) and interaction analyses showed that this association was disorder specific (left hemisphere: Bonferroni corrected P=0.003; right hemisphere: Bonferroni corrected P=0.03). There were no associations between oxytocin polymorphisms and amygdala activation in the total sample, among AD patients or HC. Conclusions Rs237902 was associated with amygdala activation in response to fearful/angry faces only in patients with SCZ. Our findings indicate that the endogenous oxytocin system could serve as a contributing factor in biological underpinnings of emotion processing and that this contribution is disorder specific

Distinct multivariate brain morphological patterns and their added predictive value with cognitive and polygenic risk scores in mental disorders

The brain underpinnings of schizophrenia and bipolar disorders are multidimensional, reflecting complex pathological processes and causal pathways, requiring multivariate techniques to disentangle. Furthermore, little is known about the complementary clinical value of brain structural phenotypes when combined with data on cognitive performance and genetic risk. Using data-driven fusion of cortical thickness, surface area, and gray matter density maps (GMD), we found six biologically meaningful patterns showing strong group effects, including four statistically independent multimodal patterns reflecting co-occurring alterations in thickness and GMD in patients, over and above two other independent patterns of widespread thickness and area reduction. Case-control classification using cognitive scores alone revealed high accuracy, and adding imaging features or polygenic risk scores increased performance, suggesting their complementary predictive value with cognitive scores being the most sensitive features. Multivariate pattern analyses reveal distinct patterns of brain morphology in mental disorders, provide insights on the relative importance between brain structure, cognitive and polygenetic risk score in classification of patients, and demonstrate the importance of multivariate approaches in studying the pathophysiological substrate of these complex disorders

Demographic data and clinical characterization of individuals participating in a faces matching functional MRI study.

<p>Abbreviations: BD, bipolar disorder; HC, healthy controls; SD, standard deviation; WASI, Wechsler Abbreviated Scale of Intelligence; IDS, Inventory of Depressive Symptoms; YMRS, Young Mania Rating Scale; PANSS P score, Positive and Negative Syndrome Scale positive subscale; GAF-S, Global Assessment of Functioning–symptom score; GAF-F, Global Assessment of Functioning–function score; BD PGRS, bipolar disorder polygenic risk score; ms, milliseconds.</p><p>BD PGRS values are reported as z-scores (with SD in brackets).</p><p>Complete behavioral data (response times and accuracy rates per condition) were available for 80/85 BD and 119/121 HC. For the remaining individuals (5 BD, 2 HC), an accuracy rate for each session (i.e. a combined rate for negative faces and shapes, and for positive faces and shapes) was available and was used to confirm that the participants paid attention to the task (accuracy rate: 97.4% and 96.0%, respectively).</p><p>^a Mean age at fMRI scanning. Age range was 18 to 63.</p><p>^b IDS score at scanning was available for 60/85 individuals (70.6%).</p><p>^c YMRS score at scanning was available for 69/85 individuals (81.2%).</p><p>^d PANSS P score at scanning was available for 38/85 individuals (44.7%).</p><p>^e Last six months</p><p>Demographic data and clinical characterization of individuals participating in a faces matching functional MRI study.</p

Bipolar disorder polygenic risk score is positively correlated with BOLD activation in the right inferior frontal gyrus in the entire sample (N = 206) including bipolar disorder cases and healthy controls for the Negative Faces > Shapes contrast.

<p>Color bar indicates z values. Coordinates are given in MNI space. Y = 18 (coronal view), Z = 12 (transversal view). Abbreviations: R, right; A, anterior.</p

Significant clusters at whole-brain level for diagnostic category and polygenic risk score analyses, corrected for sex and age.

<p>*Remains significant after Bonferroni correction (8 independent tests)</p><p>^#P < 0.05 with IQ and education in model</p><p>Abbrevations: Pos, Positive; Neg, Negative; HC, healthy controls; BD, bipolar disorder; PGRS, polygenic risk score; L, left; R, right. ‘+’, positively associated; ‘-’, negatively associated.</p><p>Coordinates are given in MNS space.</p><p>Significant clusters at whole-brain level for diagnostic category and polygenic risk score analyses, corrected for sex and age.</p