Orbitofrontal sulcogyral morphology: its distribution, structural and functional associations, and predictive value in different diagnostic groups

Bipolar affective disorder and schizophrenia are highly heritable psychiatric illnesses and the leading causes of worldwide disability. The orbitofrontal cortex (OFC) is a region of the frontal lobe with wide spread connectivity with other brain areas involved in reward, motivation and emotion. Evidence from various neuroimaging, genetic, post-mortem and brain lesion studies suggest that orbitofrontal cortex may play a role in pathophysiology of mental illnesses. This thesis sought to investigate the pathogenesis of major psychiatric illnesses through the investigation of orbitofrontal morphology in schizophrenia and bipolar disorder and through its associations with brain structure and function. Orbitofrontal morphology and its structural and functional associations were examined in healthy controls, patients with schizophrenia or bipolar affective disorder, and those at high genetic risk using functional and structural MRI. In the first study we found that the orbitofrontal type III is more frequent and the orbitofrontal type I is less common in the right hemisphere in patients with schizophrenia while in patients with bipolar disorder type III appears more often in both left and right hemispheres. We then sought to examine the relationship of orbitofrontal morphology to disease risk in a study of 146 people at high risk of developing schizophrenia and 110 people at high risk of developing bipolar disorder. We discovered that in the unaffected high risk groups the orbitofrontal type III predicted the development of later psychiatric illnesses, when combined with anterior cingulate morphology. Finally we showed, in a further study, that OFC morphology was associated with measures of schizotypy, brain structure, brain function and cognition. In conclusion, orbitofrontal morphology is linked to major psychiatric disorder and has significant structural and functional associations. As orbitofrontal sulcogyral patterns are formed in early life a fuller awareness of their relevance to brain function holds out the prospect that we could use such measures as an indicator of vulnerability to the development of illness later in life. This work points to the potential for the foundation of a theory of predictive associations between morphological patterns and the development of psychosis

The polygenic risk for bipolar disorder influences brain regional function relating to visual and default state processing of emotional information

Genome-wise association studies have identified a number of common single-nucleotide polymorphisms (SNPs), each of small effect, associated with risk to bipolar disorder (BD). Several risk-conferring SNPs have been individually shown to influence regional brain activation thus linking genetic risk for BD to altered brain function. The current study examined whether the polygenic risk score method, which models the cumulative load of all known risk-conferring SNPs, may be useful in the identification of brain regions whose function may be related to the polygenic architecture of BD. We calculated the individual polygenic risk score for BD (PGR-BD) in forty-one patients with the disorder, twenty-five unaffected first-degree relatives and forty-six unrelated healthy controls using the most recent Psychiatric Genomics Consortium data. Functional magnetic resonance imaging was used to define task-related brain activation patterns in response to facial affect and working memory processing. We found significant effects of the PGR-BD score on task-related activation irrespective of diagnostic group. There was a negative association between the PGR-BD score and activation in the visual association cortex during facial affect processing. In contrast, the PGR-BD score was associated with failure to deactivate the ventromedial prefrontal region of the default mode network during working memory processing. These results are consistent with the threshold-liability model of BD, and demonstrate the usefulness of the PGR-BD score in identifying brain functional alternations associated with vulnerability to BD. Additionally, our findings suggest that the polygenic architecture of BD is not regionally confined but impacts on the task-dependent recruitment of multiple brain regions

The influence of polygenic risk for bipolar disorder on neural activation assessed using fMRI

Genome-wide association studies (GWAS) have demonstrated a significant polygenic contribution to bipolar disorder (BD) where disease risk is determined by the summation of many alleles of small individual magnitude. Modelling polygenic risk scores may be a powerful way of identifying disrupted brain regions whose genetic architecture is related to that of BD. We determined the extent to which common genetic variation underlying risk to BD affected neural activation during an executive processing/language task in individuals at familial risk of BD and healthy controls. Polygenic risk scores were calculated for each individual based on GWAS data from the Psychiatric GWAS Consortium Bipolar Disorder Working Group (PGC-BD) of over 16 000 subjects. The familial group had a significantly higher polygene score than the control group (P=0.04). There were no significant group by polygene interaction effects in terms of association with brain activation. However, we did find that an increasing polygenic risk allele load for BD was associated with increased activation in limbic regions previously implicated in BD, including the anterior cingulate cortex and amygdala, across both groups. The findings suggest that this novel polygenic approach to examine brain-imaging data may be a useful means of identifying genetically mediated traits mechanistically linked to the aetiology of BD

Altered orbitofrontal sulcogyral patterns in gambling disorder: a multicenter study

Gambling disorder is a serious psychiatric condition characterized by decision-making and reward processing impairments that are associated with dysfunctional brain activity in the orbitofrontal cortex (OFC). However, it remains unclear whether OFC functional abnormalities in gambling disorder are accompanied by structural abnormalities. We addressed this question by examining the organization of sulci and gyri in the OFC. This organization is in place very early and stable across life, such that OFC sulcogyral patterns (classified into Types I, II, and III) can be regarded as potential pre-morbid markers of pathological conditions. We gathered structural brain data from nine existing studies, reaching a total of 165 individuals with gambling disorder and 159 healthy controls. Our results, supported by both frequentist and Bayesian statistics, show that the distribution of OFC sulcogyral patterns is skewed in individuals with gambling disorder, with an increased prevalence of Type II pattern compared with healthy controls. Examination of gambling severity did not reveal any significant relationship between OFC sulcogyral patterns and disease severity. Altogether, our results provide evidence for a skewed distribution of OFC sulcogyral patterns in gambling disorder and suggest that pattern Type II might represent a pre-morbid structural brain marker of the disease. It will be important to investigate more closely the functional implications of these structural abnormalities in future work.Y.L. was supported by the National Natural Science Foundation of China (Grant No. 31600929) and the Fundamental Research Funds for the Central Universities (010914380002). G.S. was supported by a Veni grant from the Netherlands Organization for Scientific Research (Grant No. 016.155.218). J.J. was supported by the Academy of Finland (Grant No. 295580), the Finnish Medical Foundation, and the Finnish Foundation for Alcohol Studies. V.K. was supported by the Academy of Finland (Grant No. 256836) and the Finnish Foundation for Alcohol Studies. S.G. and H.R.S. were supported by the Danish Council for Independent Research in Social Sciences through a grant to Thomas Ramsøy (“Decision Neuroscience Project”; Grant No. 0601-01361B) and by the Lundbeck Foundation through a Grant of Excellence (“ContAct”; Grant No. R59 A5399). A.G. was supported by Deutsche Forschungsgemeinschaft (DFG) HE2597/15–1, HE2597/15–2, and DFG Graduiertenkolleg 1589/2 “Sensory Computation in Neural Systems”. N.R.-S. was supported by a research grant by the Senatsverwaltung für Gesundheit und Soziales, Berlin, Germany (Grant No. 002–2008/I B 35). C.M.R.d.L. and J.C.P. were supported by a grant from the Spanish Government (Ministerio de Economía y Competitividad, Secretaría de Estado de Investigación, Desarrollo e Innovación; Convocatoria 2017 de Proyectos I+D de Excelencia, Spain; co-funded by the Fondo Europeo de Desarrollo Regional, FEDER, European Union; Grant No. PSI2017–85488-P). J.-C. D. was supported by “LABEX ANR-11-LABEX-0042” of Université de Lyon within the program Investissements d’Avenir (ANR-11-IDEX-007) operated by the French National Research Agency and by a grant from the Fondation pour la Recherche Médicale (Grant No. DPA20140629796)

Impact of cross-disorder polygenic risk on frontal brain activation with specific effect of schizophrenia risk

AbstractEvidence suggests that there is shared genetic aetiology across the major psychiatric disorders conferred by additive effects of many common variants. Measuring their joint effects on brain function may identify common neural risk mechanisms. We investigated the effects of a cross-disorder polygenic risk score (PGRS), based on additive effects of genetic susceptibility to the five major psychiatric disorders, on brain activation during performance of a language-based executive task. We examined this relationship in healthy individuals with (n=82) and without (n=57) a family history of bipolar disorder to determine whether this effect was additive or interactive dependent on the presence of family history. We demonstrate a significant interaction for polygenic loading×group in left lateral frontal cortex (BA9, BA6). Further examination indicated that this was driven by a significant positive correlation in those without a family history (i.e. healthy unrelated volunteers), with no significant relationships in the familial group. We then examined the effect of the individual diagnoses contributing to the PGRS to determine evidence of disorder-specificity. We found a significant association with the schizophrenia polygenic score only, with no other significant relationships. These findings indicate differences in left lateral frontal brain activation in association with increased cross-disorder PGRS in individuals without a family history of psychiatric illness. Lack of effects in the familial group may reflect epistatic effects, shared environmental influences or effects not captured by the PGRS. The specific relationship with loading for schizophrenia is notably consistent with frontal cortical inefficiency as a circumscribed phenotype of psychotic disorders

DISC1 genetics, biology and psychiatric illness

Psychiatric disorders are highly heritable, and in many individuals likely arise from the combined effects of genes and the environment. A substantial body of evidence points towards DISC1 being one of the genes that influence risk of schizophrenia, bipolar disorder and depression, and functional studies of DISC1 consequently have the potential to reveal much about the pathways that lead to major mental illness. Here, we review the evidence that DISC1 influences disease risk through effects upon multiple critical pathways in the developing and adult brain

Social well-being of students (the case of empirical research, Kazan)

Abstract. In experimental article various theoretical points of view on subjective wellbeing and social mood of the population are offered. Results of detailed empirical research of social well-being of students of the Kazan federal university are designated. It is presented in a context of intensity of carried-out global processes, such as transformation in the form of integration and joining to the Kazan University of a Number of regional higher education institutions and at the same time with it process of preparation and carrying out FISU of a sporting event in Kazan in 2013. The revealed tendencies are peculiar to students as a whole and during research show dynamics of the social opinion focused on quality and a standard of students living, an image and lifestyle of youth; emphasize aspects of social tension and social health