Voxel-based Functional Brain Network Segregation And Integration In Schizophrenia And Unaffected Genetic High Risk Individuals

Objective: Schizophrenia(SZ)is a severe and chronic mental disorder with unknown etiology,and high disability/fatality rate.The lifetime prevalence of SZ in the general population is about 0.7-1%,which brings suffering and heavy economic burden to the patients themselves and their families.SZ is a highly heritable disease with neurodevelopmental origins.First-degree relatives of individuals with SZ(GHR individuals)have almost a 10-fold increased risk of developing SZ and their lifetime prevalence is 13%.However,despite the increased genetic risk,most GHR does not later develop SZ.The GHR population provides an unique opportunity to identify vulnerability and resiliency factors when comparing them with affected individuals and healthy controls(HCs).At present,the relationship between illness onset,genetic susceptibility,and resilience and their underlying mechanisms remain unclear.The human brain is a complex system,and the onset of mental disorders is usually not caused by an abnormality in a certain brain area,but are related to the dysfunction of multiple brain regions.With the development of brain function imaging and the concept of the human connectome,network analysis of brain connectivity has begun to yield important insights into brain organization of psychiatric disorders.The functional brain network is an intuitive description of the dynamic interaction and integration of different neurons,clusters or brain regions on the brain structure network.Due to the limitations of technology,the current research on human brain functional networks is mainly limited to macroscale(brain areas).Previous studies have found function networks abnormalities in SZ and other psychiatric disorders.Functional network is heavily influenced by neurodevelopment processes and can be characterized by the degree of segregation and integration.Human brain functional network has two major fundamental organizational principles: segregation(specialized processing within interconnected brain regions)and integration(of different brain areas in terms of functional and effective connectivity).Optimal brain function occurs when there is balance between segregation and integration,which is vital for effective information processing and synthesis.Degrees of segregation and integration could be reflected in global network properties.However,although global network parameters can reflect the overall functional segregation and integration of the brain,they cannot identify the specific brain regions that are changed.Therefore,we can further reflect the functional segregation and integration through the connection distance and distance strength,and further clarify the specific brain areas that have changed.Connection distance is one of the important attributes of functional network,which can reflect the segregation and integration of brain,with short-range connections reflecting segregation and long-range connections reflecting integration,and this could lead to the discovery of explicit alteration regions.Previous studies have found that there are abnormal brain functional connectivity distance in a variety of mental disorders,such as bipolar disorder and major depressive disorder.This study examines functional segregation and integration in SZ and their first-degree relatives(GHR)to better understand the dynamic changes in vulnerability and resiliency,and disease markers.In this study,we used voxel-based graph analysis of resting-state functional magnetic resonance imaging(R-f MRI)to minimize parcellation-dependent effects on brain networks and examine global network properties as well as connections between and within regions.Methods: Resting-state functional magnetic resonance imaging data acquired from 137 SZ,89 GHR,and 210 healthy controls(HCs).All participants provided written informed consent by themselves or by their parents/guardians if they were under 18 years old after a complete description of the study.SZ participants met Diagnostic and Statis-tical Manual of Mental Disorders,Fourth Edition(DSM-IV)diagnostic criteria for SZ and not any other Axis I disorder.GHR participants were first-degree relatives of individuals with SZ and did not meet criteria for any DSM-IV Axis I disorder.HC participants did not have current or lifetime Axis I disorder or history of psychotic,mood,or other Axis I disorders in firstdegree relatives as determined by detailed family history.Demographic and clinical data of participants were collected.Symptom severity was measured using the Brief Psychiatric Rating Scale(BPRS),and cognitive function was assessed using the Wisconsin Card Sorting Test(WCST).Individual functional network construction was constrained at a voxel level within a gray matter mask of 45,381 voxels.We computed Pearson's correlations between all pairs of nodes(GM voxels),resulting in a 45,381 × 45,381 correlation matrix for each subject.Global network properties were then computed at voxel level to quantify balance between segregation and integration.Interregional functional associations were examined based on Euclidean distance between regions and reflect degree of segregation and integration.Distance strength maps were used to localize regions of altered distance-based functional connectivity.Results:(1)Global network properties was significantly decreased in SZ compared to HC,with no differences in GHR.(2)In three-group comparison,significant differences were noted in short-range connectivity(primarily in the primary sensory,motor and their association cortices,and the thalamus)and medium/long-range connectivity(in the prefrontal cortices [PFC]).(3)Specific to SZ,we found decreased short-range distance strength and increased medium/long-range distance strength.(4)We observed similarities and differences between SZ and HR.SZ and HR were similar in of short-range distance strength in right lingual and left postcentral gyrus,and different in medium/long-range distance strength in left orbital frontal cortex(OFC).Conclusion: We observed disrupted balance between segregation and integration in SZ,whereas relatively preserved in GHR.Similarities and differences between SZ and HR,specific changes of SZ were found.Alterations specific to SZ observed in this study may indicate disease-related functional network impairments.The similarities between SZ and GHR found herein may implicate genetic susceptibility to SZ.The differences between SZ and GHR involving the OFC could reflect resiliency to SZ.These might reflect dynamic changes of segregation in primary cortices and integration in PFC in vulnerability and resilience,and disease markers in SZ.Identification of such markers could improve prediction of psychotic conversion in GHR individuals and contribute to the development of more effective diagnosis and early intervention in SZ.