Variability of structurally constrained and unconstrained functional connectivity in schizophrenia.
Spatial variation in connectivity is an integral aspect of the brain's architecture. In the absence of this variability, the brain may act as a single homogenous entity without regional specialization. In this study, we investigate the variability in functional links categorized on the basis of the presence of direct structural paths (primary) or indirect paths mediated by one (secondary) or more (tertiary) brain regions ascertained by diffusion tensor imaging. We quantified the variability in functional connectivity using an unbiased estimate of unpredictability (functional connectivity entropy) in a neuropsychiatric disorder where structure-function relationship is considered to be abnormal; 34 patients with schizophrenia and 32 healthy controls underwent DTI and resting state functional MRI scans. Less than one-third (27.4% in patients, 27.85% in controls) of functional links between brain regions were regarded as direct primary links on the basis of DTI tractography, while the rest were secondary or tertiary. The most significant changes in the distribution of functional connectivity in schizophrenia occur in indirect tertiary paths with no direct axonal linkage in both early (P=0.0002, d=1.46) and late (P=1×10(-17), d=4.66) stages of schizophrenia, and are not altered by the severity of symptoms, suggesting that this is an invariant feature of this illness. Unlike those with early stage illness, patients with chronic illness show some additional reduction in the distribution of connectivity among functional links that have direct structural paths (P=0.08, d=0.44). Our findings address a critical gap in the literature linking structure and function in schizophrenia, and demonstrate for the first time that the abnormal state of functional connectivity preferentially affects structurally unconstrained links in schizophrenia. It also raises the question of a continuum of dysconnectivity ranging from less direct (structurally unconstrained) to more direct (structurally constrained) brain pathways underlying the progressive clinical staging and persistence of schizophrenia.
Centre for Computational Systems Biology, Fudan University, Shanghai, People's Republic of China.|School of Mathematical Sciences, Fudan University, Shanghai, People's Republic of China.|Department of Computer Science, University of Warwick, Coventry, United Kingdom.
Ye
Y
Yao
Translational Neuroimaging in Mental Health, Division of Psychiatry & Applied Psychology, Institute of Mental Health, Nottingham, United Kingdom.|Early Intervention in Psychosis, Nottinghamshire Healthcare NHS Foundation Trust, Nottingham, United Kingdom.
Lena
L
Palaniyappan
Translational Neuroimaging in Mental Health, Division of Psychiatry & Applied Psychology, Institute of Mental Health, Nottingham, United Kingdom.
Peter
P
Liddle
Centre for Computational Systems Biology, Fudan University, Shanghai, People's Republic of China.|Department of Medical Imaging, Jinling Hospital, Nanjing University School of Medicine, Nanjing, People's Republic of China.
Jie
J
Zhang
Sir Peter Mansfield Imaging Centre, School of Physics and Astronomy, University of Nottingham, United Kingdom.
Susan
S
Francis
Centre for Computational Systems Biology, Fudan University, Shanghai, People's Republic of China.|School of Mathematical Sciences, Fudan University, Shanghai, People's Republic of China.|Department of Computer Science, University of Warwick, Coventry, United Kingdom.|Shanghai Center for Mathematical Sciences, Fudan University, Shanghai, People's Republic of China.|School of Life Sciences and Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, People's Republic of China.
Jianfeng
J
Feng
D000328:Adult; D001921:Brain / Q000473:pathology / Q000503:physiopathology*; D056324:Diffusion Tensor Imaging / Q000379:methods*; D005260:Female; D059907:Functional Neuroimaging / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009415:Nerve Net / Q000473:pathology / Q000503:physiopathology*; D012559:Schizophrenia / Q000473:pathology / Q000503:physiopathology*
Schizophrenia; diffusion tensor imaging; functional MRI; functional connectivity; functional connectivity entropy; structurally constrained; structurally unconstrained