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Schizotype has been conceptualized as a continuum with symptoms of schizophrenia with marked genetic, neurobiological, sensory-cognitive overlaps. Hierarchical organization represents a general organizing principle for both the brain connectome supporting sensation-to-cognition continuum and gene expression patterns. However, the underlying changes in neuroimaging maps reflecting the cortical hierarchy that mechanistically link gene expressions to schizotypy are unclear. Using a large cohort of resting state-fMRI data from 1013 healthy young adults, the present study investigated schizotypy-associated sensorimotor-to-transmodal connectome hierarchy and assessed the connectome hierarchy similarity between schizotypy and schizophrenia. Furthermore, the normative and differential postmortem gene expression data were employed to investigate the transcriptional profiles associated with the schizotypy-associated connectome hierarchy. We found that schizotypy was associated with a compressed functional connectome hierarchy, including compressed global topography and focal alterations in sensory and transmodal cognitive areas, suggesting diminished functional system differentiation. Interestingly, the pattern of schizotypy-related hierarchy is tightly correlated with the pattern of hierarchy organization observed in schizophrenia. Notably, schizotypy-related connectome hierarchy was most closely colocated with expression of schizophrenia-related genes compared with other psychiatric disorders, with the correlated genes being enriched in biological processes well-known involved in schizophrenia, i.e., transsynaptic and receptor signaling, calcium ion binding, and channel activity. These findings not only shed light on the neurobiological and molecular genetic mechanisms underlying the sensory-cognitive deficits in schizotypy, but also provide new insights into the neurobiological continuum of psychosis thus advanced our understanding of how genetic propensity for schizophrenia-alike traits play an enduring role in creating biological vulnerability to psychosis.

Some patients after mild traumatic brain injury (mTBI) experience microstructural damages in the long-distance white matter (WM) connections, which disrupts the functional connectome of large-scale brain networks that support cognitive function. Patterns of WM structural damage following mTBI were well documented using diffusion tensor imaging (DTI). However, the functional organization of WM and its association with gray matter functional networks (GM-FNs) and its DTI metrics remain unknown. The present study adopted resting-state functional magnetic resonance imaging to explore WM functional properties in mTBI patients (108 acute patients, 48 chronic patients, 46 healthy controls [HCs]). Eleven large-scale WM functional networks (WM-FNs) were constructed by the k-means clustering algorithm of voxel-wise WM functional connectivity (FC). Compared with HCs, acute mTBI patients observed enhanced FC between inferior fronto-occipital fasciculus (IFOF) WM-FN and primary sensorimotor WM-FNs, and cortical primary sensorimotor GM-FNs. Further, acute mTBI patients showed increased DTI metrics (mean diffusivity, axial diffusivity, and radial diffusivity) in deep WM-FNs and higher-order cognitive WM-FNs. Moreover, mTBI patients demonstrated full recovery of FC and partial recovery of DTI metrics in the chronic stage. Additionally, enhanced FC between IFOF WM-FN and anterior cerebellar GM-FN was correlated with impaired information processing speed. Our findings provide novel evidence for functional and structural alteration of WM-FNs in mTBI patients. Importantly, the convergent damage of the IFOF network might imply its crucial role in our understanding of the pathophysiology mechanism of mTBI patients.

BackgroundSchizophrenia has been primarily conceptualized as a disorder of high-order cognitive functions with deficits in executive brain regions. Yet due to the increasing reports of early sensory processing deficit, recent models focus more on the developmental effects of impaired sensory process on high-order functions. The present study examined whether this pathological interaction relates to an overarching system-level imbalance, specifically a disruption in macroscale hierarchy affecting integration and segregation of unimodal and transmodal networks.MethodsWe applied a novel combination of connectome gradient and stepwise connectivity analysis to resting-state fMRI to characterize the sensorimotor-to-transmodal cortical hierarchy organization (96 patients v. 122 controls).ResultsWe demonstrated compression of the cortical hierarchy organization in schizophrenia, with a prominent compression from the sensorimotor region and a less prominent compression from the frontal−parietal region, resulting in a diminished separation between sensory and fronto-parietal cognitive systems. Further analyses suggested reduced differentiation related to atypical functional connectome transition from unimodal to transmodal brain areas. Specifically, we found hypo-connectivity within unimodal regions and hyper-connectivity between unimodal regions and fronto-parietal and ventral attention regions along the classical sensation-to-cognition continuum (voxel-level corrected, p < 0.05).ConclusionsThe compression of cortical hierarchy organization represents a novel and integrative system-level substrate underlying the pathological interaction of early sensory and cognitive function in schizophrenia. This abnormal cortical hierarchy organization suggests cascading impairments from the disruption of the somatosensory−motor system and inefficient integration of bottom-up sensory information with attentional demands and executive control processes partially account for high-level cognitive deficits characteristic of schizophrenia.

To comprehensively investigate the white matter (WM) features of cerebellum in patients with schizophrenia, and further assess the correlation between altered WM features and clinical and cognitive assessments. Forty-two patients and fifty-two matched healthy controls (HCs) of the Collaborative Informatics and Neuroimaging Suite Data Exchange tool were involved in this study. The cerebellar WM volume was calculated by voxel-based morphometry. And tract-based spatial statistics was used to analysis the diffusion changes in patients when compared to HCs. Furthermore, we investigated the correlation between altered imaging feature and clinical, cognitive assessments. Compared to HCs, the schizophrenia patients did not reveal difference in cerebellar WM volume and schizophrenia patients showed decreased fractional anisotropy and increased radial diffusivity in left middle cerebellar peduncles and inferior cerebellar peduncles in voxel-wise but not in tract-wise. Critically, these cerebellar changes were associated with disease duration in schizophrenia patients. And significant correlation between the altered cerebellar WM features and cognitive assessments only revealed in HCs but disrupted in schizophrenia patients. The present findings suggested that the voxel-wise WM integrity analysis might was the more sensitive way to investigate the structural abnormalities in schizophrenia patients. Middle cerebellar peduncles and inferior cerebellar peduncles may be a crucial neurobiological substrate of cognition and thus might be regarded as a biomarker for treatment.

For decades, schizophrenia has been primarily conceptualized as a disorder of high-order cognitive functions with deficits in executive brain regions. Yet due to the increasing reports of early sensory processing deficit, recent models focus more on the developmental effects of impaired sensory process on high-order functions. The present study examined whether this pathological interaction relates to an overarching system-level imbalance, specifically a disruption in macroscale hierarchy affecting integration and segregation of unimodal and transmodal networks. We applied a novel combination of connectome gradient and stepwise connectivity analysis to resting-state functional magnetic resonance imaging (rsfMRI) to characterize the sensorimotor-to-transmodal cortical hierarchy organization (96 patients vs. 122 controls). Using these techniques, we demonstrated compression of the cortical hierarchy organization in schizophrenia, with a prominent compression from the sensorimotor region and a less prominent compression from the frontal-parietal region, resulting in a diminished separation between sensory and fronto-parietal cognitive systems. Further analyses suggested reduced differentiation related to atypical functional connectome transition from unimodal to transmodal brain areas. Specifically, we found hypo-connectivity within unimodal regions and hyper-connectivity between unimodal regions and frontoparietal and ventral attention regions along the classical sensation-to-cognition continuum established in prior neuroanatomical work. The compression of cortical hierarchy organization represents a novel and integrative system-level substrate underlying the pathological interaction of early sensory and cognitive function in schizophrenia. This abnormal cortical hierarchy organization suggests cascaded impairments stemming from the disrupted somatosensory-motor system and inefficient integration of bottom-up sensory information with attentional demands and executive control processes partially account for high-level cognitive deficits characteristic of schizophrenia.

Intra-cortical myelin is a myelinated part of the cerebral cortex that is responsible for the spread and synchronization of neuronal activity in the cortex. Recent animal studies have established a link between obesity and impaired oligodendrocyte maturation vis-à-vis cells that produce and maintain myelin, however, the association between obesity and intra-cortical myelination remains to be established. To investigate the effects of obesity on intra-cortical myelin in living humans, we employed a large, demographically well-characterized sample of healthy young adults drawn from the Human Connectome Project (n = 1066). Intra-cortical myelin was assessed using a novel T1-w/T2-w ratio method. Linear regression analysis was used to investigate the association between body mass index (BMI), an indicator of obesity, and intra-cortical myelination, adjusting for covariates of no interest. We observed BMI was related to lower intra-cortical myelination in regions previously identified to be involved in reward processing (i.e., medial orbitofrontal cortex, rostral anterior cingulate cortex), attention (i.e., visual cortex, inferior/middle temporal gyrus), and salience detection (i.e., insula, supramarginal gyrus) in response to viewing food cues (corrected p &lt, 0.05). In addition, higher BMIs were associated with more intra-cortical myelination in regions associated with somatosensory processing (i.e., the somatosensory network) and inhibitory control (i.e., lateral inferior frontal gyrus, frontal pole). These findings were also replicated after controlling for key potential confounding factors including total intracranial volume, substance use, and fluid intelligence. Findings suggested that altered intra-cortical myelination may represent a novel microstructure-level substrate underlying prior abnormal obesity-related brain neural activity, and lays a foundation for future investigations designed to evaluate how living habits, such as dietary habit and physical activity, affect intra-cortical myelination.

Schizophrenia is a complex mental disorder with disorganized communication among large-scale brain networks, as demonstrated by impaired resting-state functional connectivity (rsFC). Individual rsFC studies, however, vary greatly in their methods and findings. We searched for consistent patterns of network dysfunction in schizophrenia by using a coordinate-based meta-analysis. Fifty-six seed-based voxel-wise rsFC datasets from 52 publications (2115 patients and 2297 healthy controls) were included in this meta-analysis. Then, coordinates of seed regions of interest (ROI) and between-group effects were extracted and coded. Seed ROIs were categorized into seed networks by their location within an a priori template. Multilevel kernel density analysis was used to identify brain networks in which schizophrenia was linked to hyper-connectivity or hypo-connectivity with each a priori network. Our results showed that schizophrenia was characterized by hypo-connectivity within the default network (DN, self-related thought), affective network (AN, emotion processing), ventral attention network (VAN, processing of salience), thalamus network (TN, gating information) and somatosensory network (SS, involved in sensory and auditory perception). Additionally, hypo-connectivity between the VAN and TN, VAN and DN, VAN and frontoparietal network (FN, external goal-directed regulation), FN and TN, and FN and DN were found in schizophrenia. Finally, the only instance of hyper-connectivity in schizophrenia was observed between the AN and VAN. Our meta-analysis motivates an empirical foundation for a disconnected large-scale brain networks model of schizophrenia in which the salience processing network (VAN) plays the core role, and its imbalanced communication with other functional networks may underlie the core difficulty of patients to differentiate self-representation (inner world) and environmental salience processing (outside world).