Compressed sensorimotor-to-transmodal hierarchical organization in schizophrenia.

BACKGROUND: 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. METHODS: We 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). RESULTS: 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 fronto-parietal and ventral attention regions along the classical sensation-to-cognition continuum (voxel-level corrected, p < 0.05). CONCLUSIONS: 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 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.

Cerebello-cerebral connectivity in idiopathic generalized epilepsy.

PURPOSE: The present study aims to investigate structural and functional connectivity (SC and FC) in cerebello-cerebral circuit in idiopathic generalized epilepsy (IGE). METHODS: Diffusion tensor imaging and resting-state imaging data were collected from 57 patients with IGE and 66 controls in the present study. First, we performed bidirectional probabilistic fiber tracking between cerebellum and cerebral cortex, consisting of cerebellar efferent and afferent fibers. Then, strength of structural connectivity (SCS), fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) were extracted and compared between groups. Finally, cerebellar FC with cerebral cortex was evaluated with seeding at dentate nucleus. Between-group comparisons were performed using t tests with a significant level setting at p < 0.05 with threshold-free cluster enhancement correction. RESULTS: The patients with IGE showed decreased SCS in cerebellar efferent fibers to sensorimotor cortex in anterior corona radiate and increased SCS in efferent fibers to occipital cortex in posterior corona radiata. The SCS in cerebellar afferent fibers in corticospinal tract from frontal and in retrolenticular part of the internal capsule from occipital cortices were increased in IGE, and SCS in afferent fibers in posterior limb of internal capsule from parietal cortex was decreased. Decreased FA and increased MD and RD were observed in cerebello-cerebral tracts. Besides, decreased cerebellar FC with putamen and motor cortex was observed in IGE. CONCLUSION: The patients with IGE demonstrated distinct alterations in efferent and afferent pathways between cerebellum and different cerebral cortices, which might be the pathological anatomical basis for cerebellar modulation effect on epileptic activities and contribute to motor deficits. KEY POINTS: • IGE showed decreased SCS in cerebellar efferent fibers to the sensorimotor cortex and increased SCS in efferent fibers to the occipital cortex. • Patients demonstrated increased SCS in cerebellar afferent fibers from the frontal and the occipital cortex and decreased SCS in afferent fibers from parietal cortex. • Decreased FC between motor-related regions and dentate nucleus was observed in IGE.

White Matter Connectivity Pattern Associate with Characteristics of Scalp EEG Signals.

The rhythm of electroencephalogram (EEG) depends on the neuroanatomical-based parameters such as white matter (WM) connectivity. However, the impacts of these parameters on the specific characteristics of EEG have not been clearly understood. Previous studies demonstrated that, these parameters contribute the inter-subject differences of EEG during performance of specific task such as motor imagery (MI). Though researchers have worked on this phenomenon, the idea is yet to be understood in terms of the mechanism that underlies such differences. Here, to tackle this issue, we began our investigations by first examining the structural features related to scalp EEG characteristics, which are event-related desynchronizations (ERDs), during MI using diffusion MRI. Twenty-four right-handed subjects were recruited to accomplish MI tasks and MRI scans. Based on the high spatial resolution of the structural and diffusion images, the motor-related WM links, such as basal ganglia (BG)-primary somatosensory cortex (SM1) pathway and supplementary motor area (SMA)-SM1 connection, were reconstructed by using probabilistic white matter tractography. Subsequently, the relationships of WM characteristics with EEG signals were investigated. These analyses demonstrated that WM pathway characteristics, including the connectivity strength and the positional characteristics of WM connectivity on SM1 (defined by the gyrus-sulcus ratio of connectivity, GSR), have a significant impact on ERDs when doing MI. Interestingly, the high GSR of WM connections between SM1 and BG were linked to the better ERDs. These results therefore, indicated that the connectivity in the gyrus of SM1 interacted with MI network which played the critical role for the scalp EEG signal extraction of MI to a great extent. The study provided the coupling mechanism between structural and dynamic physiological features of human brain, which would also contribute to understanding individual differences of EEG in MI-brain computer interface.

Functional Connectome Hierarchy in Schizotypy and Its Associations With Expression of Schizophrenia-Related Genes.

BACKGROUND AND HYPOTHESIS: Schizotypy has been conceptualized as a continuum of symptoms with marked genetic, neurobiological, and sensory-cognitive overlaps to schizophrenia. Hierarchical organization represents a general organizing principle for both the cortical connectome supporting sensation-to-cognition continuum and gene expression variability across the cortex. However, a mapping of connectome hierarchy to schizotypy remains to be established. Importantly, the underlying changes of the cortical connectome hierarchy that mechanistically link gene expressions to schizotypy are unclear. STUDY DESIGN: The present study applied novel connectome gradient on resting-state fMRI data from 1013 healthy young adults to investigate schizotypy-associated sensorimotor-to-transmodal connectome hierarchy and assessed its similarity with the connectome hierarchy of schizophrenia. Furthermore, normative and differential postmortem gene expression data were utilized to examine transcriptional profiles linked to schizotypy-associated connectome hierarchy. STUDY RESULTS: We found that schizotypy was associated with a compressed functional connectome hierarchy. Moreover, the pattern of schizotypy-related hierarchy exhibited a positive correlation with the connectome hierarchy observed in schizophrenia. This pattern was closely colocated with the expression of schizophrenia-related genes, with the correlated genes being enriched in transsynaptic, receptor signaling and calcium ion binding. CONCLUSIONS: The compressed connectome hierarchy suggests diminished functional system differentiation, providing a novel and holistic system-level basis for various sensory-cognition deficits in schizotypy. Importantly, its linkage with schizophrenia-altered hierarchy and schizophrenia-related gene expression yields new insights into the neurobiological continuum of psychosis. It also provides mechanistic insight into how gene variation may drive alterations in functional hierarchy, mediating biological vulnerability of schizotypy to schizophrenia.

Alterations of cerebellar white matter integrity and associations with cognitive impairments in schizophrenia.

"Cognitive dysmetria" theory of schizophrenia (SZ) has highlighted that the cerebellum plays a critical role in understanding the pathogenesis and cognitive impairment in SZ. Despite some studies have reported the structural disruption of the cerebellum in SZ using whole brain approach, specific focus on the voxel-wise changes of cerebellar WM microstructure and its associations with cognition impairments in SZ were less investigated. To further explore the voxel-wise structural disruption of the cerebellum in SZ, the present study comprehensively examined volume and diffusion features of cerebellar white matter in SZ at the voxel level (42 SZ vs. 52 controls) and correlated the observed alterations with the cognitive impairments measured by MATRICS Consensus Cognitive Battery. Combing voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) methods, we found, compared to healthy controls (HCs), SZ patients did not show significant alteration in voxel-level cerebellar white matter (WM) volume and tract-wise and skeletonized DTI features. In voxel-wise DTI features of cerebellar peduncles, compared to HCs, SZ patients showed decreased fractional anisotropy and increased radial diffusivity mainly located in left middle cerebellar peduncles (MCP) and inferior cerebellar peduncles (ICP). Interestingly, these alterations were correlated with overall composite and different cognitive domain (including processing speed, working memory, and attention vigilance) in HCs but not in SZ patients. The present findings suggested that the voxel-wise WM integrity analysis might be a more sensitive way to investigate the cerebellar structural abnormalities in SZ patients. Correlation results suggested that inferior and MCP may be a crucial neurobiological substrate of cognition impairments in SZ, thus adding the evidence for taking the cerebellum as a novel therapeutic target for cognitive impairments in SZ patients.

The Association between Body Mass Index and Intra-Cortical Myelin: Findings from the Human Connectome Project.

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 < 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.

A Longitudinal Study of White Matter Functional Network in Mild Traumatic Brain Injury.

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.

Dysfunction of Large-Scale Brain Networks in Schizophrenia: A Meta-analysis of Resting-State Functional Connectivity.

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).

Abnormal brain activation during threatening face processing in schizophrenia: A meta-analysis of functional neuroimaging studies.

Impairment of face perception in schizophrenia is a core aspect of social cognitive dysfunction. This impairment is particularly marked in threatening face processing. Identifying reliable neural correlates of the impairment of threatening face processing is crucial for targeting more effective treatments. However, neuroimaging studies have not yet obtained robust conclusions. Through comprehensive literature search, twenty-one whole brain datasets were included in this meta-analysis. Using seed-based d-Mapping, in this voxel-based meta-analysis, we aimed to: 1) establish the most consistent brain dysfunctions related to threating face processing in schizophrenia; 2) address task-type heterogeneity in this impairment; 3) explore the effect of potential demographic or clinical moderator variables on this impairment. Main meta-analysis indicated that patients with chronic schizophrenia demonstrated attenuated activations in limbic emotional system along with compensatory over-activation in medial prefrontal cortex (MPFC) during threatening faces processing. Sub-task analyses revealed under-activations in right amygdala and left fusiform gyrus in both implicit and explicit tasks. The remaining clusters were found to be differently involved in different types of tasks. Moreover, meta-regression analyses showed brain abnormalities in schizophrenia were partly modulated by age, gender, medication and severity of symptoms. Our results highlighted breakdowns in limbic-MPFC circuit in schizophrenia, suggesting general inability to coordinate and contextualize salient threat stimuli. These findings provide potential targets for neurotherapeutic and pharmacological interventions for schizophrenia.

Disrupted Coupling Between the Spontaneous Fluctuation and Functional Connectivity in Idiopathic Generalized Epilepsy.

Purpose: The purpose of this study was to comprehensively evaluate alterations of resting-state spontaneous brain activity in patients with idiopathic generalized epilepsy (IGE) and its subgroups [juvenile myoclonic epilepsy (JME) and generalized tonic-clonic seizures (GTCS)]. Methods: Resting state functional magnetic resonance imaging (fMRI) data were acquired from 60 patients with IGE and 60 healthy controls (HCs). Amplitude of low frequency fluctuation (ALFF), global functional connectivity density (gFCD), local FCD (lFCD), and long range FCD (lrFCD) were used to evaluate spontaneous brain activity in the whole brain. Moreover, the coupling between ALFF and FCDs (gFCD, lFCD, and lrFCD) was analyzed on both voxel-wise and subject-wise levels. Two-sample t-tests were used to analyze the difference in ALFF, FCDs and coupling on a subject-wise level between the two groups. Nonparametric permutation tests were used to evaluate differences in coupling on a voxel-wise level. Key findings: Patients with IGE and its subgroups showed reduced ALFF, gFCD and lrFCD in posterior regions of the default mode network (DMN). In addition, decreased ALFF and increased coupling with FCD were found in the cerebellum, while decreased coupling was observed in the bilateral pre- and postcentral gyrus in IGE compared with the coupling in HCs. Similar findings were found in the analysis between each of the two subgroups of IGE (JME and GTCS) and HCs, and JME patients had increased coupling in the cerebellum and bilateral middle occipital gyrus compared with coupling in the GTCS patients. Significance: This study demonstrated a multifactor abnormality of the DMN in IGE and emphasized that the abnormality in the cerebellum was associated with dysfunctional motor symptoms during seizures and might participate in the regulation of GSWDs in IGE.

Microstructural alterations of white matter in juvenile myoclonic epilepsy.

Juvenile myoclonic epilepsy (JME) is a common type of idiopathic generalized epilepsy that is characterized by myoclonic jerks of the upper limbs and generalized tonic-clonic seizures. Frontal cognitive dysfunctions and abnormal coupling of the thalamocortical system have been found in neuropsychological and neuroimaging studies. This study intended to explore white matter (WM) measurement changes in JME using MRI. Twenty-six patients with JME and 25 healthy controls (HC) were recruited for the acquisition of diffusion MRI and structural MRI data. Then, a tract-based spatial statistics approach was used to investigate the disease effects on WM microstructural diffusion characteristics. Subsequently, the associations between clinical features and characteristics of the tracts that connect the impacted regions were also evaluated. Compared with HC, JME showed an increased mean diffusivity in the anterior corpus callosum connected to the bilateral frontal lobe. Decreased axial diffusivity was observed in the body of the corpus callosum connected to the bilateral supplementary motor area as well as, in the region connecting the left thalamic radiation, the superior longitudinal fasciculus and corticospinal tract. Furthermore, the microstructural metrics of the tracts connecting these regions, especially the projection fibres that connect the cerebral cortex, subcortical regions and cerebellum, were correlated with disease duration. These findings likely reflect the alterations in WM microstructural connectivity, which may be associated with frontal cognitive and motor dysfunction in JME. In addition, the projection fibres connecting these impacted regions are progressively affected by the disease duration. Based on our findings, we propose that the cerebellum may play a potential role in the pathomechanism of JME.

Shared abnormality of white matter integrity in schizophrenia and bipolar disorder: A comparative voxel-based meta-analysis.

Patients with schizophrenia and bipolar disorder (BD) shared a significant overlap in genetic susceptibility, pharmacological treatment responses, neuropsychological deficits, and epidemiological features. However, it remains unknown whether these clinical overlaps are mediated by shared or disorder-specific abnormalities of white matter integrity. In this voxel-based meta-analytic comparison of whole-brain white matter integrity, we aimed to identify the shared or disorder-specific structural abnormalities between schizophrenia and BD. A comprehensive literature search was conducted up to February 2016 to identify studies that compared between patients and healthy controls (HC) by using whole-brain diffusion approach (schizophrenia: 24 datasets with 754 patients vs. 775 HC; BD: 23 datasets with 705 patients vs. 679 HC). Voxel-wise meta-analyses were conducted and restricted to unified template using seed-based d-Mapping. Abnormal white matter integrity was calculated within each condition and a direct comparison of effect size was performed of alterations between two conditions. Two regions with significant reductions of fractional anisotropy (FA) characterized abnormal water diffusion in both disorders: the genu of the corpus callosum (CC) and posterior cingulum fibers. There was no significant difference found between the two disorders. Our results highlighted shared impairments of FA at genu of the CC and left posterior cingulum fibers, which suggests that, phenotypic overlap between schizophrenia and BD could be related to common brain circuit dysfunction.