Macroscale Thalamic Functional Organization Disturbances and Underlying Core Cytoarchitecture in Early-Onset Schizophrenia.

BACKGROUND AND HYPOTHESIS: Schizophrenia is a polygenetic mental disorder with heterogeneous positive and negative symptom constellations, and is associated with abnormal cortical connectivity. The thalamus has a coordinative role in cortical function and is key to the development of the cerebral cortex. Conversely, altered functional organization of the thalamus might relate to overarching cortical disruptions in schizophrenia, anchored in development. STUDY DESIGN: Here, we contrasted resting-state fMRI in 86 antipsychotic-naive first-episode early-onset schizophrenia (EOS) patients and 91 typically developing controls to study whether macroscale thalamic organization is altered in EOS. Employing dimensional reduction techniques on thalamocortical functional connectome (FC), we derived lateral-medial and anterior-posterior thalamic functional axes. STUDY RESULTS: We observed increased segregation of macroscale thalamic functional organization in EOS patients, which was related to altered thalamocortical interactions both in unimodal and transmodal networks. Using an ex vivo approximation of core-matrix cell distribution, we found that core cells particularly underlie the macroscale abnormalities in EOS patients. Moreover, the disruptions were associated with schizophrenia-related gene expression maps. Behavioral and disorder decoding analyses indicated that the macroscale hierarchy disturbances might perturb both perceptual and abstract cognitive functions and contribute to negative syndromes in patients. CONCLUSIONS: These findings provide mechanistic evidence for disrupted thalamocortical system in schizophrenia, suggesting a unitary pathophysiological framework.

Individual-based morphological brain network organization and its association with autistic symptoms in young children with autism spectrum disorder.

Individual-based morphological brain networks built from T1-weighted magnetic resonance imaging (MRI) reflect synchronous maturation intensities between anatomical regions at the individual level. Autism spectrum disorder (ASD) is a socio-cognitive and neurodevelopmental disorder with high neuroanatomical heterogeneity, but the specific patterns of morphological networks in ASD remain largely unexplored at the individual level. In this study, individual-based morphological networks were constructed by using high-resolution structural MRI data from 40 young children with ASD (age range: 2-8 years) and 38 age-, gender-, and handedness-matched typically developing children (TDC). Measurements were recorded as threefold. Results showed that compared with TDC, young children with ASD exhibited lower values of small-worldness (i.e., σ) of individual-level morphological brain networks, increased morphological connectivity in cortico-striatum-thalamic-cortical (CSTC) circuitry, and decreased morphological connectivity in the cortico-cortical network. In addition, morphological connectivity abnormalities can predict the severity of social communication deficits in young children with ASD, thus confirming an associational impact at the behavioral level. These findings suggest that the morphological brain network in the autistic developmental brain is inefficient in segregating and distributing information. The results also highlight the crucial role of abnormal morphological connectivity patterns in the socio-cognitive deficits of ASD and support the possible use of the aberrant developmental patterns of morphological brain networks in revealing new clinically-relevant biomarkers for ASD.

The pulse: transient fMRI signal increases in subcortical arousal systems during transitions in attention.

Studies of attention emphasize cortical circuits for salience monitoring and top-down control. However, subcortical arousal systems have a major influence on dynamic cortical state. We hypothesize that task-related increases in attention begin with a "pulse" in subcortical arousal and cortical attention networks, which are reflected indirectly through transient fMRI signals. We conducted general linear model and model-free analyses of fMRI data from two cohorts and tasks with mixed block and event-related design. 46 adolescent subjects at our center and 362 normal adults from the Human Connectome Project participated. We identified a core shared network of transient fMRI increases in subcortical arousal and cortical salience/attention networks across cohorts and tasks. Specifically, we observed a transient pulse of fMRI increases both at task block onset and with individual task events in subcortical arousal areas including midbrain tegmentum, thalamus, nucleus basalis and striatum; cortical-subcortical salience network regions including the anterior insula/claustrum and anterior cingulate cortex/supplementary motor area; in dorsal attention network regions including dorsolateral frontal cortex and inferior parietal lobule; as well as in motor regions including cerebellum, and left hemisphere hand primary motor cortex. The transient pulse of fMRI increases in subcortical and cortical arousal and attention networks was consistent across tasks and study populations, whereas sustained activity in these same networks was more variable. The function of the transient pulse in these networks is unknown. However, given its anatomical distribution, it could participate in a neuromodulatory surge of activity in multiple parallel neurotransmitter systems facilitating dynamic changes in conscious attention.

Putamen volume predicts real-time fMRI neurofeedback learning success across paradigms and neurofeedback target regions.

Real-time fMRI guided neurofeedback training has gained increasing interest as a noninvasive brain regulation technique with the potential to modulate functional brain alterations in therapeutic contexts. Individual variations in learning success and treatment response have been observed, yet the neural substrates underlying the learning of self-regulation remain unclear. Against this background, we explored potential brain structural predictors for learning success with pooled data from three real-time fMRI data sets. Our analysis revealed that gray matter volume of the right putamen could predict neurofeedback learning success across the three data sets (n = 66 in total). Importantly, the original studies employed different neurofeedback paradigms during which different brain regions were trained pointing to a general association with learning success independent of specific aspects of the experimental design. Given the role of the putamen in associative learning this finding may reflect an important role of instrumental learning processes and brain structural variations in associated brain regions for successful acquisition of fMRI neurofeedback-guided self-regulation.

Temporal Lobe Epilepsy Shows Distinct Functional Connectivity Patterns in Different Thalamic Nuclei.

Background: The thalamus, as a key relay of neuronal information flow between subcortical structures and cortical networks, has been implicated in focal limbic seizures propagation, awareness maintenance, and seizure-related cognitive deficits. However, the specific functional alterations between different thalamic nuclei and subcortical-cortical systems in temporal lobe epilepsy (TLE) remain largely unknown. Methods: We examined thalamic functional connectivity (FC) in 26 TLE patients and 30 healthy controls matched for sex, age, and education. The anterior (ANT), ventral posterior medial, and central lateral nuclei of thalamus were employed to establish whole-brain seed-to-voxel thalamic FC maps. Secondary Pearson's correlation analysis was conducted to assess associations between the abnormal thalamic FC and the memory performance in TLE. Results: Seed-based FC analyses revealed typical distinct FC patterns within each thalamic nuclei in both controls and TLE patients. The TLE showed significantly decreased FC between different thalamic nuclei and subcortical-cortical networks, including the limbic structures, midbrain, sensorimotor network, medial prefrontal cortex, temporal-occipital fusiform gyrus, and cerebellum. Verification analyses yielded similar patterns of thalamic FC changes in TLE. Importantly, the decreased FC between the ANT and hippocampal pathway was correlated with the poorer memory performance of TLE. Conclusion: These findings suggest that the distinct thalamocortical FC patterns are damaged to some extent in TLE patients. Importantly, the specific pathology of the ANT-hippocampal pathway in TLE may be a potential factor that contributes to memory deficits. Our study may pave the way for improved treatments and cognitive function by directly targeting different thalamocortical circuits for TLE.

Improved Resting-State Functional Dynamics in Post-stroke Depressive Patients After Shugan Jieyu Capsule Treatment.

Shugan Jieyu Capsule (SG), a Chinese herbal medicine mainly composed of Acanthopanax and Hypericum perforatum, has been used to ameliorate cognitive impairments and emotional problems induced by post-stroke depression (PSD), while the altered brain dynamics underlying the ameliorative effects of SG have remained unclear. Our study focused on investigating the potential neurobiological mechanisms of SG in improving the cognitive function of PSD patients via resting-state functional magnetic resonance imaging (fMRI). Fifteen PSD patients (mean ages: 64.13 ± 6.01 years) were instructed to take 0.72 g of SG twice a day for 8 weeks. PSD patients underwent fMRIs, the 24-item Hamilton Depression Scale (HAMD-24) and the Montreal Cognitive Assessment (MoCA) at baseline and the end of intervention, and these assessments were also performed on twenty-one healthy controls (HC) (mean ages: 60.67 ± 6.95 years). Additionally, the dynamic amplitude of low-frequency fluctuations (dALFF) and functional connectivity (dFC) were determined to reveal changes in dynamic functional patterns. We found that taking SG significantly reduced the depressive symptoms assessed by HAMD-24 and improved cognitive functions assessed by MoCA in PSD patients. Furthermore, at baseline, PSD patients showed decreased dALFF in the right precuneus and increased dFC between the right precuneus and left angular gyrus, compared with HC. After intervention, the dALFF and dFC variances of the abnormal patterns were reversed. Additionally, the dALFF variance in the right precuneus was positively correlated with MoCA scores in PSD patients after SG treatment. Collectively, our results indicate that SG may improve the cognitive function of PSD patients through alteration of brain dynamics. Our findings lay a foundation for the exploration of the neurobiological mechanisms of SG in ameliorating symptoms of PSD patients.

The thalamic functional gradient and its relationship to structural basis and cognitive relevance.

The human thalamus is an integrative hub richly connected with cortical networks, involving diverse cognitive functions. Emerging evidence suggests that multiscale structural and functional gradients integrate various information across modalities into an abstract representation. However, the presence of functional gradients in the thalamus and its relationship to structural properties and cognitive functions remain unknown. We estimated the functional gradients of the thalamus in two independent normal cohorts using a novel diffusion embedding analysis. We identified two main axes of the functional connectivity patterns, and examined associations with thalamic anatomy, morphology, intrinsic geometry, and specific behavioral relevance. We found that the dominant gradient indicated a lateral/medial axis across the thalamus and captured associations with anatomical nuclei and gray matter volume. The second gradient was an anterior/posterior axis and provided a behavioral characterization from lower level perception to higher level cognition. Furthermore, these two gradients strongly correlated with spatial distance, indicating the prominence of intrinsic geometry in functional hierarchies. These findings were replicated in an independent dataset. Overall, our findings suggested that macroscale gradients showed a coordination of structural and functional interactions, with hierarchical organization contributing to behavior characterization.

Subcortical structural covariance in young children with autism spectrum disorder.

Abnormalities in the structure of subcortical regions are central to numerous behaviors affected by autism spectrum disorder (ASD), and these regions may undergo atypical coordinated neurodevelopment. However, relatively little is known about morphological correlations among subcortical structures in young children with ASD. In this study, using volumetric-based methodology and structural covariance approach, we investigated structural covariance of subcortical brain volume in 40 young children with ASD (<7.5 years old) and 38 age-, gender-, and handedness-matched typically developing (TD) children. Results showed that compared with TD children, children with ASD exhibited decreased structural covariation between the left and right cerebral hemispheres, specifically between the left and right thalami, right globus pallidus and left nucleus accumbens, and left globus pallidus and right nucleus accumbens. Compared with TD children, children with ASD exhibited increased structural covariation between adjacent regions, such as between the right globus pallidus and right putamen. Additionally, abnormalities in subcortical structural covariance can predict social communication and repetitive and stereotypic behavior in young children with ASD. Overall, these results suggest decreased long-range structural covariation and enhanced local covariation in subcortical structures in children with ASD, highlighting aberrant developmental coordination or synchronized maturation between subcortical regions that play crucial roles in social cognition and behavior in ASD.

Disconnectivity between the raphe nucleus and subcortical dopamine-related regions contributes altered salience network in schizophrenia.

Numerous studies strongly have suggested the significant role of serotonin in the pathomechanism of schizophrenia. However, few studies have directly explored the altered serotonin function in schizophrenia. In the current study, we explored the altered serotonin function in first-episode treatment-naive patients with schizophrenia with resting-state functional magnetic resonance imaging. A total 42 first-episode treatment-naive patients with schizophrenia and carefully matched healthy controls are included in the study. Considering that the raphe nucleus providing a substantial proportion of the serotonin innervation to the forebrain, the raphe nucleus was chosen as the seed to construct voxel-based functional connectivity (FC) maps. In the results, subcortical dopamine-related regions presented decreased FC with the raphe nucleus, such as the bilateral striatum, pallidum, and thalamus, in patients with schizophrenia. Decreased FC in these regions was significantly correlated with the total negative scores in PANSS. Furthermore, these regions presented with decreased FC connection to salience network. Our results presented that the raphe nucleus played an important role in the dysfunction of subcortical DA-related regions, and contributed to the altered salience network in schizophrenia. Our study emphasized the importance of the raphe nucleus in the pathophysiology of schizophrenia.

Disruption of functional connectivity among subcortical arousal system and cortical networks in temporal lobe epilepsy.

Growing evidence has demonstrated widespread brain network alterations in temporal lobe epilepsy (TLE). However, the relatively accurate portrait of the subcortical-cortical relationship for impaired consciousness in TLE remains unclear. We proposed that consciousness-impairing seizures may invade subcortical arousal system and corresponding cortical regions, resulting in functional abnormalities and information flow disturbances between subcortical and cortical networks. We performed resting-state fMRI in 26 patients with TLE and 30 matched healthy controls. All included patients were diagnosed with impaired awareness during focal temporal lobe seizures. Functional connectivity density was adopted to determine whether local or distant network alterations occurred in TLE, and Granger causality analysis (GCA) was utilized to assess the direction and magnitude of causal influence among these altered brain networks further. Patients showed increased local functional connectivity in several arousal structures, such as the midbrain, thalamus, and cortical regions including bilateral prefrontal cortex (PFC), left superior temporal pole, left posterior insula, and cerebellum (P < 0.05, FDR corrected). GCA analysis revealed that the casual effects among these regions in patients were significantly sparser than those in controls (P < 0.05, uncorrected), including decreased excitatory and inhibitory effects among the midbrain, thalamus and PFC, and decreased inhibitory effect from the cerebellum to PFC. These findings suggested that consciousness-impairing seizures in TLE are associated with functional alterations and disruption of information process between the subcortical arousal system and cortical network. Understanding the functional networks and innervation pathway involved in TLE can provide insights into the mechanism underlying seizure-related loss of consciousness.

Thalamocortical dysconnectivity in paroxysmal kinesigenic dyskinesia: Combining functional magnetic resonance imaging and diffusion tensor imaging.

BACKGROUND: Paroxysmal kinesigenic dyskinesia is associated with macrostructural and microstructural abnormalities in the thalamus. OBJECTIVES: To examine functional and structural connectivity of thalamocortical networks in paroxysmal kinesigenic dyskinesia and to further investigate the effect of mutation of the proline-rich transmembrane protein 2 on thalamocortical networks. METHODS: Patients with paroxysmal kinesigenic dyskinesia (n = 20), subdivided into proline-rich transmembrane protein 2-mutated (n = 8) and nonmutated patients (n = 12) and healthy controls (n = 20) underwent resting-state functional MRI and diffusion imaging scan. The functional properties of correlations in neural activity (functional connectivity) and the structural properties of white matter probabilistic tractography (structural connectivity) were analyzed to characterize thalamocortical networks. Furthermore, the effect of proline-rich transmembrane protein 2 mutation on functional and structural connectivity of thalamocortical networks were examined using one-way analysis of variance among three groups. RESULTS: Patients had increased functional and structural connectivity between ventral lateral/anterior thalamic nuclei and a lateral motor area, as compared to controls. This functional connectivity positively correlated with disease duration. Interestingly, proline-rich transmembrane protein 2-mutated patients showed decreased functional connectivity and preserved structural connectivity, between mediodorsal nucleus and prefrontal cortex, compared to nonmutated patients and controls. CONCLUSIONS: Thalamomotor/premotor hyperconnectivity suggests abnormal communication between thalamus and motor cortex in patients. Furthermore, thalamoprefrontal hypoconnectivity in proline-rich transmembrane protein 2-mutated patients might indicate that proline-rich transmembrane protein 2 mutations result in inefficient thalamoprefrontal integration. Our findings facilitate a deeper understanding of the crucial role of thalamocortical dysconnectivity in the pathophysiological mechanisms of paroxysmal kinesigenic dyskinesia. © 2017 International Parkinson and Movement Disorder Society.

Frequency-selective alteration in the resting-state corticostriatal-thalamo-cortical circuit correlates with symptoms severity in first-episode drug-naive patients with schizophrenia.

Schizophrenia is a prototypical disorder of brain connectivity with altered neural activity in regions extending throughout the brain. Regions, including the subcortex and cortex, present activity mainly within a specific frequency band in resting-state. Whether these altered resting-state functional connections also present frequency specificity is unknown. In the present study, empirical mode decomposition, which is a pure data-driven method suitable for nonlinear and nonstationary signals, was used to decompose blood-oxygen-level-dependent (BOLD) signals into different intrinsic frequency bands. Our study included 42 first-episode drug-naive patients with schizophrenia and 38 controls. Significant aberration in functional connectivity was observed only at a higher frequency range (the peak spectral density power was 0.06Hz). In this frequency band, patients with schizophrenia showed significantly increased functional connections between the bilateral cuneus and right supplementary motor area, reduced connections within the basal ganglia, and reduced connections between the dorsal striatum and left supplementary motor area. The dysfunction of the frontal gyrus significantly correlated with the dysfunction of the basal ganglia. Notably, these altered connections were significantly correlated with symptom severity. Our results demonstrate that frequency-selective altered corticostriatal-thalamo-cortical circuits in patients with schizophrenia are associated with symptoms severity.

Atypical effective connectivity of thalamo-cortical circuits in autism spectrum disorder.

Autism spectrum disorder (ASD) is a neurodevelopment disorder characterized by atypical connectivity within and across multiple brain systems. We aimed to explore information transmission from the sensory periphery to information processing centers of the brain across thalamo-cortical circuits in ASD. A large multicenter dataset from the autism brain imaging data exchange was utilized. A thalamus template derived from the Automatic Anatomic Labeling atlas was subdivided into six subregions corresponding to six cortical regions using a "winner-takes-all" strategy. Granger causality analysis (GCA) was then applied to calculate effective connectivity from subregions of the thalamus to the corresponding cortical regions. Results demonstrate reduced effective connectivity from the thalamus to left prefrontal cortex (P = 0.023), right posterior parietal cortex (P = 0.03), and bilateral temporal cortex (left: P = 0.014; right: P = 0.015) in ASD compared with healthy control (HC) participants. The GCA values of the thalamus-bilateral temporal cortex connections were significantly negatively correlated with communication scores as assessed by the autism diagnostic observation schedule in the ASD group (left: P = 0.037; right: P = 0.007). Age-related analyses showed that the strengths of the thalamus-bilateral temporal cortex connections were significantly positively correlated with age in the HC group (left: P = 0.013; right: P = 0.016), but not in the ASD group (left: P = 0.506; right: P = 0.219). These results demonstrate impaired thalamo-cortical information transmission in ASD and suggest that atypical development of thalamus-temporal cortex connections may relate to communication deficits in the disorder. Autism Res 2016, 9: 1183-1190. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

An Investigation of the Differences and Similarities between Generated Small-World Networks for Right- and Left-Hand Motor Imageries.

In this study, small-world network analysis was performed to identify the similarities and differences between functional brain networks for right- and left-hand motor imageries (MIs). First, Pearson correlation coefficients among the nodes within the functional brain networks from healthy subjects were calculated. Then, small-world network indicators, including the clustering coefficient, the average path length, the global efficiency, the local efficiency, the average node degree, and the small-world index, were generated for the functional brain networks during both right- and left-hand MIs. We identified large differences in the small-world network indicators between the functional networks during MI and in the random networks. More importantly, the functional brain networks underlying the right- and left-hand MIs exhibited similar small-world properties in terms of the clustering coefficient, the average path length, the global efficiency, and the local efficiency. By contrast, the right- and left-hand MI brain networks showed differences in small-world characteristics, including indicators such as the average node degree and the small-world index. Interestingly, our findings also suggested that the differences in the activity intensity and range, the average node degree, and the small-world index of brain networks between the right- and left-hand MIs were associated with the asymmetry of brain functions.

Neural mechanism of unconscious perception of surprised facial expression.

Previous functional neuroimaging studies have uncovered partly separable neural substrates for perceiving different facial expressions presented below the level of conscious awareness. However, as one of the six basic emotions, the neural mechanism of unconsciously perceiving surprised faces has not yet been investigated. Using a backward masking procedure, we studied the neural activities in response to surprised faces presented below the threshold of conscious visual perception by means of functional magnetic resonance imaging (fMRI). Eighteen healthy adults were scanned while viewing surprised faces, which presented for 33 ms and immediately "masked" by a neutral face for 467 ms. As a control, they viewed masked happy or neutral faces as well. In comparison to both control conditions, masked surprised faces yielded significantly greater activation in the parahippocampal gyrus and fusiform gyrus, which associated previously with novelty detection. In the present study, automatic activation of these areas to masked surprised faces was investigated as a function of individual differences in the ability of identifying and differentiating one's emotions, as assessed by the 20-item Toronto Alexithymia Scale (TAS-20). The correlation results showed that, the subscale, Difficulty Identifying Feelings, was negatively correlated with the neural response of these areas to masked surprised faces, which suggest that decreased activation magnitude in specific brain regions may reflect increased difficulties in recognizing one's emotions in everyday life. Additionally, we confirmed activation of the right amygdala and right thalamus to the masked surprised faces, which was previously proved to be involved in the unconscious emotional perception system.

Neuroanatomical differences between familial and sporadic schizophrenia and their parents: an optimized voxel-based morphometry study.

Symptomatic differences have been reported between patients with familial and sporadic schizophrenia. The present study examined neuroanatomical differences between the two subgroups and their parents using voxel-based morphometry. High-resolution T1-weighted images were obtained using 3 Tesla magnetic resonance imaging from 20 patients with schizophrenia (familial subgroup, n=10; sporadic subgroup, n=10), 20 of their parents (familial subgroup, n=10; sporadic subgroup, n=10) and 20 healthy volunteers. Gray matter density (GMD) was compared between groups on a voxel-by-voxel basis. Compared with the sporadic patients, the familial patients had significantly reduced GMD in the thalamus bilaterally. Reduction of GMD in bilateral thalami was also found in familial parents in comparison with sporadic parents. Compared with controls, both familial and sporadic patients had lower GMD involving bilateral insula, right temporal lobe, right occipital lobe, left lenticular nucleus and right cerebellum. However, only familial patients showed lower GMD than controls in the right thalamus. Compared with controls, only familial parents showed lower GMD in the right insula extending to the right temporal lobe and the right parietal lobule. The present data suggest that familial schizophrenia is associated with more severe structural abnormalities than sporadic schizophrenia, especially in the thalamus.