Altered brain complexity in first-episode antipsychotic-naïve patients with schizophrenia: A whole-brain voxel-wise study.

BACKGROUND: Measures of cortical topology are believed to characterize large-scale cortical networks. Previous studies used region of interest (ROI)-based approaches with predefined templates that limit analyses to linear pair-wise interactions between regions. As cortical topology is inherently complex, a non-linear dynamic model that measures the brain complexity at the voxel level is suggested to characterize topological complexities of brain regions and cortical folding. METHODS: T1-weighted brain images of 150 first-episode antipsychotic-naïve schizophrenia (FES) patients and 161 healthy comparison participants (HC) were examined. The Chaos analysis approach was applied to detect alterations in brain structural complexity using the largest Lyapunov exponent (Lambda) as the key measure. Then, the Lambda spatial series was mapped in the frequency domain using the correlation of the Morlet wavelet to reflect cortical folding complexity. RESULTS: A widespread voxel-wise decrease in Lambda values in space and frequency domains was observed in FES, especially in frontal, parietal, temporal, limbic, basal ganglia, thalamic, and cerebellar regions. The widespread decrease indicates a general loss of brain topological complexity and cortical folding. An additional pattern of increased Lambda values in certain regions highlights the redistribution of complexity measures in schizophrenia at an early stage with potential progression as the illness advances. Strong correlations were found between the duration of untreated psychosis and Lambda values related to the cerebellum, temporal, and occipital gyri. CONCLUSIONS: Our findings support the notion that defining brain complexity by non-linear dynamic analyses offers a novel approach for identifying structural brain alterations related to the early stages of schizophrenia.

Progressive alterations of resting-state hypothalamic dysconnectivity in schizophrenia.

BACKGROUND: The hypothalamus may be involved in the pathogenesis of schizophrenia. Investigating hypothalamus dysfunction in schizophrenia and probing how it is related to symptoms and responds to antipsychotic medication is crucial for understanding the potential mechanism of hypothalamus dysfunction under the long-term illness. METHODS: We recruited 216 patients with schizophrenia, including 140 antipsychotic-naïve first-episode patients (FES, including 44 patients with 1-year follow-up data), 76 chronically treated schizophrenia (CTS), and 210 healthy controls (HC). Hypothalamic seed-based functional connectivity (FC) was calculated and compared among the FES, CTS, and HC groups using analysis of covariance. Exploratory analysis was conducted between the FES patients at baseline and after 1-year follow-up. Significantly altered hypothalamic FCs were then related to clinical symptomology, while age- and illness-related regression analyses were also conducted and compared between diagnostic groups. RESULTS: The FES patients showed decreased hypothalamic FCs with the midbrain and right thalamus, whereas the CTS patients showed more severe decreased hypothalamic FCs with the midbrain, right thalamus, left putamen, right caudate, and bilateral anterior cingulate cortex compared to HCs. These abnormalities were not correlated to the symptomology or illness duration, or not reversed by the antipsychotic treatment. Age-related hypothalamic FC decrease was also identified in the abovementioned regions, and a faster age-related decline of the hypothalamic FC was observed with the left putamen and bilateral anterior cingulate cortex. CONCLUSION: Age-related hypothalamic FC decrease extends the functional alterations that characterize the neurodegenerative nature of schizophrenia. Future studies are required to further probe the hormonal or endocrinal underpinnings of such alterations and trace the precise progressive trajectories.

Applications of MRI in Schizophrenia: Current Progress in Establishing Clinical Utility.

Schizophrenia is a severe mental illness that significantly impacts the lives of affected individuals and with increasing mortality rates. Early detection and intervention are crucial for improving outcomes but the lack of validated biomarkers poses great challenges in such efforts. The use of magnetic resonance imaging (MRI) in schizophrenia enables the investigation of the disorder's etiological and neuropathological substrates in vivo. After decades of research, promising findings of MRI have been shown to aid in screening high-risk individuals and predicting illness onset, and predicting symptoms and treatment outcomes of schizophrenia. The integration of machine learning and deep learning techniques makes it possible to develop intelligent diagnostic and prognostic tools with extracted or selected imaging features. In this review, we aimed to provide an overview of current progress and prospects in establishing clinical utility of MRI in schizophrenia. We first provided an overview of MRI findings of brain abnormalities that might underpin the symptoms or treatment response process in schizophrenia patients. Then, we summarized the ongoing efforts in the computer-aided utility of MRI in schizophrenia and discussed the gap between MRI research findings and real-world applications. Finally, promising pathways to promote clinical translation were provided. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 3.

Sex-related cortical asymmetry in antipsychotic-naïve first-episode schizophrenia.

Schizophrenia has been considered to exhibit sex-related clinical differences that might be associated with distinctly abnormal brain asymmetries between sexes. One hundred and thirty-two antipsychotic-naïve first-episode patients with schizophrenia and 150 healthy participants were recruited in this study to investigate whether cortical asymmetry would exhibit sex-related abnormalities in schizophrenia. After a 1-yr follow-up, patients were rescanned to obtain the effect of antipsychotic treatment on cortical asymmetry. Male patients were found to show increased lateralization index while female patients were found to exhibit decreased lateralization index in widespread regions when compared with healthy participants of the corresponding sex. Specifically, the cortical asymmetry of male and female patients showed contrary trends in the cingulate, orbitofrontal, parietal, temporal, occipital, and insular cortices. This result suggested male patients showed a leftward shift of asymmetry while female patients showed a rightward shift of asymmetry in these above regions that related to language, vision, emotion, and cognition. Notably, abnormal lateralization indices remained stable after antipsychotic treatment. The contrary trends in asymmetry between female and male patients with schizophrenia together with the persistent abnormalities after antipsychotic treatment suggested the altered brain asymmetries in schizophrenia might be sex-related disturbances, intrinsic, and resistant to the effect of antipsychotic therapy.

The difference in volumetric alternations of the orbitofrontal-limbic-striatal system between major depressive disorder and anxiety disorders: A systematic review and voxel-based meta-analysis.

BACKGROUND: Major depressive disorder (MDD) and anxiety disorders (ANX) are psychiatric disorders with high mutual comorbidity rates that might indicate some shared neurobiological pathways between them, but they retain diverse phenotypes that characterize themselves specifically. However, no consistent evidence exists for common and disorder-specific gray matter volume (GMV) alternations between them. METHODS: A systematic review and meta-analysis on voxel-based morphometry studies of patients with MDD and ANX were performed. The effect of comorbidity was explicitly controlled during disorder-specific analysis and particularly investigated in patient with comorbidity. RESULTS: A total of 45 studies with 54 datasets comprising 2196 patients and 2055 healthy participants met the inclusion criteria. Deficits in the orbitofrontal cortex, striatum, and limbic regions were found in MDD and ANX. The disorder-specific analyses showed decreased GMV in the bilateral anterior cingulate cortex, right striatum, hippocampus, and cerebellum in MDD, while decreased GMV in the left striatum, amygdala, insula, and increased cerebellar volume in ANX. A totally different GMV alternation pattern was shown involving bilateral temporal and parietal gyri and left fusiform gyrus in patients with comorbidity. LIMITATIONS: Owing to the design of included studies, only partial patients in the comorbid group had a secondary comorbidity diagnosis. CONCLUSION: Patients with MDD and ANX shared a structural disruption in the orbitofrontal-limbic-striatal system. The disorder-specific effects manifested their greatest severity in distinct lateralization and directionality of these changes that differentiate MDD from ANX. The comorbid group showed a totally different GMV alternation pattern, possibly suggesting another illness subtype that requires further investigation.

The acute effects of repetitive transcranial magnetic stimulation on laminar diffusion anisotropy of neocortical gray matter.

Repetitive transcranial magnetic stimulation (rTMS) is increasingly used to treat neuropsychiatric disorders. Inhibitory and excitatory regimens have been both adopted but the exact mechanism of action remains unclear, and investigating their differential effects on laminar diffusion profiles of neocortex may add important evidence. Twenty healthy participants were randomly assigned to receive a low-frequency/inhibitory or high-frequency/excitatory rTMS targeting the left dorsolateral prefrontal cortex (DLPFC). With the brand-new submillimeter diffusion tensor imaging of whole brain and specialized surface-based laminar analysis, fractional anisotropy (FA) and mean diffusion (MD) profiles of cortical layers at different cortical depths were characterized before/after rTMS. Inhibitory and excitatory rTMS both showed impacts on diffusion metrics of somatosensory, limbic, and sensory regions, but different patterns of changes were observed-increased FA with inhibitory rTMS, whereas decreased FA with excitatory rTMS. More importantly, laminar analysis indicated laminar specificity of changes in somatosensory regions during different rTMS patterns-inhibitory rTMS affected the superficial layers contralateral to the DLPFC, while excitatory rTMS led to changes in the intermediate/deep layers bilateral to the DLPFC. These findings provide novel insights into acute neurobiological effects on diffusion profiles of rTMS that may add critical evidence relevant to different protocols of rTMS on neocortex.

Convergent and distinct neural structural and functional patterns of mild cognitive impairment: a multimodal meta-analysis.

Mild cognitive impairment (MCI) is regarded as a transitional stage between normal aging and Alzheimer's disease. Numerous voxel-based morphometry (VBM) and resting-state fMRI (rs-fMRI) studies have provided strong evidence of abnormalities in the structure and intrinsic function of brain regions in MCI. Studies have recently begun to explore their association but have not employed systematic information in this pursuit. Herein, a multimodal meta-analysis was performed, which included 43 VBM datasets (1,247 patients and 1,352 controls) of gray matter volume (GMV) and 42 rs-fMRI datasets (1,468 patients and 1,605 controls) that combined 3 metrics: amplitude of low-frequency fluctuation, the fractional amplitude of low-frequency fluctuation, and regional homogeneity. Compared to controls, patients with MCI displayed convergent reduced regional GMV and altered intrinsic activity, mainly in the default mode network and salience network. Decreased GMV alone in ventral medial prefrontal cortex and altered intrinsic function alone in bilateral dorsal anterior cingulate/paracingulate gyri, right lingual gyrus, and cerebellum were identified, respectively. This meta-analysis investigated complex patterns of convergent and distinct brain alterations impacting different neural networks in MCI patients, which contributes to a further understanding of the pathophysiology of MCI.

Growth hormone deficiency interferes with dynamic brain networks in short children.

PURPOSE: This study aimed to explore the disparities in dynamic brain networks between children with growth hormone deficiency (GHD) and idiopathic short stature (ISS, non-growth hormone deficiency). METHODS: This study enrolled 65 children with GHD and 60 sex- and age-matched children with ISS. Resting-state functional magnetic resonance imaging (rs-fMRI) was performed for all participants to obtain information on dynamic regional homogeneity (dReHo) and functional connectivity (FC) in dynamic (dFC) or static (sFC) state. The rs-fMRI metrics were subsequently compared between the GHD and ISS groups. RESULTS: Compared to the ISS group, the GHD group showed significant dynamic abnormalities in intra-networks of the central executive and cerebellar networks and in inter-networks of the central executive network to attentional, sensorimotor, and visual networks, as well as cerebellar network to default mode, sensorimotor, and visual networks. In addition, FC changes in the dynamic state were different from those in the static state. CONCLUSIONS: The abnormal dynamics in intra- and inter-networks involved in cognitive, emotional, and motor functions in children with GHD extend the knowledge on brain functional alterations in children with GHD as reflected by dynamic changes in macroscopic neural activity patterns. These findings may help explain how GHD leads to various behavioral and cognitive deficits in children with short stature.

Structural connectivity associated with familial risk for mental illness: A meta-analysis of diffusion tensor imaging studies in relatives of patients with severe mental disorders.

Schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD) are heritable conditions with overlapping genetic liability. Transdiagnostic and disorder-specific brain changes associated with familial risk for developing these disorders remain poorly understood. We carried out a meta-analysis of diffusion tensor imaging (DTI) studies to investigate white matter microstructure abnormalities in relatives that might correspond to shared and discrete biomarkers of familial risk for psychotic or mood disorders. A systematic search of PubMed and Embase was performed to identify DTI studies in relatives of SCZ, BD, and MDD patients. Seed-based d Mapping software was used to investigate global differences in fractional anisotropy (FA) between overall and disorder-specific relatives and healthy controls (HC). Our search identified 25 studies that met full inclusion criteria. A total of 1,144 relatives and 1,238 HC were included in the meta-analysis. The overall relatives exhibited decreased FA in the genu and splenium of corpus callosum (CC) compared with HC. This finding was found highly replicable in jack-knife analysis and subgroup analyses. In disorder-specific analysis, compared to HC, relatives of SCZ patients exhibited the same changes while those of BD showed reduced FA in the left inferior longitudinal fasciculus (ILF). The present study showed decreased FA in the genu and splenium of CC in relatives of SCZ, BD, and MDD patients, which might represent a shared familial vulnerability marker of severe mental illness. The white matter abnormalities in the left ILF might represent a specific familial risk for bipolar disorder.

Cerebellar gray matter volume changes in patients with schizophrenia: A voxel-based meta-analysis.

Background: In schizophrenia, the structural changes in the cerebellum are associated with patients' cognition and motor deficits. However, the findings are inconsistent owing to the heterogeneity in sample size, magnetic resonance imaging (MRI) scanners, and other factors among them. In this study, we conducted a meta-analysis to characterize the anatomical changes in cerebellar subfields in patients with schizophrenia. Methods: Systematic research was conducted to identify studies that compare the gray matter volume (GMV) differences in the cerebellum between patients with schizophrenia and healthy controls with a voxel-based morphometry (VBM) method. A coordinate-based meta-analysis was adopted based on seed-based d mapping (SDM) software. An exploratory meta-regression analysis was conducted to associate clinical and demographic features with cerebellar changes. Results: Of note, 25 studies comprising 996 patients with schizophrenia and 1,109 healthy controls were included in the present meta-analysis. In patients with schizophrenia, decreased GMVs were demonstrated in the left Crus II, right lobule VI, and right lobule VIII, while no increased GMV was identified. In the meta-regression analysis, the mean age and illness duration were negatively associated with the GMV in the left Crus II in patients with schizophrenia. Conclusion: The most significant structural changes in the cerebellum are mainly located in the posterior cerebellar hemisphere in patients with schizophrenia. The decreased GMVs of these regions might partly explain the cognitive deficits and motor symptoms in patients with schizophrenia.

Altered functional synchrony between gray and white matter as a novel indicator of brain system dysconnectivity in schizophrenia.

BACKGROUND: There is increasing evidence that blood oxygenation level-dependent signaling in white matter (WM) reflects WM functional activity. Whether this activity is altered in schizophrenia remains uncertain, as does whether it is related to established alterations of gray matter (GM) or the microstructure of WM tracts. METHODS: A total of 153 antipsychotic-naïve schizophrenia patients and 153 healthy comparison subjects were assessed by resting-state functional magnetic resonance imaging, diffusion tensor imaging, and high-resolution T1-weighted imaging. We tested for case-control differences in the functional activity of WM, and examined their relation to the functional activity of GM and WM microstructure. The relations between fractional anisotropy (FA) in WM and GM-WM functional synchrony were investigated as well. Then, we examined the associations of identified abnormalities to age, duration of untreated psychosis (DUP), and symptom severity. RESULTS: Schizophrenia patients displayed reductions of the amplitude of low-frequency fluctuations (ALFF), GM-WM functional synchrony, and FA in widespread regions. Specifically, the genu of corpus callosum not only had weakening in the synchrony of functional activity but also had reduced ALFF and FA. Positive associations were found between FA and functional synchrony in the genu of corpus callosum as well. No significant association was found between identified abnormalities and DUP, and symptom severity. CONCLUSIONS: The widespread weakening in the synchrony of functional activity of GM and WM provided novel evidence for functional alterations in schizophrenia. Regarding the WM function as a component of brain systems and investigating its alternation represent a promising direction for future research.

Microstructural Abnormalities of White Matter Across Tourette Syndrome: A Voxel-Based Meta-Analysis of Fractional Anisotropy.

Introduction: Tourette syndrome (TS) is a neuropsychiatric disorder with multiple motor and vocal tics whose neural basis remains unclear. Diffusion tensor imaging (DTI) studies have demonstrated white matter microstructural alternations in TS, but the findings are inconclusive. In this study, we aimed to elucidate the most consistent white matter deficits in patients with TS. Method: By systematically searching online databases up to December 2020 for all DTI studies comparing fractional anisotropy (FA) between patients with TS and healthy controls (HCs), we conducted anisotropic effect size-signed differential mapping (AES-SDM) meta-analysis to investigate FA differences in TS, as well as performed meta-regression analysis to explore the effects of demographics and clinical characteristics on white matter abnormalities among TS. Results: A total of eight datasets including 168 patients with TS and 163 HCs were identified. We found that TS patients showed robustly decreased FA in the corpus callosum (CC) and right inferior longitudinal fasciculus (ILF) compared with HCs. These two regions preserved significance in the sensitivity analysis. No regions of increased FA were reported. Meta-regression analysis revealed that age, sex, tic severity, or illness duration of patients with TS were not linearly correlated with decreased FA. Conclusion: Patients with TS display deficits of white matter microstructure in the CC and right ILF known to be important for interhemispheric connections as well as long association fiber bundles within one hemisphere. Because the results reported in the primary literature were highly variable, future investigations with large samples would be required to support the identified white matter changes in TS.

The Effects of Antipsychotic Treatment on the Brain of Patients With First-Episode Schizophrenia: A Selective Review of Longitudinal MRI Studies.

A large number of neuroimaging studies have detected brain abnormalities in first-episode schizophrenia both before and after treatment, but it remains unclear how these abnormalities reflect the effects of antipsychotic treatment on the brain. To summarize the findings in this regard and provide potential directions for future work, we reviewed longitudinal structural and functional imaging studies in patients with first-episode schizophrenia before and after antipsychotic treatment. A total of 36 neuroimaging studies was included, involving 21 structural imaging studies and 15 functional imaging studies. Both anatomical and functional brain changes in patients after treatment were consistently observed in the frontal and temporal lobes, basal ganglia, limbic system and several key components within the default mode network (DMN). Alterations in these regions were affected by factors such as antipsychotic type, course of treatment, and duration of untreated psychosis (DUP). Over all we showed that: (a) The striatum and DMN were core target regions of treatment in schizophrenia, and their changes were related to different antipsychotics; (b) The gray matter of frontal and temporal lobes tended to reduce after long-term treatment; and (c) Longer DUP was accompanied with faster hippocampal atrophy after initial treatment, which was also associated with poorer outcome. These findings are in accordance with previous notions but should be interpreted with caution. Future studies are needed to clarify the effects of different antipsychotics in multiple conditions and to identify imaging or other biomarkers that may predict antipsychotic treatment response. With such progress, it may help choose effective pharmacological interventional strategies for individuals experiencing recent-onset schizophrenia.

Functional Alterations of White Matter in Chronic Never-Treated and Treated Schizophrenia Patients.

BACKGROUND: Schizophrenia is one of the most severe psychiatric disorders and dysfunction of gray matter (GM) has been usually investigated by resting-state functional (f)MRI. However, functional organization of white matter (WM) in chronic schizophrenia remains unclear. PURPOSE: To investigate the WM functional alterations in chronic never-treated schizophrenia and the effects of long-term antipsychotic treatment. STUDY TYPE: Prospective. SUBJECTS: Twenty-five never-treated, 41 matched antipsychotic-treated schizophrenia, and 25 healthy comparison subjects. FIELD STRENGTH/SEQUENCE: Resting state (rs)-fMRI, T1 -weighted images (T1 WI), and diffusion tensor imaging (DTI) covering the whole brain were acquired with a 3.0T scanner. ASSESSMENT: Amplitude of low-frequency fluctuations (ALFF) in WM and the correlation coefficients between WM and GM were examined and compared among the three participant groups by two reviewers independently. Independent component analysis (ICA) was added to evaluate WM-fMRI signals. Statistical Tests: Analysis of covariance (ANCOVA); Pearson correlation analysis. RESULTS: Never-treated patients demonstrated lower ALFF in splenium of corpus callosum (SCC) relative to treated patients and controls (P < 0.001, false discovery rate [FDR]-corrected). While the extracted independent component also located in SCC and showed significantly decreased connectivity in never-treated patients when compared to controls (P < 0.05, FDR-corrected). The correlation coefficients of WM-GM displayed greater reductions in the genu of corpus callosum (GCC), pontine crossing tract (PC), bilateral cingulum (hippocampus) (CGH), and bilateral corticospinal tract (CST) in treated patients relative to controls (P < 0.05, FDR-corrected). DATA CONCLUSION: These findings provide new insight into WM functional alterations over the long-term course of schizophrenia with and without the potential effects of antipsychotic medication. Functional change and abnormal connectivity in SCC were both found greater in untreated patients than treated patients relative to healthy controls, suggesting that long-term antipsychotic treatment may show some protective effects on WM functional organization. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2020;52:752-763.

Characteristic alteration of subcortical nuclei shape in medication-free patients with obsessive-compulsive disorder.

BACKGROUND: Subcortical nuclei are important components in the pathology model of obsessive-compulsive disorder (OCD), and subregions of these structures subserve different functions that may distinctively contribute to OCD symptoms. Exploration of the subregional-level profile of structural abnormalities of these nuclei is needed to develop a better understanding of the neural mechanism of OCD. METHODS: A total of 83 medication-free, non-comorbid OCD patients and 93 age- and sex-matched healthy controls were recruited, and high-resolution T1-weighted MR images were obtained for all participants. The volume and shape of the subcortical nuclei (including the nucleus accumbens, amygdala, caudate, pallidum, putamen and thalamus) were quantified and compared with an automated parcellation approach and vertex-wise shape analysis using FSL-FIRST software. Sex differences in these measurements were also explored with an exploratory subgroup analysis. RESULTS: Volumetric analysis showed no significant differences between patients and healthy control subjects. Relative to healthy control subjects, the OCD patients showed an expansion of the lateral amygdala (right hemisphere) and right pallidum. These deformities were associated with illness duration and symptom severity of OCD. Exploratory subgroup analysis by sex revealed amygdala deformity in male patients and caudate deformity in female patients. CONCLUSIONS: The lateral amygdala and the dorsal pallidum were associated with OCD. Neuroanatomic evidence of sexual dimorphism was also found in OCD. Our study not only provides deeper insight into how these structures contribute to OCD symptoms by revealing these subregional-level deformities but also suggests that gender effects may be important in OCD studies.