Subcortical volumetric alterations in four major psychiatric disorders: a mega-analysis study of 5604 subjects and a volumetric data-driven approach for classification.

Differential diagnosis is sometimes difficult in practical psychiatric settings, in terms of using the current diagnostic system based on presenting symptoms and signs. The creation of a novel diagnostic system using objective biomarkers is expected to take place. Neuroimaging studies and others reported that subcortical brain structures are the hubs for various psycho-behavioral functions, while there are so far no neuroimaging data-driven clinical criteria overcoming limitations of the current diagnostic system, which would reflect cognitive/social functioning. Prior to the main analysis, we conducted a large-scale multisite study of subcortical volumetric and lateralization alterations in schizophrenia, bipolar disorder, major depressive disorder, and autism spectrum disorder using T1-weighted images of 5604 subjects (3078 controls and 2526 patients). We demonstrated larger lateral ventricles volume in schizophrenia, bipolar disorder, and major depressive disorder, smaller hippocampus volume in schizophrenia and bipolar disorder, and schizophrenia-specific smaller amygdala, thalamus, and accumbens volumes and larger caudate, putamen, and pallidum volumes. In addition, we observed a leftward alteration of lateralization for pallidum volume specifically in schizophrenia. Moreover, as our main objective, we clustered the 5,604 subjects based on subcortical volumes, and explored whether data-driven clustering results can explain cognitive/social functioning in the subcohorts. We showed a four-biotype classification, namely extremely (Brain Biotype [BB] 1) and moderately smaller limbic regions (BB2), larger basal ganglia (BB3), and normal volumes (BB4), being associated with cognitive/social functioning. Specifically, BB1 and BB2-3 were associated with severe and mild cognitive/social impairment, respectively, while BB4 was characterized by normal cognitive/social functioning. Our results may lead to the future creation of novel biological data-driven psychiatric diagnostic criteria, which may be expected to be useful for prediction or therapeutic selection.

Cerebral cortical structural alteration patterns across four major psychiatric disorders in 5549 individuals.

According to the operational diagnostic criteria, psychiatric disorders such as schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and autism spectrum disorder (ASD) are classified based on symptoms. While its cluster of symptoms defines each of these psychiatric disorders, there is also an overlap in symptoms between the disorders. We hypothesized that there are also similarities and differences in cortical structural neuroimaging features among these psychiatric disorders. T1-weighted magnetic resonance imaging scans were performed for 5,549 subjects recruited from 14 sites. Effect sizes were determined using a linear regression model within each protocol, and these effect sizes were meta-analyzed. The similarity of the differences in cortical thickness and surface area of each disorder group was calculated using cosine similarity, which was calculated from the effect sizes of each cortical regions. The thinnest cortex was found in SZ, followed by BD and MDD. The cosine similarity values between disorders were 0.943 for SZ and BD, 0.959 for SZ and MDD, and 0.943 for BD and MDD, which indicated that a common pattern of cortical thickness alterations was found among SZ, BD, and MDD. Additionally, a generally smaller cortical surface area was found in SZ and MDD than in BD, and the effect was larger in SZ. The cosine similarity values between disorders were 0.945 for SZ and MDD, 0.867 for SZ and ASD, and 0.811 for MDD and ASD, which indicated a common pattern of cortical surface area alterations among SZ, MDD, and ASD. Patterns of alterations in cortical thickness and surface area were revealed in the four major psychiatric disorders. To our knowledge, this is the first report of a cross-disorder analysis conducted on four major psychiatric disorders. Cross-disorder brain imaging research can help to advance our understanding of the pathogenesis of psychiatric disorders and common symptoms.

Dynamics of corticocortical brain functional connectivity relevant to therapeutic response to biologics in inflammatory arthritis.

Aberrant functional connectivity (FC) of the brain regions, evaluated by functional magnetic resonance imaging (fMRI), affects clinical courses in inflammatory arthritis (IA). The static analysis methods would be simplistic to estimate the whole picture of resting-state brain function because blood oxygen level-dependent (BOLD) signals fluctuate over time. The effects of FC dynamics on clinical course are unknown in IA. Therefore, we aimed to evaluate dynamic FC for therapeutic responsiveness to biologics in IA patients. We analyzed resting-state fMRI data of 64 IA patients in 2 cohorts. Dynamic FC was derived as a correlation coefficient of the windowed BOLD signal time series. We determined representative whole-brain dynamic FC patterns by k-means++ cluster analysis, leading to 4 distinct clusters. In the first cohort, occurrence probability of the distinct cluster was associated with favorable therapeutic response in disease activity and patients' global assessment, which was validated by the second cohort. The whole-brain FC of the distinct cluster indicated significantly increased corticocortical connectivity, and probabilistically decreased after therapy in treatment-effective patients compared with -ineffective patients. Taken together, frequent emergence of corticocortical connections was associated with clinical outcomes in IA. The coherence of corticocortical interactions might affect pain modulation, possibly relevant to therapeutic satisfaction.

Aberrant functional connectivity between anterior cingulate cortex and left insula in association with therapeutic response to biologics in inflammatory arthritis.

BACKGROUND: Brain activity is reported to be associated with individual pain susceptibility and inflammatory status, possibly contributing to disease activity assessment in inflammatory arthritis (IA) including rheumatoid arthritis (RA) and spondyloarthritis (SpA). However, what alteration of brain function associated with disease activity and therapeutic effectiveness in IA remains unclear. We aimed to identify the alterations of brain functional connectivity (FC) shared in both RA and SpA, and evaluate its relationship to anti-rheumatic treatment response using functional magnetic resonance imaging (MRI). PATIENTS AND METHODS: Structural and resting-state functional MRI data were acquired from patients with IA, patients with osteoarthritis (OA) and heathy controls (HCs). Two datasets were adopted to derive (51 IA, 56 OA, and 17 HCs) and validate (31 IA) the observations. 33 IA patients in the derivation dataset and all the patients in validation dataset required biological treatment and were clinically evaluated before and after therapy. Via whole-brain pair-wise FC analyses, we analyzed IA-specific FC measures relevant to therapeutic response to biologics. RESULTS: The value of FC between left insular cortex (IC) and anterior cingulate cortex (ACC) was significantly low in IA patients compared with OA patients and HCs. We demonstrated that the FC between left anterior long insular gyrus as a subdivision of IC and ACC was significantly associated with therapeutic response to biologics regarding the improvement of patients' global assessment (PGA) in both derivation and validation datasets. CONCLUSION: Disease-specific resting-state FC provides a means to assess the therapeutic improvement of PGA and would be a clinical decision-making tool with predictability for treatment response in both RA and SpA.

Microstructural Alterations in Bipolar and Major Depressive Disorders: A Diffusion Kurtosis Imaging Study.

BACKGROUND: Identifying structural and functional abnormalities in bipolar (BD) and major depressive disorders (MDD) is important for understanding biological processes. HYPOTHESIS: Diffusion kurtosis imaging (DKI) may be able to detect the brain's microstructural alterations in BD and MDD and any differences between the two. STUDY TYPE: Prospective. SUBJECTS: In all, 16 BD patients, 19 MDD patients, and 20 age- and gender-matched healthy volunteers. FIELD STRENGTH/SEQUENCE: DKI at 3.0T. ASSESSMENT: The major DKI indices of the brain were compared voxel-by-voxel among the three groups. Significantly different voxels were tested for correlation with clinical variables (ie, Young Mania Rating Scale [YMRS], 17-item Hamilton Depression Rating Scale [17-HDRS], Montgomery-Åsberg Depression Rating Scale, total disease duration, duration of current episode, and the number of past manic/depressive episodes). The performance of the DKI indices in identifying microstructural alterations was estimated. STATISTICAL TESTS: One-way analysis of variance (ANOVA) was used for group comparison of DKI indices. The performance of these indices in detecting microstructural alterations was determined by receiver operating characteristic (ROC) analysis. Pearson's product-moment correlation analyses were used to test the correlations of these indices with clinical variables. RESULTS: DKI revealed widespread microstructural alterations across the brain in each disorder (P < 0.05). Some were significantly different between the two disorders. Mean kurtosis (MK) in the gray matter of the right inferior parietal lobe was able to distinguish BD and MDD with an accuracy of 0.906. A strong correlation was revealed between MK in that region and YMRS in BD patients (r = -0.641, corrected P = 0.042) or 17-HDRS in MDD patients (r = -0.613, corrected P = 0.030). There were also strong correlations between a few other DKI indices and disease duration (r = -0.676 or 0.626, corrected P < 0.05). DATA CONCLUSION: DKI detected microstructural brain alterations in BD and MDD. Its indices may be useful to distinguish the two disorders or to reflect disease severity and duration. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 3 J. Magn. Reson. Imaging 2020;52:1187-1196.

Mean kurtosis alterations of cerebral white matter in patients with schizophrenia revealed by diffusion kurtosis imaging.

INTRODUCTION: Diffusion kurtosis imaging can provide a better understanding of microstructural white matter (WM) changes where crossing fibers exist, compared with conventional diffusion tensor imaging. Here, we aimed to examine the differences of mean kurtosis (MK) and fractional anisotropy (FA) values between patients with schizophrenia and control subjects using voxel-based analysis (VBA). Additionally, we examined the correlation between these values and severity of clinical symptoms in patients with schizophrenia. METHODS: MK and FA values were acquired with a 3.0T scanner from 31 patients with schizophrenia and 31 age-, handedness-, and sex-matched healthy controls. VBA was used to compare the MK and FA maps of the patients with schizophrenia and healthy controls. We also performed a correlation analysis between the MK and FA values of the regions with significant differences and the positive and negative syndrome scale scores in patients with schizophrenia. RESULTS: Compared to FA values, voxels with MK decrease were more widespread across bilateral cerebral the WM of patients with schizophrenia. The MK values of left superior longitudinal fasciculus were significantly negatively correlated with the severity of positive symptoms (r=-0.451, P=0.011). There was no significant correlation between MK and FA values and other clinical variables. CONCLUSION: The diffusion kurtosis indices are suitable for evaluating altered WM structures in the human brain as they may detect white matter alterations of crossing fibers alterations of WM in schizophrenia and assess the clinical state of patients.

Impaired integrity of the brain parenchyma in non-geriatric patients with major depressive disorder revealed by diffusion tensor imaging.

Diffusion tensor imaging (DTI) is considered to be able to non-invasively quantify white matter integrity. This study aimed to use DTI to evaluate white matter integrity in non-geriatric patients with major depressive disorder (MDD) who were free of antidepressant medication. DTI was performed on 19 non-geriatric patients with MDD, free of antidepressant medication, and 19 age-matched healthy subjects. Voxel-based and histogram analyses were used to compare fractional anisotropy (FA) and mean diffusivity (MD) values between the two groups, using two-sample t tests. The abnormal DTI indices, if any, were tested for correlation with disease duration and severity, using Pearson product-moment correlation analysis. Voxel-based analysis showed clusters with FA decrease at the bilateral frontal white matter, anterior limbs of internal capsule, cerebellum, left putamen and right thalamus of the patients. Histogram analysis revealed lower peak position of FA histograms in the patients. FA values of the abnormal clusters and peak positions of FA histograms of the patients exhibited moderate correlation with disease duration and severity. These results suggest the implication of frontal-subcortical circuits and cerebellum in MDD, and the potential utility of FA in evaluation of brain parenchymal integrity.

Hyperintense putaminal rim at 1.5 T: prevalence in normal subjects and distinguishing features from multiple system atrophy.

BACKGROUND: Hyperintense putaminal rim (HPR) is an important magnetic resonance imaging (MRI) sign for multiple system atrophy (MSA). Recent studies have suggested that it can also be observed in normal subjects at 3 T. Whether it can be observed in normal subjects at 1.5 T is not known. This study aimed to determine whether HPR could be observed in normal subjects at 1.5 T; and if so, to establish its prevalence, the MRI characteristics, and the features which distinguish from HPR in MSA patients. METHODS: Axial T2-weighted images of 130 normal subjects were evaluated for the prevalence of HPR, its age and gender distribution, laterality, maximum dimension, association with hypointensity of nearby putamen, and presence of discontinuity. To distinguish from that observed in MSA, axial T2-weighted images of 6 MSA patients with predominant parkinsonism (MSA-P) and 15 MSA patients with predominant cerebellar symptoms (MSA-C) were also evaluated. The characteristics of HPR were compared between these patients and age-matched normal subjects. The mean diffusivity (MD) values of putamen were also compared. Fisher's exact test, t-test, and one way analysis of variance were used to determine significance at corrected p < 0.05. RESULTS: HPR was observed in 38.5% of normal subjects. Age and gender predilection and laterality were not observed. In most cases, it occupied the full length or anterior half of the lateral margin of putamen, and was continuous throughout its length. Maximum transverse dimension was 2 mm. There was no association with hypointensity of nearby putamen. However, in MSA-P, HPR was located predominantly at the posterolateral aspect of putamen, and associated with putaminal atrophy. Discontinuity of HPR was more frequently observed in MSA-P. On visual analysis, the characteristics of HPR were similar between MSA-C patients and normal subjects. Patients with MSA of either type had significantly higher MD values of putamen than normal subjects. CONCLUSIONS: HPR can be observed in 38.5% of normal subjects at 1.5 T. Thin linear hyperintensity without discontinuity, occupying the full length or anterior half of the lateral margin of the putamen, is suggestive of "normal." In doubtful cases, measurement of the MD values of nearby putamen may be valuable.

Mapping of cerebral oxygen extraction fraction changes with susceptibility-weighted phase imaging.

PURPOSE: To develop a map to detect changes in oxygen extraction fraction (OEF) utilizing susceptibility-weighted (SW) phase images and to correlate such changes in OEF with those in cerebral blood flow (CBF). MATERIALS AND METHODS: The study protocol was approved by the institutional review board, and written informed consent was obtained from all subjects. Eight healthy volunteers (mean age ± standard deviation, 29.8 years ± 4.6) were included in the study. Subjects were evaluated by using SW imaging, and the change in OEF was calculated by subtracting the image at baseline from one of the images obtained during six different conditions, including two at resting state, three different types of respiratory challenges, and one drug challenge with acetazolamide. Arterial spin labeling was carried out to measure CBF, while SW imaging was used to generate maps of change in OEF in response to a given condition. Statistical tests included one-way analysis of variance and Dunnett multiple comparisons to compare among the six conditions the magnitude of change from baseline for both OEF and CBF, by using the OEF change at resting state (resting 1) as the control. RESULTS: Hyperventilation caused a statistically significant decrease in CBF (-29.3%, P < .001) and an increase in OEF (+5.2%, P < .001) compared with the control, resting 1 (+2.2%, -0.7%, respectively). Acetazolamide caused a significant increase in CBF (+39.7%, P < .001) and a decrease in OEF (-3.4%, P = .040). Carbogen also induced a CBF increase (+16.2%); however, the change was not significant (P = .090), even though OEF decreased significantly (-4.2%, P = .003). Oxygen administration resulted in a significant CBF decrease (-27.2%, P < .001), whereas OEF showed no significant difference (-0.6%, P > .99). CONCLUSION: Maps of changes in OEF generated from SW phase images revealed changes in OEF corresponding to anticipated changes in CBF induced by various conditions; SW phase imaging might, in the future, be applied to evaluate cerebrovascular and other cerebral disorders in which changes in oxygen metabolism are important for planning therapeutic strategies.

Estimation of skeletal muscle energy metabolism in Machado-Joseph disease using (31)P-MR spectroscopy.

The aim of this study was to determine if muscle energy metabolism, as measured by (31)P-magnetic resonance spectroscopy (MRS), is a metabolic marker for the efficacy of treatment of Machado-Joseph disease (MJD). We obtained (31)P-MRS in the calf muscle of 8 male patients with MJD and 11 healthy men before, during, and after a 4 minute plantar flexion exercise in a supine position. The data showed that there was a significant difference between the groups in terms of the PCr/(Pi + PCr) ratio at rest (P = 0.03) and the maximum rate of mitochondrial ATP production (V(max)) (P < 0.01). In addition, V(max) was inversely correlated with the scale for the assessment and rating of ataxia score (r = -0.34, P = 0.04). The MJD group also showed a reduction in V(max) over the course of 2 years (P < 0.05). These data suggest that this noninvasive measurement of muscle energy metabolism may represent a surrogate marker for MJD.

Microstructural white matter abnormalities of multiple system atrophy: in vivo topographic illustration by using diffusion-tensor MR imaging.

PURPOSE: To determine whether diffusion-tensor (DT) imaging can demonstrate microstructural white matter abnormalities of multiple system atrophy (MSA) and to correlate these imaging findings with clinical signs and symptoms. MATERIALS AND METHODS: Institutional review board approval and written informed consent were obtained. DT imaging was performed in 16 patients with MSA with predominant cerebellar symptoms (MSA-C) (mean age, 60.0 years + or - 5.1 [standard deviation]; range, 51-69 years) and 16 age-matched healthy subjects. Fractional anisotropy (FA) and mean diffusivity (MD) were compared voxel-by-voxel between the two groups by using a two-sample t test. Overlap maps were created to illustrate areas with FA and MD alterations. Correlation between DT imaging indexes and Barthel index score, scale for assessment and rating of ataxia (SARA) score, severity of orthostatic hypotension, age of disease onset, and disease duration was tested by using Spearman rank or Pearson product-moment correlation analysis. T2-weighted and proton density-weighted images of the patients were visually assessed. RESULTS: Widespread areas of FA reduction and MD elevation were observed in supra- and infratentorial white matter structures in patients with MSA (P < .05, false discovery rate corrected). Significant correlation (P < .01) between DT imaging indexes and Barthel index score, SARA score, severity of orthostatic hypotension, and disease duration was observed for multiple areas with FA and/or MD alterations. T2-weighted and proton density-weighted images showed no significant abnormality in supratentorial white matter. CONCLUSION: DT imaging may help identify the microstructural white matter abnormalities of MSA-C. DT imaging may be useful for severity assessment of MSA-C.

Early detection of global cerebral anoxia: improved accuracy by high-b-value diffusion-weighted imaging with long echo time.

BACKGROUND AND PURPOSE: Early and accurate detection of global cerebral anoxia is important for determination of prognosis and further management. We evaluated whether accuracy in early detection of global cerebral anoxia was improved by high-b-value diffusion-weighted imaging (DWI) with long echo time (TE). METHODS: Routine DWI (b = 1000 s/mm(2); TE = 139 ms), high-b-value DWI (b = 3000 s/mm(2); TE = 190 ms), T2-weighted imaging (T2WI), and fluid-attenuated inversion recovery (FLAIR) imaging were acquired in six patients who experienced cardiopulmonary arrest within 24 hours and six volunteers. Region of interest-based analysis was performed. Regions of interest of patients showing significant decrease in apparent diffusion coefficient (ADC) values than volunteers were considered abnormal. Three neuroradiologists independently assessed images of the patients for conspicuity of hyperintensity within regions of interest. Receiver operating characteristic (ROC) analysis was performed, and the area under the curve (Az) was compared among sequences and observers. Average contrast and contrast-to-noise ratios between abnormal regions of interest and regions of interest of normal surrounding parenchyma were calculated. RESULTS: For all observers, high-b-value DWIs achieved the largest Az, and FLAIR imaging the lowest Az. Az of routine DWI and T2WI were between these values. High-b-value DWI and FLAIR imaging showed no significant interobserver variation in Az, whereas routine DWI and T2WI did. High-b-value DWI also achieved the largest contrast and contrast-to-noise ratios. CONCLUSION: High-b-value DWI with long TE improved accuracy in early detection of global cerebral anoxia. Application of the sequence would facilitate early diagnosis.