Effect of phase-encoding direction on group analysis of resting-state functional magnetic resonance imaging.

AIM: Echo-planar imaging is a common technique used in functional magnetic resonance imaging (fMRI); however, it suffers from image distortion and signal loss because of large susceptibility effects that are related to the phase-encoding direction of the scan. Despite this relation, the majority of neuroimaging studies has not considered the influence of phase-encoding direction. Here, we aimed to clarify how phase-encoding direction can affect the outcome of an fMRI connectivity study of schizophrenia (SCZ). METHODS: Resting-state fMRI using anterior to posterior (A-P) and posterior to anterior (P-A) directions was used to examine 25 patients with SCZ and 37 matched healthy controls (HC). We conducted a functional connectivity (FC) analysis using independent component analysis and performed three group comparisons: (i) A-P versus P-A (all participants); (ii) SCZ versus HC for the A-P and P-A datasets; and (iii) the interaction between phase-encoding direction and participant group. RESULTS: The estimated FC differed between the two phase-encoding directions in areas that were more extensive than those where signal loss has been reported. Although FC in the SCZ group was lower than that in the HC group for both directions, the A-P and P-A conditions did not exhibit the same specific pattern of differences. Further, we observed an interaction between participant group and the phase-encoding direction in the left temporoparietal junction and left fusiform gyrus. CONCLUSION: Phase-encoding direction can influence the results of FC studies. Thus, appropriate selection and documentation of phase-encoding direction will be important in future resting-state fMRI studies.

The contribution of cortical thickness and surface area to gray matter asymmetries in the healthy human brain.

Human cortical gray matter (GM) is structurally asymmetrical and this asymmetry has been discussed to be partly responsible for functional lateralization of human cognition and behavior. Past studies on brain asymmetry have shown mixed results so far, with some studies focusing on the global shapes of the brain's surface, such as gyrification patterns, while others focused on regional brain volumes. In this study, we investigated cortical GM asymmetries in a large sample of right-handed healthy volunteers (n = 101), using a surface-based method which allows to analyze brain cortical thickness and surface area separately. As a result, substantially different patterns of symmetry emerged between cortical thickness and surface area measures. In general, asymmetry is more prominent in the measure of surface compared to that of thickness. Such a detailed investigation of structural asymmetries in the normal brain contributes largely to our knowledge of normal brain development and also offers insights into the neurodevelopmental basis of psychiatric disorders, such as schizophrenia.

Association of homocysteine with white matter dysconnectivity in schizophrenia.

Several studies have shown white matter (WM) dysconnectivity in people with schizophrenia (SZ). However, the underlying mechanism remains unclear. We investigated the relationship between plasma homocysteine (Hcy) levels and WM microstructure in people with SZ using diffusion tensor imaging (DTI). Fifty-three people with SZ and 83 healthy controls (HC) were included in this retrospective observational study. Tract-Based Spatial Statistics (TBSS) were used to evaluate group differences in WM microstructure. A significant negative correlation between plasma Hcy levels and WM microstructural disruption was noted in the SZ group (Spearman's ρ = -.330, P = 0.016) but not in the HC group (Spearman's ρ = .041, P = 0.712). These results suggest that increased Hcy may be associated with WM dysconnectivity in SZ, and the interaction between Hcy and WM dysconnectivity could be a potential mechanism of the pathophysiology of SZ. Further, longitudinal studies are required to investigate whether high Hcy levels subsequently cause WM microstructural disruption in people with SZ.

Disorganization of Semantic Brain Networks in Schizophrenia Revealed by fMRI.

OBJECTIVES: Schizophrenia is a mental illness that presents with thought disorders including delusions and disorganized speech. Thought disorders have been regarded as a consequence of the loosening of associations between semantic concepts since the term "schizophrenia" was first coined by Bleuler. However, a mechanistic account of this cardinal disturbance in terms of functional dysconnection has been lacking. To evaluate how aberrant semantic connections are expressed through brain activity, we characterized large-scale network structures of concept representations using functional magnetic resonance imaging (fMRI). STUDY DESIGN: We quantified various concept representations in patients' brains from fMRI activity evoked by movie scenes using encoding modeling. We then constructed semantic brain networks by evaluating the similarity of these semantic representations and conducted graph theory-based network analyses. STUDY RESULTS: Neurotypical networks had small-world properties similar to those of natural languages, suggesting small-worldness as a universal property in semantic knowledge networks. Conversely, small-worldness was significantly reduced in networks of schizophrenia patients and was correlated with psychological measures of delusions. Patients' semantic networks were partitioned into more distinct categories and had more random within-category structures than those of controls. CONCLUSIONS: The differences in conceptual representations manifest altered semantic clustering and associative intrusions that underlie thought disorders. This is the first study to provide pathophysiological evidence for the loosening of associations as reflected in randomization of semantic networks in schizophrenia. Our method provides a promising approach for understanding the neural basis of altered or creative inner experiences of individuals with mental illness or exceptional abilities, respectively.

Association between enhanced carbonyl stress and decreased apparent axonal density in schizophrenia by multimodal white matter imaging.

Carbonyl stress is a condition featuring increased rich reactive carbonyl compounds, which facilitate the formation of advanced glycation end products including pentosidine. We previously reported the relationship between enhanced carbonyl stress and disrupted white matter integrity in schizophrenia, although which microstructural component is disrupted remained unclear. In this study, 32 patients with schizophrenia (SCZ) and 45 age- and gender-matched healthy volunteers (HC) were recruited. We obtained blood samples for carbonyl stress markers (plasma pentosidine and serum pyridoxal) and multi-modal magnetic resonance imaging measures of white matter microstructures including apparent axonal density (intra-cellular volume fraction (ICVF)) and orientation (orientation dispersion index (ODI)), and inflammation (free water (FW)). In SCZ, the plasma pentosidine level was significantly increased. Group comparison revealed that mean white matter values were decreased for ICVF, and increased for FW. We found a significant negative correlation between the plasma pentosidine level and mean ICVF values in SCZ, and a significant negative correlation between the serum pyridoxal level and mean ODI value in HC, regardless of age. Our results suggest an association between enhanced carbonyl stress and axonal abnormality in SCZ.

Molecular diagnosis of 405 individuals with autism spectrum disorder.

Autism spectrum disorder (ASD) is caused by combined genetic and environmental factors. Genetic heritability in ASD is estimated as 60-90%, and genetic investigations have revealed many monogenic factors. We analyzed 405 patients with ASD using family-based exome sequencing to detect disease-causing single-nucleotide variants (SNVs), small insertions and deletions (indels), and copy number variations (CNVs) for molecular diagnoses. All candidate variants were validated by Sanger sequencing or quantitative polymerase chain reaction and were evaluated using the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines for molecular diagnosis. We identified 55 disease-causing SNVs/indels in 53 affected individuals and 13 disease-causing CNVs in 13 affected individuals, achieving a molecular diagnosis in 66 of 405 affected individuals (16.3%). Among the 55 disease-causing SNVs/indels, 51 occurred de novo, 2 were compound heterozygous (in one patient), and 2 were X-linked hemizygous variants inherited from unaffected mothers. The molecular diagnosis rate in females was significantly higher than that in males. We analyzed affected sibling cases of 24 quads and 2 quintets, but only one pair of siblings shared an identical pathogenic variant. Notably, there was a higher molecular diagnostic rate in simplex cases than in multiplex families. Our simulation indicated that the diagnostic yield is increasing by 0.63% (range 0-2.5%) per year. Based on our simple simulation, diagnostic yield is improving over time. Thus, periodical reevaluation of ES data should be strongly encouraged in undiagnosed ASD patients.

Cortical changes in patients with schizophrenia across two ethnic backgrounds.

While it is known that cultural background influences the healthy brain, less is known about how it affects cortical changes in schizophrenia. Here, we tested whether schizophrenia differentially affected the brain in Japanese and German patients. In a sample of 155 patients with a diagnosis of schizophrenia and 191 healthy controls from Japan and Germany, we acquired 3 T-MRI of the brain. We subsequently compared cortical thickness and cortical surface area to identify whether differences between healthy controls and patients might be influenced by ethnicity. Additional analyses were performed to account for effects of duration of illness and medication. We found pronounced interactions between schizophrenia and cultural background in the cortical thickness of several areas, including the left inferior and middle temporal gyrus, as well as the right lateral occipital cortex. Regarding cortical surface area, interaction effects appeared in the insula and the occipital cortex, among others. Some of these brain areas are related to the expression of psychotic symptoms, which are known to differ across cultures. Our results indicate that cultural background impacts cortical structures in different ways, probably resulting in varying clinical manifestations, and call for the inclusion of more diverse samples in schizophrenia research.

Enhanced carbonyl stress and disrupted white matter integrity in schizophrenia.

Carbonyl stress is a state caused by an increase in rich reactive carbonyl compounds (RCOs); RCOs facilitate the formation of advanced glycation end products (AGEs), which are associated with various age-related illnesses. Recently, enhanced carbonyl stress and lower levels of pyridoxal, a kind of vitamin B6 that scavenges RCOs, have been shown to be associated with schizophrenia. Meanwhile, lower levels of pyridoxal have been reported to decrease myelination through the biochemical process of carbonyl stress. Despite a number of reports on white matter disruption in schizophrenia, it is unclear whether this disruption is related to enhanced carbonyl stress. Therefore, we investigated the relationship between carbonyl stress and white matter integrity in schizophrenia using diffusion tensor imaging. A total of 53 patients with schizophrenia and 83 age- and gender-matched healthy controls were recruited. We used plasma pentosidine, an AGE, and serum pyridoxal as carbonyl stress markers. Between-group differences in these carbonyl stress markers and their relationships with white matter integrity were investigated using Tract-Based Spatial Statistics. In the schizophrenia group, plasma pentosidine level was significantly higher and serum pyridoxal level was lower than those of controls. There was a significant negative correlation between plasma pentosidine and white matter integrity in the schizophrenia group, but not in the control group. Our findings suggest that enhanced carbonyl stress is a possible underlying mechanism of white matter microstructural disruption in schizophrenia.

Anti-PDHA1 antibody is detected in a subset of patients with schizophrenia.

Autoantibodies have been implicated in schizophrenia aetiology. Here, novel autoantibodies were isolated from patients with schizophrenia. Autoantibody candidates were searched using two-dimensional gel electrophoresis and western blotting with rat brain proteins as antigens and two sera pools (25 schizophrenia patients versus 25 controls) as antibodies. Immunoreactive antigens were identified by mass spectrometry. Antibody prevalence were evaluated by western blotting using human recombinant proteins. Furthermore, brain magnetic resonance imaging data (regional brain volumes and diffusion tensor imaging measures) were compared. Two proteins of the mitochondrial respiration pathway were identified as candidate antigens. Three patients with schizophrenia, but no controls, expressed antibodies targeting one of the candidate antigens, i.e., pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial (PDHA1, EC 1.2.4.1), which is related to mitochondrial energy production. Anti-PDHA1 antibody-positive patients (n = 3) had increased volumes in the left occipital fusiform gyrus compared to both controls (n = 23, p = 0.017) and antibody-negative patients (n = 16, p = 0.009), as well as in the left cuneus compared to antibody-negative patients (n = 16, p = 0.018). This is the first report of an anti-PDHA1 antibody in patients with schizophrenia. Compatible with recent findings of mitochondrial dysfunction in schizophrenia, this antibody may be involved in the pathogenesis of a specific subgroup of schizophrenia.

Gray matter volume reductions in patients with schizophrenia: A replication study across two cultural backgrounds.

Structural gray matter (GM) volume reductions in patients with schizophrenia have rarely been replicated across two different sites, the impact of culture and clinical characteristics remains unresolved. Hence, we assessed GM volume reductions in patients with schizophrenia using 3 T magnetic resonace imaging to replicate results across two independent and culturally different backgrounds (Germany, Japan), and to investigate the impact of brain volume reductions on clinical characteristics. In total, 163 German (80 patients) and 203 Japanese (83 patients) participants were included in the analysis. Voxel-based morphometry (VBM) was used to investigate structural differences between the groups and across the two sites, comparing local GM volumes. Clinical variables were used to analyze effects unrelated to the socio-cultural background. Across both data sets, widespread GM reductions in frontal and temporal cortical parts were found between patients and controls, indicating strong effects of diagnosis and only small effects of site. The investigation of clinical characteristics revealed the strongest effects for chlorpromazine equivalents on GM volume reductions primarily in the Japanese sample. Although the effects of site are small, several brain regions do not overlap between the two groups. Thus, GM may be affected differently at the two sites in patients with schizophrenia.

The effect of duration of illness and antipsychotics on subcortical volumes in schizophrenia: Analysis of 778 subjects.

BACKGROUND: The effect of duration of illness and antipsychotic medication on the volumes of subcortical structures in schizophrenia is inconsistent among previous reports. We implemented a large sample analysis utilizing clinical data from 11 institutions in a previous meta-analysis. METHODS: Imaging and clinical data of 778 schizophrenia subjects were taken from a prospective meta-analysis conducted by the COCORO consortium in Japan. The effect of duration of illness and daily dose and type of antipsychotics were assessed using the linear mixed effect model where the volumes of subcortical structures computed by FreeSurfer were used as a dependent variable and age, sex, duration of illness, daily dose of antipsychotics and intracranial volume were used as independent variables, and the type of protocol was incorporated as a random effect for intercept. The statistical significance of fixed-effect of dependent variable was assessed. RESULTS: Daily dose of antipsychotics was positively associated with left globus pallidus volume and negatively associated with right hippocampus. It was also positively associated with laterality index of globus pallidus. Duration of illness was positively associated with bilateral globus pallidus volumes. Type of antipsychotics did not have any effect on the subcortical volumes. DISCUSSION: A large sample size, uniform data collection methodology and robust statistical analysis are strengths of the current study. This result suggests that we need special attention to discuss about relationship between subcortical regional brain volumes and pathophysiology of schizophrenia because regional brain volumes may be affected by antipsychotic medication.

Distinct Patterns of Cerebral Cortical Thinning in Schizophrenia: A Neuroimaging Data-Driven Approach.

Schizophrenia is an etiologically and clinically heterogeneous disorder. Although neuroimaging studies have revealed brain alterations in schizophrenia, most studies have assumed that the disorder is a single entity, neglecting the diversity of alterations observed in the disorder. The current study sought to explore the distinct patterns of altered cortical thickness in patients with schizophrenia and healthy individuals using a data-driven approach. Unsupervised clustering using self-organizing maps followed by a K-means algorithm was applied to regional cortical thickness data in 108 schizophrenia patients and 121 healthy controls. After clustering, the clinical characteristics and cortical thickness patterns of each cluster were assessed. Unsupervised clustering revealed that a 6-cluster solution was the most appropriate in this sample. There was substantial overlap between the patterns of cortical thickness in schizophrenia patients and healthy controls, although the distributions of the patients and controls differed across the clusters. The patterns of altered cortical thickness in schizophrenia exhibited cluster-specific features; patients within a cluster exhibited the most extensive cortical thinning, particularly in the medial prefrontal and temporal regions, while those in other clusters exhibited reduced cortical thickness in the medial frontal region or temporal lobe. Furthermore, in the schizophrenia group, extensive cortical thinning was correlated with a higher dosage of antipsychotic medication, while preserved cortical thickness appeared to be linked to less negative symptoms. This data-driven neuroimaging approach revealed distinct patterns of cortical thinning in schizophrenia, possibly reflecting the etiological heterogeneity of the disorder.

Lateralization of intrinsic frontoparietal network connectivity and symptoms in schizophrenia.

It has been frequently reported that schizophrenia patients have reduced functional lateralization in the areas related to language processing. Furthermore, there is evidence supporting that schizophrenia patients have disrupted functional connectivity in the bilateral frontoparietal networks (FPNs), of which the left is strongly associated with a cognition-language paradigm, using resting-state functional magnetic resonance imaging (rsfMRI). To examine the laterality of resting-state functional connectivity in schizophrenia, we investigated the bilateral FPNs. We investigated 41 schizophrenia and 35 healthy participants using independent component analysis for rsfMRI. We extracted mean connectivity values of both left and right FPNs and calculated their laterality index by (left - right)/(left + right). Subsequently, we investigated group differences of these values and the correlation between these values and symptoms. In schizophrenia, mean connectivity values of both left and right FPNs were significantly lower than in healthy controls, whereas their laterality indices were not significantly different. However, correlation analyses revealed that the laterality index was negatively correlated with positive symptoms, and that mean connectivity of left FPN was negatively correlated with depressive symptoms in schizophrenia. Our results suggest that language-related networks and their laterality might be one of the neural correlates of schizophrenia symptoms.

Creativity and positive symptoms in schizophrenia revisited: Structural connectivity analysis with diffusion tensor imaging.

Both creativity and schizotypy are suggested to be manifestations of the hyperactivation of unusual or remote concepts/words. However, the results of studies on creativity in schizophrenia are diverse, possibly due to the multifaceted aspects of creativity and difficulties of differentiating adaptive creativity from pathological schizotypy/positive symptoms. To date, there have been no detailed studies comprehensively investigating creativity, positive symptoms including delusions, and their neural bases in schizophrenia. In this study, we investigated 43 schizophrenia and 36 healthy participants using diffusion tensor imaging. We used idea, design, and verbal (semantic and phonological) fluency tests as creativity scores and Peters Delusions Inventory as delusion scores. Subsequently, we investigated group differences in every psychological score, correlations between fluency and delusions, and relationships between these scores and white matter integrity using tract-based spatial statistics (TBSS). In schizophrenia, idea and verbal fluency were significantly lower in general, and delusion score was higher than in healthy controls, whereas there were no group differences in design fluency. We also found positive correlation between phonological fluency and delusions in schizophrenia. By correlation analyses using TBSS, we found that the anterior part of corpus callosum was the substantially overlapped area, negatively correlated with both phonological fluency and delusion severity. Our results suggest that the anterior interhemispheric dysconnectivity might be associated with executive dysfunction, and disinhibited automatic spreading activation in the semantic network was manifested as uncontrollable phonological fluency or delusions. This dysconnectivity could be one possible neural basis that differentiates pathological positive symptoms from adaptive creativity.