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The hierarchical characteristics of the brain are prominent in the pharmacological treatment of psychiatric diseases, primarily targeting cellular receptors that extend upward to intrinsic connectivity within a region, interregional connectivity, and, consequently, clinical observations such as an electroencephalogram (EEG). To understand the long-term effects of neuropharmacological intervention on neurobiological properties at different hierarchical levels, we explored long-term changes in neurobiological parameters of an N-methyl-D-aspartate canonical microcircuit model (CMM-NMDA) in the default mode network (DMN) and auditory hallucination network (AHN) using dynamic causal modeling of longitudinal EEG in clozapine-treated patients with schizophrenia. The neurobiological properties of the CMM-NMDA model associated with symptom improvement in schizophrenia were found across hierarchical levels, from a reduced membrane capacity of the deep pyramidal cell and intrinsic connectivity with the inhibitory population in DMN and intrinsic and extrinsic connectivity in AHN. The medication duration mainly affects the intrinsic connectivity and NMDA time constant in DMN. Virtual perturbation analysis specified the contribution of each parameter to the cross-spectral density (CSD) of the EEG, particularly intrinsic connectivity and membrane capacitances for CSD frequency shifts and progression. It further reveals that excitatory and inhibitory connectivity complements frequency-specific CSD changes, notably the alpha frequency band in DMN. Positive and negative synergistic interactions exist between neurobiological properties primarily within the same region in patients treated with clozapine. The current study shows how computational neuropharmacology helps explore the multiscale link between neurobiological properties and clinical observations and understand the long-term mechanism of neuropharmacological intervention reflected in clinical EEG., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Abstract: Accumulating evidence indicates that the autophagy process is involved in the pathogenesis of schizophrenia. Autophagy plays a fundamental role in neuronal survival and function, and autophagy-related genes have been suggested to be associated with the pathogenesis of schizophrenia. The Unc-51-like autophagy activating kinase 2 (ULK2) gene has been implicated in autophagy regulation; therefore, we hypothesized that ULK2 polymorphisms may be associated with schizophrenia susceptibility.This study explored the association between polymorphisms of ULK2 and schizophrenia.Two single nucleotide polymorphisms (SNPs) (rs55730189 and rs150122) of ULK2 were genotyped in 279 patients with schizophrenia and 403 healthy individuals using Fluidigm SNPtype assays. We analyzed the genotype distribution of 2 SNPs and haplotypes between patients with schizophrenia and control subjects.The T allele frequency of rs55730189 showed a significant association between patients with schizophrenia and control subjects (P = .003). Genotype frequencies of rs55710189 were found to be significantly different between patients with schizophrenia and control subjects (odds ratio = 6.89, 95% confidence interval = 1.91-24.90, P < .001 in the dominant model [C/T + T/T vs C/C], OR = 6.50, 95% confidence interval = 1.83-23.01, P < .001 in the log-additive model (C/T vs T/T vs C/C)]. In haplotype analysis, the TT haplotype for these 2 SNPs was significantly associated with schizophrenia (P < .001, χ2 = 12.231).Our findings suggest that specific ULK2 polymorphisms may be associated with susceptibility to schizophrenia in the Korean population., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Postmortem studies reveal that the brain pH in schizophrenia patients is lower than normal. The exact cause of this low pH is unclear, but increased lactate levels due to abnormal energy metabolism appear to be involved. Schizophrenia patients display distinct changes in mitochondria number, morphology, and function, and such changes promote anaerobic glycolysis, elevating lactate levels. pH can affect neuronal activity as H + binds to numerous proteins in the nervous system and alters the structure and function of the bound proteins. There is growing evidence of pH change associated with cognition, emotion, and psychotic behaviors. Brain has delicate pH regulatory mechanisms to maintain normal pH in neurons/glia and extracellular fluid, and a change in these mechanisms can affect, or be affected by, neuronal activities associated with schizophrenia. In this review, we discuss the current understanding of the cause and effect of decreased brain pH in schizophrenia based on postmortem human brains, animal models, and cellular studies. The topic includes the factors causing decreased brain pH in schizophrenia, mitochondria dysfunction leading to altered energy metabolism, and pH effects on the pathophysiology of schizophrenia. We also review the acid/base transporters regulating pH in the nervous system and discuss the potential contribution of the major transporters, sodium hydrogen exchangers (NHEs), and sodium-coupled bicarbonate transporters (NCBTs), to schizophrenia.

Previous studies have suggested the involvement of Nogo-A/RTN4 in the pathogenesis of schizophrenia. We investigated an association between the promoter haplotypes of RTN4 comprised of rs1348528-rs1822618-rs2241958 and schizophrenia. A significant association between the rare TGA haplotype and schizophrenia was shown (p < 0.0001). Additionally, the promoter activity was profoundly decreased by the TGA haplotype. These results suggested that the TGA haplotype of RTN4 may contribute to the susceptibility of schizophrenia., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: In the tradition of phenomenology, minimal selfdisturbance has been suggested as a manifestation of the core pathogenesis of schizophrenia; however, the underlying neural mechanism remains unclear. Here, in line with the concept of "cognitive dysmetria," we investigated the cerebro-cerebellar default mode network (DMN) connectivity and its association with pre-reflective minimal selfdisturbance in individuals at ultra-high risk (UHR) for psychosis and patients with first-episode schizophrenia (FES)., Methods: Thirty-three UHR individuals, 18 FES patients, and 56 healthy controls (HCs) underwent functional magnetic resonance imaging during rest at baseline. Seed-based functional connectivity (FC) analysis was performed using the cerebellar DMN seeds from the bilateral Crus I, followed by between-group comparisons. Correlation analysis was conducted to examine the relationship between the cerebro-cerebellar FC and the self-reported severity of minimal self-disturbance in the UHR and FES groups, respectively., Results: FES participants showed significantly reduced cerebellar FC with the left presupplementary motor area (preSMA), right anterior prefrontal cortex (aPFC), and precuneus compared to HCs, while UHR participants showed an intermediate decrease between the other two groups, particularly in the left preSMA and right aPFC. Minimal self-disturbance, which appeared at similar levels in both UHR and FES groups, was significantly associated with cerebro-cerebellar FC, although each group presented different patterns of associations., Conclusions: Aberrant cerebro-cerebellar FC, which may be closely related to minimal self-disturbance, may be able to provide meaningful insights into the real gestalt of schizophrenia and contribute to further research to predict future psychosis in UHR individuals., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: Patients with schizophrenia often have impaired cognition and abnormal conflict control. Conflict control is influenced by the emotional values of stimuli. This study investigated the neural basis of negative emotion interference with conflict control in schizophrenia., Methods: Seventeen patients with schizophrenia and 20 healthy controls underwent functional magnetic resonance imaging while performing the emotional Simon task, in which positive or negative emotional pictures were located in congruent or incongruent positions. Analysis was focused on identifying brain regions with the significant interaction among group, emotion, and conflict in whole brain voxel-wise analysis, and abnormality in their functional connectivity in the patient group., Results: The regions showing the targeted interaction was the right amygdala, which exhibited significantly reduced activity in the negative congruent (t = -2.168, p = 0.036) and negative incongruent (t = -3.273, p = 0.002) conditions in patients versus controls. The right amygdala also showed significantly lower connectivity with the right dorsolateral prefrontal cortex in the cognitive and emotional loading contrast (negative incongruent-positive congruent) in patients versus controls (t = -5.154, p < 0.01), but not in the cognitive-only or emotional-only loading contrast., Conclusions: These results suggest that negative emotion interferes with cognitive conflict resolution in patients with schizophrenia due to amygdala-dorsolateral prefrontal cortex disconnection. Based on these findings, interventions targeting conflict control under negative emotional influence may promote cognitive rehabilitation in patients with schizophrenia., (© 2018 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

Background: Immunological alterations and dysregulation of the inflammatory response have been suggested to play a crucial role in schizophrenia pathophysiology. Growing evidence supports the involvement of chemokines in brain development, thus many chemokines have been studied in relation with schizophrenia. The C-C motif chemokine ligand 11 (CCL11) has been shown to be related with synaptic plasticity and neurogenesis. Moreover, altered levels of CCL11 have been observed in schizophrenia patients. Therefore, we examined whether single nucleotide polymorphisms (SNPs) of the CCL11 in the promoter region contribute to susceptibility to schizophrenia., Methods: Four promoter SNPs [rs17809012 (-384T>C), rs16969415 (-426C>T), rs17735961 (-488C>A), and rs4795896 (576G>A)] were genotyped in 254 schizophrenia patients and 405 control subjects using Fluidigm SNPtype assays., Results: The genotype frequency of CCL11 rs4795896 (-576G>A) showed significant association with schizophrenia in a recessive model (AA vs. GG/AG, p < 0.0001) and in a log-additive model (AG vs. AA vs. GG, p < 0.0001). The allele frequency of rs4795896 also showed a significant association with schizophrenia (p < 0.0001). Furthermore, haplotype analysis revealed that GCT, ACT, and GCC haplotypes containing rs4795896, rs17735961 and rs17809012 were significantly associated with schizophrenia (p = 0.0044, p < 0.0001, and p < 0.0001, respectively)., Conclusion: Our results suggest that CCL11 promotor polymorphism is associated with increased risk for the development of schizophrenia in a Korean population., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Prenatal exposure to infectious or inflammatory insults can increase the risk of developing neuropsychiatric disorders such as bipolar disorder, autism, and schizophrenia in later life. Gamma-butyrobetaine hydroxylase (BBOX 1) is an enzyme responsible for the biosynthesis of l-carnitine, a key molecule in fatty acid metabolism. This cytosolic dimeric protein belongs to the dioxygenase family. In this study, we investigated whether BBOX 1 expression was related to psychiatric disorder in an animal model. We also conducted a case-control study using 284 schizophrenia patients and 409 controls with single-nucleotide polymorphisms (SNPs) in the 5'-near region of BBOX 1. BBOX 1 expression was increased in the medial frontal cortex of a mouse model of schizophrenia induced by maternal immune activation. Furthermore, the genotype and allele frequencies of two SNPs (rs7939644 and rs10767592) were significantly associated with schizophrenia susceptibility. Our results suggest that BBOX 1 might be associated with maternal immune activation and schizophrenia susceptibility. Therefore, it might be involved in the pathophysiology of schizophrenia., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Introduction: Patients with schizophrenia exhibit several cognitive deficits, including memory impairment. Problems with recognition memory can hinder socially adaptive behavior. Previous investigations have suggested that altered activation of the frontotemporal area plays an important role in recognition memory impairment. However, the cerebral networks related to these deficits are not known. The aim of this study was to elucidate the brain networks required for recognizing socially relevant information in patients with schizophrenia performing an old-new recognition task., Methods: Sixteen patients with schizophrenia and 16 controls participated in this study. First, the subjects performed the theme-identification task during functional magnetic resonance imaging. In this task, pictures depicting social situations were presented with three words, and the subjects were asked to select the best theme word for each picture. The subjects then performed an old-new recognition task in which they were asked to discriminate whether the presented words were old or new. Task performance and neural responses in the old-new recognition task were compared between the subject groups. An independent component analysis of the functional connectivity was performed., Results: The patients with schizophrenia exhibited decreased discriminability and increased activation of the right superior temporal gyrus compared with the controls during correct responses. Furthermore, aberrant network activities were found in the frontopolar and language comprehension networks in the patients., Conclusions: The functional connectivity analysis showed aberrant connectivity in the frontopolar and language comprehension networks in the patients with schizophrenia, and these aberrations possibly contribute to their low recognition performance and social dysfunction. These results suggest that the frontopolar and language comprehension networks are potential therapeutic targets in patients with schizophrenia.

Abnormal abstract thinking is a major cause of social dysfunction in patients with schizophrenia, but little is known about its neural basis. In this study, we aimed to determine the characteristic abstract thinking-related brain responses in patients using a task reflecting social situations. We conducted functional magnetic resonance imaging while 16 patients with schizophrenia and 16 healthy controls performed a theme-identification task, in which various emotional pictures depicting social situations were presented. Compared with healthy controls, the patients showed significantly decreased activity in the left frontopolar and right orbitofrontal cortices during theme identification. Activity in these two regions correlated well in the controls, but not in patients. Instead, the patients exhibited a close correlation between activity in both sides of the frontopolar cortex, and a positive correlation between the right orbitofrontal cortex activity and degrees of theme identification. Reduced activity in the left frontopolar and right orbitofrontal cortices and the underlying aberrant connectivity may be implicated in the patients' deficits in abstract thinking. These newly identified features of the neural basis of abnormal abstract thinking are important as they have implications for the impaired social behavior of patients with schizophrenia during real-life situations., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

The association between polymorphisms of glutathione-related enzyme (GST) genes and the risk of schizophrenia has been investigated in many published studies. However, their results were inconclusive. Therefore, we performed a meta-analysis to explore the association between the GSTM1, GSTT1, and GSTP1 polymorphisms and the risk of schizophrenia. Twelve case-control studies were included in this meta-analysis. The odds ratio (OR) and 95% confidence interval (95% CI) were used to investigate the strength of the association. Our meta-analysis results revealed that GSTM1, GSTT1, and GSTP1 polymorphisms were not related to risk of schizophrenia (p > 0.05 in each model). Further analyses based on ethnicity, GSTM polymorphism showed weak association with schizophrenia in East Asian population (OR = 1.314, 95% CI = 1.025-1.684, p = 0.031). In conclusion, our meta-analysis indicated the GSTM1 polymorphism may be the only genetic risk factor for schizophrenia in East Asian population. However, more meta-analysis with a larger sample size were needed to provide more precise evidence.

Amotivation in schizophrenia is assumed to involve dysfunctional dopaminergic signaling of reward prediction or anticipation. It is unclear, however, whether the translation of neural representation of reward value to behavioral drive is affected in schizophrenia. In order to examine how abnormal neural processing of response valuation and initiation affects incentive motivation in schizophrenia, we conducted functional MRI using a deterministic reinforcement learning task with variable intervals of contingency reversals in 20 clinically stable patients with schizophrenia and 20 healthy controls. Behaviorally, the advantage of positive over negative reinforcer in reinforcement-related responsiveness was not observed in patients. Patients showed altered response valuation and initiation-related striatal activity and deficient rostro-ventral anterior cingulate cortex activation during reward approach initiation. Among these neural abnormalities, rostro-ventral anterior cingulate cortex activation was correlated with positive reinforcement-related responsiveness in controls and social anhedonia and social amotivation subdomain scores in patients. Our findings indicate that the central role of the anterior cingulate cortex is in translating action value into driving force of action, and underscore the role of the cingulo-striatal network in amotivation in schizophrenia., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The development of diffusion tensor imaging (DTI) has provided information about microstructural changes in the brain. Most DTI studies have focused on white matter (WM). Few DTI studies have examined the gray matter (GM) in schizophrenia and, to date, there has been no attempt to identify the relationship between water diffusivity and symptom severity in schizophrenia. The present study aimed to examine microstructural deficits in the dorsal prefrontal cortex (DPFC) and temporal cortex in schizophrenia patients using fractional anisotropy (FA) and water diffusivity. This study also explored the relationship between DTI measurements and psychotic symptoms. Magnetic resonance imaging (MRI) and DTI were used to study 19 schizophrenia patients and 19 healthy controls. Fractional anisotropy, axial diffusivity, radial diffusivity, and regional volumes were measured in the prefrontal cortex and temporal cortex. On DTI measurements, patients showed increased axial and radial diffusivities in the prefrontal cortex and temporal cortex, but they did not demonstrate any difference in fractional anisotropy and regional volumes. Additionally, axial and radial diffusivities were significantly correlated with positive symptom scores in all regions of interest. These results indicate that water diffusivity measurements, including axial and radial diffusivities, can be used to identify microstructural changes in the gray matter in schizophrenia that may be related to symptom severity., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Altered transmission of gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter, may contribute to the development of schizophrenia. The purpose of the present study was to investigate the presence of GABA-A/benzodiazepine (BZ) receptor binding abnormalities in individuals at ultra-high risk (UHR) for psychosis in comparison with normal controls using [(18)F]-fluoroflumazenil (FFMZ) positron emission tomography (PET). In particular, we set regions of interest in the striatum (caudate, putamen, and nucleus accumbens) and medial temporal area (hippocampus and parahippocampal gyrus)., Methods: Eleven BZ-naive people at UHR and 15 normal controls underwent PET scanning using [(18)F]-FFMZ to measure GABA-A/BZ receptor binding potential. The regional group differences between UHR individuals and normal controls were analyzed using Statistical Parametric Mapping 8 software. Participants were evaluated using the structured interview for prodromal syndromes and neurocognitive function tasks., Results: People at UHR demonstrated significantly reduced binding potential of GABA-A/BZ receptors in the right caudate., Conclusions: Altered GABAergic transmission and/or the imbalance of inhibitory and excitatory systems in the striatum may be present at the putative prodromal stage and play a pivotal role in the pathophysiology of psychosis.

Monoamine oxidase A (MAOA) catalyzes monoamine neurotransmitters including dopamine, 5-hydroxytryptamine (5-HT, serotonin), and norepinephrine. MAOA also plays a key role in emotional regulation. The aim of this study was to investigate the associations between the exonic single nucleotide polymorphisms (SNPs) of the MAOA gene located on the X chromosome and schizophrenia. We also analyzed the relationships between these SNPs and the common clinical symptoms of schizophrenia such as persecutory delusion, auditory hallucinations, affective disturbances, and poor concentration. Two hundred seventy five Korean schizophrenia patients and 289 control subjects were recruited. Three SNPs [rs6323 (Arg294Arg), rs1137070 (Asp470Asp), and rs3027407 (3'-untranslated region)] of the MAOA gene were selected and genotyped by direct sequencing. The common clinical symptoms of schizophrenia according to the Operation Criteria Checklist were analyzed. Three examined SNPs showed no associations with male and female schizophrenia, respectively (p>0.05). In the analysis of the common clinical symptoms of schizophrenia patients, three examined SNPs were associated with affective disturbances, especially restricted affect and blunted affect in male schizophrenia, respectively (restricted affect, p=0.002, OR=2.71, 95% CI 1.45-5.00; blunted affect, p=0.009, OR 2.25, 95% CI 1.22-4.12). The SNPs were not associated with other clinical symptoms of schizophrenia (persecutory delusion, auditory hallucinations, and poor concentration). These results suggest that exonic SNPs (rs6323, rs1137070, and rs3027407) of the MAOA gene may be contributed to affective disturbances of Korean males schizophrenia, especially restricted affect and blunted affect.

Aberrant emotional salience attribution has been reported to be an important clinical feature in patients with schizophrenia. Real life stimuli that incorporate both positive and negative emotional traits lead to affective asymmetry such as negativity bias and positivity offset. In this study, we investigated the neural correlates of emotional salience attribution in patients with schizophrenia when affective asymmetry was processed. Fifteen patients with schizophrenia and 14 healthy controls were scanned using functional magnetic resonance imaging (fMRI) while performing an emotion judgment task in which two pictures were juxtaposed. The task consisted of responding to affective asymmetry condition (ambivalent and neutral) and affective symmetry conditions (positive and negative), and group comparisons were performed for each condition. Significantly higher activity in the medial prefrontal cortex and inferior frontal gyrus was observed for the ambivalent condition than for the other conditions in controls, but not in patients. Compared with controls, patients showed decreased activities in the dorsolateral prefrontal cortex, dorsal anterior cingulate cortex, insula, and putamen for the ambivalent condition, but no changes were observed for the neutral condition. Multiple prefrontal hypoactivities during salience attribution of negativity bias in schizophrenia may underlie deficits in the integrative processing of emotional information. Regional abnormalities in the salience network may be the basis of defective emotional salience attribution in schizophrenia, which is likely involved in symptom formation and social dysfunction.

Blunted affect is a relatively enduring schizophrenic symptom and its presence brings about poor functioning and outcomes. Functional impairment in the mirror neuron system which is involved in both motor execution and imitation may be a neural basis of blunted affect, but it is not proved yet. Fifteen patients with schizophrenia and 16 healthy controls performed the facial expression task during functional magnetic resonance imaging. The task was to reproduce facial expressions in response to the face or word stimuli for happiness, sadness, and meaningless expression. Brain activities during facial expressions in patients compared with controls and their relationship with affective flattening were analyzed. Compared to controls, patients exhibited decreased activity in the widespread dorsal frontal regions and increased activity in the ventral frontal and subcortical regions. Patients also demonstrated significant negative correlation of the severity of affective flattening with activities in the mirror neuron system, such as the premotor cortex, motor cortex, and inferior parietal lobule. Emotional expression in patients with schizophrenia may be related to hypoactivity of the dorsal system and hyperactivity of the ventral system. An imbalance of these two systems may contribute to blunted affect. Directly addressing blunted affect using emotional expression provides a new perspective that functional disturbance of the mirror neuron system may play an important role in manifestation of blunted affect in schizophrenia., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Immunological dysregulation has been suggested to be involved in the pathogenesis of schizophrenia. Accumulating evidences further implicate that activated inflammatory processes may be particularly relevant for the precipitation of negative and cognitive symptoms of schizophrenia. Toll-like receptor 2 (TLR2) plays an important role in innate immunity by sensing a variety of pathogens and inducing an acquired immunity. In the present study, we investigated whether the coding region of single nucleotide polymorphisms (SNPs) of the TLR2 gene was associated with schizophrenia as well as with clinical symptoms in schizophrenia patients. The study population consisted of 286 Korean schizophrenia patients and 305 Korean control subjects. The assessment of the Scale for the Assessment of Negative Symptoms was used to evaluate the negative symptoms of schizophrenia; the operational criteria checklist was used to measure general psychopathology. We selected two cSNPs [rs3804099 (Asn199Asn) and rs3804100 (Ser450Ser)] considering their heterozygosity and minor allele frequency. SNP genotyping was conducted using direct sequencing. We did not find any significant associations between SNPs and schizophrenia in the genotype and allelic frequencies. On the other hand, in the analysis of cognitive symptoms, rs3804099 showed significant differences in schizophrenia patients with poor concentration in the dominant model (TC/CC vs. TT, p=0.0099). Also, rs3804100 showed a significant association with poor concentration in the co-dominant (TC vs. TT, p=0.014) and the dominant models (TC/CC vs. TT, p=0.0035). We obtained no significant support for the association of the TLR2 gene with susceptibility to schizophrenia in the Korean population. However, our results provide possibility that C allele of rs3804099 and rs3804100 may be associated with poor concentration in schizophrenia patients. Further studies with larger samples are required to confirm our results., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Having a relationship with one's parents is a fundamental social interaction and is a significant environmental factor in the long-term course of illness in schizophrenia. We explored subjective reports regarding the communicative relationship with parents and the implicit behavioral and neural responses of patients toward stimuli that referred to parents. Fourteen outpatients with schizophrenia and 15 healthy volunteers with living parents were scanned using a functional magnetic resonance imaging while performing an imaginary sentence completion test that involved contemplation of their mothers and fathers. In patients with schizophrenia, subjective reports of better communicative fluency with one's mother were associated with faster response time and lower incomplete rate, reflecting favorable responses toward mothers. Relative to control participants, patients with schizophrenia demonstrated greater neural activation in the superior temporal sulcus and the parahippocampal gyrus for parental stimuli. When patients with schizophrenia contemplated their mothers, activities in these regions were associated with a level of negative symptoms or affective ambivalence in patients. The results indicated that parental cues are processed in a more socially driven manner, and that perceived communicative relationships with one's parents can be used to estimate implicit responses, especially in relation to mothers in patients with schizophrenia. Furthermore, the findings of the current study suggest that affective ambivalence toward one's mother is one such implicit response and emphasize the importance of prudent family interventions in the psychiatric rehabilitation of patients with schizophrenia.

Tissue inhibitors of metalloproteinases (TIMPs) are involved in synaptic plasticity, neuronal cell differentiation and neuroprotection in the central nervous system. To investigate whether TIMP4 polymorphisms are associated with schizophrenia and autism spectrum disorders (ASDs), 480 patients (schizophrenia, n=287; ASDs, n=193) and 296 controls were enrolled. Clinical symptoms of schizophrenia and ASDs were assessed using the operation criteria checklist for psychotic illness (OPCRIT) and Childhood Autism Rating Scale (CARS), respectively. One promoter single nucleotide polymorphism (SNP; rs3755724, -55C/T) and one exonic SNP (rs17035945, 3'-untranslated region) were selected. SNPStats and SNPAnalyzer Pro programs were used to calculate odds ratios. Multiple logistic regression models were performed to analyze the genetic data. Based on the results, these two SNPs were not associated with schizophrenia and ASD. In the analysis of clinical features of schizophrenia, rs3755724 was nominally associated with schizophrenia with poor concentration (P=0.044 in the codominant2 model, P=0.041 in the log-additive model and P=0.043 in allele frequency). These results suggest that TIMP4 is not associated with the development of schizophrenia and ASD in the population studied.

The α-amino-3-hydroxy-5-methyl-4-propionic acid (AMPA) receptors are important for glutamate synaptic transmission in the central nervous system. Glutamate receptor, ionotropic, AMPA receptor 1 gene (GRIA1) belongs to the family of AMPA receptors. There is increasing evidence that AMPA receptors dysfunction may be related to an increased susceptibility to schizophrenia. The aim of this study was therefore to investigate whether genetic polymorphisms of GRIA1 are associated with schizophrenia and their clinical symptoms (hallucinations and delusions) in Korean population. Five single nucleotide polymorphisms (rs1428920, rs1552834, rs1422889, rs10035143, and rs2926835) of the GRIA1 were genotyped in 218 schizophrenia patients and 380 healthy controls, using a direct sequencing. All patients were evaluated by the Operational Criteria Checklist for Psychotic Illness. The genotype and allelic frequencies of rs1428920 and rs2926835 showed significant association between schizophrenia and controls (rs1428920, permutation p = 0.008, 0.008; rs2926835, permutation p = 0.038, 0.041, respectively). A significantly increased risk of schizophrenia was associated with the A allele of rs1428920 and rs2926835 of GRIA1. Furthermore, we found that rs1428920 was weakly associated with hallucinations of schizophrenia, but this significance disappeared after multiple testing (permutation p = 0.119). These results suggest that GRIA1 polymorphism may have influence upon the risk of developing schizophrenia.

Aim: Attention deficit has been reported in both schizophrenia patients and patients with major depressive disorder (MDD). The aim of this study was to elucidate the deficits in sustained attention and associated neural network dysfunctions in schizophrenia patients and MDD patients, and to investigate the difference between the two patient groups., Methods: Twelve schizophrenia patients, 12 patients with non-psychotic MDD, and 12 healthy control subjects participated in this study. A sustained attention to response task (SART) was used to measure attention capacity. Cerebral blood flow (CBF) during attention tasks was measured using H(2) (15) O positron emission tomography. Statistical parametric mapping and analysis of covariance were performed to compare the behavioral performance and CBF changes during SART among three groups., Results: Behavioral performances were not significantly different among the three groups except for an increased commission error rate in the schizophrenia group. Regional CBF during SART was significantly reduced in the left inferior frontal gyrus, the left cuneus, and the right superior parietal lobule and increased in the right superior frontal gyrus and the right cuneus in the schizophrenia group compared to the healthy control group. In the MDD group, neither significant regional CBF difference nor behavioral deficit was found compared to the healthy control group., Conclusion: Behavioral performance deficit and perfusion changes in the prefrontal and parietal cortices during SART were observed only in the schizophrenia group. Prefrontal and parietal network dysfunction for sustained attention may be involved in the pathophysiology of schizophrenia., (© 2012 The Authors. Psychiatry and Clinical Neurosciences © 2012 Japanese Society of Psychiatry and Neurology.)

Objective: The aim of this study was to investigate the association between the exonic single nucleotide polymorphisms (SNPs) of synapsin I (SYN1) (rs1142636, Asn170Asn, Xp11.23) and SYN2 (rs2289708, 3'-untranslated region, 3p25) in schizopherenia., Methods: Two hundred eighty six schizophrenia patients and 304 control subjects were recruited. SNPs with a know heterozygosity and minor allele frequency (MAF) > 0.1 in Asian populations were selected and genotyped by direct sequencing., Results: The allelic frequencies of rs1142636 (SYN1) were associated with schizophrenia (P < 0.05), respectively. The allelic frequency of rs1142636 in all subjects was associated with schizophrenia [P = 0.000059, OR = 2.17 (95% CI = 1.47-3.18)]. The C allele frequency of rs1142636 was higher in schizophrenia (20.8%) than that in controls (10.8%). In the analysis of gender, the allelic frequency of rs1142636 was also strongly associated with female schizophrenia [P = 0.0001, OR = 2.65 (95% CI = 1.61-4.36)], but not with male schizophrenia. The C allele frequency of rs1142636 was higher in female schizophrenia (22.2%) than that in female controls (9.7%). The rs2289708 SNP (SYN2) did not show any association between schizophrenia and controls., Conclusions: These results suggest that the C allele of a synonymous SNP (rs1142636, Asn170Asn, Xp11.23) in SYN1 may be a risk factor for the susceptibility of Koreran female schizophrenia., (Copyright © 2012 Wiley Periodicals, Inc.)

Emotional memory dysfunction may be associated with anhedonia in schizophrenia. This study aimed to investigate the neurobiological basis of emotional memory and its relationship with anhedonia in schizophrenia specifically in emotional memory relate brain regions of interest (ROIs) including the amygdala, hippocampus, nucleus accumbens, and ventromedial prefrontal cortex. Fourteen patients with schizophrenia and 16 healthy subjects performed a word-image associative encoding task, during which a neutral word was presented with a positive, neutral, or control image. Subjects underwent functional magnetic resonance imaging while performing the recognition task. Correlation analyses were performed between the percent signal change (PSC) in the ROIs and the anhedonia scores. We found no group differences in recognition accuracy and reaction time. The PSC of the hippocampus in the positive and neutral conditions, and the PSC in the nucleus accumbens in the control condition, appeared to be negatively correlated with the Physical Anhedonia Scale (PAS) scores in patients with schizophrenia, while significant correlations with the PAS scores were not observed in healthy subjects. This study provides further evidences of the role of the hippocampus and nucleus accumbens in trait physical anhedonia and possible associations between emotional memory deficit and trait physical anhedonia in patients with schizophrenia., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Thrombospondin 1 (THBS1), a multi-domain glycoprotein, is secreted from astrocytes and promotes synaptogenesis. Increasing evidence has suggested that not only various markers for synaptic pathology, but also astrocytes are affected in schizophrenia. In this study, we investigated whether coding region single nucleotide polymorphisms (cSNPs) of the THBS1 gene were associated with schizophrenia and with the clinical symptoms of schizophrenia patients. We genotyped two cSNPs [rs2228261 (Asn470Asn) and rs2292305 (Thr523Ala)] using direct sequencing in 220 schizophrenia patients and 376 control subjects. In this study, rs2228261 revealed significant association with schizophrenia in both codominant (TT vs. CC, P = 0.009, OR = 2.10, 95% CI = 1.23-3.59) and recessive models (TT vs. CC/CT, P = 0.0012, OR = 2.28, 95% CI = 1.38-3.77). Also, rs2292305 was associated with schizophrenia in the recessive model (GG vs. AA/AG, P = 0.0052, OR = 2.05, 95% CI = 1.24-3.38). Additionally, in the analysis of the haplotype, the CA and TG haplotypes consisting of rs2228261 and rs2292305 were associated with schizophrenia in the dominant (P = 0.019, OR = 1.79, 95% CI = 1.10-2.90) and recessive models, respectively (P = 0.0086, OR = 0.51, 95% CI = 0.31-0.84). In further analysis according to the clinical symptoms, rs2292305 showed a weak association with the poor concentration symptoms of schizophrenia patients in the dominant model (AG/GG vs. AA, P = 0.024, OR = 2.04, 95% CI = 1.09-3.83). The results suggest that the THBS1 gene may contribute to the susceptibility of schizophrenia.

Schizophrenia has been associated with an imbalance in inflammatory cytokines. Leukemia inhibitory factor receptor α (LIFR) is an integral component of the glycoprotein 130-LIFR signaling complex, which participates in signal transduction by members of the interleukin (IL)-6 cytokine family. The aim of this study was to investigate whether genetic polymorphisms of the LIFR gene are associated with schizophrenia in the Korean population. We also explored possible associations between the polymorphisms and the clinical symptoms of schizophrenia. We selected three single nucleotide polymorphisms (SNPs) (rs2071237 -200C/G, rs2071236 -254C/T and rs6862038 -962A/G) on the promoter region of the LIFR gene and recruited 204 schizophrenia patients and 367 control subjects from the Korean population. All patients were evaluated according to the Operational Criteria Checklist for Psychotic Illness. SNP genotyping was performed by direct sequencing. An analysis of multiple logistic regression models (co-dominant 1, co-dominant 2, dominant, recessive and overdominant) was performed to evaluate odds ratios (ORs), 95% confidence intervals (CIs) and p-values. No significant difference was revealed between schizophrenia patients and controls. However, a significant association was detected between the LIFR gene polymorphisms and schizophrenia patients with persecutory delusion (rs2071236, OR=2.18, 95% CI=1.20-3.94, P=0.009 in the overdominant model; rs6862038, OR=2.08, 95% CI=1.16-3.74, P=0.013 in the overdominant model). The present study suggests that the LIFR gene may be related to schizophrenia with persecutory delusion in the Korean population.

We investigated the association of single nucleotide polymorphisms of solute carrier family 6 member 11 (SLC6A11) (rs2304725, rs2272400, and rs2245532), SLC6A12 (rs216250 and rs557881) and SLC6A13 (rs2289954) with schizophrenia and its clinical symptoms. We found that rs216250 of SLC6A12 was correlated with the Scale for the Assessment of Negative Symptoms (SANS) scores., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Schizophrenia patients commonly have sleep disturbances. In this study, we investigated whether single nucleotide polymorphisms (SNPs) in the promoter region of the melatonin receptor genes (MTNR1A and MTNR1B) were associated with schizophrenia and with sleep problems such as insomnia and hypersomnia in schizophrenia patients. We genotyped two promoter SNPs [rs2119882 (-184T/C) of MTNR1A and rs4753426 (-1193C/T) of MTNR1B] using direct sequencing in 289 schizophrenia patients and 505 control subjects. We found that rs2119882 of MTNR1A was associated with schizophrenia in recessive model [CC vs. TT/TC, p = 0.013, odds ratio (OR) = 1.69, 95% confidence interval (CI) = 1.12-2.55]. Interestingly, in an analysis of clinical phenotypes, we found that rs2119882 of MTNR1A was also associated with insomnia symptoms of schizophrenia (recessive model, p = 0.010, OR = 2.24, 95% CI = 1.21-4.14), but not with hypersomnia symptoms as determined using the Operational Criteria checklist. However, rs4753426 of MTNR1B was not associated with either schizophrenia or clinical phenotypes. Our results suggest that MTNR1A may be a susceptibility gene for schizophrenia and may be associated with insomnia symptoms exhibited in schizophrenia patients.

The aim of this study was to characterize the association between trait anhedonia and regional gray matter volume in patients with schizophrenia. Forty-six patients with schizophrenia and 56 healthy controls underwent magnetic resonance imaging (MRI) to acquire high-resolution T1-weighted images. Trait anhedonia was measured using the Chapman Revised Physical Anhedonia Scale (PAS). Voxel-based morphometry was performed to investigate brain volume correlates of trait anhedonia. Several brain regions in the patient group, including the left precuneus and right posterior cingulate (PCC), were found to show significantly less correlation with PAS scores than those of the control group. Post-hoc analysis revealed that negative correlations between the regional gray matter volume and the PAS scores in the patient group were found at a trend level in the left precuneus and the right PCC. In conclusion, these findings suggest that trait anhedonia in patients with schizophrenia could possibly be associated with a volume deficit in brain regions related to default-mode, which reflects the impairment of self-referential processing and reward anticipation., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Decision making in an emotionally conflicting situation is important in social life. We aimed to address the similarity and disparity of neural correlates involved in processing ambivalent stimuli in patients with schizophrenia and patients with depression. Behavioral task-related hemodynamic responses were measured using [15O]H2O positron emission tomography (PET) in 12 patients with schizophrenia and 12 patients with depression. The task was a modified word-stem completion task, which was designed to evoke ambivalence in forced and non-forced choice conditions. The prefrontal cortex and the cerebellum were found to show increased activity in the healthy control group. In the schizophrenia group, activity in these two regions was negligible. In the depression group, the pattern of activity was altered and a functional compensatory recruitment of the inferior parietal regions was suggested. The prefrontal cortex seems to be associated with the cognitive control to resolve the conflict toward the ambivalent stimuli, whereas the cerebellum reflects the sustained working memory to search for compromise alternatives. The deficit of cerebellar activation in the schizophrenia group might underlie the inability to search and consider compromising responses for conflict resolution.

Anhedonia, as a deficit symptom, may be associated with default-mode hypofrontality in schizophrenia. To explore whether trait anhedonia in schizophrenia pertains to altered hypofrontal resting state brain function, resting state metabolic activities were compared and correlated with the Physical and Social Anhedonia Scale scores in 29 patients with schizophrenia and 21 healthy controls using (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET). In patients with schizophrenia, Physical Anhedonia Scale scores showed a trend-level negative correlation with the hypoactive dorsomedial prefrontal metabolism while Positive and Negative Symptom Scale (PANSS) negative subscale scores positively correlated with hyperactive cerebellar metabolism. Voxelwise correlation analysis showed physical anhedonia correlates in resting state activities of the supplementary motor area, ventromedial and dorsolateral prefrontal cortex, insular gyrus, and the precuneus in patients with schizophrenia while no frontal metabolic correlates were found in healthy controls. The hypoactive dorsomedial prefrontal metabolism correlated with physical anhedonia-correlated resting state regional activities. These findings provide further evidence for the relation of functional hypofrontality to the deficit syndrome and possible involvement of the functional imbalance in the cortico-cerebellar-thalamic-cortical circuit in the resting state brain function of schizophrenia.

Objective: Few neuroimaging studies have been conducted regarding clinical associations between auditory hallucinations (AHs) and affective disturbances in patients with schizophrenia. This study aimed to elucidate the neurobiological basis of emotional disturbances in schizophrenic patients with persisting AHs., Methods: Using functional magnetic resonance imaging (fMRI), the cortical responsiveness during the processing of laughing and crying sounds was measured and compared between 14 hallucinating schizophrenic patients, 14 nonhallucinating schizophrenic patients and 28 normal controls., Results: The hallucinating patients showed differential neural activities in various areas including the amygdala, the hippocampus, the cingulate, the prefrontal cortex, and the parietal cortex, compared with the nonhallucinating patients and the normal controls. In particular, compared with the nonhallucinators, the hallucinators revealed reduced activation in the left amygdala and the bilateral hippocampus during the processing of crying sounds., Conclusion: Our findings suggest that the persistence of AHs in schizophrenia may induce functional disturbances of the emotion-related interconnected neural networks, including reduced responsiveness in the amygdala and hippocampus to negative stimuli.

We examined whether deficient prefrontal control over the semantic network exists in patients with schizophrenia. Fourteen patients with schizophrenia and 14 healthy controls performed a comparison task, judging semantic congruity according to an abstract category in an event-related functional MRI paradigm. In the control group, prefrontal-temporal networks consisting of the left inferior frontal gyrus and right inferior frontal sulcus converging at the left posterior superior temporal sulcus were identified as activated during semantic demand of incongruence. In the patients with schizophrenia, we observed a loss of the recruitment of the right inferior frontal sulcus and the prefrontal-temporal network. These findings indicate that cognitive modulation of semantic processing may be dysfunctional in patients with schizophrenia.

Patients with schizophrenia have impairment in cognitive-emotional interaction that is reflected in delusion formation and poor social functioning. Although monitoring deficits in the anterior cingulate have been observed in schizophrenia, the involvement of the affective division of the anterior cingulate implicated in cognitive modulation of emotional processing has not been directly addressed in schizophrenia. In this study, we examined the function of the affective division of the anterior cingulate and the related neural systems by using a modified emotional Stroop fMRI paradigm. Fourteen patients with schizophrenia and fourteen healthy controls performed an emotional appraisal task with semantically relevant emotional interferences during fMRI scanning. The patients with schizophrenia were significantly less efficient than the healthy controls during the emotional incongruence trials. When emotionally incongruent trials were compared to congruent trials, relative deactivations of the subgenual cingulate gyrus and the ventromedial prefrontal cortex observed in the healthy controls were not found in the patient group and activities of these regions inversely correlated with emotional interference to performance efficiency and response accuracy respectively in the patient group. In addition, relative activation in the dorsolateral prefrontal cortex was observed only in the patient group. These findings suggest that deficit in cognitive modulation over emotional interference in patients with schizophrenia may be explained by failure in suppressing the affective division of the anterior cingulate despite attentional effort. This may provide evidence for the failure in suppressing the bottom-up processing of emotion during cognitive-emotional interaction in schizophrenia.

Diffusion properties of the thalamocortical pathways were compared between 30 schizophrenic patients and 22 healthy age-matched and sex-matched volunteers. T1-weighted and diffusion tensor images were used for cortical parcellation and probabilistic tractography to generate population-based thalamocortical pathway maps. The weighted fractional anisotropy and the longitudinal and transversal diffusivity of each pathway were calculated for individual participants. Patients with schizophrenia demonstrated decreased anisotropy and increased longitudinal and transversal diffusivity within the pathways from the mediodorsal nucleus and the pulvinar to the orbitofrontal and parietal-occipital-temporal lobes. Anisotropy decreases and diffusivity increases were correlated with positive and negative syndrome scale scores. Alterations in global diffusion properties within the thalamocortical pathways imply the disruption of brain circuitry in schizophrenic patients.

To further clarify schizophrenia (SCZ), disrupted in schizophrenia 1 (DISC1) is a promising candidate gene expressed predominantly within the hippocampus. Several lines of evidence suggest that DISC1 may be involved in susceptibility to SCZ. In this study, we investigated whether genetic polymorphisms in the coding region of DISC1 were associated with several SCZ clinical phenotypes in a Korean population. To examine any association between DISC1 and SCZ, we genotyped three clinical single nucleotide polymorphisms (SNPs) (rs3738401, R264Q; rs3738402, L465L; rs821616, S704C) in the coding region of the DISC1 gene using the Illumina Sentrix Array Matrix chip and direct sequencing in 303 patients with SCZ and 300 healthy controls. Our case-control analysis showed that none of these SNPs was associated with SCZ. In further endophenotype stratification, however, we found a significant association between rs821616 and the poor concentration subgroup of SCZ, determined using the Operational Criteria Checklist (codominant model, p=0.015). Our results suggest that DISC1 may be a susceptibility gene for poor concentration among Korean patients with SCZ.

Objective: The thalamus, which consists of multiple subnuclei, has been of particular interest in the study of schizophrenia. This study aimed to identify abnormalities in the connectivity-based subregions of the thalamus in patients with schizophrenia., Methods: Thalamic volume was measured by a manual tracing on superimposed images of T1-weighted and diffusion tensor images in 30 patients with schizophrenia and 22 normal volunteers. Cortical regional volumes automatically measured by a surface-based approach and thalamic subregional volumes measured by a connectivity-based technique were compared between the two groups and their correlations between the connected regions were calculated in each group., Results: Volume reduction was observed in the bilateral orbitofrontal cortices and the left cingulate gyrus on the cortical side, whereas in subregions connected to the right orbitofrontal cortex and bilateral parietal cortices on the thalamic side. Significant volumetric correlations were identified between the right dorsal prefrontal cortex and its related thalamic subregion and between the left parietal cortex and its related thalamic subregion only in the normal group., Conclusions: Our results suggest that patients with schizophrenia have a structural deficit in the corticothalamic systems, especially in the orbitofrontal-thalamic system. Our findings may present evidence of corticothalamic connection problems in schizophrenia.

White matter (WM) abnormalities in schizophrenia may offer important clues to a better understanding of the disconnectivity associated with the disorder. The aim of this study was to elucidate a WM basis of auditory hallucinations in schizophrenia through the simultaneous investigation of WM tract integrity and WM density. Diffusion tensor images (DTIs) and structural T1 magnetic resonance images (MRIs) were taken from 15 hallucinating schizophrenic patients, 15 non-hallucinating schizophrenic patients and 22 normal controls. Voxel-based analyses and post-hoc region of interest analyses were obtained to compare the three groups on fractional anisotropy (FA) derived from DTI as well as WM density derived from structural MRIs. In both the hallucinating and non-hallucinating groups, FA of the WM regions was significantly decreased in the left superior longitudinal fasciculus (SLF), whereas WM density was significantly increased in the left inferior longitudinal fasciculus (ILF). The mean FA value of the left frontal part of the SLF was positively correlated with the severity score of auditory hallucinations in the hallucinating patient group. Our findings show that WM changes were mainly observed in the frontal and temporal areas, suggesting that disconnectivity in the left fronto-temporal area may contribute to the pathophysiology of schizophrenia. In addition, pathologic WM changes in this region may be an important step in the development of auditory hallucinations in schizophrenia.

Both post-mortem and neuroimaging studies have contributed significantly to what we know about the brain and schizophrenia. MRI studies of volumetric reduction in several brain regions in schizophrenia have confirmed early speculations that the brain is disordered in schizophrenia. There is also a growing body of evidence suggesting that a disturbance in connectivity between different brain regions, rather than abnormalities within the separate regions themselves, are responsible for the clinical symptoms and cognitive dysfunctions observed in this disorder. Thus an interest in white matter fiber tracts, subserving anatomical connections between distant, as well as proximal, brain regions, is emerging. This interest coincides with the recent advent of diffusion tensor imaging (DTI), which makes it possible to evaluate the organization and coherence of white matter fiber tracts. This is an important advance as conventional MRI techniques are insensitive to fiber tract direction and organization, and have not consistently demonstrated white matter abnormalities. DTI may, therefore, provide important new information about neural circuitry, and it is increasingly being used in neuroimaging studies of psychopathological disorders. Of note, in the past five years 18 DTI studies in schizophrenia have been published, most describing white matter abnormalities. Questions still remain, however, regarding what we are measuring that is abnormal in this disease, and how measures obtained using one method correspond to those obtained using other methods? Below we review the basic principles involved in MR-DTI, followed by a review of the different methods used to evaluate diffusion. Finally, we review MR-DTI findings in schizophrenia.

The purpose of the study is to propose a new framework for surface-based statistical parametric mapping of PET images using MRI-based cortical surface analysis, including partial volume correction, intensity normalization and spatial normalization on the cortical surface. Maximum PET intensities along the path between inner and outer layer of the cortical gray matter are mapped onto the cortical surface to generate a metabolic activity surface map. For the partial volume correction, the metabolic activity surface map was divided by the partial volume effect map. The regional metabolic activity was normalized by the global activity iteratively calculated at the surface nodes, statistically independent of the group, as measured by F statistics. After surface-based spatial normalization, a statistical evaluation of both cortical thickness and cortical metabolic activity was conducted on the normalized surfaces of 16 patients with schizophrenia and 16 age- and gender-matched healthy controls. The patients with schizophrenia were found to have significant cortical thinning in the temporal and inferior frontal cortices. Accordingly, their PET imaging was significantly affected by the partial volume effect, indicating that partial volume correction could change the statistical results. After correction of the partial volume effects, the patients showed hyperactivity in the temporal cortex, whereas hypoactivity in the prefrontal cortex, predominantly in the left hemisphere. Our results demonstrate that anatomical factors affect an analysis for functional data from the PET, and therefore the importance of combining anatomy and function in the analysis of imaging data for schizophrenia should be considered.

Background: The hippocampus has been shown to be abnormal in schizophrenia. The fornix is one of the main fiber tracts connecting the hippocampus with other brain regions. Few studies have evaluated the fornix in schizophrenia, however. A focus on fornix abnormalities and their association with hippocampal abnormalities might figure importantly in our understanding of the pathophysiology of schizophrenia., Methods: Line-scan diffusion tensor imaging (DTI) was used to evaluate diffusion in the fornix in 24 male patients with chronic schizophrenia and 31 male control subjects. Maps of fractional anisotropy (FA) and mean diffusivity (D(m)), which are indices sensitive to white-matter integrity, were generated to quantify diffusion within the fornix. We used high spatial resolution magnetic resonance imaging (MRI) to measure hippocampal volume., Results: FA and cross-sectional area of the fornix were significantly reduced in patients compared with control subjects. D(m) was significantly increased, whereas hippocampal volume was bilaterally reduced in patients. Reduced hippocampal volume was correlated with increased mean D(m) and reduced cross-sectional area of the fornix for patients. Patients also showed a significant correlation between reduced scores on neuropsychologic measures of declarative-episodic memory and reduced hippocampal volumes., Conclusions: These findings demonstrate a disruption in fornix integrity in patients with schizophrenia.

Schizophrenia has been suggested to be the result of both macroscopic and microscopic abnormalities in the brain. Although no definitive clinico-pathological correlations have been found to reconcile the many facets inherent in this disorder, the recent development of the magnetic resonance diffusion tensor imaging (DTI) has allowed us to gather useful information regarding the microcircuitry of the brain. Specifically, the apparent diffusion coefficient (ADC) reflects the degree of diffusion barriers and heterosynaptic communication for the brain neurotransmitter. Nineteen patients with DSM-IV schizophrenia and 21 age- and sex-matched control subjects participated in DTI, and the severity of the patients' symptoms was evaluated according to the Positive and Negative Syndrome Scale (PANSS). The ADC values were determined and compared between patients and control subjects via voxel-based morphometry. The results show an increased ADC in the bilateral fronto-temporal regions of the schizophrenic patients, as compared with those of the control subjects. In addition, the ADC values in the area of the right insular were correlated with the negative syndromes from the PANSS. Our findings of increased water diffusivity in the fronto-temporal regions of schizophrenic patients and the correlation between negative symptom scales and the ADC in the right insular region indicate that damaged brain microcircuitry might contribute to the pathophysiology of schizophrenia. These findings contribute towards integrating micro and macrostructural abnormalities and syndromes of schizophrenia.

Patients with schizophrenia exhibit deficits in semantic processing, which can form the basis of thought disorders. The objective of this study was to explore functional connectivity between the activated areas during semantic processing in schizophrenia. Twelve patients with schizophrenia and 12 healthy controls were studied with [15O]H2O positron-emission tomography during semantic judgment. The expected activation in the left inferior occipitotemporal cortex significantly correlated with several other regional activations in normal study participants, but with no other regional activations in patients with schizophrenia. This finding suggests that schizophrenia involves a disconnection of semantic networks. The resultant distortion in semantic processing may have an impact on thought disorders.