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Despite previous neuroimaging studies demonstrating morphological abnormalities of the thalamus and other subcortical structures in patients with schizophrenia, the potential role of the thalamus and its subdivisions in the pathophysiology of this illness remains elusive. It is also unclear whether similar changes of these structures occur in individuals at high risk for psychosis. In this study, magnetic resonance imaging was employed with the Multiple Automatically Generated Templates (MAGeT) brain segmentation algorithm to determine volumes of the thalamic subdivisions, the striatum (caudate, putamen, and nucleus accumbens), and the globus pallidus in 62 patients with schizophrenia, 38 individuals with an at-risk mental state (ARMS) [4 of whom (10.5%) subsequently developed schizophrenia], and 61 healthy subjects. Cognitive function of the patients was assessed by using the Brief Assessment of Cognition in Schizophrenia (BACS) and the Schizophrenia Cognition Rating Scale (SCoRS). Thalamic volume (particularly the medial dorsal and ventral lateral nuclei) was smaller in the schizophrenia group than the ARMS and control groups, while there were no differences for the striatum and globus pallidus. In the schizophrenia group, the reduction of thalamic ventral lateral nucleus volume was significantly associated with lower BACS score. The pallidal volume was positively correlated with the dose of antipsychotic treatment in the schizophrenia group. These results suggest that patients with schizophrenia, but not those with ARMS, exhibit volume reduction in specific thalamic subdivisions, which may underlie core clinical features of this illness.

Background Reduced gray matter volumes in the superior temporal gyrus and its subregions, such as Heschl's gyrus (HG) and the planum temporale (PT), have been reported in schizophrenia (Sz). However, it remains unclear whether patients exhibit an altered sulcogyral pattern on the superior temporal plane. Methods This magnetic resonance imaging study examined the distribution of HG duplication patterns [i.e., single HG, common stem duplication (CSD), or complete posterior duplication (CPD)] and their relationships with clinical variables and gray matter volumes in the HG and PT of 64 first-episode (FE) patients with Sz and 64 healthy controls. Results The prevalence of duplicated HG patterns was significantly higher and gray matter volumes in the HG and PT of both hemispheres were smaller in FESz patients than in healthy controls. The right CPD pattern in the FESz group was associated with less severe positive symptoms. In the FESz and control groups, CSD and CPD patterns correlated with larger volumes in the HG and PT, respectively. Conclusion The present results revealed an altered HG duplication pattern at the earliest phase of Sz, which may reflect early neurodevelopmental anomalies. However, reduced HG and PT volumes in the FESz were not explained by this sulcogyral pattern only, supporting the complex superior temporal pathology of Sz.

Aim Increased brain gyrification in diverse cortical regions has been reported in patients with schizophrenia, possibly reflecting deviations in early neurodevelopment. However, it remains unknown whether patients with schizotypal disorder exhibit similar changes. Methods This magnetic resonance imaging study investigated brain gyrification in 46 patients with schizotypal disorder (29 male, 17 female), 101 patients with schizophrenia (55 male, 46 female), and 77 healthy controls (44 male, 33 female). T1-weighted magnetic resonance images were obtained for each participant. Using FreeSurfer software, the local gyrification index (LGI) of the entire cortex was compared across the groups. Results Both schizophrenia and schizotypal disorder patients showed a significantly higher LGI in diverse cortical regions, including the bilateral prefrontal and left parietal cortices, as compared with controls, but its extent was broader in schizophrenia especially for the right prefrontal and left occipital regions. No significant correlations were found between the LGI and clinical variables (e.g., symptom severity, medication) for either of the patient groups. Conclusion Increased LGI in the frontoparietal regions was common to both patient groups and might represent vulnerability to schizophrenia, while more diverse changes in schizophrenia patients might be associated with the manifestation of florid psychosis.

This MRI study examined the surface morphology of the orbitofrontal cortex (OFC) and its relation to social and cognitive functions in 38 individuals with at-risk mental state (ARMS) and 63 schizophrenia patients in comparison with 61 healthy controls. The ARMS and schizophrenia groups had increased right OFC Type III expression and fewer orbital sulci, which were partly associated with social and cognitive impairments. OFC underdevelopment may underlie vulnerability to psychosis, as well as the core clinical features of the illness.

Reduced amplitude of duration mismatch negativity (dMMN) has been reported in psychotic disorders and at-risk mental state (ARMS); however, few longitudinal MMN studies have examined the amplitude changes during the course of psychosis. We compared dMMN amplitude between ARMS individuals with later psychosis onset and those without, and we longitudinally examined potential dMMN changes around psychosis onset. Thirty-nine ARMS subjects and 22 healthy controls participated in this study. Of the 39 ARMS subjects, 11 transitioned to psychosis (at-risk mental state with later psychosis onset [ARMS-P]) during follow-up and 28 did not (at-risk mental state without later psychosis onset [ARMS-NP]). dMMN was measured twice using an auditory oddball paradigm with a mean interval of 2 years. Follow-up dMMN data were available for all but four ARMS-P subjects. dMMN amplitude at baseline was smaller in ARMS-P subjects compared with control and ARMS-NP subjects. Additionally, ARMS-P subjects displayed a longitudinal decline in dMMN amplitude, which was not present in control and ARMS-P subjects. We also observed a progressive decline in dMMN amplitude during the transition period, suggesting dynamic brain changes associated with the psychosis onset. Our findings implicate dMMN amplitude as a biological predictor of future psychosis onset in high-risk individuals, which may be used for early detection and intervention of psychosis.

Previous structural magnetic resonance imaging studies of psychotic disorders have demonstrated volumetric alterations in subcortical (ie, the basal ganglia, thalamus) and temporolimbic structures, which are involved in high-order cognition and emotional regulation. However, it remains unclear whether individuals at high risk for psychotic disorders with minimal confounding effects of medication exhibit volumetric changes in these regions. This multicenter magnetic resonance imaging study assessed regional volumes of the thalamus, caudate, putamen, nucleus accumbens, globus pallidus, hippocampus, and amygdala, as well as lateral ventricular volume using FreeSurfer software in 107 individuals with an at-risk mental state (ARMS) (of whom 21 [19.6%] later developed psychosis during clinical follow-up [mean = 4.9 years, SD = 2.6 years]) and 104 age- and gender-matched healthy controls recruited at 4 different sites. ARMS individuals as a whole demonstrated significantly larger volumes for the left caudate and bilateral lateral ventricles as well as a smaller volume for the right accumbens compared with controls. In male subjects only, the left globus pallidus was significantly larger in ARMS individuals. The ARMS group was also characterized by left-greater-than-right asymmetries of the lateral ventricle and caudate nucleus. There was no significant difference in the regional volumes between ARMS groups with and without later psychosis onset. The present study suggested that significant volume expansion of the lateral ventricle, caudate, and globus pallidus, as well as volume reduction of the accumbens, in ARMS subjects, which could not be explained only by medication effects, might be related to general vulnerability to psychopathology.

Changes in the surface morphology of the orbitofrontal cortex (OFC), such as a fewer orbital sulci and altered sulcogyral pattern of the 'H-shaped' orbital sulcus, have been reported in schizophrenia, possibly reflecting abnormal neurodevelopment during gestation. However, whether high-risk subjects for developing psychosis also exhibit these gross morphologic anomalies is not well documented. This multicenter MRI study from four scanning sites in Japan investigated the distribution of the number of intermediate and posterior orbital sulci, as well as the OFC sulcogyral pattern, in 125 individuals with an at-risk mental state (ARMS) [of whom 22 later developed psychosis (ARMS-P) and 89 did not (ARMS-NP)] and 110 healthy controls. The ARMS group as a whole had a significantly lower number of intermediate and posterior orbital sulci compared with the controls, which was associated with prodromal symptomatology. However, there was no group difference in OFC pattern distribution. The ARMS-P and -NP groups did not differ in OFC surface morphology. These results suggest that gross morphology of the OFC in high-risk subjects may at least partly reflect neurodevelopmental pathology related to vulnerability to psychosis.

Deficit schizophrenia is a homogeneous subtype characterized by a trait-like feature of primary and prominent negative symptoms, but the etiologic factors related to this specific subtype remain largely unknown. This magnetic resonance imaging study aimed to examine gross brain morphology that probably reflects early neurodevelopment in 38 patients with deficit schizophrenia, 37 patients with non-deficit schizophrenia, and 59 healthy controls. Potential brain neurodevelopmental markers investigated in this study were the adhesio interthalamica (AI), cavum septi pellucidi (CSP), and surface morphology (i.e., olfactory sulcus depth, sulcogyral pattern, and number of orbital sulci) of the orbitofrontal cortex (OFC). The subtype classification of schizophrenia patients was based on the score of Proxy for the Deficit Syndrome. The deficit schizophrenia group had a significantly shorter AI compared with the non-deficit group and controls. The deficit group, but not the non-deficit group, was also characterized by an altered distribution of the OFC sulcogyral pattern, as well as fewer posterior orbital sulcus compared with controls. Other neurodevelopmental markers did not differentiate the deficit and non-deficit subgroups. These results suggest that the deficit subtype of schizophrenia and its clinical manifestation may be at least partly related to prominent neurodevelopmental pathology.

Background Previous magnetic resonance imaging (MRI) studies in patients with schizophrenia have demonstrated reduced cortical thickness predominantly in the fronto-temporal regions, but several MRI studies of regional cortical thickness in individuals at clinical high-risk for psychosis have reported inconsistent results. In addition, it remains elusive whether abnormalities of the cortical thickness in individuals at risk of psychosis, if present, are related to their functional outcome. Methods T1-weighted structural MR scans were obtained from 107 individuals with at-risk mental state (ARMS), of whom 21 (19.6%) later developed psychosis during clinical follow-up (mean = 4.9 years, SD = 2.6 years), as well as 104 age- and gender- matched healthy control subjects recruited at 4 scanning sites (University of Toyama, Toho University, Tohoku University, and The University of Tokyo). ARMS individuals were subdivided into good (ARMS-G, n = 77) and poor (ARMS-P, n = 13) outcome groups based on the Global Assessment of Functioning (GAF) scores both at baseline and 1-year follow-up. After preprocessing MR images using FreeSurfer software (ver.5.3.), we continuously measured the cortical thickness of entire cortex. A general linear model controlling for age, gender, and sites was used to estimate group differences. To correct for multiple comparisons, a Monte Carlo simulation procedure was used. This study was approved by the Committees on Medical Ethics of each site. After a complete description of the study was provided, written informed consent was obtained from all subjects. Results Compared with the controls, ARMS individuals exhibited significantly reduced cortical thickness in the superior and inferior frontal gyri, parahippocampal gyri, fusiform gyri, temporal pole cortices, and insula cortices bilaterally, as well as in the left middle frontal gyrus and right precuneus cortex. ARMS individuals also showed significantly increased cortical thickness in the left pre- and postcentral gyrus and right pericalcarine cortex in comparison to the controls. Within ARMS population, ARMS-P individuals had significantly reduced cortical thickness in the right paracentral lobule compared with ARMS-G individuals. Discussion Cortical thinning in the fronto-temporal regions as well as cortical thickening in the posterior cortices seen in ARMS individuals might be associated with general vulnerability to psychopathology. Furthermore, cortical thickness of the right paracentral lobule could be a predictive marker for functional outcome in ARMS population.

Olfactory impairment has been reported in patients with schizophrenia and individuals with a high risk of psychosis, but its neural basis is largely unknown. We used magnetic resonance imaging to investigate the morphology of the olfactory sulcus (an indicator of olfactory system development) and its relation to olfactory function in 38 persons with an at-risk mental state (ARMS), 62 patients with schizophrenia, and 61 healthy controls. Odor detection and identification were examined with a T & T olfactometer. Compared with the controls, the olfactory sulcus was significantly shallower and odor identification was inferior among the ARMS and schizophrenia subjects. Across all subjects, but not within each group, the olfactory sulcus depth was significantly related to better identification of odors. Our results support the concept that olfactory sulcus morphology reflects the neurodevelopmental process of the olfactory system., Anatomy; Medical imaging; Neuroscience; Psychiatry; Schizophrenia; Olfactory sulcus; At-risk mental state; Neurodevelopment; Olfaction

Schizotypal disorder is characterized by odd behavior and attenuated forms of schizophrenic features without the manifestation of overt and sustained psychoses. Past studies suggest that schizotypal disorder shares biological and psychological commonalties with schizophrenia. Structural magnetic resonance imaging (MRI) studies have demonstrated both common and distinct regional gray matter changes between schizophrenia and schizotypal disorder. However, no study has compared cortical thickness, which is thought to be a specific indicator of cortical atrophy, between schizophrenia and schizotypal disorder. The subjects consisted of 102 schizophrenia and 46 schizotypal disorder patients who met the International Classification of Diseases, 10th edition criteria and 79 gender- and age-matched healthy controls. Each participant underwent a T1-weighted 3-D MRI scan using a 1.5-Tesla scanner. Cortical thickness was estimated using FreeSurfer. Consistent with previous studies, schizophrenia patients exhibited wide-spread cortical thinning predominantly in the frontal and temporal regions as compared with healthy subjects. Patients with schizotypal disorder had a significantly reduced cortical thickness in the left fusiform and parahippocampal gyri, right medial superior frontal gyrus, right inferior frontal gyrus, and right medial orbitofrontal cortex as compared with healthy controls. Schizophrenia patients had thinner cortices in the left precentral and paracentral gyri than those with schizotypal disorder. Common cortical thinning patterns observed in schizophrenia and schizotypal disorder patients may be associated with vulnerability to psychosis. Our results also suggest that distinct cortical changes in schizophrenia and schizotypal disorder may be associated with the differences in the manifestation of clinical symptoms among these disorders.

An altered orbitofrontal sulcogyral pattern has been reported in the schizophrenia-spectrum, but it remains unknown whether they also have differences in the number of intermediate and posterior orbital sulci compared with healthy subjects. This magnetic resonance imaging study investigated the number of these sulci in 102 schizophrenia patients, 47 schizotypal disorder patients, and 84 controls. Both patient groups had a significantly lower number of both sulci bilaterally compared with controls, which was weakly associated with the severity of negative symptoms. Our results may reflect the neurodevelopmental pathology related to vulnerability to psychosis.

Objectives: Increased pituitary volume, which probably reflects hypothalamic-pituitary-adrenal (HPA) hyperactivity, has been reported in patients with schizophrenia and individuals at risk of psychosis. On the basis of potential role of abnormal HPA axis function on cognitive impairments in psychosis, we aimed to examine possible relations between the pituitary volume and socio-cognitive impairments in these subjects. Methods: This magnetic resonance imaging study examined the pituitary gland volume in 38 subjects with at-risk mental state (ARMS) [of whom 4 (10.5%) exhibited the transition to schizophrenia], 63 patients with schizophrenia, and 61 healthy controls. Social and cognitive functions of the ARMS and schizophrenia groups were assessed using the Brief Assessment of Cognition in Schizophrenia (BACS), the Schizophrenia Cognition Rating Scale (SCoRS), and the Social and Occupational Functioning Assessment Scale (SOFAS). Results: Both the ARMS and schizophrenia groups had a significantly larger pituitary volume compared to controls. In the schizophrenia group, the pituitary volume was negatively associated with the BACS working memory score. No association was found between the pituitary volume and clinical variables (medication, symptom severity) in either clinical group. Conclusion: Our findings support the notion of common HPA hyperactivity in the ARMS and schizophrenia groups, but abnormal HPA axis function may contribute differently to cognitive deficits according to the illness stages of schizophrenia.

A few magnetic resonance imaging (MRI) studies reported reduced pineal gland volume in chronic schizophrenia (Sz), implicating the involvement of melatonin in the pathophysiology of the illness. However, it is not known whether this abnormality, if present, exists at the early illness stages and/or develops progressively over the course of the illness. This MRI study examined pineal gland volume in 64 patients with first-episode schizophrenia (FESz), 40 patients with chronic Sz, 22 individuals with at-risk mental state (ARMS), and 84 healthy controls. Longitudinal changes in pineal volume (mean inter-scan interval = 2.5 ± 0.7 years) were also examined in a subsample of 23 FESz, 16 chronic Sz, and 21 healthy subjects. In the cross-sectional comparison, the ARMS, FESz, and chronic Sz groups had significantly smaller pineal volume to the same degree as compared with healthy controls. A longitudinal comparison demonstrated that pineal volume did not change over time in any group. There was no association between pineal volume and clinical variables (e.g., symptom severity, medication) in the ARMS and Sz groups. The results suggest that a smaller pineal gland may be a static vulnerability marker of Sz, which probably reflects an early neurodevelopmental abnormality.

BackgroundPatients with the deficit form of schizophrenia (D-SZ) are characterized by severe primary negative symptoms and differ from patients with the non-deficit form of schizophrenia (ND-SZ) in several aspects. No study has measured brain gyrification, which is a potential marker of neurodevelopment, in D-SZ and ND-SZ.MethodsWe obtained magnetic resonance scans from 135 schizophrenia patients and 50 healthy controls. The proxy scale for deficit syndrome (PDS) was used for the classification of D-SZ and ND-SZ. The local gyrification index (LGI) of the entire cortex was measured using FreeSurfer. Thirty-seven D-SZ and 36 ND-SZ patients were included in the LGI analyses. We compared LGI across the groups.ResultsSZ patients exhibited hyper-gyral patterns in the bilateral dorsal medial prefrontal and ventromedial prefrontal cortices, bilateral anterior cingulate gyri and right lateral parietal/occipital cortices as compared with HCs. Although patients with D-SZ or ND-SZ had higher LGI in similar regions compared with HC, the hyper-gyral patterns were broader in ND-SZ. ND-SZ patients exhibited a significantly higher LGI in the left inferior parietal lobule relative to D-SZ patients. Duration of illness inversely associated with LGI in broad regions only among ND-SZ patients.ConclusionsThe common hyper-gyral patterns among D-SZ and ND-SZ suggest that D-SZ and ND-SZ may share neurodevelopmental abnormalities. The different degrees of cortical gyrification seen in the left parietal regions, and the distinct correlation between illness chronicity and LGI observed in the prefrontal and insular cortices may be related to the differences in the clinical manifestations among D-SZ and ND-SZ.

Aims While olfaction is a sense closely associated with the limbic system and emotions, the relation between emotional status and olfactory functioning has not been well documented. This study aimed to examine the possible effect of anxiety on olfaction in healthy subjects. Methods We investigated the effect of state and trait anxiety on the detection and recognition thresholds for five different odors in 124 healthy subjects (62 men and 62 women, mean age = 27.2 years) using a T&T olfactometer. Results While the influences of age, socioeconomic status, IQ, and smoking history on olfaction were not significant, women had a lower recognition threshold for the odor of sweet fruit and a higher detection threshold for that of rotten food as compared with men. Both state and trait anxiety ratings were significantly associated with reduced olfactory ability, especially for identification of rose odor. Conclusions These findings suggest that emotional status affects olfactory functioning in healthy subjects. Our findings may also partly explain the mild olfactory impairment reported in clinical conditions, such as anxiety disorders.

Odor identification deficits are well documented in patients with schizophrenia, but it remains unclear whether individuals at clinical high-risk for psychosis exhibit similar changes and whether their olfactory function is related to social/cognitive functions and symptomatology. In this study, we investigated odor detection sensitivity and identification ability in 32 individuals with at-risk mental state (ARMS), 59 schizophrenia patients, and 169 healthy controls using a T&T olfactometer. The ARMS and schizophrenia subjects were administered the Brief Assessment of Cognition in Schizophrenia (BACS), the Schizophrenia Cognition Rating Scale (SCoRS), and the Social and Occupational Functioning Assessment Scale (SOFAS) to assess their cognitive and social functions, and the Positive and Negative Syndrome Scale (PANSS) for clinical symptoms. Both the ARMS and schizophrenia subjects had lower odor identification ability when compared with healthy controls, while no significant difference was found in the odor detection sensitivity. The lower odor identification ability in the ARMS group correlated with the severity of negative symptoms and weakly correlated with lower performance on the BACS verbal fluency test. The olfactory measures of schizophrenia patients did not correlate with illness duration, medication, symptom severity, and social and cognitive functions. For the ARMS and schizophrenia groups, the olfactory measures did not correlate with the SOFAS and SCoRS scores. These findings suggest that high-risk subjects for psychosis already show odor identification deficits similar to those observed in schizophrenia patients, which probably reflect a biological trait related to vulnerability to psychosis.

Individuals with Clinical High-Risk state for Psychosis (CHR-P) are reported to exhibit impaired quality of life (QOL) similar to that observed in schizophrenia, but its determinants remain unclear. We investigated the QOL of 33 subjects with CHR-P, 45 patients with schizophrenia, and 63 healthy subjects using the Quality of Life Scale (QLS). The CHR-P and schizophrenia groups were administered the Brief Assessment of Cognition in Schizophrenia (BACS), the Schizophrenia Cognition Rating Scale (SCoRS), and the Social and Occupational Functioning Assessment Scale (SOFAS) for socio-cognitive functions; and the Positive and Negative Syndrome Scale (PANSS) and the State-Trait Anxiety Inventory for clinical symptoms. The CHR-P group was also assessed using the Beck Depression Inventory. The CHR-P and schizophrenia groups had a significantly lower QLS score to the same degree compared with controls, which was predominantly associated with the SOFAS, SCoRS, and PANSS negative/general scores. For the CHR-P, the severity of anxiety and depressive symptoms was also correlated with a lower QLS score. Regression analyses demonstrated that the QLS score was predicted by SOFAS (for both groups) and SCoRS (for CHR-P) scores. Our findings suggest the importance of addressing socio-cognitive dysfunctions as well as anxiety and depressive symptoms for better QOL in CHR-P.

Background: Despite the fact that only a part of the individuals with at-risk mental state (ARMS) for psychosis do develop psychosis, biological markers of future transition to psychosis have not been well documented. Structural abnormality of the anterior cingulate gyrus (ACG), which probably exists prior to the onset of psychosis, could be such a risk marker. Methods: We conducted a multicenter magnetic resonance imaging (MRI) study of 3 scanning sites in Japan. 1.5-T 3D MRI scans were obtained from 73 ARMS subjects and 74 age- and gender-matched healthy controls. We measured thickness, volume, and surface area of the ACG using labeled cortical distance mapping and compared these measures among healthy controls, ARMS subjects who later converted to overt psychosis (ARMS-C), and those who did not (ARMS-NC). Results: Seventeen of 73 (23%) ARMS subjects developed overt psychosis within the follow-up period. The thickness of the left ACG was significantly reduced in ARMS-C relative to healthy subjects (P = .026) while both ARMS-C (P = .001) and ARMS-NC (P = .01) had larger surface areas of the left ACG compared with healthy controls. Conclusion: Further studies will be needed to identify potential markers of future transition to psychosis though cortical thinning of the ACG might be one of the candidates.

Background Anomalies of brain gyrification have been reported in schizophrenia, possibly reflecting its neurodevelopmental pathology. However, it remains elusive whether individuals at risk for psychotic disorders exhibit deviated gyrification patterns, and whether such findings, if present, are predictive of transition to psychotic disorders. Methods This multicenter magnetic resonance imaging study investigated brain gyrification and its relationship to later transition to psychotic disorders in a large sample of at-risk mental state (ARMS) individuals. T1-weighted magnetic resonance imaging scans were obtained from 104 ARMS individuals, of whom 21 (20.2%) exhibited the transition to psychotic disorders during clinical follow-up (mean = 4.9 years, SD = 2.6 years), and 104 healthy control subjects at 4 different sites. The local gyrification index (LGI) of the entire cortex was compared across the groups using FreeSurfer software. Results Compared with the control subjects, ARMS individuals showed a significantly higher LGI in widespread cortical areas, including the bilateral frontal, temporal, parietal, and occipital regions, which was partly associated with prodromal symptomatology. ARMS individuals who exhibited the transition to psychotic disorders showed a significantly higher LGI in the left occipital region compared with individuals without transition. Conclusions These findings suggested that increased LGI in diverse cortical regions might represent vulnerability to psychopathology, while increased LGI in the left occipital cortex might be related to subsequent manifestation of florid psychotic disorders as a possible surrogate marker.

An altered sulcogyral pattern in the orbitofrontal cortex (OFC) has been implicated in schizophrenia as a possible marker of abnormal neurodevelopment, while its genetic mechanism remains unknown. This magnetic resonance imaging study investigated the relationship between the polymorphism of YWHAE (rs28365859), a gene encoding 14-3-3epsilon that is a Disrupted-in-Schizophrenia 1 (DISC1)-interacting molecule associated with neuronal development, and the OFC subtypes of the ‘H-shaped’ sulcus (Types I, II, and III) in a Japanese sample of 72 schizophrenia patients and 86 healthy controls. The schizophrenia patients had significantly increased Type III (p = 0.004) and decreased Type I (p = 0.013) expression on the right hemisphere compared to the controls. The subjects carrying the protective C allele showed a decrease in Type III (p = 0.005) and an increase in Type I (p = 0.017) compared to the G allele homozygotes, especially for the healthy subjects in the left hemisphere. These results suggest a possible role for the YWHAE genotype in the early development of the OFC sulcogyral pattern, but its effect alone is not likely to explain the altered sulcogyral pattern in schizophrenia.

Previous neuroimaging studies of gyrification, a possible marker of early neurodevelopment, in schizophrenia patients have reported inconsistent results. In addition, it remains unclear whether aberrant gyrification in schizophrenia patients, if present, is associated with cognitive impairment, which is one of the core features of schizophrenia. Magnetic resonance images were obtained from 62 patients with first-episode schizophrenia and 57 healthy control subjects. Using FreeSurfer software, local gyrification index (LGI) of the entire cortex was compared between the groups. The relationship between LGI and performance in the Wisconsin Card Sorting Test (WCST) was also examined in a subgroup of patients (n= 28). Compared with the controls, the patients showed a significantly higher LGI in a wide range of bilateral frontal regions as well as in the right inferior parietal and bilateral occipital regions. The number of WCST categories archived in patients was negatively correlated with the LGI mainly in the rostral middle frontal and anterior cingulate regions in the right hemisphere. Our findings suggested a widespread hypergyrification pattern in schizophrenia patients, which supported early neurodevelopmental abnormalities. Our results also suggested that executive dysfunction in schizophrenia patients may be at least partly related to aberrant neurodevelopment, especially in the right frontal regions.

Background Increased gyrification in diverse cortical areas has been reported in patients with schizophrenia, which is considered to reflect deviations in early neurodevelopment. Schizotypal personality disorder (SPD) is thought to be a prototypic disorder within the schizophrenia spectrum, which shares biological and psychological commonalities with schizophrenia as a neurobiological basis for vulnerability factors. However, to the best of our knowledge, no magnetic resonance imaging (MRI) studies have investigated the gyrification pattern in SPD. Methods T1-weighted structural MRI scans were obtained by 1.5-T scanner from 101 patients with schizophrenia, 46 patients with SPD, and 77 age- and gender- matched healthy control subjects. Using FreeSurfer software (version 5.3.), the local gyrification indices (LGIs) of entire cortex were obtained with the method of Schaer and colleagues. Clinical symptoms of the patients were rated with the Scale for the Assessment of Positive Symptoms (SAPS) and the Scale for the Assessment of Negative Symptoms (SANS) at the time of scanning. A general linear model controlling for age, gender, medication dose, and duration of medication was used to compare the LGIs across the groups and to conduct vertex-by-vertex whole brain LGI correlation analyses with clinical variables. This study was approved by the Committee on the Medical Ethics of Toyama University based on the declaration of Helsinki. After a complete description of the study was provided, written informed consent was obtained from all subjects. Results Compared with the controls, the patients with schizophrenia showed significantly higher LGI in widespread cortical areas including the bilateral frontal, parietal, and occipital regions. The patients with SPD demonstrated significantly higher LGI in the bilateral frontal and left parietal regions compared with the controls. Compared with the patients with SPD, the patients with schizophrenia showed significantly higher LGI in the left occipital and right frontal regions. Both SAPS and SANS total scores were positively correlated with LGI in the bilateral temporal regions in patients with schizophrenia, and were negatively correlated with LGI in the bilateral occipital regions in patients with SPD. Discussion Increased LGI in the bilateral frontal regions may be the common morphological substrates for the schizophrenia spectrum, possibly representing vulnerability to schizophrenia. In addition, increased LGI in the left occipital and right frontal regions preferentially observed in schizophrenia may have a critical role in manifestation of florid psychotic symptoms.

Cytochrome P450 oxidoreductase (POR) deficiency is a rare autosomal recessive disorder characterized by skeletal dysplasia, adrenal dysfunction, disorders of sex development (DSD), and maternal virilization during pregnancy. Although multiple studies have been performed for this condition, several matters remain to be clarified, including the presence of manifesting heterozygosity and the underlying factors for clinical variability.The objective of the study was to examine such unresolved matters by detailed molecular studies and genotype-phenotype correlations.Thirty-five Japanese patients with POR deficiency participated in the study.Mutation analysis revealed homozygosity for R457H in cases 1-14 (group A), compound heterozygosity for R457H and one apparently null mutation in cases 15-28 (group B), and other combinations of mutations in cases 29-35 (group C). In particular, FISH and RT-PCR sequencing analyses revealed an intragenic microdeletion in one apparent R457H homozygote, transcription failure of apparently normal alleles in three R457H heterozygotes, and nonsense mediated mRNA decay in two frameshift mutation-positive cases examined. Genotype-phenotype correlations indicated that skeletal features were definitely more severe, and adrenal dysfunction, 46,XY DSD, and pubertal failure were somewhat more severe in group B than group A, whereas 46,XX DSD and maternal virilization during pregnancy were similar between two groups. Notable findings also included the contrast between infrequent occurrence of 46,XY DSD and invariable occurrence of 46,XX DSD and pubertal growth pattern in group A mimicking that of aromatase deficiency.The results argue against the heterozygote manifestation and suggest that the residual POR activity reflected by the R457H dosage constitutes the underlying factor for clinical variability in some features but not other features, probably due to the simplicity and complexity of POR-dependent metabolic pathways relevant to each phenotype.

A 40-year-old man experienced cardiopulmonary arrest after intramuscular injection of 20 mg of butylscopolamine bromide. No pathological changes were found at autopsy, and 1.19 microg/mL of butylscopolamine bromide was detected in his serum. Since he had taken no other drugs, his severe symptoms were thought to have been caused by an anaphylactic reaction to butylscopolamine bromide. Butylscopolamine bromide has been used for many years worldwide, and is considered to be a safe drug, with no reports of severe side effects following intramuscular injection. Since an anaphylactic reaction may not be related to a particular medication, the possibility of such a severe reaction must be considered, even during administration of an ostensibly safe drug such as butylscopolamine bromide.

While olfaction is a sense closely associated with the limbic system and emotions, the relation between emotional status and olfactory functioning has not been well documented. This study aimed to examine the possible effect of anxiety on olfaction in healthy subjects.We investigated the effect of state and trait anxiety on the detection and recognition thresholds for five different odors in 124 healthy subjects (62 men and 62 women, mean age = 27.2 years) using a TT olfactometer.While the influences of age, socioeconomic status, IQ, and smoking history on olfaction were not significant, women had a lower recognition threshold for the odor of sweet fruit and a higher detection threshold for that of rotten food as compared with men. Both state and trait anxiety ratings were significantly associated with reduced olfactory ability, especially for identification of rose odor.These findings suggest that emotional status affects olfactory functioning in healthy subjects. Our findings may also partly explain the mild olfactory impairment reported in clinical conditions, such as anxiety disorders.

Morphological changes in the orbitofrontal cortex (OFC), such as an altered sulcogyral pattern of the ‘H-shaped’ orbital sulcus and a shallow olfactory sulcus, have been demonstrated in schizophrenia, possibly reflecting deviations in early neurodevelopment. However, it remains unclear whether patients with schizotypal features exhibit similar OFC changes. This magnetic resonance imaging study examined the OFC sulcogyral pattern (Types I, II, III, and IV) and olfactory sulcus morphology in 102 patients with schizophrenia, 47 patients with schizotypal disorder, and 84 healthy controls. The OFC sulcogyral pattern distribution between the groups was significantly different on the right hemisphere, with the schizophrenia patients showing a decrease in Type I (vs controls and schizotypal patients) and an increase in Type III (vs controls) expression. However, the schizotypal patients and controls did not differ in the OFC pattern. There were significant group differences in the olfactory sulcus depth bilaterally (schizophrenia patients

Increasing evidence has implicated the role of Disrupted-in-Schizophrenia-1 (DISC1), a potential susceptibility gene for schizophrenia, in early neurodevelopmental processes. However, the effect of its genotype variation on brain morphologic changes related to neurodevelopmental abnormalities in schizophrenia remains largely unknown. This magnetic resonance imaging study examined the association between DISC1 Ser704Cys polymorphism and a range of brain neurodevelopmental markers [cavum septi pellucidi (CSP), adhesio interthalamica (AI), olfactory sulcus depth, and sulcogyral pattern (Types I, II, III, and IV) in the orbitofrontal cortex (OFC)] in an all Japanese sample of 75 schizophrenia patients and 87 healthy controls. The Cys carriers had significantly larger CSP than the Ser homozygotes for both schizophrenia patients and healthy controls. The Cys carriers also exhibited a reduction in the Type I pattern of the right OFC in the healthy controls, but not in the schizophrenia patients. The DISC1 Ser704Cys polymorphism did not affect the AI and olfactory sulcus depth in either group. These results suggested a possible role of the DISC1 genotype in the early neurodevelopment of human brains, but failed to show its specific role in the neurodevelopmental pathology of schizophrenia.

Expression systems for the sal gene encoding salicylate hydroxylase from Pseudomonas putida S-1 were examined and some constructs were expressed in these systems. By cultivation of Escherichia coli BL21 (DE3)/pSAH8 in LB medium at 37 degrees C with isopropyl-b-D-thiogalactopyranoside as the inducer, salicylate hydroxylase was overexpressed mainly in the form of inclusion bodies. Lower temperature cultivation at 20 degrees C after induction resulted in a large amount of the enzyme in the soluble form. The E. coli clone harboring the recombinant plasmid produced a 45 kDa protein that appeared to be electrophoretically and immunochemically identical to the P. putida enzyme and contained the same N-terminal amino acid sequence. This recombinant DNA product also exhibited properties characteristic of a flavoprotein and was fully functional as salicylate hydroxylase. Based on chemical modification of the salicylate hydroxylase from P. putida, Lys163 was previously proposed to be the NADH binding site. In this study, to obtain a better understanding of the predicted role of Lys163, this residue in the active center of salicylate hydroxylase was replaced with Arg, Gly, or Glu by conventional site-directed mutagenesis. Kinetic studies using these mutant enzymes and the recombinant enzyme revealed increases in apparent K(m) values for NADH in the order of wild-type enzyme > K163R > K163G > K163E, with some decreases in V(max). Examination of the recombinant enzyme and K163G indicated that the pH dependency of K(m) on NADH with pK(a) 10.5 is lost by mutation despite the lack of changes in V(max) values, suggesting a requirement for the lysine residue as the NADH binding site. Based on these results, Lys163 is proposed to play a role in the binding of NADH at the active site through an ionic bond rather than playing a role in catalysis.

The acid digestion method has been widely used for the diagnosis of death by drowning, but it is not always sensitive. However, there has been no definitive method to replace acid digestion until now. We speculate that bacteria are more useful markers than plankton for the diagnosis of death by drowning. In this study, from the preserved blood samples of 32 freshwater drowning cases, specific DNA fragments of Aeromonas sobria, one of the most common aquatic bacteria, were examined using PCR. The DNA fragments of the bacterium were detected from 27 of 32 cases with first round PCR or nested-PCR. The remaining 5 cases in which bacterial DNA was not detected had longer storage periods for the blood samples and shorter time intervals from drowning to death. These results indicate that the present method can be applied to the diagnosis of death by drowning.

A number of clinico-statistical observation on temporomandibular arthrosis reported that the incidence was the highest in the adults in the twenties. This lead us to pinpoint to the age of twenties and observe the status of stomatognathic system to examine the way temporomandibular arthrosis had developed.The adults concerened the study were 75 for male and 45 for female in the twenties, each of whom was questioned and tested. Sirognathograph Analysing System was used to the analysis of chewing movements. It resulted in discovering symptoms of temporomandibular arthrosis in 61.2% male and 55.6% female. Clinically, patients presented with the noise in general and the pain especially among female. The patients with symptoms of temporomandibular arthrosis had the normal maximum opening volume, the slightly increased index of DMFT, the reduced Type I pattern in the pattern classification (Kuwahara classification) of frontal projection of chewing movements. The incidence of reverse pattern, crossover pattern or both was high in male patients. Furthermore, the male patients with symptoms of temporomandibular arthrosis had the reduced maximum opening and closing velocity and occlusal phase period, while they gave the increase in the cycle, opening phase period, closing phase period and each coefficient of varia-tion.

p120-Catenin contributes to the cadherin-mediated adhesion and aggregation of cells. μ-Calpain was activated and p120-catenin was degraded after 36 h of ischemia in differentiated SH-SY5Y cells. Calpain inhibitors Cbz-Val-Phe-H (MDL28170, 20 μM) and N-acetyl-leucyl-leucyl-norleucinal (ALLN, 20 μM) increased the levels of dephosphorylated p120-catenin, aggregation, and cell survival as detected by reduced LDH release in ischemic cells. However, a proteasome inhibitor lactacystin had no such effects. This is the first report of the calpain-mediated degradation of p120-catenin and an association between the level of dephosphorylated p120-catenin and cell aggregation in ischemic neuronal cells.

Deuterohemins III and XIII were coupled with apomyoglobin to examine the influence of the modified heme-globin contacts on the functions of the reconstituted holoproteins. Owing to the molecular symmetry of the prosthetic groups, the resultant proteins are free from the heme orientational disorder. The coordination structures of the two reconstituted myoglobins were found to be normal and closely similar to each other. The equilibrium ligand bindings also resembled with each other in both ferric and ferrous states. The results demonstrate that the different local heme-globin contacts affect the structure and function of the reconstituted myoglobins only slightly. The results therefore suggest that the two asymmetric deuteroheme IX isomers, which are inverted about the α,γ-meso carbon axis of the heme, also exhibit very similar functions in myoglobin.

We report on a 3-month-old girl with Miller-Dieker syndrome resulting from a maternal full-cryptic translocation t(10;17)(q26.3;p13.3) detectable only by using fluorescence in situ hybridization (FISH). Parental studies using FISH are crucial for genetic counselling in cases of Miller-Dieker syndrome with submicroscopic deletion at 17p13.3. In a family with a parental cryptic translocation and high recurrence risk, prenatal diagnosis using FISH is feasible. © 1995 Wiley-Liss, Inc.

We describe a further patient with the Coffin-Siris syndrome who presented at 4 months with recurrent hypoglycemia attacks. Detailed examination was undertaken at 7 months but the cause of hypoglycemia was not detected. Hypoglycemia seems to be a previously undescribed finding in the Coffin-Siris syndrome.

To investigate the effect of obesity and hypertension on left ventricular (LV) mass in children, we performed echocardiography and measured the height, weight, and blood pressure of 267 healthy children (145 boys and 122 girls) aged 12 years. The percentage of body fat was estimated using bioelectric impedance to derive the total adipose weight and lean body weight. End-diastolic measurements of LV parameters were obtained from M-mode echocardiograms. The LV mass was calculated by using the formula of Devereux et al. A strong positive correlation was demonstrated between non-normalized LV mass and height or other measures of body size. Systolic blood pressure was weakly correlated with non-normalized LV mass in boys. The impact of height on LV mass differed between boys and girls. Thus, different allometric formulas to normalize the LV mass for height were determined, using the height to the 3.1 and 1.9 powers for boys and girls, respectively. Regression analysis revealed that only total adipose weight affected the normalized LV mass, and that the effect of total adipose weight was greater in girls than in boys. The obese children had a significantly greater normalized LV mass than the nonobese children. The increase in the LV mass due to obesity appeared to be eccentric, because of the lack of an association between the indices of obesity and relative wall thickness. Our data indicate that appropriate normalization of LV mass is necessary for each study population, and that LV hypertrophy due to obesity begins in childhood.

Setleis syndrome is characterized by bitemporal skin depressions resembling forceps marks, abnormalities of the eyelashes, and "leonine" facial appearance. The cause is unknown, although autosomal recessive inheritance has been proposed. Recently, two families were reported in which one of the parents of a patient with Setleis syndrome showed mild manifestations, suggesting autosomal dominant inheritance. We describe a 9-month-old Japanese boy with typical Setleis syndrome. His father, who has normal intelligence, has bitemporal focal dermal dysplasia but a normal face. His paternal second cousin also has Setleis syndrome. This family shows autosomal dominant inheritance including father-to-son transmission of Setleis syndrome with variable expressivity and reduced penetrance. Careful examination of the relatives of patients with Setleis syndrome is recommended.

Mutations in the human homologue of Drosophila patched (PTCH) have been identified in patients with nevoid basal cell carcinoma syndrome (NBCCS; also called Gorlin syndrome) as well as sporadic basal cell carcinomas and medulloblastomas. However, using PCR-SSCP analysis, mutations in PTCH have been found in only a fraction (about one third to a half) of NBCCS patients. In this study, we determined the whole genomic organizations of the PTCHgene and developed a new set of more accurate primers for the analysis of mutations in PTCH. Using these primers, we examined 8 Japanese NBCCS patients for mutations in all PTCH exons by direct sequencing of the PCR products. As a result, we identified 5 novel PTCH mutations in 6 out of 8 patients including 2 sisters as well as 5 polymorphisms, two of them, 1704G>C and 2928G>C were novel. Four of these mutations, 900delC, 1247insT, 1999delC and 933+5G>T, cause protein truncation due to the insertion or deletion of a single nucleotide or aberrant splicing. The remaining mutation, 1514G>A was a missense alteration (G509D). Interestingly, the amino acid substitution, G509V, has been reported previously in an NBCCS patient, suggesting an important role of this amino acid residue in the function of PTCH protein. The difference in the detection rate of PTCH mutations among NBCCS between previous reports and ours is due to the difference either in ethnicity or in the detection methods. © 2003 Wiley-Liss, Inc.