Pyridoxamine: A novel treatment for schizophrenia with enhanced carbonyl stress.

AIM: The aim of this clinical trial was to obtain proof of concept for high-dose pyridoxamine as a novel treatment for schizophrenia with enhanced carbonyl stress. METHODS: Ten Japanese schizophrenia patients with high plasma pentosidine, which is a representative biomarker of enhanced carbonyl stress, were recruited in a 24-week, open trial in which high-dose pyridoxamine (ranging from 1200 to 2400 mg/day) was administered using a conventional antipsychotic regimen. Main outcomes were the total change in Positive and Negative Syndrome Scale score and the Brief Psychiatric Rating Scale score from baseline to end of treatment at week 24 (or at withdrawal). RESULTS: Decreased plasma pentosidine levels were observed in eight patients. Two patients showed marked improvement in their psychological symptoms. A patient who harbors a frameshift mutation in the Glyoxalase 1 gene also showed considerable reduction in psychosis accompanied with a moderate decrease in plasma pentosidine levels. A reduction of greater than 20% in the assessment scale of drug-induced Parkinsonism occurred in four patients. Although there was no severe suicide-related ideation or behavior, Wernicke's encephalopathy-like adverse drug reactions occurred in two patients and were completely suppressed by thiamine supplementation. CONCLUSION: High-dose pyridoxamine add-on treatment was, in part, effective for a subpopulation of schizophrenia patients with enhanced carbonyl stress. Further randomized, placebo-controlled trials with careful monitoring will be required to validate the efficacy of high-dose pyridoxamine for these patients.

The regulation of soluble receptor for AGEs contributes to carbonyl stress in schizophrenia.

Our previous study showed that enhanced carbonyl stress is closely related to schizophrenia. The endogenous secretory receptor for advanced glycation end-products (esRAGE) is a splice variant of the AGER gene and is one of the soluble forms of RAGE. esRAGE is considered to be a key molecule for alleviating the burden of carbonyl stress by entrapping advanced glycation end-products (AGEs). In the current study, we conducted genetic association analyses focusing on AGER, in which we compared 212 schizophrenic patients to 214 control subjects. We also compared esRAGE levels among a subgroup of 104 patients and 89 controls and further carried out measurements of total circulating soluble RAGE (sRAGE) in 25 patients and 49 healthy subjects. Although the genetic association study yielded inconclusive results, multiple regression analysis indicated that a specific haplotype composed of rs17846798, rs2071288, and a 63 bp deletion, which were in perfect linkage disequilibrium (r2 = 1), and rs2070600 (Gly82Ser) were significantly associated with a marked decrease in serum esRAGE levels. Furthermore, compared to healthy subjects, schizophrenia showed significantly lower esRAGE (p = 0.007) and sRAGE (p = 0.03) levels, respectively. This is the first study to show that serum esRAGE levels are regulated by a newly identified specific haplotype in AGER and that a subpopulation of schizophrenic patients are more vulnerable to carbonyl stress.

Chronic exposure to carbon monoxide in two elderly patients using a kotatsu, a traditional Japanese charcoal-based heater.

We report on two elderly patients with cognitive impairments, for whom chronic carbon monoxide (CO) exposure was suspected based on elevated carboxyhaemoglobin levels in their serum. On their initial visits, cognitive impairment and brain magnetic resonance imaging findings in both patients were compatible with the diagnosis of Alzheimer's-type dementia. However, after discontinuation of the use of a kotatsu, a charcoal-based heater, their serum carboxyhaemoglobin levels normalized and their physical symptoms resolved. Their cognitive function also slightly improved. The causal relationship between physical symptoms and cognitive impairment after chronic CO poisoning is uncertain; however, it is possible that chronic exposure to low CO levels exacerbated the clinical manifestation in our patients.

Patterns of hippocampal atrophy differ among Alzheimer's disease, amnestic mild cognitive impairment, and late-life depression.

AIM: This study investigated whether the characteristic changes in hippocampal atrophy seen in coronal scans are useful for differentiating Alzheimer's disease (AD), amnestic mild cognitive impairment (aMCI), and major depressive disorder (MDD). METHODS: Subjects included 58 patients with AD, 33 with aMCI, 20 with MDD, and 22 normal controls, all aged 60 years or older. For each subject, eight coronal short TI inversion recovery images perpendicular to the hippocampal longitudinal axis were obtained. Images were manually measured using the conventional region of interest method of quantitative analysis. RESULTS: The overall trend in the corrected volumes of the hippocampus was AD < aMCI < MDD < normal controls. We found atrophy in all slices in AD, atrophy centred on the hippocampal head in aMCI, and atrophy in the slice of the hippocampal body 12 mm from the amygdala in MDD. CONCLUSIONS: The present study suggested that our method of comparing hippocampal atrophy by region may be useful in distinguishing AD, aMCI, MDD, and normal controls.

N-methyl-d-aspartate receptor coagonist d-serine suppresses intake of high-preference food.

d-Serine is abundant in the forebrain and physiologically important for modulating excitatory glutamatergic neurotransmission as a coagonist of synaptic N-methyl-d-aspartate (NMDA) receptor. NMDA signaling has been implicated in the control of food intake. However, the role of d-serine on appetite regulation is unknown. To clarify the effects of d-serine on appetite, we investigated the effect of oral d-serine ingestion on food intake in three different feeding paradigms (one-food access, two-food choice, and refeeding after 24-h fasting) using three different strains of male mice (C57Bl/6J, BKS, and ICR). The effect of d-serine was also tested in leptin signaling-deficient db/db mice and sensory-deafferented (capsaicin-treated) mice. The expression of orexigenic neuropeptides [neuropeptide Y (Npy) and agouti-related protein (Agrp)] in the hypothalamus was compared in fast/refed experiments. Conditioned taste aversion for high-fat diet (HFD) was tested in the d-serine-treated mice. Under the one-food-access paradigm, some of the d-serine-treated mice showed starvation, but not when fed normal chow. HFD feeding with d-serine ingestion did not cause aversion. Under the two-food-choice paradigm, d-serine suppressed the intake of high-preference food but not normal chow. d-Serine also effectively suppressed HFD intake but not normal chow in db/db mice and sensory-deafferented mice. In addition, d-serine suppressed normal chow intake after 24-h fasting despite higher orexigenic gene expression in the hypothalamus. d-Serine failed to suppress HFD intake in the presence of L-701,324, the selective and full antagonist at the glycine-binding site of the NMDA receptor. Therefore, d-serine suppresses the intake of high-preference food through coagonism toward NMDA receptors.

[Cotard's Syndrome in Three Patients with Schizophrenia--Pathology of Involutional and Senile-onset Endogenous Psychosis].

A large number of case studies on Cotard's syndrome have reported that this syndrome develops after repeated episodes of depression in the presenile stage of life. Therefore, it has been defined as a severe type of affective spectrum disorder. This report describes three patients who exhibited symptoms characteristic of Cotard's syndrome, such as negative thoughts and delusions of immortality, in the presenile and senile stages of their lives. They also had a history of long-term treatment for schizophrenia based on a diagnosis in early adulthood. Our review of reports on Cotard's syndrome revealed that the syndrome is more prevalent among presenile and senile female patients, who initially visit psychiatrists in their involutional and presenile stages of life with symptoms of an affective spectrum disorder, and later exhibit the symptoms of Cotard's syndrome. The results of the three case studies suggest that biological factors related to aging and sex differences may be associated with the development of Cotard's syndrome, regardless of the primary disorder. The pathology of "involutional and senile-onset endogenous psychosis," including Cotard's syndrome, is also discussed.

Comparison of alterations in cerebral hemoglobin oxygenation in late life depression and Alzheimer's disease as assessed by near-infrared spectroscopy.

BACKGROUND: Patients with Alzheimer's disease (AD) often present with apathy symptoms resembling the decreased motivation observed in depressed patients. Therefore, differentiating the initial phase of AD from late life depression may be difficult in some cases. Near-infrared spectroscopy (NIRS) is a functional neuroimaging modality that uses near-infrared light to measure changes in hemoglobin concentration on the cortical surface during activation tasks. The objective of this study was to investigate differences in brain activation associated with late life depression and with AD by means of NIRS. METHODS: NIRS was performed in 30 patients with depression, 28 patients with AD, and 33 healthy controls, all aged 60 years or older. During two tasks, a verbal fluency task and a visuospatial task, changes in oxygenated hemoglobin concentration in the frontal and parietal cortices were investigated. RESULTS: In the visuospatial task, cortical activation was lower in the depressed group than in the AD group, and significant differences were observed in the parietal cortex. CONCLUSIONS: NIRS can detect differences in brain activation between patients with late life depression and those with AD. NIRS is a promising tool for the differential diagnosis of late life depression and AD.

Supported employment for adults with severe mental illness.

BACKGROUND: People who suffer from severe mental disorder experience high rates of unemployment. Supported employment is an approach to vocational rehabilitation that involves trying to place clients in competitive jobs without any extended preparation. The Individual placement and support (IPS) model is a carefully specified form of supported employment. OBJECTIVES: 1. To review the effectiveness of supported employment compared with other approaches to vocational rehabilitation or treatment as usual.2. Secondary objectives were to establish how far:(a) fidelity to the IPS model affects the effectiveness of supported employment,(b) the effectiveness of supported employment can be augmented by the addition of other interventions. SEARCH METHODS: We searched the Cochrane Schizophrenia Group Trials Register (February 2010), which is compiled by systematic searches of major databases, handsearches and conference proceedings. SELECTION CRITERIA: All relevant randomised clinical trials focusing on people with severe mental illness, of working age (normally 16 to 70 years), where supported employment was compared with other vocational approaches or treatment as usual. Outcomes such as days in employment, job stability, global state, social functioning, mental state, quality of life, satisfaction and costs were sought. DATA COLLECTION AND ANALYSIS: Two review authors (YK and KK) independently extracted data. For binary outcomes, we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention-to-treat basis. For continuous data, we estimated mean difference (MD) between groups and its 95% (CI). We employed a fixed-effect model for analyses. A random-effects model was also employed where heterogeneity was present. MAIN RESULTS: A total of 14 randomised controlled trials were included in this review (total 2265 people). In terms of our primary outcome (employment: days in competitive employment, over one year follow-up), supported employment seems to significantly increase levels of any employment obtained during the course of studies (7 RCTs, n = 951, RR 3.24 CI 2.17 to 4.82, very low quality of evidence). Supported employment also seems to increase length of competitive employment when compared with other vocational approaches (1 RCT, n = 204, MD 70.63 CI 43.22 to 94.04, very low quality evidence). Supported employment also showed some advantages in other secondary outcomes. It appears to increase length (in days) of any form of paid employment (2 RCTs, n = 510, MD 84.94 CI 51.99 to 117.89, very low quality evidence) and job tenure (weeks) for competitive employment (1 RCT, n = 204, MD 9.86 CI 5.36 to 14.36, very low quality evidence) and any paid employment (3 RCTs, n = 735, MD 3.86 CI -2.94 to 22.17, very low quality evidence). Furthermore, one study indicated a decreased time to first competitive employment in the long term for people in supported employment (1 RCT, n = 204, MD -161.60 CI -225.73 to -97.47, very low quality evidence). A large amount of data were considerably skewed, and therefore not included in meta-analysis, which makes any meaningful interpretation of the vast amount of data very difficult. AUTHORS' CONCLUSIONS: The limited available evidence suggests that supported employment is effective in improving a number of vocational outcomes relevant to people with severe mental illness, though there appears to exist some overall risk of bias in terms of the quality of individual studies. All studies should report a standard set of vocational and non-vocational outcomes that are relevant to the consumers and policy-makers. Studies with longer follow-up should be conducted to answer or address the critical question about durability of effects.

Cavum septum pellucidum and cavum vergae with late-onset catatonia.

Associations between large cavum septum pellucidum and functional psychosis disorders, especially schizophrenia, have been reported. We report a case of late-onset catatonia associated with enlarged CSP and cavum vergae. A 66-year-old woman was presented with altered mental status and stereotypic movement. She was initially treated with aripiprazole and lorazepam. After 4 weeks, she was treated with electroconvulsive therapy. By 10 treatments, echolalia vanished, and catatonic behavior was alleviated. Developmental anomalies in the midline structure may increase susceptibility to psychosis, even in the elderly.

A review of recent case reports of cenesthopathy in Japan.

Idiopathic abnormal bodily sensations, or cenesthesic symptoms, are exhibited in a wide variety of mental illnesses. In Japan, patients with abnormal bodily sensations are often diagnosed with cenesthopathy. This study reviewed recent case reports of cenesthopathy. Of the 100 identified cases, young patients were more commonly men with predominant bodily cenesthesic symptoms, while older patients (≥40 years) were more commonly women with cenesthesic symptoms restricted to the oral cavity (oral cenesthopathy).

Association of cognitive performance with interleukin-6 receptor Asp358Ala polymorphism in healthy adults.

Wechsler adult intelligence scale-revised was performed in 576 healthy adults to examine whether a functional polymorphism (Asp358Ala) of the IL-6 receptor (IL-6R) gene is associated with cognitive performance. Verbal intelligence quotient in Asp homozygotes was significantly higher compared to Ala carriers (P = 0.005). Compared to Ala carriers, Asp homozygotes performed better in the verbal subtests requiring long-term memory stores. Elevated IL-6 and soluble IL-6R levels in Ala carriers may have negative impact on acquiring verbal cognitive ability requiring long-term memory.

What is the subtype of dementia in patients with fragility hip fracture?

INTRODUCTION: Cognitive function is an important factor that affects functional recovery after hip fracture (HipFx) surgery. The literature on the pathophysiology of dementia in HipFx patients is scarce. We performed a differential diagnosis of dementia in HipFx patients using clinical and brain MRI findings. METHODS: This is a prospective study in which brain MRI was evaluated for patients with HipFx for research purposes. One-hundred-and-five HipFx patients (85 females and 20 males) who underwent surgery and were subsequently able to undergo brain MRI at our hospital were evaluated. The mean age was 84 years. The presence of dementia was determined based on clinical findings and whether the patient meets its diagnostic criteria according to the International Classification of Diseases 10th Edition (ICD-10). The differential diagnosis of dementia was made based on brain MRI findings and the dementia diagnostic flow chart published in the Clinical Practice Guideline for Dementia 2017 (Japanese Society of Neurology). The Voxel-based Specific Regional Analysis System for Alzheimer's Disease (VSRAD) advance 2 diagnostic software was used to evaluate atrophy of the para-hippocampal gyrus. RESULTS: Fifty-six (53%) patients were clinically diagnosed with dementia according to the ICD-10 criteria. The MRI findings were diverse: Alzheimer's disease (AD)-type, asymptomatic multiple ischemic cerebral lesions, past symptomatic cerebral infarction or cerebral hemorrhage, Binswanger's disease (BW)-type, chronic subdural hematoma, disproportionately enlarged subarachnoidal hydrocephalus (DESH), and their combinations thereof. A combination of MRI and clinical findings of dementia patients demonstrated the following distribution of dementia subtypes: AD (n = 20), vascular dementia (n = 33), AD and BW vascular dementia (n = 3). CONCLUSION: This study revealed that the brain MRI findings of HipFx patients were diverse. Although vascular dementia is found to be common in this particular population, this could be an incidental finding. Further study is warranted to clarify the specificity of our findings by increasing the number of patients, setting the control, and investigating whether dementia subtypes affect postoperative gait acquisition and fall risk.

Association of interleukin-1ß genetic polymorphisms with cognitive performance in elderly females without dementia.

Interleukin-1ß (IL-1ß) is considered to have a role in age-related cognitive decline. A recent study has shown that a promoter polymorphism of the IL-1ß gene (rs16944) is associated with cognitive performance in elderly males without dementia. In this study, we examined whether polymorphisms of the IL-1ß gene also influence cognitive functions in elderly females. Cognitive functions were assessed by the Wechsler adult intelligence scale-revised (WAIS-R) in 99 elderly (60 years) females without dementia. We selected five tagging polymorphisms from the IL-1ß gene and examined the associations with the WAIS-R scores. Significant associations were found between verbal intelligence quotient (IQ) and the genotypes of rs1143634 and rs1143633 (P=0.0037 and P=0.010, respectively). No significant associations of rs16944 genotype were found with verbal or performance IQ. However, individuals homozygous for the G allele of rs16944 achieved higher scores in digit span compared with their counterpart, which is consistent with the previous findings in males. These results suggest that IL-1ß gene variation may have a role in cognitive functions in aging females as well as males.

Modulation of cortisol responses to the DEX/CRH test by polymorphisms of the interleukin-1beta gene in healthy adults.

BACKGROUND: Recently, hypothalamus-pituitary-adrenal (HPA) axis function assessed with the combined dexamethasone (DEX)/corticotropin releasing hormone (CRH) test has been shown to be associated with response to antidepressant treatment. A polymorphism (rs16944) in the interleukin-1beta (IL-1ß) gene has also been reported to be associated with the medication response in depression. These findings prompted us to examine the possible association between IL-1ß gene polymorphisms and HPA axis function assessed with the DEX/CRH test. METHODS: DEX/CRH test was performed in 179 healthy volunteers (45 males: mean age 40.5 ± 15.8 years; 134 females: mean age 47.1 ± 13.2 years). Five tagging single nucleotide polymorphisms (SNPs) of IL-1ß gene (rs2853550, rs1143634, rs1143633, rs1143630, rs16944) were selected at an r2 threshold of 0.80 with a minor allele frequency > 0.1. Genotyping was performed by the TaqMan allelic discrimination assay. A two-way factorial analysis of variance (ANOVA) was performed with the DEX/CRH test results as the dependent variable and genotype and gender as independent variables. To account for multiple testing, P values < 0.01 were considered statistically significant for associations between the genotypes and the cortisol levels. RESULTS: The cortisol levels after DEX administration (DST-Cortisol) showed significant associations with the genotypes of rs16944 (P = 0.00049) and rs1143633 (P = 0.0060), with no significant gender effect or genotype × gender interaction. On the other hand, cortisol levels after CRH administration (DEX/CRH-Cortisol) were affected by gender but were not significantly influenced by the genotype of the examined SNPs, with no significant genotype × gender interaction. CONCLUSIONS: Our results suggest that genetic variations in the IL-1ß gene contribute to the HPA axis alteration assessed by DST-Cortisol in healthy subjects. On the other hand, no significant associations of the IL-1ß gene polymorphisms with the DEX/CRH-Cortisol were observed. Confirmation of our findings in futures studies may add new insight into the communication between the immune system and the HPA axis.

Possible association between interleukin-1ß gene and schizophrenia in a Japanese population.

BACKGROUND: Several lines of evidence have implicated the pro-inflammatory cytokine interleukin-1beta (IL-1ß) in the etiology of schizophrenia. Although a number of genetic association studies have been reported, very few have systematically examined gene-wide tagging polymorphisms. METHODS: A total of 533 patients with schizophrenia (302 males: mean age ± standard deviation 43.4 ± 13.0 years; 233 females; mean age 44.8 ± 15.3 years) and 1136 healthy controls (388 males: mean age 44.6 ± 17.3 years; 748 females; 46.3 ± 15.6 years) were recruited for this study. All subjects were biologically unrelated Japanese individuals. Five tagging polymorphisms of IL-1ß gene (rs2853550, rs1143634, rs1143633, rs1143630, rs16944) were examined for association with schizophrenia. RESULTS: Significant difference in allele distribution was found between patients with schizophrenia and controls for rs1143633 (P = 0.0089). When the analysis was performed separately in each gender, significant difference between patients and controls in allele distribution of rs1143633 was observed in females (P = 0.0073). A trend towards association was also found between rs16944 and female patients with schizophrenia (P = 0.032). CONCLUSIONS: The present study shows the first evidence that the IL-1ß gene polymorphism rs1143633 is associated with schizophrenia susceptibility in a Japanese population. The results suggest the possibility that the influence of IL-1ß gene variations on susceptibility to schizophrenia may be greater in females than in males. Findings of the present study provide further support for the role of IL-1ß in the etiology of schizophrenia.

Comparison of diagnostic names of mental illnesses in medical documents before and after the adoption of a new Japanese translation of 'schizophrenia'.

AIM: The name of a disease entered in medical documents often differs from the true diagnosis in psychiatric practice. We examined the effects of different translations of 'schizophrenia' into Japanese on the usage of disease names in documents. METHODS: We conducted a retrospective survey of the names of diseases used in the medical documents of 250 outpatients with schizophrenia or depression. These patients had attended our department of psychiatry between 1998 and 2000. We also investigated the names of the diseases of 226 outpatients who had first visited our department between 2003 and 2007. We defined the diagnosis (based on ICD-10) as the 'ICD-10 disease name' and the name of the disease written in medical documents as the 'disease name in documents'. We classified the documents that were used to apply for national psychiatric care and welfare services as 'official documents' and those submitted to others as 'private documents'. RESULTS: Prior to 2000, the term 'seishin-bunretsu-byo' ('split-mind disease'; old translation of 'schizophrenia') was used in 72.3% of official documents and 3.6% of private documents. In 2003 and later, the term 'togo-shitcho-sho' ('integration disorder'; new translation of 'schizophrenia') was used in 98.0% of official documents and 21.7% of private documents. CONCLUSION: The use of 'togo-shitcho-sho' in official documents has become established. On the other hand, terms such as 'nervous breakdown' and 'depressive state' are still commonly used in private documents after the adoption of the new Japanese translation of schizophrenia.

[Psychiatric occupational therapy practice in Shinshu University Hospital--collaboration with psychiatrist].

This report describes psychiatric occupational therapy practice and collaboration between occupational therapists and psychiatrists at Shinshu University Hospital. Collaboration with psychiatrists enables us to provide the following occupational therapy programs. (1) Individual occupational therapy approaches for patients at the early recovery stage in the psychiatric ward. (2) Psychoeducational interventions by a multi-disciplinary team (MDs, nurses, OTRs, PSWs, CPs). (3) Occupational therapy approaches used in combination with m-ECT for severe psychiatric disorders. (4) Recovery support programs for psychiatric outpatients. It is suggested that occupational therapists should collaborate with psychiatrists in order to facilitate rehabilitation services for people with psychiatric disorders.

Nasu-Hakola disease: The first case reported by Nasu and review: The 50th Anniversary of Japanese Society of Neuropathology.

Nasu-Hakola disease (NHD) was first reported separately by Nasu and Hakola around the same time in the 1970s. It is an autosomal recessive inherited disorder characterized by progressive dementia and repeated pathological fractures during adolescence. It has recently been demonstrated that NHD is caused by a mutation in the TREM2 or DAP12 gene. The present paper demonstrates the first patient reported by Nasu and reviews NHD. The patient was a man who died at the age 38 years. His family history was unremarkable. There was no abnormal developmental history. At the age of 26, the patient suffered a pathological fracture of the right tibia, and X-ray confirmed bone resorption in the right tibia. As for mental status, the patient tended to be euphoric. After that, bone resorption was also seen in other long bones. At the age of 33, the patient could not walk after suffering a right femoral neck fracture. He was apathetic and exhibited behavioral abnormalities. At the age of 38, he could not move or speak and subsequently died. General pathological examination showed yellow opaque gelatinous substances in the medullary cavities, matching translucent cystic lesions in the femur, tibia, and fibula on X-rays. Light microscopy showed numerous membranocystic changes in the substances. The brain weighed 1050 g. Symmetric systemic cerebral atrophy, in particular atrophy of the cerebral white matter in the occipital and temporal lobes, was confirmed. Histological examination showed white matter degeneration and diffuse sclerosis accompanied by astroglial proliferation. Severe demyelination was confirmed. Axonal degeneration and destruction were marked. In demyelinated areas, fat granule cells appeared, and lipid granule-positive cells aggregated around vessels. Cerebral cortical neurons were relatively maintained. In the brain, no membranocystic lesions could be recognized. In the DAP12 gene, the patient had a conversion of nucleotide at position 116 resulting in serine 38 to asparagine substitution.

Neuroanatomical correlates of attention-deficit-hyperactivity disorder accounting for comorbid oppositional defiant disorder and conduct disorder.

AIM: An increasing number of neuroimaging studies have been conducted to uncover the pathophysiology of attention-deficit-hyperactivity disorder (ADHD). The findings are inconsistent, however, at least partially due to methodological differences. In the present study voxel-based morphometry (VBM) was used to evaluate brain morphology in ADHD subjects after taking into account the confounding effect of oppositional defiant disorder (ODD) and conduct disorder (CD) comorbidity. METHODS: Eighteen children with ADHD and 17 age- and gender-matched typically developing subjects underwent high-spatial resolution magnetic resonance imaging. The regional gray matter volume differences between the children with ADHD and controls were examined with and without accounting for comorbid ODD and CD in a voxel-by-voxel manner throughout the entire brain. RESULTS: The VBM indicated significantly smaller regional gray matter volume in regions including the bilateral temporal polar and occipital cortices and the left amygdala in subjects with ADHD compared with controls. Significantly smaller regional gray matter volumes were demonstrated in more extensive regions including the bilateral temporal polar cortices, bilateral amygdala, right occipital cortex, right superior temporal sulcus, and left middle frontal gyrus after controlling for the confounding effect of comorbid ODD and CD. CONCLUSION: Morphological abnormalities in ADHD were seen not only in the regions associated with executive functioning but also in the regions associated with social cognition. When the effect of comorbid CD and ODD was taken into account, there were more extensive regions with significantly smaller volume in ADHD compared to controls.