Tomonori Seo

Mismatch Negativity and Cognitive Performance for the Prediction of Psychosis in Subjects with At-Risk Mental State

Background A shorter duration of untreated psychosis has been associated with better prognosis in schizophrenia. In this study, we measured the duration mismatch negativity (dMMN), an event-related potential, and cognitive performance in subjects with at-risk mental state (ARMS), patients with first-episode or chronic schizophrenia, and healthy volunteers. The main interest was to determine if these neurocognitive measures predict progression to overt schizophrenia in ARMS subjects. Methodology/Principal Findings Seventeen ARMS subjects, meeting the criteria of the Comprehensive Assessment of At-Risk Mental State, 31 schizophrenia patients (20 first-episode and 11 chronic) and healthy controls (N = 20) participated in the study. dMMN was measured by an auditory odd-ball paradigm at baseline. Neuropsychological performance was evaluated by the Japanese version of the Brief assessment of cognitive function of schizophrenia (BACS-J). The first-episode schizophrenia group showed significantly smaller amplitudes at frontal electrodes than did control subjects whereas chronic patients elicited smaller amplitudes at frontal and central electrodes, consistent with previous reports. During the follow-up period, 4 out of the 17 ARMS subjects transitioned to schizophrenia (converters) while 13 did not (non-converters). Specifically, dMMN amplitudes of non-converters did not differ from those of healthy controls, while converters showed significantly smaller dMMN amplitudes at some electrodes compared to control subjects. Converters performed significantly worse on tests of working memory, verbal fluency, and attention/information processing than did non-converters. There was a significant positive correlation between dMMN amplitudes at the frontal electrodes and verbal fluency, as measured by the BACS, in the AMRS subjects as a whole. Conclusions/Significance ARMS subjects who later developed schizophrenia elicited smaller dMMN amplitudes to begin with, compared to non-converters. Notably, we have provided the first evidence for the ability of verbal fluency to predict dMMN amplitudes in ARMS subjects. These findings are expected to add to the efforts for early diagnosis and intervention of schizophrenia.

Neonatal exposure to MK-801, an N-methyl-d-aspartate receptor antagonist, enhances methamphetamine-induced locomotion and disrupts sensorimotor gating in pre- and postpubertal rats

Administration of non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists (e.g. phencyclidine, MK-801) has been shown to elicit behavioral abnormalities related to symptoms of schizophrenia, such as spontaneous locomotor activity and impaired sensorimotor gating, as represented by deficits of prepulse inhibition (PPI). We sought to determine whether transient blockade of NMDA receptors at the neonatal stage would produce dopamine supersensitivity around puberty, as manifested by these behavioral measures. For this purpose, we examined methamphetamine (MAP; 1.0mg/kg, i.p.)-induced locomotor activity and PPI in pre- (postnatal day; PD 36-38) or post- (PD 64-66) puberty in rats administered MK-801 (0.2mg/kg/day, s.c.) between PD 7 and PD 10. Neonatal MK-801 treatment augmented MAP-induced hyperlocomotion especially in the early adulthood, whereas spontaneous locomotor activity and rearing were not changed. MK-801 administration also disrupted PPI without affecting startle amplitudes around puberty. These findings suggest that transient exposure to MK-801 in the neonatal stage causes exaggerated dopamine transmission and cognitive deficits, particularly in the post-puberty stage.

Criterion and Construct Validity of the CogState Schizophrenia Battery in Japanese Patients with Schizophrenia

Background The CogState Schizophrenia Battery (CSB), a computerized cognitive battery, covers all the same cognitive domains as the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery but is briefer to conduct. The aim of the present study was to evaluate the criterion and construct validity of the Japanese language version of the CSB (CSB-J) in Japanese patients with schizophrenia. Methodology/Principal Findings Forty Japanese patients with schizophrenia and 40 Japanese healthy controls with matching age, gender, and premorbid intelligence quotient were enrolled. The CSB-J and the Brief Assessment of Cognition in Schizophrenia, Japanese-language version (BACS-J) were performed once. The structure of the CSB-J was also evaluated by a factor analysis. Similar to the BACS-J, the CSB-J was sensitive to cognitive impairment in Japanese patients with schizophrenia. Furthermore, there was a significant positive correlation between the CSB-J composite score and the BACS-J composite score. A factor analysis showed a three-factor model consisting of memory, speed, and social cognition factors. Conclusions/Significance This study suggests that the CSB-J is a useful and rapid automatically administered computerized battery for assessing broad cognitive domains in Japanese patients with schizophrenia.

LORETA Current Source Density for Duration Mismatch Negativity and Neuropsychological Assessment in Early Schizophrenia

Introduction Patients with schizophrenia elicit cognitive decline from the early phase of the illness. Mismatch negativity (MMN) has been shown to be associated with cognitive function. We investigated the current source density of duration mismatch negativity (dMMN), by using low-resolution brain electromagnetic tomography (LORETA), and neuropsychological performance in subjects with early schizophrenia. Methods Data were obtained from 20 patients meeting DSM-IV criteria for schizophrenia or schizophreniform disorder, and 20 healthy control (HC) subjects. An auditory odd-ball paradigm was used to measure dMMN. Neuropsychological performance was evaluated by the brief assessment of cognition in schizophrenia Japanese version (BACS-J). Results Patients showed smaller dMMN amplitudes than those in the HC subjects. LORETA current density for dMMN was significantly lower in patients compared to HC subjects, especially in the temporal lobes. dMMN current density in the frontal lobe was positively correlated with working memory performance in patients. Conclusions This is the first study to identify brain regions showing smaller dMMN current density in early schizophrenia. Further, poor working memory was associated with decreased dMMN current density in patients. These results are likely to help understand the neural basis for cognitive impairment of schizophrenia.

Electrophysiological and Neuropsychological Predictors of Conversion to Schizophrenia in At-Risk Subjects

Patients with schizophrenia show neurophysiological and psychological disturbances before the onset of the illness. Mismatch negativity (MMN), an event-related potential, has been shown to be associated with cognitive function. Specifically, duration MMN (dMMN) amplitudes have been indicated to predict progression to overt schizophrenia in subjects with at-risk mental state. The aim of this article is to provide a hypothesis that a combined assessment of dMMN and neuropsychological performance would enhance accuracy for predicting conversion to schizophrenia in at-risk subjects. Data from these neurocognitive modalities in subjects with first-episode schizophrenia (FES) are also presented. There is accumulated evidence that converters to schizophrenia among at-risk subjects show significantly smaller dMMN amplitudes than those in healthy control (HC) subjects at the frontal lead before the onset. In fact, the amplitudes in these converters have been reported to be similar to those in FES to begin with. dMMN current source density, by means of low-resolution brain electromagnetic tomography, was significantly lower in FES than HC subjects, especially in some medial temporal regions which are implicated in the pathophysiology of schizophrenia. Importantly, dMMN current density in the frontal lobe was positively correlated with working memory performance in FES subjects. These findings indicate the utility of the combination of electrophysiological/neuropsychological assessments for early intervention into patients with schizophrenia and high-risk people.

Effect of Tandospirone on Mismatch Negativity and Cognitive Performance in Schizophrenia: A Case Report

To the Editors: D isturbances of cognitive function, evaluated by neurophysiological and psychological measures, have been shown to predict outcome in patients with schizophrenia. Mismatch negativity (MMN) is an event-related potential (ERP) generated in response to occasional variations of acoustic stimuli and is suggested to reflect preattentive cognitive operations. Specifically, reduced MMN amplitudes in response to frequent-deviant stimuli have been associated with the pathophysiology of schizophrenia, including decreased gray matter volumes of the prefrontal cortex and superior temporal gyrus. A limited number of studies report the ability of dopamine, serotonin (5-HT), and N-methyl-D-aspartate acid (NMDA) transmissions to modulate MMN in healthy human subjects. Here, we report a case of schizophrenia in which adjunctive use of tandospirone, a 5-HT1A partial agonist and anxiolytic, was effective for enhancing MMN and improving cognitive performance.

Serotonin-1A receptor gene polymorphism and the ability of antipsychotic drugs to improve attention in schizophrenia

IntroductionThe purpose of this study was to determine if the functional single nucleotide polymorphisms of rs6259 C(-1019)G in the promoter region, which regulates serotonin 5-HT1A receptor transcription, affects the ability of antipsychotic drugs to improve attention in patients with schizophrenia.MethodsSubjects were neuroleptic-free and meeting DSM-IV-TR criteria for schizophrenia. Psychopathology and attention were evaluated with the Scale for the Assessment of Positive Symptoms (SAPS) and the Scale for the Assessment of Negative Symptoms (SANS) at baseline and 3 months after treatment with atypical antipsychotic drugs (AAPDs). DNA was extracted from peripheral blood following standard procedures. Genotyping was performed with HS-Taq assay (LaboPass™).ResultsData were available from 30 subjects (male/female=19/11), in which 17 had the CC genotype, three had the GG genotype, and 10 were heterozygous. The 3-month treatment with AAPDs was associated with significant improvements in positive and negative symptoms, but not attention as measured by SANS-Attention subscale in the entire subject group. There were no significant differences in the degree of improvements of SAPS and SANS scores between the CC genotype group and the (C/G plus G/G) combined group. On the other hand, improvement of attention was significantly greater for the former group compared to the latter group (P<0.016), suggesting a detrimental influence of the G-allele.ConclusionThese results provide additional support to the role of 5-HT1A receptors in some of the cognitive disturbances of schizophrenia. Further studies with a larger number of subjects are warranted.

Effect of transient blockade of N-methyl-D-aspartate receptors at neonatal stage on stress-induced lactate metabolism in the medial prefrontal cortex of adult rats: Role of 5-HT1A receptor agonism

Decreased activity of the medial prefrontal cortex (mPFC) has been considered a basis for core symptoms of schizophrenia, an illness associated with a neurodevelopmental origin. Evidence from preclinical and clinical studies indicates that serotonin (5‐HT)1A receptors play a crucial role in the energy metabolism of the mPFC. This study was undertaken to determine (1) if transient blockade of N‐methyl‐D‐aspartate receptors during the neonatal stage inhibit energy demands in response to stress, as measured by extracellular lactate concentrations, in the mPFC at the young adult stage, and (2) if tandospirone, a 5‐HT1A partial agonist, reverses the effect of the neonatal insult on energy metabolism. Male pups received MK‐801 (0.20 mg/kg) on postnatal days (PDs) 7–10. On PD 63, footshock stress‐induced lactate levels were measured using in vivo microdialysis technique. Tandospirone (0.1, 1.0, and 5.0 mg/kg) was administered once daily for 14 days before the measurement of lactate levels. Neonatal MK‐801 treatment suppressed footshock stress‐induced lactate production in the mPFC, but not caudate‐putamen, whereas basal lactate levels were not significantly changed in either brain region. The MK‐801‐induced suppression of footshock stress‐induced lactate production in the mPFC was attenuated by tandospirone at 1.0mg/kg/day, but not 0.1 or 5.0 mg/kg/day, which is an effect antagonized by coadministration of WAY‐100635, a selective 5‐HT1A antagonist. These results suggest a role for impaired lactate metabolism in some of the core symptoms of schizophrenia, for example, negative symptoms and cognitive deficits. The implications for the ability of 5‐HT1A agonism to ameliorate impaired lactate production in the mPFC of this animal model are discussed. Synapse, 2012.

T-817MA, but Not Haloperidol and Risperidone, Restores Parvalbumin-Positive γ-Aminobutyric Acid Neurons in the Prefrontal Cortex and Hippocampus of Rats Transiently Exposed to MK-801 at the Neonatal Period

The number of parvalbumin (PV)-positive γ-aminobutyric acid (GABA) neurons is decreased in the brain of rats transiently exposed to MK-801, an N-methyl-D-aspartate (NMDA) receptor blocker, in the neonatal stage (Uehara et al. (2012)). T-817MA [1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl} azetidin-3-ol maleate] is a neuroprotective agent synthesized for the treatment of psychiatric disorders characterized by cognitive disturbances, such as dementia. We herein sought to determine whether T-817MA, haloperidol (HPD), or risperidone (RPD) would ameliorate the decrease in the number of PV-positive GABA neurons in the medial prefrontal cortex (mPFC) and hippocampus of the model animals. Rats were treated with MK-801 (0.2 mg/kg/day) or vehicle on postnatal days (PD) 7–10, and the number of PV-positive neurons in the mPFC and hippocampus were measured on PDs 63. T-817MA (20 mg/kg), HPD (1 mg/kg), or RPD (1 mg/kg) were administered during PDs 49–62. Fourteen-day administration of T-817MA reversed the decrease in the number of PV-positive neurons in the above brain regions of rats given MK-801, whereas HPD and RPD were ineffective. These results indicate that T-817MA provides a novel pharmacologic strategy to enhance cognitive function in patients with schizophrenia.

Associations between daily living skills, cognition, and real-world functioning across stages of schizophrenia; a study with the Schizophrenia Cognition Rating Scale Japanese version

Cognitive function is impaired in patients with schizophrenia-spectrum disorders, even in their prodromal stages. Specifically, the assessment of cognitive abilities related to daily-living functioning, or functional capacity, is important to predict long-term outcome. In this study, we sought to determine the validity of the Schizophrenia Cognition Rating Scale (SCoRS) Japanese version, an interview-based measure of cognition relevant to functional capacity (i.e. co-primary measure). For this purpose, we examined the relationship of SCoRS scores with performance on the Brief Assessment of Cognition in Schizophrenia (BACS) Japanese version, a standard neuropsychological test battery, and the Social and Occupational Functioning Assessment Scale (SOFAS), an interview-based social function scale. Subjects for this study (n = 294) included 38 patients with first episode schizophrenia (FES), 135 with chronic schizophrenia (CS), 102 with at-risk mental state (ARMS) and 19 with other psychiatric disorders with psychosis. SCoRS scores showed a significant relationship with SOFAS scores for the entire subjects. Also, performance on the BACS was significantly correlated with SCoRS scores. These associations were also noted within each diagnosis (FES, CS, ARMS). These results indicate the utility of SCoRS as a measure of functional capacity that is associated both with cognitive function and real-world functional outcome in subjects with schizophrenia-spectrum disorders.