Yuko Higuchi

Cognitive functioning related to quality of life in schizophrenia

The present study compared the cognitive function of patients with schizophrenia to that of healthy subjects, and investigated the relationships between cognitive function and quality of life (QOL). Participants consisted of 53 patients meeting DSM-IV criteria for schizophrenia and 31 normal controls. All participants completed a neuropsychological test battery assessing executive function, verbal memory, and social knowledge. QOL was rated using the Schizophrenia Quality of Life Scale. Patients with schizophrenia showed lower performance across various cognitive measures of memory, including the Sentence Memory Test, the Verbal Learning Test, and the Script Test, as well as the Rule Shift Cards Test of executive function. Multiple regression analyses were used to evaluate the neuropsychological measures and clinical symptoms to predict QOL. The QOL total score, the social initiative score or the empathy score were significantly predicted by the Script or/and the Sentence Memory. Neuropsychological functioning was unrelated to most QOL scores in the presence of clinical symptoms, while ability of empathy in the QOL was predicted by performance of the Sentence Memory Test. These results demonstrated patients with schizophrenia have deficits in executive function, memory and learning, and social knowledge, and that social knowledge and memory are related to QOL. Thus, in patients with schizophrenia, deficits in social knowledge appear to be associated with current QOL in general, and specifically with the capacity for empathy and social initiative.

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.

Neural Basis for the Ability of Atypical Antipsychotic Drugs to Improve Cognition in Schizophrenia

Cognitive impairments are considered to largely affect functional outcome in patients with schizophrenia, other psychotic illnesses, or mood disorders. Specifically, there is much attention to the role of psychotropic compounds acting on serotonin (5-HT) receptors in ameliorating cognitive deficits of schizophrenia. It is noteworthy that atypical antipsychotic drugs (AAPDs), e.g., clozapine, melperone, risperidone, olanzapine, quetiapine, aripiprazole, perospirone, blonanserin, and lurasidone, have variable affinities for these receptors. Among the 5-HT receptor subtypes, the 5-HT1A receptor is attracting particular interests as a potential target for enhancing cognition, based on preclinical and clinical evidence. The neural network underlying the ability of 5-HT1A agonists to treat cognitive impairments of schizophrenia likely includes dopamine, glutamate, and gamma-aminobutyric acid neurons. A novel strategy for cognitive enhancement in psychosis may be benefited by focusing on energy metabolism in the brain. In this context, lactate plays a major role, and has been shown to protect neurons against oxidative and other stressors. In particular, our data indicate chronic treatment with tandospirone, a partial 5-HT1A agonist, recover stress-induced lactate production in the prefrontal cortex of a rat model of schizophrenia. Recent advances of electrophysiological measures, e.g., event-related potentials, and their imaging have provided insights into facilitative effects on cognition of some AAPDs acting directly or indirectly on 5-HT1A receptors. These findings are expected to promote the development of novel therapeutics for the improvement of functional outcome in people with schizophrenia.

Electrophysiological basis for the ability of olanzapine to improve verbal memory and functional outcome in patients with schizophrenia: A LORETA analysis of P300

Abnormality of P300 waveforms of event-related potentials (ERPs) has been suggested to represent an aspect of the pathophysiology of schizophrenia. Previous work points to the contribution of altered neural function in discrete brain regions in the left hemisphere to psychotic symptoms and cognitive deficits of schizophrenia. In this study, we sought to determine: 1) if patients with schizophrenia elicit a decreased P300 current source density in brain areas, such as the superior temporal gyrus (STG); 2) if decreased P300 generator density in the left STG is recovered by treatment with the most widely-used antipsychotic drug olanzapine; and 3) if the recovery of P300 source density is associated with improvements of cognitive and functional status. P300 in response to an auditory oddball task, as well as verbal learning memory, psychopathology, and quality of life were evaluated in 16 right-handed patients with schizophrenia before and after treatment with olanzapine for 6 months. ERP data were also obtained from 16 right-handed age and gender-matched normal volunteers. Low resolution electromagnetic tomography (LORETA) analysis was used to obtain current density images of P300. Patients with schizophrenia showed significantly smaller LORETA values in several brain regions in the left side, particularly STG, middle frontal gyrus, and precentral gyrus, compared with control subjects. Six-month treatment with olanzapine significantly increased P300 source density only in the left STG. Positive symptoms, negative symptoms, verbal learning memory, and quality of life were also improved during treatment. Significant correlations were found between the increase in LORETA values of left STG vs. improvements of negative symptoms, as measured by Scale for the Assessment of the Negative Symptoms, and verbal learning memory, as measured by the Japanese Verbal Learning Test. Improvement of quality of life, as evaluated by the Quality of Life Scale, were significantly associated with an increase in LORETA values of middle frontal gyrus, and tended to correlate with that of precentral gyrus. The results of this study suggest that changes in cortical activity, as measured by ERPs, are responsible for the ability of some antipsychotic drugs to improve cognition and functional outcome in patients with schizophrenia.

Effect of perospirone on P300 electrophysiological activity and social cognition in schizophrenia: a three-dimensional analysis with sloreta.

The purpose of this study was to determine if perospirone, a second generation antipsychotic drug and partial agonist at serotonin-5-HT(1A) receptors, enhances electrophysiological activity, such as event-related potentials (ERPs), in frontal brain regions, as well as cognitive function in subjects with schizophrenia. P300 current source images were obtained by means of standardized low resolution brain electromagnetic tomography (sLORETA) before and after treatment with perospirone for 6 months. Perospirone significantly increased P300 current source density in the left superior frontal gyrus, and improved positive symptoms and performance on the script tasks, a measure of verbal social cognition, while verbal learning memory tended to be improved. There was a significant correlation between the changes in P300 amplitude on the left frontal lead and those in social cognition. These results suggest the changes in three-dimensional distribution of cortical activity, as demonstrated by sLORETA, may mediate some of the actions of antipsychotic drugs. The distinct cognition-enhancing profile of perospirone in patients with schizophrenia may be related to its actions on 5-HT(1A) receptors.

Voxel-based analysis of P300 electrophysiological topography associated with positive and negative symptoms of schizophrenia.

Abnormal P300 waveforms of the event-related potentials during the auditory oddball task are one of the most consistent findings in patients with schizophrenia. In the present study, we sought to test the hypothesis that the abnormal P300 waveform results from composite representation of neural activity in anatomically distinct brain regions responsible for the manifestation of positive and negative symptoms. We used the low-resolution brain electromagnetic tomography (LORETA) to obtain current density images of the P300 component from 26 patients with schizophrenia. The statistical parametric mapping (SPM) was applied to the LORETA images in order to identify brain regions that are related with the severity of psychotic symptoms as evaluated by the Brief Psychiatric Rating Scale (BPRS). The BPRS Total score was negatively correlated with the P300 current density in the left superior temporal gyrus (r=-0.615, corrected p=0.009) and that in the right medial frontal region (r=-0.571, corrected p=0.019) by means of SPM single-subject covariates model. These brain regions were included in the region-specific P300 sources as represented by the current density maxima (corrected p<0.05) using SPM one-sample t-test. A subsequent region-of-interest analysis of Pearson correlations revealed specific relationships between the Positive subscale score and the mean current density in the left superior temporal gyrus (r=-0.528, p=0.005) and between the Negative subscale score and the mean current densities in the medial frontal region (r=-0.551, p=0.003) and left superior temporal gyrus (r=-0.499, p=0.009). These results indicate that functional disturbances of neural networks involving the medial prefrontal and superior temporal regions may be responsible for the generation of positive and the negative psychotic symptoms of schizophrenia.

Essential polyunsaturated fatty acids and social cognition in schizophrenia

Abnormal metabolism of essential polyunsaturated fatty acids (EPUFAs), a component of phospholipids in neural membranes, has been suggested to be related to the pathophysiology of schizophrenia. The purpose of this study was to examine the relationship between EPUFA concentrations in erythrocyte membranes, a peripheral measure of phospholipid composition in the brain, and clinical variables, such as cognitive performance relevant to social functions, in patients with schizophrenia. Erythrocyte membrane levels of EPUFAs, saturated fatty acids, and monounsaturated acids were measured in 25 patients with schizophrenia and 32 age- and gender-matched 32 normal volunteers. The script tasks, a measure of social cognition, and the Brief Psychiatric Rating Scale were administered to the patients. The levels of EPUFAs, but not those of saturated or monosaturated fatty acids, were significantly lower in patients than in normal controls. The degree of a decrease in EPUFA levels was positively correlated with severity of positive symptoms and impairment of frequency judgment performance on the script tasks, while no such correlations were found with negative symptoms, attention as measured by the Wechsler Adult Intelligence Scale-Revised-Digit Span, or verbal memory as measured by the Auditory Verbal Learning Test. These results provide the first suggestion for a contribution of decreased levels of EPUFAs to impaired social cognition, as represented by event schema, in patients with schizophrenia.

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.

Electrical brain activity and response to olanzapine in schizophrenia: a study with LORETA images of P300.

The aim of this study was to evaluate the change in the distribution for the P300 generator, as demonstrated by Low Resolution Electromagnetic Tomography (LORETA) images, in patients with schizophrenia during treatment with olanzapine. Data were obtained from five right-handed patients treated with olanzapine for 6 months. Five right-handed normal volunteers also participated in the study. LORETA images of P300 in response to the odd-ball auditory discrimination task revealed a left dominant lateralized high current source density in the temporal lobes in all control subjects. Although this pattern of brain activation was not evident in patients at baseline, 6-month treatment with olanzapine recovered the left dominant pattern of the electrical density in the temporal regions, such as the Heschl gyrus, and improved performance on a test of verbal learning and memory. Scores of the Brief Psychiatric Rating Scale and the Global Assessment of Functioning Scale also improved during treatment. These results provide the first suggestion that enhancement of verbal memory and the functional status by treatment with some antipsychotic drugs may be associated with modulations of the anatomical configuration of electrical brain activity in patients with schizophrenia.