Tatsuya Nagasawa

P300 and the thought disorder factor extracted by factor-analytic procedures in schizophrenia

BACKGROUND In order to clarify the clinical significance of P300 as a biologic marker that can reflect schizophrenic symptomatology, many previous studies have evaluated the relationship of P300 with the symptoms on the basis of a positive/negative dichotomy, but yielded inconsistent conclusions. Such a dichotomy has been criticized as being too reductionistic. Recently, most studies with factor-analytic procedures have extracted some symptom factors outside this dichotomy. Therefore, it is important to examine associations of P300 with the symptom factors extracted by these statistical analyses. METHODS In the present study, the amplitudes of P300 were measured by using an auditory oddball paradigm for 73 schizophrenics whose psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS). RESULTS The principal component analysis of the PANSS items revealed five factors labeled the thought disorder, negative, hostile/excitable, delusional/hallucinatory, and depressive factors. The score for the thought disorder factor correlated negatively with the amplitude of P300 recorded at Pz T5, and T6, but that for the other factors did not. CONCLUSIONS These findings suggest that the reduction of P300 amplitudes recorded at the midline parietal and bilateral temporoparietal regions may be one of the electrophysiologic indices representing the thought disorder clinically observed in schizophrenia.

Frontal areas contribute to reduced global coordination of resting-state gamma activities in drug-naïve patients with schizophrenia

Schizophrenia has been postulated to involve impaired neuronal cooperation in large-scale neural networks, including cortico-cortical circuitry. Alterations in gamma band oscillations have attracted a great deal of interest as they appear to represent a pathophysiological process of cortical dysfunction in schizophrenia. Gamma band oscillations reflect local cortical activities, and the synchronization of these activities among spatially distributed cortical areas has been suggested to play a central role in the formation of networks. To assess global coordination across spatially distributed brain regions, Omega complexity (OC) in multichannel EEG was proposed. Using OC, we investigated global coordination of resting-state EEG activities in both gamma (30-50 Hz) and below-gamma (1.5-30 Hz) bands in drug-naïve patients with schizophrenia and investigated the effects of neuroleptic treatment. We found that gamma band OC was significantly higher in drug-naïve patients with schizophrenia compared to control subjects and that a right frontal electrode (F3) contributed significantly to the higher OC. After neuroleptic treatment, reductions in the contribution of frontal electrodes to global OC in both bands correlated with the improvement of schizophrenia symptomatology. The present study suggests that frontal brain processes in schizophrenia were less coordinated with activity in the remaining brain. In addition, beneficial effects of neuroleptic treatment were accompanied by improvement of brain coordination predominantly due to changes in frontal regions. Our study provides new evidence of improper intrinsic brain integration in schizophrenia by investigating the resting-state gamma band activity.

Auditory P300 amplitude as a state marker for positive symptoms in schizophrenia: cross-sectional and retrospective longitudinal studies

The amplitude of the P300 component of the auditory event-related brain potential (ERP) is consistently reduced in schizophrenia. To determine whether this P300 abnormality can be used as a state marker to reflect the severity of symptoms, we examined both cross-sectionally and longitudinally the relationship between auditory P300 amplitude and symptom severity in patients with schizophrenia. For the cross-sectional study, ERP was elicited by an auditory oddball paradigm, and symptom severity was quantitatively measured by means of the Positive and Negative Syndrome Scale in 93 patients with schizophrenia or schizophreniform disorder (DSM-III-R). For the longitudinal study, ERP and psychopathology measured twice at an average interval of 238 days for 20 patients were retrospectively analyzed. The cross-sectional data showed that P300 amplitude correlated negatively with the positive but not with the negative syndrome scale score. The longitudinal data also showed a significant negative correlation between changes in P300 amplitude and in the positive syndrome scores of the first and second tests. In particular, P300 amplitude recorded at the left, but not right, posterior temporal region significantly correlated with the positive syndrome in both the cross-sectional and longitudinal studies. These findings support the hypotheses that auditory P300 amplitude recorded in the left hemisphere can be used as a state marker to reflect the severity of the positive symptoms and that the positive symptoms may be caused by a possible left-hemisphere deficit in schizophrenia.

State-dependent changes in intrahemispheric EEG coherence for patients with acute exacerbation of schizophrenia

Abnormalities of electroencephalographic (EEG) coherence in schizophrenia are thought to reflect functional disconnections between different brain regions associated with the onset of this disease. To clarify whether these abnormalities change in a symptom-dependent manner in individual patients, we analyzed the coherence of resting EEGs recorded at two time points with a 36.6-day interval during the course of treatment for 14 patients who had been hospitalized for acute exacerbation of schizophrenia. Symptom severity was quantitatively measured by means of the Brief Psychiatric Rating Scale (BPRS). Beta (13-20 Hz) coherence for the left frontal (F7)-temporal (T5) electrode pair was less than that for the corresponding right pair (F8-T6) at the initial test. At the second test, when symptoms had improved, the left frontal-temporal beta coherence had increased, resulting in disappearance of the laterality. This change in beta coherence for the left frontal-temporal pair correlated negatively with the change in the total BPRS score, particularly the positive symptom score. Similar correlations were found for eight patients who had been drug-free at the first examination. These results suggest that a functional disconnection between the frontal and the temporal lobe in the left hemisphere may be associated with the generation of acute psychotic symptoms in schizophrenia.

Regional cerebral blood flow in male schizophrenic patients performing an auditory discrimination task

Regional cerebral blood flow (rCBF) was measured in 11 schizophrenic patients amid 10 normal controls, both at rest and while performing an auditory discrimination task. Single photon emission computed tomography with technetium-99m hexamethylpropylene amine oxime was used for quantitative evaluation of rCBF. The schizophrenic patients showed greater rCBF in the temporal and parietal regions at rest than the controls, but no abnormalities were found in frontal perfusion. During task performance. on the other hand, the patients showed a reduced frontal rCBF. whereas there was no group difference in rCBF in the temporal and parietal regions. In addition, the left> right hemisphere asymmetries of rCBF observed in the controls during task performance were not present in the patients. although there was no group difference in hemisphere laterality in rCBF at rest. These findings suggest that the employment of a cognitive task for neuroimaging studies is useful for detecting abnormalities of brain activation. such as hypofrontality and altered hemisphere laterality. in patients with schizophrenia.

Functional Connectivity between Hemispheres and Schizophrenic Symptoms: A Longitudinal Study of Interhemispheric EEG Coherence in Patients with Acute Exacerbations of Schizophrenia

To clarify whether interhemispheric electroencephalogram (EEG) coherence reflecting functional connectivity between the two cerebral hemispheres can change in a symptom-dependent manner in schizophrenia, we measured resting EEG and symptom severity twice at an average interval of 32.7 days during the course of treatment in 15 patients hospitalized for acute exacerbations of schizophrenia. Symptom severity was estimated quantitatively by means of the Brief Psychiatric Rating Scale (BPRS). Correlation analysis showed that increases in the beta-band coherence for frontal electrode pairs during the treatment were associated with improvement in the total score and the score on the positive subscale of BPRS. This result suggests that functional disconnection between the left and right frontal lobes may be related to the generation of psychotic symptoms and can normalize following antipsychotic treatment.

Reduced prefrontal activation during performance of the Iowa Gambling Task in patients with bipolar disorder

The Iowa Gambling Task (IGT) is a complex decision-making task in which monetary wins and losses guide the development of strategies. The objective of this study was to evaluate hemodynamic responses of patients with bipolar disorder (BD) during performance of the IGT using near-infrared spectroscopy (NIRS). Participants comprised 13 patients and 15 healthy control subjects who were matched for age, sex, handedness, and intelligence quotient. Relative changes in oxygenated and deoxygenated hemoglobin (oxy-Hb and deoxy-Hb) levels in the frontal region were measured using a 46-channel NIRS system. All subjects were evaluated using NIRS during a verbal fluency task (VFT) and the IGT. During performance of the IGT, BD patients showed significantly decreased oxy-Hb levels in the bilateral orbitofrontal cortex (OFC) and left prefrontal cortex (PFC) compared with normal control subjects. However, during the VFT, patients with BD showed no significant changes in oxy-Hb levels compared with control subjects. Changes in oxy-Hb levels in the bilateral OFC and the PFC during the IGT were negatively correlated with total scores on the Hamilton Rating Scale for Depression (HAM-D). Although the IGT was useful for differentiating patients with BP from control subjects, no significant differences in autonomic activity were observed.

Neuropsychological Correlates of an Attention-Related Negative Component Elicited in an Auditory Oddball Paradigm in Schizophrenia

An attention-related, negative component can be detected between the N100 peak and 200 ms after stimulus by subtracting event-related potentials (ERPs) elicited to background tones when subjects ignore tones, from ERPs elicited to background tones when subjects attend to tones to detect target tones in an oddball paradigm. To clarify the cognitive significance of this component in schizophrenia, we examined the correlations of 24 patients between the amplitude and latency of the negative component and results obtained using neuropsychological measurement methods, including the Wisconsin Card Sorting Test, the Trail Making Test, the Verbal Fluency Test and some subtests from the Wechsler Memory Scale. The latency prolongation of the negative component correlated positively with the difference in performance time between parts A and B of the Trail Making Test, which estimates set shift, a frontal-lobe executive function, but not with any other neuropsychological measurements, while the amplitude showed no such correlation. These results suggest that the latency prolongation of the attention-related, negative component induced in an auditory oddball paradigm may serve as an index for frontal dysfunction in schizophrenia.

Individual analysis of EEG band power and clinical drug response in schizophrenia.

The main purpose of this study was to investigate the relationship between short-term clinical outcome and changes in electroencephalogram (EEG) power after drug treatment in patients with schizophrenia, and also to compare two different methods for quantitative EEG analysis. EEG power analysis was performed by both conventional fixed frequency band and adjusted frequency band based on individual alpha frequency (IAF) in 16 drug-naive patients before and after drug administration. In the theta bands determined by both conventional fixed band and IAF methods, the EEG power after treatment was larger than that before treatment. In addition, there was a correlation between EEG power and clinical drug response evaluated by changes in BPRS score. With regard to this correlation, IAF methods showed no apparent advantage over methods using conventional fixed frequency bands. Conventional quantitative EEG analysis can still serve as a useful tool for the assessment of short-term outcome of drug treatment.

Reconsidering Animal Models of Major Depressive Disorder in the Elderly.

Major depressive disorder (MDD) is a common psychiatric illness with high morbidity that poses a huge burden to healthcare systems worldwide. According to the World Health Organization, the lifetime prevalence of MDD is approximately 3–17% globally (Richards, 2011). However, after major, but limited, success with selective serotonin reuptake inhibitors (SSRIs) or serotonin–noradrenaline reuptake inhibitors, few promising therapeutic approaches have been developed from preclinical studies using current animal models of MDD, despite intensive research involving laborious methods and substantial costs. Traditionally, most research using rodent models of MDD has been conducted using relatively young adult animals, aged approximately 8 weeks, to avoid any involvement of aging-related biological factors. The major rationale of this strategy is based on epidemiological findings that the occurrence of MDD displays a robust peak in young adults rather than in the elderly (Jorm, 2000; Copeland et al., 2004; Blazer and Hybels, 2005). Further, the elderly may have aging-related factors rendering this group an inappropriate model of “genuine” MDD. A critical question is whether this strategy is indeed appropriate. Despite the consistent findings of a lower lifetime prevalence rate of MDD in the elderly than in young adults, there remain persistent doubts regarding the underdiagnosis of MDD in the elderly (Hoertel et al., 2013). It has been heavily argued that patients diagnosed with MDD in youth will often be rediagnosed with a bipolar disorder (Lish et al., 1994; Leonpacher et al., 2015). Thus, a considerable number of cases of MDD in young adults may be misdiagnosed. In addition, MDD in the elderly has distinct biological/environmental backgrounds and consequences compared with that in young adults. In this opinion article, we primarily shed light on the significance of MDD in the elderly (known as geriatric MDD or late-onset depression) and problems associated with the methodology of preclinical studies undertaken to investigate the characteristics and treatment of this disorder.