Kenji Kirihara

Hierarchical Organization of Gamma and Theta Oscillatory Dynamics in Schizophrenia

BACKGROUND Schizophrenia patients have deficits across a broad range of important cognitive and clinical domains. Synchronization of oscillations in the gamma frequency range (~40 Hz) is associated with many normal cognitive functions and underlies at least some of the deficits observed in schizophrenia patients. Recent studies have demonstrated that gamma oscillations are modulated by the phase of theta waves, and this cross-frequency coupling indicates that a complex and hierarchical organization governs neural oscillatory dynamics. The aims of the present study were to determine if schizophrenia patients have abnormalities in the amplitude, synchrony, and cross-frequency coupling of gamma and theta oscillations in response to gamma-frequency steady-state stimulation and if abnormal neural oscillatory dynamics are associated with cognitive deficits in schizophrenia. METHODS Schizophrenia patients (n = 234) and healthy control subjects (n = 188) underwent electroencephalography testing in response to 40-Hz auditory steady-state stimulation. Cognitive functions were assessed with a battery of neuropsychological tests. RESULTS Schizophrenia patients had significantly reduced gamma intertrial phase coherence, increased theta amplitude, and intact cross-frequency coupling relative to healthy control subjects. In schizophrenia patients, increased theta amplitude was associated with poor verbal memory performance. CONCLUSIONS Results suggest that schizophrenia patients have specific alterations in both gamma and theta oscillations, but these deficits occur in the context of an intact hierarchical organization of their cross-frequency modulation in response to 40-Hz steady-state stimulation. Cortical oscillatory dynamics may be useful for understanding the neural mechanisms that underlie the disparate cognitive and functional impairments of schizophrenia.

Neural substrates of normal and impaired preattentive sensory discrimination in large cohorts of nonpsychiatric subjects and schizophrenia patients as indexed by MMN and P3a change detection responses

OBJECTIVE Schizophrenia (SZ) patients have information processing deficits, spanning from low level sensory processing to higher-order cognitive functions. Mismatch negativity (MMN) and P3a are event-related potential (ERP) components that are automatically elicited in response to unattended changes in ongoing, repetitive stimuli that provide a window into abnormal information processing in SZ. MMN and P3a are among the most robust and consistently identified deficits in SZ, yet the neural substrates of these responses and their associated deficits in SZ are not fully understood. This study examined the neural sources of MMN and P3a components in a large cohort of SZ and nonpsychiatric control subjects (NCS) using Exact Low Resolution Electromagnetic Tomography Analyses (eLORETA) in order to identify the neural sources of MMN and P3a as well as the brain regions associated with deficits commonly observed among SZ patients. METHODS 410 SZ and 247 NCS underwent EEG testing using a duration-deviant auditory oddball paradigm (1-kHz tones, 500ms SOA; standard p=0.90, 50-ms duration; deviant tones P=0.10, 100-ms duration) while passively watching a silent video. Voxel-by-voxel within- (MMN vs. P3a) and between-group (SZ vs. NCS) comparisons were performed using eLORETA. RESULTS SZ had robust deficits in MMN and P3a responses measured at scalp electrodes consistent with other studies. These components mapped onto neural sources broadly distributed across temporal, frontal, and parietal regions. MMN deficits in SZ were associated with reduced activations in discrete medial frontal brain regions, including the anterior-posterior cingulate and medial frontal gyri. These early sensory discriminatory MMN impairments were followed by P3a deficits associated with widespread reductions in the activation of attentional networks (frontal, temporal, parietal regions), reflecting impaired orienting or shifts of attention to the infrequent stimuli. CONCLUSIONS MMN and P3a are dissociable responses associated with broadly distributed patterns of neural activation. MMN deficits among SZ patients appear to be primarily accounted for by reductions in medial prefrontal brain regions that are followed by widespread dysfunction across cortical networks associated with P3a in a manner that is consistent with hierarchical information processing models of cognitive deficits in SZ patients. Impairments in automatic stimulus discrimination may contribute to higher-order cognitive and psychosocial deficits in SZ.

Gamma oscillations in schizophrenia: Mechanisms and clinical significance

Brain oscillations are increasingly used for understanding complex psychiatric disorders. Gamma (30-50Hz) oscillations have warranted special attention due to their omnipresence in cognitive tasks. For patients with schizophrenia (SCZ), a disease associated with poor cognition, abnormal gamma oscillations have been reported in many experimental paradigms. The goal of this paper is to review the literature on gamma oscillations in SCZ. The review is structured into four sections. First, the functional role, neurobiology, and analysis of brain oscillations, especially gamma oscillations will be outlined. Second, the neurobiological abnormalities of SCZ in relation to gamma oscillations will be reviewed. Third, selected paradigms for investigating irregular gamma oscillations in SCZ will be discussed in detail. Finally, a discussion on the limitations of current findings and potential future research directions will be provided. The reviewed evidence suggests that gamma oscillations are disrupted in SCZ and could account for cognitive disturbances in this disorder. With additional analysis and experimentation, these indices may ultimately serve as endophenotypes that facilitate the development of etiologically based diagnostic methods, foster early identification and treatment, and advance our understanding of the complex genetic mechanisms involved in this disorder.

Association between lower P300 amplitude and smaller anterior cingulate cortex volume in patients with posttraumatic stress disorder: a study of victims of Tokyo subway sarin attack

Previous investigations of auditory P300 event-related potentials have provided electrophysiological evidence for attentional problems in patients with posttraumatic stress disorder (PTSD). The present study sought to evaluate the relationship between P300 deficits and underlying brain morphological abnormalities in never-treated, comorbidity-free patients with PTSD following the Tokyo subway sarin attack. Out of 47 victims recruited, 8 victims with PTSD and 13 victims without PTSD were identified. Correlational analyses were performed between auditory P300 amplitude at Pz electrode site elicited in an oddball task and anterior cingulate gray matter volume that was shown to be reduced in our previous study using voxel-based morphometry on magnetic resonance imaging. Victims with PTSD showed significantly lower amplitudes of P300 compared with victims without PTSD, and the lower P300 amplitudes at Pz were significantly associated with higher avoidance/numbing scores in the PTSD group. Furthermore, in the PTSD group only, the P300 amplitudes showed a trend toward significant positive correlation with voxel densities of the anterior cingulate cortex gray matter. These results provide the first evidence that electrophysiological deficits of controlled attention observed in patients with PTSD may be linked to underlying brain morphological abnormalities.

Mismatch Negativity as a “Translatable” Brain Marker Toward Early Intervention for Psychosis: A Review

Recent reviews and meta-analyses suggest that reducing the duration of untreated psychosis leads to better symptomatic and functional outcome in patients with psychotic disorder. Early intervention attenuates the symptoms of individuals at clinical high-risk (HR) for psychosis and may delay or prevent their transition to psychosis. Identifying biological markers in the early stages of psychotic disorder is an important step toward elucidating the pathophysiology, improving prediction of the transition to psychosis, and introducing targeted early intervention for help-seeking individuals aiming for better outcome. Mismatch negativity (MMN) is a component of event-related potentials that reflects preattentive auditory sensory memory and is a promising biomarker candidate for schizophrenia. Reduced MMN amplitude is a robust finding in patients with chronic schizophrenia. Recent reports have shown that people in the early stages of psychotic disorder exhibit attenuation of MMN amplitude. MMN in response to duration deviants and in response to frequency deviants reveals different patterns of deficits. These findings suggest that MMN may be useful for identifying clinical stages of psychosis and for predicting the risk of development. MMN may also be a “translatable” biomarker since it reflects N-methyl-d-aspartte receptor function, which plays a fundamental role in schizophrenia pathophysiology. Furthermore, MMN-like responses can be recorded in animals such as mice and rats. This article reviews MMN studies conducted on individuals with HR for psychosis, first-episode psychosis, recent-onset psychosis, and on animals. Based on the findings, the authors discuss the potential of MMN as a clinical biomarker for early intervention for help-seeking individuals in the early stages of psychotic disorder, and as a translatable neurophysiological marker for the preclinical assessment of pharmacological agents used in animal models that mimic early stages of the disorder.

Auditory mismatch negativity and P3a in response to duration and frequency changes in the early stages of psychosis

BACKGROUND A shorter duration of untreated psychosis in patients with schizophrenia results in better symptomatic and functional outcomes. Therefore, identifying biological markers in the early stages of psychosis is an important step toward early detection and intervention. Mismatch negativity (MMN) and P3a are leading candidate biomarkers. MMN measures differ in their sensitivity to varying deviants. However, this has not been fully addressed in assessing the early stages of psychosis. In the current study, we examined MMN/P3a to duration deviant (dMMN/dP3a) and frequency deviant (fMMN/fP3a) in the early stages of psychosis. To our knowledge, this is the first study that examined both MMN/P3a to duration deviant (dMMN/dP3a) and frequency deviant (fMMN/fP3a) in the early stages of psychosis. METHODS Participants consisted of 20 patients with first episode schizophrenia (FES), 21 ultra-high risk (UHR) individuals, and 22 healthy controls (HC). We measured dMMN/dP3a and fMMN/fP3a ERP components by means of a 64 electrodes-cap for EEG recording, and we used two-tone auditory oddball paradigms with 2000 stimuli. RESULTS The amplitude of dMMN was significantly reduced in FES and UHR compared to HC. The amplitude of fMMN showed no significant difference among the three groups. The amplitudes of dP3a and fP3a were significantly reduced in FES and UHR compared to HC. CONCLUSION These findings suggest that dMMN may have higher sensitivity than fMMN whereas dP3a and fP3a may have similar sensitivity in the early stages of psychosis.

Differential Alterations of Auditory Gamma Oscillatory Responses Between Pre-onset High-risk Individuals and First-episode Schizophrenia

Alterations in gamma-band auditory steady-state response (ASSR) are the most robust finding of abnormal neural oscillations in patients with first-episode (FES) and chronic schizophrenia. Gamma-band ASSRs may indicate GABAergic interneuron dysfunction. Nevertheless, it is unknown whether abnormal gamma-band ASSRs are present before the onset of psychosis. Subjects were 15 ultra-high-risk (UHR) individuals, 13 FES patients, and 21 healthy control (HC) subjects. We performed electroencephalogram recordings and measured ASSRs in each group as they were presented with click trains at 20, 30, and 40 Hz. We then conducted time-frequency analyses and calculated intertrial phase coherence and event-related spectral perturbation. The time course of gamma-band ASSRs showed significantly different features among groups. Compared with the HC group, the UHR group was characterized by intact early-latency (0-100 ms) and reduced late-latency (300-500 ms) ASSRs. In contrast, both early- and late-latency ASSRs were significantly reduced in the FES group. Gamma-band ASSRs were correlated with clinical symptoms and attentional functioning in FES (|rs| > 0.70). These results suggest differential alterations of gamma-band ASSRs between UHR and FES groups. The late-latency ASSR alteration may represent a biomarker for early detection of psychosis, while the early-latency ASSR abnormality may develop through the onset of psychosis.

Confirmation of a relationship between reduced auditory P300 amplitude and thought disorder in schizophrenia

We have previously reported an association between reduced amplitude of auditory P300 event-related potential and severity of positive thought disorder as assessed by the Comprehensive Index of Positive Thought Disorder in a sample of patients with chronic schizophrenia. Here we replicate those findings using a different measure, Thought Disorder Index (TDI), in a new larger sample of 55 patients. The auditory P300 amplitude showed a significant negative correlation with scores on TDI. This correlation was relatively more pronounced in the left temporal region than in the right temporal region. These results further suggest that electrophysiological abnormalities of information processing may underlie positive thought disorder in schizophrenia.

Neurophysiological impairment in emotional face processing is associated with low extraversion in schizophrenia

Patients with schizophrenia have low extraversion and high neuroticism. These personality traits affect the everyday life of patients with schizophrenia, making it important to investigate neurobiological basis of personality traits. In healthy people, extraversion is associated with hemodynamic responses in the amygdala and electrophysiological brain activity such as event-related potential and event-related desynchronization during emotional face processing. Patients with schizophrenia show abnormal neural activity during emotional face processing, such as an N170 amplitude reduction. However, few studies to date have reported an association between personality traits and neural activity during emotional face processing in schizophrenia. In the present study, we examined N170 during emotional face processing, and association with personality traits in patients with schizophrenia. Fifteen male patients with chronic schizophrenia and 15 healthy male subjects participated in this study. Patients with schizophrenia had reduced N170 amplitudes (p=0.007). While healthy subjects had increased N170 amplitudes in response to emotional faces compared with neutral faces (p=0.003), patients with schizophrenia showed no difference in N170 amplitudes between emotional and neutral faces (p=0.60). Reduced N170 amplitude in response to neutral faces was correlated with low extraversion scores in patients with schizophrenia (r(s)=-0.69, p=0.005). The abnormal N170 and its association with extraversion in schizophrenia were found at the right rather than the left posterior temporal electrode. An abnormal N170 in schizophrenia may reflect impairments in the structural encoding of emotional faces, and indiscrimination between emotional and neutral faces at this stage of information processing. The association between abnormal N170 amplitudes and extraversion suggests that abnormal neural activity in the early stages of emotional face processing may underlie low extraversion characteristic of schizophrenia.

Auditory P300 latency prolongation with age in schizophrenia: Gender and subcomponent effects

Previous studies showing prolongation of auditory P300b latency with increasing age provided support for post-onset progressive change in schizophrenia. We sought to extend the findings by evaluating the effects of gender and the subcomponents (P3b versus P3a) in schizophrenia (N=108) and controls (N=70). P3b latency significantly correlated with age in schizophrenia (Spearmans rho=0.214, P=0.026) and in male patients with schizophrenia (rho=0.260, P=0.049) whereas, it did not reach significance in female patients with schizophrenia (rho=0.174, P=0.23). P3a latency showed no correlation. Our findings may provide evidence for progressive change in the brain function in schizophrenia, and this change may be slower in female than male patients. P3b may serve as a more sensitive index for cognitive decline than P3a.