Cortical white matter microstructural alterations underlying the impaired gamma-band auditory steady-state response in schizophrenia.

The gamma-band auditory steady-state response (ASSR), primarily generated from the auditory cortex, has received substantial attention as a potential brain marker indicating the pathophysiology of schizophrenia. Previous studies have shown reduced gamma-band ASSR in patients with schizophrenia and demonstrated correlations with impaired neurocognition and psychosocial functioning. Recent studies in clinical and healthy populations have suggested that the neural substrates of reduced gamma-band ASSR may be distributed throughout the cortices surrounding the auditory cortex, especially in the right hemisphere. This study aimed to investigate associations between the gamma-band ASSR and white matter alterations in the bundles broadly connecting the right frontal, parietal and occipital cortices to clarify the networks underlying reduced gamma-band ASSR in patients with schizophrenia. We measured the 40 Hz ASSR using electroencephalography and diffusion tensor imaging in 42 patients with schizophrenia and 22 healthy comparison subjects. The results showed that the gamma-band ASSR was positively correlated with fractional anisotropy (an index of white matter integrity) in the regions connecting the right frontal, parietal and occipital cortices in healthy subjects (ß = 0.41, corrected p = 0.075, uncorrected p = 0.038) but not in patients with schizophrenia (ß = 0.17, corrected p = 0.46, uncorrected p = 0.23). These findings support our hypothesis that the generation of gamma-band ASSR is supported by white matter bundles that broadly connect the cortices and that these relationships may be disrupted in schizophrenia. Our study may help characterize and interpret reduced gamma-band ASSR as a useful brain marker of schizophrenia.

Auditory prediction errors in sound frequency and duration generated different cortical activation patterns in the human brain: an ECoG study.

Sound frequency and duration are essential auditory components. The brain perceives deviations from the preceding sound context as prediction errors, allowing efficient reactions to the environment. Additionally, prediction error response to duration change is reduced in the initial stages of psychotic disorders. To compare the spatiotemporal profiles of responses to prediction errors, we conducted a human electrocorticography study with special attention to high gamma power in 13 participants who completed both frequency and duration oddball tasks. Remarkable activation in the bilateral superior temporal gyri in both the frequency and duration oddball tasks were observed, suggesting their association with prediction errors. However, the response to deviant stimuli in duration oddball task exhibited a second peak, which resulted in a bimodal response. Furthermore, deviant stimuli in frequency oddball task elicited a significant response in the inferior frontal gyrus that was not observed in duration oddball task. These spatiotemporal differences within the Parasylvian cortical network could account for our efficient reactions to changes in sound properties. The findings of this study may contribute to unveiling auditory processing and elucidating the pathophysiology of psychiatric disorders.

Auditory prediction and prediction error responses evoked through a novel cascade roving paradigm: a human ECoG study.

Auditory sensory processing is assumed to occur in a hierarchical structure including the primary auditory cortex (A1), superior temporal gyrus, and frontal areas. These areas are postulated to generate predictions for incoming stimuli, creating an internal model of the surrounding environment. Previous studies on mismatch negativity have indicated the involvement of the superior temporal gyrus in this processing, whereas reports have been mixed regarding the contribution of the frontal cortex. We designed a novel auditory paradigm, the "cascade roving" paradigm, which incorporated complex structures (cascade sequences) into a roving paradigm. We analyzed electrocorticography data from six patients with refractory epilepsy who passively listened to this novel auditory paradigm and detected responses to deviants mainly in the superior temporal gyrus and inferior frontal gyrus. Notably, the inferior frontal gyrus exhibited broader distribution and sustained duration of deviant-elicited responses, seemingly differing in spatio-temporal characteristics from the prediction error responses observed in the superior temporal gyrus, compared with conventional oddball paradigms performed on the same participants. Moreover, we observed that the deviant responses were enhanced through stimulus repetition in the high-gamma range mainly in the superior temporal gyrus. These features of the novel paradigm may aid in our understanding of auditory predictive coding.

Gamma-band harmonic responses for beta-band auditory steady-state response are intact in patients with early stage schizophrenia.

Gamma oscillations, thought to arise from the activity of ɣ-aminobutyric acid (GABA)ergic interneurons, have potential as a biomarker for schizophrenia. Gamma-band auditory steady-state responses (ASSRs) are notably reduced in both chronic and early-stage schizophrenia patients. Furthermore, alterations in gamma-band ASSRs have been demonstrated in animal models through translational research. However, the 40-Hz harmonic responses of the 20-Hz ASSR are not as well-characterized, despite the possibility that these harmonic oscillatory responses may reflect resonant activity in neural circuits. In this study, we investigated the 40-Hz harmonic response to the 20-Hz ASSR in the early stages of schizophrenia. The study recruited 49 participants, including 15 individuals at ultra-high-risk (UHR) for psychosis, 13 patients with first-episode schizophrenia (FES), and 21 healthy controls (HCs). The 40-Hz harmonic responses of the 20-Hz ASSR were evident in all groups. Interestingly, while previous report observed reduced 40-Hz ASSRs, the 40-Hz harmonic responses of the 20-Hz ASSR were not reduced in the UHR or FES groups. These findings suggest that the gamma-band ASSR and its harmonic responses may represent distinct aspects of pathophysiology in the early stages of schizophrenia.

Longitudinal change in mismatch negativity (MMN) but not in gamma-band auditory steady-state response (ASSR) is associated with psychological difficulties in adolescence.

Adolescence is a critical period for psychological difficulties. Auditory mismatch negativity (MMN) and gamma-band auditory steady-state response (ASSR) are representative electrophysiological indices that mature during adolescence. However, the longitudinal association between MMN/ASSR and psychological difficulties among adolescents remains unclear. We measured MMN amplitude for duration and frequency changes and ASSR twice in a subsample (n = 67, mean age 13.4 and 16.1 years, respectively) from a large-scale population-based cohort. No significant longitudinal changes were observed in any of the electroencephalography indices. Changes in SDQ-TD were significantly associated with changes in duration MMN, but not frequency MMN and ASSR. Furthermore, the subgroup with higher SDQ-TD at follow-up showed a significant duration MMN decrease over time, whereas the subgroup with lower SDQ-TD did not. The results of our population neuroscience study suggest that insufficient changes in electroencephalography indices may have been because of the short follow-up period or non-monotonic change during adolescence, and indicated that the longitudinal association with psychological difficulties was specific to the duration MMN. These findings provide new insights that electrophysiological change may underlie the development of psychosocial difficulties emerging in adolescence.

Alterations of auditory-evoked gamma oscillations are more pronounced than alterations of spontaneous power of gamma oscillation in early stages of schizophrenia.

Several animal models of schizophrenia and patients with chronic schizophrenia have shown increased spontaneous power of gamma oscillations. However, the most robust alterations of gamma oscillations in patients with schizophrenia are reduced auditory-oscillatory responses. We hypothesized that patients with early-stage schizophrenia would have increased spontaneous power of gamma oscillations and reduced auditory-oscillatory responses. This study included 77 participants, including 27 ultra-high-risk (UHR) individuals, 19 patients with recent-onset schizophrenia (ROS), and 31 healthy controls (HCs). The auditory steady-state response (ASSR) and spontaneous power of gamma oscillations measured as induced power during the ASSR period were calculated using electroencephalography during 40-Hz auditory click-trains. The ASSRs were lower in the UHR and ROS groups than in the HC group, whereas the spontaneous power of gamma oscillations in the UHR and ROS groups did not significantly differ from power in the HC group. Both early-latency (0-100 ms) and late-latency (300-400 ms) ASSRs were significantly reduced and negatively correlated with the spontaneous power of gamma oscillations in the ROS group. In contrast, UHR individuals exhibited reduced late-latency ASSR and a correlation between the unchanged early-latency ASSR and the spontaneous power of gamma oscillations. ASSR was positively correlated with the hallucinatory behavior score in the ROS group. Correlation patterns between the ASSR and spontaneous power of gamma oscillations differed between the UHR and ROS groups, suggesting that the neural dynamics involved in non-stimulus-locked/task modulation change with disease progression and may be disrupted after psychosis onset.

A first-in-human study of the anti-inflammatory profibrinolytic TMS-007, an SMTP family triprenyl phenol.

AIMS: TMS-007, an SMTP family member, modulates plasminogen conformation and enhances plasminogen-fibrin binding, leading to promotion of endogenous fibrinolysis. Its anti-inflammatory action, mediated by soluble epoxide hydrolase inhibition, may contribute to its efficacy. Evidence suggests that TMS-007 can effectively treat experimental thrombotic and embolic strokes with a wide time window, while reducing haemorrhagic transformation. We aim to evaluate the safety, pharmacokinetics and pharmacodynamics of TMS-007 in healthy volunteers. METHODS: This was a randomized, placebo-controlled, double blind, dose-escalation study, administered as a single intravenous infusion of TMS-007 in cohorts of healthy male Japanese subjects. Six cohorts were planned, but only five were completed. In each cohort (n = 8), individuals were randomized to receive one of five doses of TMS-007 (3, 15, 60, 180 or 360 mg; n = 6) or placebo (n = 2). RESULTS: TMS-007 was generally well tolerated, and no serious adverse events were attributed to the drug. A linear dose-dependency was observed for plasma TMS-007 levels. No symptoms of bleeding were observed on brain MRI analysis, and no bleeding-related responses were found on laboratory testing. The plasma levels of the coagulation factor fibrinogen and the anti-fibrinolysis factor α2 -antiplasmin levels were unchanged after TMS-007 dosing. A slight increase in the plasma level of plasmin-α2 -antiplasmin complex, an index of plasmin formation, was observed in the TMS-007 group in cohort 2. CONCLUSIONS: TMS-007 is generally well tolerated and exhibits favourable pharmacokinetic profiles that warrant further clinical development.

Prediction-Related Frontal-Temporal Network for Omission Mismatch Activity in the Macaque Monkey.

Sensory prediction is considered an important element of mismatch negativity (MMN) whose reduction is well known in patients with schizophrenia. Omission MMN is a variant of the MMN which is elicited by the absence of a tone previously sequentially presented. Omission MMN can eliminate the effects of sound differences in typical oddball paradigms and affords the opportunity to identify prediction-related signals in the brain. Auditory predictions are thought to reflect bottom-up and top-down processing within hierarchically organized auditory areas. However, the communications between the various subregions of the auditory cortex and the prefrontal cortex that generate and communicate sensory prediction-related signals remain poorly understood. To explore how the frontal and temporal cortices communicate for the generation and propagation of such signals, we investigated the response in the omission paradigm using electrocorticogram (ECoG) electrodes implanted in the temporal, lateral prefrontal, and orbitofrontal cortices of macaque monkeys. We recorded ECoG data from three monkeys during the omission paradigm and examined the functional connectivity between the temporal and frontal cortices by calculating phase-locking values (PLVs). This revealed that theta- (4-8 Hz), alpha- (8-12 Hz), and low-beta- (12-25 Hz) band synchronization increased at tone onset between the higher auditory cortex and the frontal pole where an early omission response was observed in the event-related potential (ERP). These synchronizations were absent when the tone was omitted. Conversely, low-beta-band (12-25 Hz) oscillation then became stronger for tone omission than for tone presentation approximately 200 ms after tone onset. The results suggest that auditory input is propagated to the frontal pole via the higher auditory cortex and that a reciprocal network may be involved in the generation of auditory prediction and prediction error. As impairments of prediction may underlie MMN reduction in patients with schizophrenia, an aberrant hierarchical temporal-frontal network might be related to this pathological condition.

The association between clinical symptoms and later subjective quality of life in individuals with ultra-high risk for psychosis and recent-onset psychotic disorder: A longitudinal investigation.

AIM: Subjective quality of life is a clinically relevant outcome that is strongly associated with the severity of clinical symptoms in individuals with ultra-high risk for psychosis and patients with recent-onset psychotic disorder. Our objective was to examine whether longitudinal changes in clinical symptoms are associated with quality of life in ultra-high risk individuals and patients with recent-onset psychotic disorder. METHODS: Individuals with ultra-high risk and patients with recent-onset psychosis disorder were recruited in the same clinical settings at baseline and were followed up with more than 6 months and less than 5 years later. We assessed five factors of clinical symptoms using the positive and negative syndrome scale, and quality of life using the World Health Organization quality of life questionnaire-short form. We used multiple regression to examine the relationships between clinical symptoms and quality of life while controlling for diagnosis, follow-up period, age, and sex. RESULTS: Data were collected from 22 individuals with ultra-high risk and 27 patients with recent-onset psychosis disorder. The multiple regression analysis results indicated that the more severe anxiety/depression was at baseline, the poorer the quality of life at follow-up. Further, improvement of anxiety/depression and disorganized thoughts were associated with improvement in quality of life. The difference in diagnosis did not affect the association between clinical symptoms and quality of life. CONCLUSION: These findings suggest that the improvement of anxiety/depression and disorganized thoughts is important in the early stages of psychosis before it becomes severe, affecting the quality of life.

Surface area in the insula was associated with 28-month functional outcome in first-episode psychosis.

Many studies have tested the relationship between demographic, clinical, and psychobiological measurements and clinical outcomes in ultra-high risk for psychosis (UHR) and first-episode psychosis (FEP). However, no study has investigated the relationship between multi-modal measurements and long-term outcomes for >2 years. Thirty-eight individuals with UHR and 29 patients with FEP were measured using one or more modalities (cognitive battery, electrophysiological response, structural magnetic resonance imaging, and functional near-infrared spectroscopy). We explored the characteristics associated with 13- and 28-month clinical outcomes. In UHR, the cortical surface area in the left orbital part of the inferior frontal gyrus was negatively associated with 13-month disorganized symptoms. In FEP, the cortical surface area in the left insula was positively associated with 28-month global social function. The left inferior frontal gyrus and insula are well-known structural brain characteristics in schizophrenia, and future studies on the pathological mechanism of structural alteration would provide a clearer understanding of the disease.

Global and Parallel Cortical Processing Based on Auditory Gamma Oscillatory Responses in Humans.

Gamma oscillations are physiological phenomena that reflect perception and cognition, and involve parvalbumin-positive γ-aminobutyric acid-ergic interneuron function. The auditory steady-state response (ASSR) is the most robust index for gamma oscillations, and it is impaired in patients with neuropsychiatric disorders such as schizophrenia and autism. Although ASSR reduction is known to vary in terms of frequency and time, the neural mechanisms are poorly understood. We obtained high-density electrocorticography recordings from a wide area of the cortex in 8 patients with refractory epilepsy. In an ASSR paradigm, click sounds were presented at frequencies of 20, 30, 40, 60, 80, 120, and 160 Hz. We performed time-frequency analyses and analyzed intertrial coherence, event-related spectral perturbation, and high-gamma oscillations. We demonstrate that the ASSR is globally distributed among the temporal, parietal, and frontal cortices. The ASSR was composed of time-dependent neural subcircuits differing in frequency tuning. Importantly, the frequency tuning characteristics of the late-latency ASSR varied between the temporal/frontal and parietal cortex, suggestive of differentiation along parallel auditory pathways. This large-scale survey of the cortical ASSR could serve as a foundation for future studies of the ASSR in patients with neuropsychiatric disorders.

Criticality in the Healthy Brain.

The excellence of the brain is its robustness under various types of noise and its flexibility under various environments. However, how the brain works is still a mystery. The critical brain hypothesis proposes a possible mechanism and states that criticality plays an important role in the healthy brain. Herein, using an electroencephalography dataset obtained from patients with psychotic disorders (PDs), ultra-high risk (UHR) individuals and healthy controls (HCs), and its dynamical network analysis, we show that the brain of HCs remains around a critical state, whereas that of patients with PD falls into more stable states. Meanwhile, the brain of UHR individuals is similar to that of PD in terms of entropy but is analogous to that of HCs in causality patterns. These results not only provide evidence for the criticality of the normal brain but also highlight the practicability of using an analytic biophysical tool to study the dynamical properties of mental diseases.

Translatability of Scalp EEG Recordings of Duration-Deviant Mismatch Negativity Between Macaques and Humans: A Pilot Study.

Mismatch negativity (MMN) is a negative deflection of the auditory event-related potential (ERP) elicited by an abrupt change in a sound presented repeatedly. In patients with schizophrenia, MMN is consistently reduced, which makes it a promising biomarker. A non-human primate (NHP) model of MMN based on scalp electroencephalogram (EEG) recordings can provide a useful translational tool, given the high structural homology of the prefrontal and auditory cortices between NHPs, such as macaques, and humans. However, in previous MMN studies, the NHP models used did not allow for comparison with humans because of differences in task settings. Moreover, duration-deviant MMN (dMMN), whose reduction is larger than that in the frequency-deviant MMN (fMMN) in patients with schizophrenia, has never been demonstrated in NHP models. In this study, we determined whether dMMN can be observed in macaque scalp EEG recordings. EEGs were recorded from frontal electrodes (Fz) in two Japanese macaques. Consistent with clinical settings, auditory stimuli consisted of two pure tones, a standard and a deviant tone, in an oddball paradigm. The deviant and standard tones differed in duration (50 and 100 ms for the standard and deviant tones, respectively). A robust dMMN with a latency of around 200 ms, comparable to that in humans, was observed in both monkeys. A comparison with fMMN showed that the dMMN latency was the longer of the two. By bridging the gap between basic and clinical research, our results will contribute to the development of innovative therapeutic strategies for schizophrenia.

Mismatch Negativity Predicts Remission and Neurocognitive Function in Individuals at Ultra-High Risk for Psychosis.

BACKGROUND: In the early intervention in psychosis, ultra-high risk (UHR) criteria have been used to identify individuals who are prone to develop psychosis. Although the transition rate to psychosis in individuals at UHR is 10% to 30% within several years, some individuals at UHR present with poor prognoses even without transition occurring. Therefore, it is important to identify biomarkers for predicting the prognosis of individuals at UHR, regardless of transition. We investigated whether mismatch negativity (MMN) in response to both duration deviant stimuli (dMMN) and frequency deviant stimuli (fMMN) could predict prognosis, including remission and neurocognitive function in individuals at UHR. MATERIALS AND METHODS: Individuals at UHR (n = 24) and healthy controls (HC; n = 18) participated in this study. In an auditory oddball paradigm, both dMMN and fMMN were measured at baseline. Remission and neurocognitive function after > 180 days were examined in the UHR group. Remission from UHR was defined as functional and symptomatic improvement using the Global Assessment of Functioning (GAF) score and Scale of Prodromal Symptoms (SOPS) positive subscales. Neurocognitive function was measured using the Brief Assessment of Cognition in Schizophrenia (BACS). We examined differences in MMN amplitude at baseline between those who achieved remission (remitters) and those who did not (non-remitters). Multiple regression analyses were performed to identify predictors for functioning, positive symptoms, and neurocognitive function. RESULTS: Compared with the HC group, the UHR group had a significantly attenuated dMMN amplitude (p = 0.003). In the UHR group, GAF scores significantly improved during the follow-up period (mean value 47.1 to 55.5, p = 0.004). The dMMN amplitude at baseline was significantly larger in the remitter (n = 6) than in the non-remitter group (n = 18) (p = 0.039). The total SOPS positive subscale scores and fMMN amplitude at baseline could predict BACS attention subscore at the follow-up point (SOPS positive subscales, p = 0.030; fMMN, p = 0.041). CONCLUSION: Our findings indicate that dMMN and fMMN predicted remission and neurocognitive function, respectively, in individuals at UHR, which suggests that there are both promising biomarker candidates for predicting prognosis in individuals at UHR.

A Predictive Coding Perspective on Mismatch Negativity Impairment in Schizophrenia.

Mismatch negativity (MMN) is a widely used biological marker for schizophrenia research. Previous studies reported that MMN amplitude was reduced in schizophrenia and that reduced MMN amplitude was associated with cognitive impairments and poor functional outcome in schizophrenia. However, the neurobiological mechanisms underlying the reduced MMN amplitude remain unclear. Recent studies suggest that reduced MMN amplitude may reflect altered predictive coding in schizophrenia. In this paper, we reviewed MMN studies that used new paradigms and computational modeling to investigate altered predictive coding in schizophrenia. Studies using the roving oddball paradigm and modified oddball paradigm revealed that the effects of conditional probability were impaired in schizophrenia. Studies using omission paradigms and many-standards paradigms revealed that prediction error, but not adaptation, was impaired in schizophrenia. A study using a local-global paradigm revealed that hierarchical structures were impaired at both local and global levels in schizophrenia. Furthermore, studies using dynamic causal modeling revealed that neural networks with hierarchical structures were impaired in schizophrenia. These findings indicate that altered predictive coding underlies the reduced MMN amplitude in schizophrenia. However, there are several unsolved questions about optimal procedures, association among paradigms, and heterogeneity of schizophrenia. Future studies using several paradigms and computational modeling may solve these questions, and may lead to clarifying the pathophysiology of schizophrenia and to the development of individualized treatments for schizophrenia.

Spatiotemporal Differentiation of MMN From N1 Adaptation: A Human ECoG Study.

Auditory mismatch negativity (MMN) is an electrophysiological response to a deviation from regularity. This response is considered pivotal to understanding auditory processing, particularly in the pre-attentive phase. However, previous findings suggest that MMN is a product of N1 adaptation/enhancement, which reflects lower-order auditory processing. The separability of these two components remains unclear and is considered an important issue in the field of neuroscience. The aim of the present study was to spatiotemporally differentiate MMN from N1 adaptation using human electrocorticography (ECoG). Auditory evoked potentials under the classical oddball (OD) task as well as the many standards (MS) task were recorded in three patients with epilepsy whose lateral cortices were widely covered with high-density electrodes. Close observation identified an electrode at which N1 adaptation was temporally separated from MMN, whereas N1 adaptation was partially incorporated into MMN at other electrodes. Since N1 adaptation occurs in the N1 population, we spatially compared MMN with N1 obtained from the MS task instead of N1 adaptation. As a result, N1 was observed in a limited area around the Sylvian fissure adjacent to A1, whereas MMN was noted in wider areas, including the temporal, frontal, and parietal lobes. MMN was thus considered to be differentiated from N1 adaptation. The results suggest that MMN is not merely a product of the neural adaptation of N1 and instead represents higher-order processes in auditory deviance detection. These results will contribute to strengthening the foundation of future research in this field.

Reduced Auditory Mismatch Negativity Reflects Impaired Deviance Detection in Schizophrenia.

The auditory mismatch negativity (MMN) is a translatable electroencephalographic biomarker automatically evoked in response to unattended sounds that is robustly associated with cognitive and psychosocial disability in patients with schizophrenia. Although recent animal studies have tried to clarify the neural substrates of the MMN, the nature of schizophrenia-related deficits is unknown. In this study, we applied a novel paradigm developed from translational animal model studies to carefully deconstruct the constituent neurophysiological processes underlying MMN generation. Patients with schizophrenia (N = 25) and healthy comparison subjects (HCS; N = 27) underwent MMN testing using both a conventional auditory oddball paradigm and a "many-standards paradigm" that was specifically developed to deconstruct the subcomponent adaptation and deviance detection processes that are presumed to underlie the MMN. Using a conventional oddball paradigm, patients with schizophrenia exhibited large effect size deficits of both duration and frequency MMN, consistent with many previous studies. Furthermore, patients with schizophrenia showed selective impairments in deviance detection but no impairment in adaptation to repeated tones. These findings support the use of the many-standards paradigm for deconstructing the constituent processes underlying the MMN, with implications for the use of these translational measures to accelerate the development of new treatments that target perceptual and cognitive impairments in schizophrenia and related disorders.

Resting-state EEG beta band power predicts quality of life outcomes in patients with depressive disorders: A longitudinal investigation.

BACKGROUND: Quality of life is severely impaired in patients with depressive disorders. Previous studies have focused on biomarkers predicting depressive symptomatology; however, studies investigating biomarkers predicting quality of life outcomes are limited. Improving quality of life is important because it is related not only to mental health but also to physical health. We need to develop a biomarker related to quality of life as a therapeutic target for patients with depressive disorders. Resting-state electroencephalography (EEG) is easy to record in clinical settings. The index of bandwidth spectral power predicts treatment response in depressive disorders and thus may be a candidate biomarker. However, no longitudinal studies have investigated whether EEG-recorded power could predict quality of life outcomes in patients with depressive disorders. METHODS: The resting-state EEG-recorded bandwidth spectral power at baseline and the World Health Organization Quality of Life (QOL)-26 scores at 3-year follow-up were measured in 44 patients with depressive disorders. RESULTS: The high beta band power (20-30 Hz) at baseline significantly predicted QOL at the 3-year follow-up after considering depressive symptoms and medication effects in a longitudinal investigation in patients with depressive disorders (ß = 0.38, p = 0.01). LIMITATIONS: We did not have healthy subjects as a comparison group in this study. CONCLUSIONS: Our findings suggest that resting-state beta activity has the potential to be a useful biomarker for predicting future quality of life outcomes in patients with depressive disorders.

Gamma-Band Auditory Steady-State Response as a Neurophysiological Marker for Excitation and Inhibition Balance: A Review for Understanding Schizophrenia and Other Neuropsychiatric Disorders.

Altered gamma oscillations have attracted considerable attention as an index of the excitation/inhibition (E/I) imbalance in schizophrenia and other neuropsychiatric disorders. The auditory steady-state response (ASSR) has been the most robust probe of abnormal gamma oscillatory dynamics in schizophrenia. Here, we review recent ASSR studies in patients with schizophrenia and other neuropsychiatric disorders. Preclinical ASSR research, which has contributed to the elucidation of the underlying pathophysiology of these diseases, is also discussed. The developmental trajectory of the ASSR has been explored and may show signs of the maturation and disruption of E/I balance in adolescence. Animal model studies have shown that synaptic interactions between parvalbumin-positive GABAergic interneurons and pyramidal neurons contribute to the regulation of E/I balance, which is related to the generation of gamma oscillation. Therefore, ASSR alteration may be a significant electrophysiological finding related to the E/I imbalance in neuropsychiatric disorders, which is a cross-disease feature and may reflect clinical staging. Future studies regarding ASSR generation, especially in nonhuman primate models, will advance our understanding of the brain circuit and the molecular mechanisms underlying neuropsychiatric disorders.