Gamma-band Auditory Steady-state Response Research Articles

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 (β = 0.41, corrected p = 0.075, uncorrected p = 0.038) but not in patients with schizophrenia (β = 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.

Differential Effects of Aripiprazole on Electroencephalography-Recorded Gamma-Band Auditory Steady-State Response, Spontaneous Gamma Oscillations and Behavior in a Schizophrenia Rat Model.

The available antipsychotics for schizophrenia (SZ) only reduce positive symptoms and do not significantly modify SZ neurobiology. This has raised the question of the robustness and translational value of methods employed during drug development. Electroencephalography (EEG)-based measures like evoked and spontaneous gamma oscillations are considered robust translational biomarkers as they can be recorded in both patients and animal models to probe a key mechanism underlying all SZ symptoms: the excitation/inhibition imbalance mediated by N-methyl-D-aspartate receptor (NMDAr) hypofunction. Understanding the effects of commercialized atypical antipsychotics on such measures could therefore contribute to developing better therapies for SZ. Yet, the effects of such drugs on these EEG readouts are unknown. Here, we studied the effect of the atypical antipsychotic aripiprazole on the gamma-band auditory steady-state response (ASSR), spontaneous gamma oscillations and behavioral features in a SZ rat model induced by the NMDAr antagonist MK-801. Interestingly, we found that aripiprazole could not normalize MK-801-induced abnormalities in ASSR, spontaneous gamma oscillations or social interaction while it still improved MK-801-induced hyperactivity. Suggesting that aripiprazole is unable to normalize electrophysiological features underlying SZ symptoms, our results might explain aripiprazole's inefficacy towards the social interaction deficit in our model but also its limited efficacy against social symptoms in patients.

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 16.1years, 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.

Decrease in gamma-band auditory steady-state response in patients with treatment-resistant schizophrenia

BackgroundThirty percent of patients with schizophrenia do not respond to non-clozapine antipsychotics and are termed treatment-resistant schizophrenia (TRS). The 40-Hz auditory steady-state response (ASSR) is a well-known to be reduced in patients with schizophrenia compared to healthy controls (HCs), suggesting impaired gamma oscillation in schizophrenia. Given no ASSR study on TRS, we aimed to examine the neurophysiological basis of TRS employing 40-Hz ASSR paradigm. MethodWe compared ASSR measures among HCs, patients with non-TRS, and patients with TRS. TRS criteria were defined by a score of 4 or higher on two items of the Positive and Negative Syndrome Scale (PANSS) positive symptoms despite standard antipsychotic treatment. Participants were examined for ASSR with 40-Hz click-train stimulus, and then time-frequency analysis was performed to calculate evoked power and phase-locking factor (PLF) of 40-Hz ASSR. ResultsA total of 79 participants were included: 27 patients with TRS (PANSS = 92.6 ± 15.8); 27 patients with non-TRS (PANSS = 63.3 ± 14.7); and 25 HCs. Evoked power in 40-Hz ASSR was lower in the TRS group than in the HC group (F2,79 = 8.37, p = 0.015; TRS vs. HCs: p = 0.012, d = 1.1) while no differences in PLF were found between the groups. ConclusionThese results suggest that glutamatergic and GABAergic neurophysiological dysfunctions are involved in the pathophysiology of TRS. Our findings warrant more comprehensive and longitudinal studies for deep phenotyping of TRS.

Test-retest reliability of mismatch negativity and gamma-band auditory steady-state response in patients with schizophrenia

Patients with schizophrenia show widespread impairments in clinical, cognitive and psychosocial functioning. Mismatch negativity (MMN) and gamma-band auditory steady-state response (ASSR) are two neurophysiological biomarkers widely used to inform diagnosis, guide treatments and track response to interventions in schizophrenia. However, evidence for the test–retest reliability of these indices across multiple sessions in schizophrenia patients remains scarce. In the present study, we included 34 schizophrenia patients (17 females) and obtained duration MMN (dMMN), frequency MMN (fMMN) and 40-Hz ASSR data across three sessions with intervals of 2 days. Event-related spectrum perturbation (ERSP) and inter-trial coherence (ITC) were calculated following Morlet wavelet time–frequency decomposition of ASSR data. The intra-class correlation coefficient (ICC) was used to quantify the reliability of MMN and ASSR measures among the three sessions. We found fair to good reliability for dMMN amplitudes but poor reliability for fMMN amplitudes. For the ASSR measures, ERSP showed good to excellent test–retest reliability while ITC had poor to fair test–retest reliability. In addition, the average of dMMN amplitudes was significantly correlated with that of ERSP across the three sessions. In summary, we established for the first time the short-term test–retest reliability of MMN and ASSR measures in schizophrenia patients. These findings demonstrate that dMMN amplitudes and ERSP of ASSR are reliable indices which may be used in longitudinal observational studies.

Source decomposition of the frontocentral auditory steady-state gamma band response in schizophrenia patients and healthy subjects.

Gamma-band auditory steady-state response (ASSR) is a neurophysiologic index that is increasingly used as a translational biomarker in the development of treatments of neuropsychiatric disorders. While gamma-band ASSR is generated by distributed networks of highly interactive temporal and frontal cortical sources, the majority of human gamma-band ASSR studies using electroencephalography (EEG) highlight activity from only a single frontocentral scalp site, Fz, where responses tend to be largest and reductions in schizophrenia patients are most evident. However, no previous study has characterized the relative source contributions to Fz, which is a necessary step to improve the concordance of preclinical and clinical EEG studies. A novel method to back-project the contributions of independent cortical source components was applied to assess the independent sources and their proportional contributions to Fz as well as source-resolved responses in 432 schizophrenia patients and 294 healthy subjects. Independent contributions of gamma-band ASSR to Fz were detected from orbitofrontal, bilateral superior/middle/inferior temporal, bilateral middle frontal, and posterior cingulate gyri in both groups. In contrast to expectations, the groups showed comparable source contribution weight to gamma-band ASSR at Fz. While gamma-band ASSR reductions at Fz were present in schizophrenia patients consistent with previous studies, no group differences in individual source-level responses to Fz were detected. Small differences in multiple independent sources summate to produce scalp-level differences at Fz. The identification of independent source contributions to a single scalp sensor represents a promising methodology for measuring dissociable and homologous biomarker targets in future translational studies.

Unique contributions of sensory discrimination and gamma synchronization deficits to cognitive, clinical, and psychosocial functional impairments in schizophrenia

BackgroundSchizophrenia patients show widespread deficits in neurocognitive, clinical, and psychosocial functioning. Mismatch negativity (MMN) and gamma-band auditory steady-state response (ASSR) are robust translational biomarkers associated with schizophrenia and associated with cognitive dysfunction, negative symptom severity, and psychosocial disability. Although these biomarkers are conceptually linked as measures of early auditory information processing, it is unclear whether MMN and gamma-band ASSR account for shared vs. non-shared variance in cognitive, clinical, and psychosocial functioning. MethodsMultiple regression analyses with MMN, gamma-band ASSR, and clinical measures were performed in large cohorts of schizophrenia outpatients (N = 428) and healthy comparison subjects (N = 283). ResultsReduced MMN (d = 0.67), gamma-band ASSR (d = −0.40), and lower cognitive function were confirmed in schizophrenia patients. Regression analyses revealed that reduced MMN amplitude showed unique associations with lower verbal learning and negative symptoms, reduced gamma-band ASSR showed a unique association with working memory deficits, and both reduced MMN amplitude and reduced gamma-band ASSR showed an association with daily functioning impairment in schizophrenia patients. ConclusionMMN and ASSR measures are non-redundant and complementary measures of early auditory information processing that are associated with important domains of functioning. Studies are needed to clarify the neural substrates of MMN and gamma-band ASSR to improve our understanding of the pathophysiology of schizophrenia and accelerate their use in the development of novel therapeutic interventions.

Hierarchical Pathways from Sensory Processing to Cognitive, Clinical, and Functional Impairments in Schizophrenia.

Cognitive impairment is a hallmark of schizophrenia and a robust predictor of functional outcomes. Impairments are found in all phases of the illness and are only moderately attenuated by currently approved therapeutics. Neurophysiological indices of sensory discrimination (ie, mismatch negativity (MMN) and P3a amplitudes) and gamma-band auditory steady-state response (ASSR; power and phase locking) are translational biomarkers widely used in the development of novel therapeutics for neuropsychiatric disorders. It is unclear whether laboratory-based EEG measures add explanatory power to well-established models that use only cognitive, clinical, and functional outcome measures. Moreover, it is unclear if measures of sensory discrimination and gamma-band ASSR uniquely contribute to putative causal pathways linking sensory discrimination, neurocognition, negative symptoms, and functional outcomes in schizophrenia. To answer these questions, hierarchical associations among sensory processing, neurocognition, clinical symptoms, and functional outcomes were assessed via structural equation modeling in a large sample of schizophrenia patients (n = 695) and healthy comparison subjects (n = 503). The results showed that the neurophysiologic indices of sensory discrimination and gamma-band ASSR both significantly contribute to and yield unique hierarchical, "bottom-up" effects on neurocognition, symptoms, and functioning. Measures of sensory discrimination showed direct effects on neurocognition and negative symptoms, while gamma-band ASSR had a direct effect on neurocognition in patients. Continued investigation of the neural mechanisms underlying abnormal networks of MMN/P3a and gamma-band ASSR is needed to clarify the pathophysiology of schizophrenia and the development of novel therapeutic interventions.

A distributed frontotemporal network underlies gamma-band synchronization impairments in schizophrenia patients.

Synaptic interactions between parvalbumin-positive γ-aminobutyric acid (GABA)-ergic interneurons and pyramidal neurons evoke cortical gamma oscillations, which are known to be abnormal in schizophrenia. These cortical gamma oscillations can be indexed by the gamma-band auditory steady-state response (ASSR), a robust electroencephalographic (EEG) biomarker that is increasingly used to advance the development of novel therapeutics for schizophrenia, and other related brain disorders. Despite promise of ASSR, the neural substrates of ASSR have not yet been characterized. This study investigated the sources underlying ASSR in healthy subjects and schizophrenia patients. In this study, a novel method for noninvasively characterizing source locations was developed and applied to EEG recordings obtained from 293 healthy subjects and 427 schizophrenia patients who underwent ASSR testing. Results revealed a distributed network of temporal and frontal sources in both healthy subjects and schizophrenia patients. In both groups, primary contributing ASSR sources were identified in the right superior temporal cortex and the orbitofrontal cortex. In conjunction with normal activity in these areas, schizophrenia patients showed significantly reduced source dipole density of gamma-band ASSR (ITC > 0.25) in the left superior temporal cortex, orbitofrontal cortex, and left superior frontal cortex. In conclusion, a distributed network of temporal and frontal brain regions supports gamma phase synchronization. We demonstrated that failure to mount a coherent physiologic response to simple 40-Hz stimulation reflects disorganized network function in schizophrenia patients. Future translational studies are needed to more fully understand the neural mechanisms underlying gamma-band ASSR network abnormalities in schizophrenia.

Decreased Gamma-Band Auditory Steady State Response is Associated With Social Functional Impairment in Patients at Clinical High Risk for Schizophrenia

Decreased Gamma-Band Auditory Steady State Response is Associated With Social Functional Impairment in Patients at Clinical High Risk for Schizophrenia

Auditory-Based Cognitive Training Drives Short- and Long-Term Plasticity in Cortical Networks in Schizophrenia

Abstract Schizophrenia patients have widespread deficits in neurocognitive functioning linked to underlying abnormalities in gamma oscillations that are readily measured by the 40 Hz auditory steady-state response (ASSR). Emerging interventions such as auditory-based targeted cognitive training (TCT) improve neurocognitive function in patients. While acute ASSR changes after 1 hour of TCT predict clinical and cognitive gains after a 30-hour course of TCT, the neural substrates of underlying short- and long-term TCT interventions are unknown. To determine the neural substrates underlying TCT-associated ASSR changes, a novel data analysis method was applied to assess the effective connectivity of gamma-band ASSR among estimated cortical sources. In this study, schizophrenia patients (N = 52) were randomized to receive either a treatment as usual (TAU; N = 22) or TAU augmented with TCT (N = 30). EEG recordings were obtained immediately before (T0) and after 1 hour of either computer games (TAU) or cognitive training (TCT; T1), and at 65 ± 15 days (mean ± SD) post-randomization (T2). Results showed increased connectivity from the left ventral middle cingulate gyrus to the left posterior cingulate gyrus, accompanied by decreased connectivity from the left Rolandic operculum (a region that includes auditory cortex) to the right ventral middle cingulate gyrus after 1 hour of TCT. After 30 hours, decreased connectivity from the frontal cortex to a region near the calcarine sulcus were detected. Auditory-based cognitive training drives short- and long-term plasticity in cortical network functioning in schizophrenia patients. These findings may help us understand the mechanisms underlying cognitive training effects in schizophrenia patients and enhance the development of pro-cognitive therapeutics.

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.

Global and Parallel Cortical Processing of Auditory Gamma Oscillatory Responses in Humans

Gamma oscillation is a physiological phenomenon that reflects higher cognitive function and parvalbumin-positive GABAergic interneuron function in animals. Gamma-band auditory steady-state response (ASSR) is the most robust index for gamma oscillation, which is impaired in patients with neuropsychiatric disorders. Although ASSR reduction is known to be selective for frequency and time, the neural basis of this phenomenon is poorly understood. We directly showed in the current study that ASSR is globally distributed among the temporal, parietal, and frontal cortices using electrocorticography (ECoG) recording from a wide range of the cortex in patients with refractory epilepsy. ASSR was composed of multiple neural circuits depending on frequency and latency. Importantly, late-latency ASSR was topographically organized along the dorsal and ventral auditory pathways according to frequency tuning characteristics. These results provide a neural basis of the frequency-time dependence of ASSR reduction in patients with neuropsychiatric disorders.

Cortical volume and 40-Hz auditory-steady-state responses in patients with schizophrenia and healthy controls.

BackgroundAbnormalities in the 40-Hz auditory steady-state response (ASSR) of the gamma range have been reported in schizophrenia (SZ) and are regarded as important pathophysiological features. Many of the previous studies reported diminished gamma oscillations in SZ, although some studies reported increased spontaneous gamma oscillations. Furthermore, brain morphological correlates of the gamma band ASSR deficits have rarely examined. We investigated different measures of the 40-Hz ASSR and their association with brain volumes and psychological measures of SZ.MethodsThe 40-Hz ASSR was measured for 80 dB click sounds (1 ms, 500-ms trains at 40-Hz, with 3050 to 3500 inter-train interval) using electroencephalography with 64 electrodes in 33 patients with SZ (male: 16, female: 17 (age range: 21–60)) and 30 healthy controls (HCs) (male: 13, female: 17 (age range: 23–64)). Four gamma oscillation measures (evoked power, spontaneous oscillations (baseline and total power), and inter-trial phase coherence (ITC)) were assessed. The source activities of the ASSR were also analyzed. Brain volumes were assessed using high-resolution magnetic resonance imaging and voxel-based morphometry and superior temporal gyrus (STG) volume measures were obtained.ResultsPatients with SZ had larger total and evoked powers and higher ITC than HCs. Both groups showed significantly different association between mean evoked power and right STG volume. In HCs but not SZ, mean evoked power showed significant positive correlation with right STG volume. In addition, the two groups showed significantly different association between verbal fluency and mean evoked power. High evoked power was significantly correlated with poor verbal fluency in SZ.ConclusionsThe current study found increased gamma oscillation in SZ and suggests significant involvement of the STG in gamma oscillations.

Gamma Band Phase Delay in Schizophrenia

BackgroundIn 1999, Kwon et al. reported several electroencephalographic gamma band auditory steady-state response (ASSR) abnormalities in schizophrenia, spawning approximately 100 subsequent studies. While many studies replicated the finding of reduced 40-Hz ASSR power in schizophrenia and extended this by showing that 40-Hz phase synchrony (phase-locking factor [PLF]) was also reduced, none attempted to replicate the original phase delay finding of Kwon et al. Accordingly, we measured the 40-Hz ASSR phase-locking angle (PLA) to assess phase delay and examined its differential sensitivity to schizophrenia, relative to power and PLF measures. MethodsTo obtain ASSRs, electroencephalography data were recorded from 28 patients with schizophrenia and 25 healthy control subjects listening to repeated 40-Hz 500-ms click trains. Evoked power, total power, PLF, and PLA were calculated after Morlet wavelet time-frequency decomposition of single trial data from electrode Fz. ResultsIn patients with schizophrenia, 40-Hz PLA was significantly reduced (i.e., phase delayed) (p < .0001) and was unrelated to reductions in their 40-Hz power or PLF. PLA discriminated patients from healthy control subjects with 85% accuracy compared with 67% for power and 65% for PLF. ConclusionsConsistent with the original Kwon et al. study, 40-Hz click train–driven gamma oscillations were phase delayed in schizophrenia. Importantly, this phase delay abnormality was substantially larger than the gamma power and phase synchrony abnormalities that have been the focus of prior 40-Hz ASSR studies in schizophrenia. PLA provides a unique neurobiological measure of gamma band abnormalities in schizophrenia, likely reflecting a distinct pathophysiological mechanism from those underlying PLF and power abnormalities.

Auditory gamma oscillations predict global symptomatic outcome in the early stages of psychosis: A longitudinal investigation

ObjectivesThe gamma-band auditory steady-state response (ASSR) is thought to reflect the function of parvalbumin-positive γ-aminobutyric acid (GABA)-ergic interneurons and may be a candidate biomarker in early psychosis. Although previous cross-sectional studies have shown that gamma-band ASSR is reduced in early psychosis, whether reduced gamma-band ASSR could be a predictor of the long-term prognosis remains unknown. MethodsIn this longitudinal study, we investigated the association between gamma-band ASSR reduction and future global symptomatic or functional outcome in early psychosis. We measured 40-Hz ASSR in 34 patients with recent-onset schizophrenia (ROSZ), 28 ultra-high risk (UHR) individuals, and 30 healthy controls (HCs) at baseline. After 1–2 years, we evaluated the global assessment of functioning (GAF) in the ROSZ (N = 20) and UHR (N = 20) groups. ResultsThe 40-Hz ASSR was significantly reduced in the ROSZ and UHR groups. The attenuated 40-Hz ASSR was correlated with the future global symptomatic outcome in the ROSZ, but not in the UHR groups. ConclusionsA reduction in the gamma-band ASSR after the onset of psychosis may predict symptomatic outcomes in early psychosis. SignificanceGamma-band ASSR may be a potentially useful biomarker of the long-term prognosis in patients with recent-onset schizophrenia.

T13. PROGRESSIVE SPONTANEOUS AND SYNCHRONY GAMMA-BAND OSCILLATION DEFICITS IN FIRST EPISODE SCHIZOPHRENIA

BackgroundDeficits in the gamma-band (30–100 Hz) auditory steady-state response (ASSR) and progressive volumetric decreases in the primary auditory cortex have been detected shortly after the onset of schizophrenia (SZ), and may be associated with symptoms such as auditory hallucinations. Disruption of gamma-band oscillation has received considerable interest, as the basic mechanisms underlying these oscillations are understood and are conserved across species. Despite the importance of abnormal gamma-band oscillations in SZ, it remains unclear whether the gamma-band ASSR deficit shows progressive change over time during the early stages of the disease. Moreover, animal models based on NMDA receptor hypofunction demonstrate an increase in spontaneous gamma power, which has been reported in chronic SZ (Hirano et al., JAMA Psychiatry 2015), yet it still remains unclear in first-episode schizophrenia (FESZ). Hence, a longitudinal electroencephalogram study of the spontaneous and synchrony gamma-band oscillation in FESZ is important to better understand the pathophysiology and trajectory of early-stage schizophrenia.MethodsSubjects were 23 FESZ (14 treated and 9 untreated with antipsychotics), and 39 matched healthy controls (HC). Dipole source localization of dense electrode EEG data was used to examine oscillatory activities in auditory cortices during auditory steady-state stimulation (20/30/40-Hz rates). ICA was used to remove artifacts. Phase locking factor (PLF) and induced power (not phase-locked) were calculated from artifact-free single trial source estimates. Clinical symptoms were assessed by SAPS and SANS. Subjects were recruited as part of the Boston CIDAR Center (www.bostoncidar.org). Test sessions (Time-1/Time-2) were 11.9 months apart.ResultsCompared to HC, FESZ showed reduced 40-Hz ASSR PLF (synchrony gamma) and increased induced gamma power (spontaneous gamma) during continuous auditory stimuli at time-1. Longitudinally, FESZ showed overall progressive reductions in 40-Hz ASSR PLF and progressive increases in induced gamma power, especially within the left auditory cortex. These progressive deficits were not related to antipsychotic medication. Progressive increase of induced gamma power was correlated with increased positive symptoms.DiscussionWe found coincide disruptions of auditory gamma-band oscillation, which showed progressive increase in spontaneous gamma (cortical excitability) and progressive decrease in synchrony gamma (cortical synchrony failure) during continuous auditory stimuli in FESZ. These two apparently distinctive circuit progressive abnormalities already occurred in the very early stage of the disease. We propose that assessing ASSR-PLF and spontaneous gamma in FESZ may provide a sensitive translatable biomarker for the integrity of neural networks that are fundamentally altered in the very early stage of SZ.

Gamma-band auditory steady-state response after frontal tDCS: A double-blind, randomized, crossover study.

The effects of transcranial direct current stimulation (tDCS) likely depend on cortical N-methyl-D-aspartic acid (NMDA) neurotransmission; however, no previous studies have reported tDCS-mediated modulation of cortical NMDA neurotransmission in humans. The gamma-band auditory steady-state response (ASSR) to a 40 Hz stimulation likely reflects the integrity of cortical NMDA neurotransmission. The present study tested whether the effect of tDCS is reflected in gamma-band ASSRs during a 40 Hz stimulation. Using a double-blind, randomized, crossover study, we performed magnetoencephalography (MEG) and measured the ASSR in 24 healthy participants during 40 Hz of auditory stimulation after prefrontal tDCS (2 mA) or sham (i.e., placebo) treatment. Our results failed to reveal significant differences in any brain between the two conditions after the application of a frequency of approximately 40 Hz. Based on these results, the ASSR is an insufficient method to detect the effect of tDCS on cortical NMDA neurotransmission. Unexpectedly, the results revealed an enhanced beta-band event-related spectral perturbation (ERSP) in the left motor cortex after tDCS compared with that observed after the sham stimuli. Given that beta-band oscillations reflect many functions in motor cortices, the tDCS for the frontal areas had some effect on the left motor cortex while the participants were focusing on not pressing the button with their right index finger. An additional study with an adequate psychological task is necessary to draw a conclusion regarding this unexpected result.

Differentiation between major depressive disorder and bipolar disorder by auditory steady-state responses

BackgroundThe auditory steady-state response (ASSR) elicited by gamma band neural oscillations has received considerable interest as a biomarker of psychiatric disorders. Although recent ASSR studies have reported that patients with bipolar disorder (BD) show altered ASSRs, little is known about ASSRs in patients with major depressive disorder (MDD). The aim of this study was to evaluate whether ASSRs in MDD subjects differed from those in BD subjects or normal controls (NC). MethodWe analyzed ASSRs in 14 MDD patients, 19 BD patients, and 29 normal control subjects. We used whole-head 306-channel magnetoencephalography to evaluate ASSR power and phase-locking factors (PLF) elicited by 20-, 30-, 40-, and 80-Hz click trains. We determined optimal sensitivity and specificity of ASSR power and PLF for the diagnosis of MDD or BD via receiver operating characteristic (ROC) curve analysis using a nonparametric approach. ResultsMDD patients exhibited no significant differences in ASSR power or PLF compared with NC subjects, while BD patients showed deficits on the ASSR measures. MDD patients showed significantly larger ASSR power and PLF for 30-, 40-, and 80-Hz stimuli compared with BD patients. The area under the curve (AUC) for the ROC analysis (MDD vs. BD) was 0.81 [95% CI=0.66–0.96, p=0.003] concerning 40-Hz ASSR power. LimitationsWe could not exclude the effect of medication and the sample size of the current study is relatively small. ConclusionsWe could differentiate between MDD and BD subjects in terms of gamma band ASSR. Our data suggest that the 40-Hz ASSR may be a potential biomarker for differentiation between MDD and BD patients.

Network Analysis of Functional Brain Connectivity Driven by Gamma-Band Auditory Steady-State Response in Auditory Hallucinations.

The auditory steady-state response (ASSR) may reflect activity from different regions of the brain. Particularly, it was reported that the gamma-band ASSR plays an important role in working memory, speech understanding, and recognition. Traditionally, the ASSR has been determined by power spectral density analysis, which cannot detect the exact overall distributed properties of the ASSR. Functional network analysis has recently been applied in electroencephalography studies. Previous studies on resting or working state found a small-world organization of the brain network. Some researchers have studied dysfunctional networks caused by diseases. The present study investigates the brain connection networks of schizophrenia patients with auditory hallucinations during an ASSR task. A directed transfer function is utilized to estimate the brain connectivity patterns. Moreover, the structures of brain networks are analyzed by converting the connectivity matrices into graphs. It is found that for normal subjects, network connections are mainly distributed at the central and frontal–temporal regions. This indicates that the central regions act as transmission hubs of information under ASSR stimulation. For patients, network connections seem unordered. The finding that the path length was larger in patients compared to that in normal subjects under most thresholds provides insight into the structures of connectivity patterns. The results suggest that there are more synchronous oscillations that cover a long distance on the cortex but a less efficient network for patients with auditory hallucinations.