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

BACKGROUND: Thirty 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. METHOD: We 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. RESULTS: A 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. CONCLUSION: These 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.

Phase Delay of the 40†Hz Auditory Steady-State Response Localizes to Left Auditory Cortex in Schizophrenia.

Background. The auditory steady state response (ASSR) is generated in bilateral auditory cortex and is the most used electroencephalographic (EEG) or magnetoencephalographic measure of gamma band abnormalities in schizophrenia. While the finding of reduced 40-Hz ASSR power and phase consistency in schizophrenia have been replicated many times, the 40-Hz ASSR phase locking angle (PLA), which assesses oscillation latency or phase delay, has rarely been examined. Furthermore, whether 40-Hz ASSR phase delay in schizophrenia is lateralized or common to left and right auditory cortical generators is unknown. Methods. Previously analyzed EEG data recorded from 24 schizophrenia patients and 24 healthy controls presented with 20-, 30-, and 40-Hz click trains to elicit ASSRs were re-analyzed to assess PLA in source space. Dipole moments in the right and left hemisphere were used to assess both frequency and hemisphere specificity of ASSR phase delay in schizophrenia. Results. Schizophrenia patients exhibited significantly reduced (ie, phase delayed) 40-Hz PLA in the left, but not the right, hemisphere, but their 20- and 30-Hz PLA values were normal. This left-lateralized 40-Hz phase delay was unrelated to symptoms or to previously reported left-lateralized PLF reductions in the schizophrenia patients. Conclusions. Consistent with sensor-based studies, the 40-Hz ASSR source-localized to left, but not right, auditory cortex was phase delayed in schizophrenia. Consistent with prior studies showing left temporal lobe volume deficits in schizophrenia, our findings suggest sluggish entrainment to 40-Hz auditory stimulation specific to left auditory cortex that are distinct from well-established deficits in gamma ASSR power and phase synchrony.

Neuronal imbalance of excitation and inhibition in schizophrenia: a scoping review of gamma-band ASSR findings.

Recent empirical findings suggest that altered neural synchronization, which is hypothesized to be associated with an imbalance of excitatory (E) and inhibitory (I) neuronal activities, may underlie a core pathophysiological mechanism in patients with schizophrenia. The auditory steady-state response (ASSR) examined by electroencephalography (EEG) and magnetoencephalography (MEG) has been proposed as a potential biomarker for evaluating altered neural synchronization in schizophrenia. For this review, we performed a comprehensive literature search for papers published between 1999 and 2021 examining ASSRs in patients with schizophrenia. Almost all EEG-ASSR studies reported gamma-band ASSR reductions, especially to 40-Hz stimuli both in power and/or phase synchronization in chronic and first-episode schizophrenia. In addition, similar to EEG-ASSR findings, MEG-ASSR deficits to 80-Hz stimuli (high gamma) have been reported in patients with schizophrenia. Moreover, the 40-Hz ASSR is likely to be a predictor of the onset of schizophrenia. Notably, increased spontaneous (or ongoing) broadband (30-100 Hz) gamma power has been reported during ASSR tasks, which resembles the increased spontaneous gamma activity reported in animal models of E/I imbalance. Further research on ASSRs and evoked and spontaneous gamma oscillations is expected to elucidate the pathophysiology of schizophrenia with translational implications.

Multi-modal imaging of the auditory-larynx motor network for voicing perception.

Voicing is one of the most important characteristics of phonetic speech sounds. Despite its importance, voicing perception mechanisms remain largely unknown. To explore auditory-motor networks associated with voicing perception, we firstly examined the brain regions that showed common activities for voicing production and perception using functional magnetic resonance imaging. Results indicated that the auditory and speech motor areas were activated with the operculum parietale 4 (OP4) during both voicing production and perception. Secondly, we used a magnetoencephalography and examined the dynamical functional connectivity of the auditory-motor networks during a perceptual categorization task of /da/-/ta/ continuum stimuli varying in voice onset time (VOT) from 0 to 40 ms in 10 ms steps. Significant functional connectivities from the auditory cortical regions to the larynx motor area via OP4 were observed only when perceiving the stimulus with VOT 30 ms. In addition, regional activity analysis showed that the neural representation of VOT in the auditory cortical regions was mostly correlated with categorical perception of voicing but did not reflect the perception of stimulus with VOT 30 ms. We suggest that the larynx motor area, which is considered to play a crucial role in voicing production, contributes to categorical perception of voicing by complementing the temporal processing in the auditory cortical regions.

Recent findings on neurofeedback training for auditory hallucinations in schizophrenia.

PURPOSE OF REVIEW: To provide recent evidence on real-time neurofeedback (NFB) training for auditory verbal hallucinations (AVH) in schizophrenia patients. RECENT FINDINGS: NFB is a promising technique that allows patients to gain control over their AVH by modulating their own speech-related/language-related networks including superior temporal gyrus (STG) and anterior cingulate cortex (ACC) using fMRI, fNIRS and EEG/MEG. A recent limited number of studies showed that while an EEG-based NFB study failed to regulate auditory-evoked potentials and reduce AVH, downregulation of STG hyperactivity and upregulation of ACC activity with fMRI-based NFB appear to alleviate treatment-resistant AVH in schizophrenia patients. A deeper understanding of AVH and development of more effective methodologies are still needed. SUMMARY: Despite recent innovations in antipsychotics, many schizophrenia patients continue to suffer from treatment-resistant AVH and social dysfunctions. Recent studies suggested that real-time NFB shows promise in enabling patients to gain control over AVH by regulating their own speech-related/language-related networks. Although fMRI-NFB is suitable for regulating localized activity, EEG/MEG-NFB are ideal for regulating the ever-changing AVH. Although there are still many challenges including logistic complexity and burden on patients, we hope that such innovative real-time NFB trainings will help patients to alleviate severe symptoms and improve social functioning.

Auditory Cortex Volume and Gamma Oscillation Abnormalities in Schizophrenia.

We investigated whether the gray matter volume of primary auditory cortex (Heschl's gyrus [HG]) was associated with abnormal patterns of auditory γ activity in schizophrenia, namely impaired γ synchronization in the 40-Hz auditory steady-state response (ASSR) and increased spontaneous broadband γ power. (The γ data were previously reported in Hirano et al, JAMA Psychiatry, 2015;72:813-821). Participants were 24 healthy controls (HC) and 23 individuals with chronic schizophrenia (SZ). The ASSR was obtained from the electroencephalogram to click train stimulation at 20, 30, and 40 Hz rates. Dipole source localization of the ASSR was used to provide a spatial filter of auditory cortex activity, from which ASSR evoked power and phase locking factor (PLF), and induced γ power were computed. HG gray matter volume was derived from structural magnetic resonance imaging at 3 T with manually traced regions of interest. As expected, HG gray matter volume was reduced in SZ compared with HC. In SZ, left hemisphere ASSR PLF and induced γ power during the 40-Hz stimulation condition were positively and negatively correlated with left HG gray matter volume, respectively. These results provide evidence that cortical gray matter structure, possibly resulting from reduced synaptic connectivity at the microcircuit level, is related to impaired γ synchronization and increased spontaneous γ activity in schizophrenia.

Phase-Amplitude Coupling of the Electroencephalogram in the Auditory Cortex in Schizophrenia.

BACKGROUND: Cross-frequency interactions may coordinate neural circuits operating at different frequencies. While neural oscillations associated with particular circuits in schizophrenia (SZ) are impaired, few studies have examined cross-frequency interactions. Here we examined phase-amplitude coupling (PAC) in the electroencephalograms of individuals with SZ and healthy control subjects (HCs). We computed PAC during the baseline period of 40-Hz auditory steady-state stimulation and rest. We hypothesized that subjects with SZ would show abnormal theta/gamma coupling during stimulation, especially in the left auditory cortex, and coupling with high frequencies would be higher during stimulation than during rest. METHODS: We reanalyzed data from 18 subjects with SZ and 18 HCs. Auditory cortex electroencephalogram activity was estimated using dipole source localization. PAC was computed using the debiased PAC measure, calculated with the generalized Morse wavelet transform. PAC clusters were identified using cluster-corrected permutation testing and interrogated in analyses of variance with correction for multiple tests. RESULTS: Overall, coupling of high beta and gamma amplitude was higher during the auditory steady-state response, while alpha/beta PAC was higher during rest. Theta/alpha PAC was higher in subjects with SZ than in HCs. Theta/gamma PAC was lateralized to the left hemisphere in HCs but was not lateralized in subjects with SZ. CONCLUSIONS: PAC involving high frequencies was state dependent and not abnormal in SZ. Increased theta/alpha PAC in subjects with SZ was consistent with other evidence of increased low-frequency activity. Hemispheric lateralization of theta/gamma PAC was reduced in subjects with SZ, consistent with evidence for left hemisphere auditory cortex abnormalities in subjects with SZ. PAC may reveal new insights into neural circuitry abnormalities in SZ and other neuropsychiatric disorders.

Increased BOLD Signals Elicited by High Gamma Auditory Stimulation of the Left Auditory Cortex in Acute State Schizophrenia.

Recent MRI studies have shown that schizophrenia is characterized by reductions in brain gray matter, which progress in the acute state of the disease. Cortical circuitry abnormalities in gamma oscillations, such as deficits in the auditory steady state response (ASSR) to gamma frequency (>30-Hz) stimulation, have also been reported in schizophrenia patients. In the current study, we investigated neural responses during click stimulation by BOLD signals. We acquired BOLD responses elicited by click trains of 20, 30, 40 and 80-Hz frequencies from 15 patients with acute episode schizophrenia (AESZ), 14 symptom-severity-matched patients with non-acute episode schizophrenia (NASZ), and 24 healthy controls (HC), assessed via a standard general linear-model-based analysis. The AESZ group showed significantly increased ASSR-BOLD signals to 80-Hz stimuli in the left auditory cortex compared with the HC and NASZ groups. In addition, enhanced 80-Hz ASSR-BOLD signals were associated with more severe auditory hallucination experiences in AESZ participants. The present results indicate that neural over activation occurs during 80-Hz auditory stimulation of the left auditory cortex in individuals with acute state schizophrenia. Given the possible association between abnormal gamma activity and increased glutamate levels, our data may reflect glutamate toxicity in the auditory cortex in the acute state of schizophrenia, which might lead to progressive changes in the left transverse temporal gyrus.

Spontaneous Gamma Activity in Schizophrenia.

IMPORTANCE: A major goal of translational neuroscience is to identify neural circuit abnormalities in neuropsychiatric disorders that can be studied in animal models to facilitate the development of new treatments. Oscillations in the gamma band (30-100 Hz) of the electroencephalogram have received considerable interest as the basic mechanisms underlying these oscillations are understood, and gamma abnormalities have been found in schizophrenia (SZ). Animal models of SZ based on hypofunction of the N-methyl-d-aspartate receptor (NMDAR) demonstrate increased spontaneous broadband gamma power, but this phenomenon has not been identified clearly in patients with SZ. OBJECTIVE: To examine spontaneous gamma power and its relationship to evoked gamma oscillations in the auditory cortex of patients with SZ. DESIGN, SETTING, AND PARTICIPANTS: We performed a cross-sectional study including 24 patients with chronic SZ and 24 matched healthy control participants at the Veterans Affairs Boston Healthcare System from January 1, 2009, through December 31, 2012. Electroencephalograms were obtained during auditory steady-state stimulation at multiple frequencies (20, 30, and 40 Hz) and during a resting state in 18 participants in each group. MAIN OUTCOMES AND MEASURES: Electroencephalographic activity in the auditory cortex was estimated using dipole source localization. Auditory steady-state response (ASSR) measures included the phase-locking factor and evoked power. Spontaneous gamma power was measured as induced (non-phase-locked) gamma power in the ASSR data and as total gamma power in the resting-state data. RESULTS: The ASSR phase-locking factor was reduced significantly in patients with SZ compared with controls for the 40-Hz stimulation (mean [SD], 0.075 [0.028] vs 0.113 [0.065]; F1,46 = 6.79 [P = .012]) but not the 20- or the 30-Hz stimulation (0.042 [0.038] vs 0.043 [0.034]; F1,46 = 0.006 [P = .938] and 0.084 [0.040] vs 0.098 [0.050]; F1,46 = 1.605 [P = .212], respectively), repeating previous findings. The mean [SD] broadband-induced (30-100 Hz) gamma power was increased in patients with SZ compared with controls during steady-state stimulation (6.579 [3.783] vs 3.984 [1.843]; F1,46 = 9.128 [P = .004]; d = 0.87) but not during rest (0.006 [0.003] vs 0.005 [0.002]; F1,34 = 1.067 [P = .309]; d = 0.35). Induced gamma power in the left hemisphere of the patients with SZ during the 40-Hz stimulation was positively correlated with auditory hallucination symptoms (tangential, ρ = 0.587 [P = .031]; radial, ρ = 0.593 [P = .024]) and negatively correlated with the ASSR phase-locking factor (baseline: ρ = -0.572 [P = .024]; ASSR: ρ = -0.568 [P = .032]). CONCLUSIONS AND RELEVANCE: Spontaneous gamma activity is increased during auditory steady-state stimulation in SZ, reflecting a disruption in the normal balance of excitation and inhibition. This phenomenon interacts with evoked oscillations, possibly contributing to the gamma ASSR deficit found in SZ. The similarity of increased spontaneous gamma power in SZ to the findings of increased spontaneous gamma power in animal models of NMDAR hypofunction suggests that spontaneous gamma power could serve as a biomarker for the integrity of NMDARs on parvalbumin-expressing inhibitory interneurons in humans and in animal models of neuropsychiatric disorders.

Preattentive dysfunction in patients with bipolar disorder as revealed by the pitch-mismatch negativity: a magnetoencephalography (MEG) study.

OBJECTIVES: Mismatch negativity (MMN) and its magnetic counterpart (MMNm) are thought to reflect an automatic process that detects a difference between an incoming stimulus and the sensory memory trace of preceding stimuli. In patients with schizophrenia, an attenuation of the MMN/MMNm amplitude has been repeatedly reported. Heschl's gyrus (HG) is one of the major generators of MMN and the functional alteration of HG has been reported in patients with bipolar disorder. The present study investigated the pitch-MMNm in patients with bipolar disorder using whole-head 306-ch magnetoencephalography (MEG). METHODS: Twenty-two patients and 22 healthy controls participated in this study. Subjects were presented with two types of auditory stimulus sequences. One consisted of 1,000 Hz standards (probability = 90%) and 1,200 Hz deviants (probability = 10%), and the other consisted of 1,000 Hz standards (90%) and 1,200 Hz deviants (10%). These two tasks were each performed twice. Event-related brain responses to standard tones were subtracted from responses to deviant tones. RESULTS: Patients with bipolar disorder showed a significant bilateral reduction in magnetic global field power (mGFP) amplitudes (p = 0.02) and dipole moments of the MMNm (p = 0.04) compared with healthy controls. Patients with admission experience showed significantly reduced mGFP amplitudes of MMNm compared with patients without admission experience (p = 0.004). Additionally, patients with more severe manic symptoms had smaller mGFP amplitudes of MMNm (ρ = -0.50, p = 0.05). CONCLUSIONS: The results of this study suggest that patients with bipolar disorder may exhibit preattentive auditory dysfunction indexed by reduced pitch-MMNm responses. Pitch-MMNm could be a potential trait marker reflecting the global severity of bipolar disorder.

Reduced high and low frequency gamma synchronization in patients with chronic schizophrenia.

Schizophrenia has been conceptualized by dysfunctional cognition and behavior related to abnormalities in neural circuitry. The functioning of the neural circuitry can be assessed using the auditory steady state response (ASSR). Moreover, in recent years, research on high (>60 Hz) gamma band oscillations has become of increasing interest. The current study used whole-head, 306-channel magnetoencephalography (MEG) and investigated low and high gamma band oscillations with the ASSR. The subjects comprised 17 patients with schizophrenia and 22 controls. The current study investigated the MEG-ASSR elicited by click trains of 20-, 30-, 40- and 80-Hz frequencies, and symptom-ASSR associations in patients with schizophrenia. The mean power, phase-locking factor, dipole moments and source locations of the ASSR were estimated. The main findings were: (1) patients with schizophrenia showed bilaterally reduced ASSR power and dipole moments specific to the 40-Hz and 80-Hz frequencies; (2) patients with schizophrenia showed less right-greater-than-left 40-Hz ASSR power and phase-locking factor compared with healthy subjects, indicating that schizophrenics may be characterized by an abnormal asymmetry of the 40-Hz ASSR; (3) increased severity of global hallucinatory experiences was significantly associated with smaller left 80-Hz MEG-ASSR in patients with schizophrenia. The current study highlights the high and low frequency gamma abnormalities and provides clear evidence that schizophrenia is characterized by abnormalities in neural circuitry.

Spatiotemporal signatures of an abnormal auditory system in stuttering.

People who stutter (PWS) can reduce their stuttering rates under masking noise and altered auditory feedback; such a response can be attributed to altered auditory input, which suggests that abnormal speech processing in PWS results from abnormal processing of auditory input. However, the details of this abnormal processing of basic auditory information remain unclear. In order to characterize such abnormalities, we examined the functional and structural changes in the auditory cortices of PWS by using a 306-channel magnetoencephalography system to assess auditory sensory gating (P50m suppression) and tonotopic organization. Additionally, we employed voxel-based morphometry to compare cortical gray matter (GM) volumes on structural MR images. PWS exhibited impaired left auditory sensory gating. The tonotopic organization in the right hemisphere of PWS is expanded compared with that of the controls. Furthermore, PWS showed a significant increase in the GM volume of the right superior temporal gyrus, consistent with the right tonotopic expansion. Accordingly, we suggest that PWS have impaired left auditory sensory gating during basic auditory input processing and that some error signals in the auditory cortex could result in abnormal speech processing. Functional and structural reorganization of the right auditory cortex appears to be a compensatory mechanism for impaired left auditory cortex function in PWS.