40†Hz Steady-State Response in Human Auditory Cortex Is Shaped by Gabaergic Neuronal Inhibition.

The 40 Hz auditory steady-state response (ASSR), an oscillatory brain response to periodically modulated auditory stimuli, is a promising, noninvasive physiological biomarker for schizophrenia and related neuropsychiatric disorders. The 40 Hz ASSR might be amplified by synaptic interactions in cortical circuits, which are, in turn, disturbed in neuropsychiatric disorders. Here, we tested whether the 40 Hz ASSR in the human auditory cortex depends on two key synaptic components of neuronal interactions within cortical circuits: excitation via N-methyl-aspartate glutamate (NMDA) receptors and inhibition via gamma-amino-butyric acid (GABA) receptors. We combined magnetoencephalography (MEG) recordings with placebo-controlled, low-dose pharmacological interventions in the same healthy human participants (13 males, 7 females). All participants exhibited a robust 40 Hz ASSR in auditory cortices, especially in the right hemisphere, under a placebo. The GABAA receptor-agonist lorazepam increased the amplitude of the 40 Hz ASSR, while no effect was detectable under the NMDA blocker memantine. Our findings indicate that the 40 Hz ASSR in the auditory cortex involves synaptic (and likely intracortical) inhibition via the GABAA receptor, thus highlighting its utility as a mechanistic signature of cortical circuit dysfunctions involving GABAergic inhibition.

Towards a youth mental health paradigm: a perspective and roadmap.

Most mental disorders have a typical onset between 12 and 25 years of age, highlighting the importance of this period for the pathogenesis, diagnosis, and treatment of mental ill-health. This perspective addresses interactions between risk and protective factors and brain development as key pillars accounting for the emergence of psychopathology in youth. Moreover, we propose that novel approaches towards early diagnosis and interventions are required that reflect the evolution of emerging psychopathology, the importance of novel service models, and knowledge exchange between science and practitioners. Taken together, we propose a transformative early intervention paradigm for research and clinical care that could significantly enhance mental health in young people and initiate a shift towards the prevention of severe mental disorders.

[Ethical Considerations of Including Minors in Clinical Trials Using the Example of the Indicated Prevention of Psychotic Disorders]. / Minderjährige in klinischen Prüfungen: Ethische Abwägungen ihres Einbezugs am Beispiel der indizierten Prävention psychotischer Erkrankungen.

Ethical Considerations of Including Minors in Clinical Trials Using the Example of the Indicated Prevention of Psychotic Disorders Abstract: As a vulnerable group, minors require special protection in studies. For this reason, researchers are often reluctant to initiate studies, and ethics committees are reluctant to authorize such studies. This often excludes minors from participating in clinical studies. This exclusion can lead to researchers and clinicians receiving only incomplete data or having to rely on adult-based findings in the treatment of minors. Using the example of the study "Computer-Assisted Risk Evaluation in the Early Detection of Psychotic Disorders" (CARE), which was conducted as an 'other clinical investigation' according to the Medical Device Regulation, we present a line of argumentation for the inclusion of minors which weighs the ethical principles of nonmaleficence (especially regarding possible stigmatization), beneficence, autonomy, and fairness. We show the necessity of including minors based on the development-specific differences in diagnostics and early intervention. Further, we present specific protective measures. This argumentation can also be transferred to other disorders with the onset in childhood and adolescence and thus help to avoid excluding minors from appropriate evidence-based care because of insufficient studies.

The coupling between the spatial and temporal scales of neural processes revealed by a joint time-vertex connectome spectral analysis.

Brain oscillations are produced by the coordinated activity of large groups of neurons and different rhythms are thought to reflect different modes of information processing. These modes, in turn, are known to occur at different spatial scales. Nevertheless, how these rhythms support different spatial modes of information processing at the brain scale is not yet fully understood. Here we use "Joint Time-Vertex Spectral Analysis" to characterize the joint spectral content of brain activity both in time (temporal frequencies) and in space over the connectivity graph (spatial connectome harmonics). This method allows us to characterize the relationship between spatially localized or distributed neural processes on one side and their respective temporal frequency bands in source-reconstructed M/EEG signals. We explore this approach on two different datasets, an auditory steady-state response (ASSR) and a visual grating task. Our results suggest that different information processing mechanisms are carried out at different frequency bands: while spatially distributed activity (which may also be interpreted as integration) specifically occurs at low temporal frequencies (alpha and theta) and low graph spatial frequencies, localized electrical activity (i.e., segregation) is observed at high temporal frequencies (high and low gamma) over restricted high spatial graph frequencies. Crucially, the estimated contribution of the distributed and localized neural activity predicts performance in a behavioral task, demonstrating the neurophysiological relevance of the joint time-vertex spectral representation.

Characterising cognitive heterogeneity in individuals at clinical high-risk for psychosis: a cluster analysis with clinical and functional outcome prediction.

Schizophrenia is characterised by cognitive impairments that are already present during early stages, including in the clinical high-risk for psychosis (CHR-P) state and first-episode psychosis (FEP). Moreover, data suggest the presence of distinct cognitive subtypes during early-stage psychosis, with evidence for spared vs. impaired cognitive profiles that may be differentially associated with symptomatic and functional outcomes. Using cluster analysis, we sought to determine whether cognitive subgroups were associated with clinical and functional outcomes in CHR-P individuals. Data were available for 146 CHR-P participants of whom 122 completed a 6- and/or 12-month follow-up; 15 FEP participants; 47 participants not fulfilling CHR-P criteria (CHR-Ns); and 53 healthy controls (HCs). We performed hierarchical cluster analysis on principal components derived from neurocognitive and social cognitive measures. Within the CHR-P group, clusters were compared on clinical and functional variables and examined for associations with global functioning, persistent attenuated psychotic symptoms and transition to psychosis. Two discrete cognitive subgroups emerged across all participants: 45.9% of CHR-P individuals were cognitively impaired compared to 93.3% of FEP, 29.8% of CHR-N and 30.2% of HC participants. Cognitively impaired CHR-P participants also had significantly poorer functioning at baseline and follow-up than their cognitively spared counterparts. Specifically, cluster membership predicted functional but not clinical outcome. Our findings support the existence of distinct cognitive subgroups in CHR-P individuals that are associated with functional outcomes, with implications for early intervention and the understanding of underlying developmental processes.

Duration of basic and attenuated-psychotic symptoms in individuals at clinical high risk for psychosis: pattern of symptom onset and effects of duration on functioning and cognition.

INTRODUCTION: Duration of risk symptoms (DUR) in people at clinical high risk for psychosis (CHR-P) has been related to poorer clinical outcomes, such as reduced functioning, but it is currently unclear how different symptoms emerge as well as their link with cognitive deficits. To address these questions, we examined the duration of basic symptoms (BS) and attenuated psychotic symptoms (APS) in a sample of CHR-P participants to test the hypothesis that BS precede the manifestation of APS. As a secondary objective, we investigated the relationship between DUR, functioning and neuropsychological deficits. METHODS: Data from 134 CHR-P participants were assessed with the Comprehensive Assessment of At-Risk Mental State and the Schizophrenia Proneness Interview, Adult Version. Global, role and social functioning and neurocognition were assessed and compared to a sample of healthy controls (n = 57). RESULTS: In CHR-P participants who reported both APS and BS, onset of BS and APS was not significantly related. When divided into short and long BS duration ( 8 years), CHR-P participants with a longer duration of BS showed evidence for an onset of BS preceding APS (n = 8, p = 0.003). However, in the short BS duration group, APS showed evidence of preceding BS (n = 56, p = 0.020). Finally, there were no significant effects of DUR on cognition or functioning measures. CONCLUSION: The present findings do not support the view that APS constitute a secondary phenomenon to BS. Moreover, our data could also not confirm that DUR has a significant effect on functioning and cognitive deficits. These findings are discussed in the context of current theories regarding emerging psychosis and the importance of DUR.

Current findings and perspectives on aberrant neural oscillations in schizophrenia.

There is now consistent evidence that neural oscillation at low- and high-frequencies constitute an important aspect of the pathophysiology of schizophrenia. Specifically, impaired rhythmic activity may underlie the deficit to generate coherent cognition and behavior, leading to the characteristic symptoms of psychosis and cognitive deficits. Importantly, the generating mechanisms of neural oscillations are relatively well-understood and thus enable the targeted search for the underlying circuit impairments and novel treatment targets. In the following review, we will summarize and assess the evidence for aberrant rhythmic activity in schizophrenia through evaluating studies that have utilized Electro/Magnetoencephalography to examine neural oscillations during sensory and cognitive tasks as well as during resting-state measurements. These data will be linked to current evidence from post-mortem, neuroimaging, genetics, and animal models that have implicated deficits in GABAergic interneurons and glutamatergic neurotransmission in oscillatory deficits in schizophrenia. Finally, we will highlight methodological and analytical challenges as well as provide recommendations for future research.

Investigating cortico-subcortical circuits during auditory sensory attenuation: A combined magnetoencephalographic and dynamic causal modeling study.

Sensory attenuation refers to the decreased intensity of a sensory percept when a sensation is self-generated compared with when it is externally triggered. However, the underlying brain regions and network interactions that give rise to this phenomenon remain to be determined. To address this issue, we recorded magnetoencephalographic (MEG) data from 35 healthy controls during an auditory task in which pure tones were either elicited through a button press or passively presented. We analyzed the auditory M100 at sensor- and source-level and identified movement-related magnetic fields (MRMFs). Regression analyses were used to further identify brain regions that contributed significantly to sensory attenuation, followed by a dynamic causal modeling (DCM) approach to explore network interactions between generators. Attenuation of the M100 was pronounced in right Heschl's gyrus (HES), superior temporal cortex (ST), thalamus, rolandic operculum (ROL), precuneus and inferior parietal cortex (IPL). Regression analyses showed that right postcentral gyrus (PoCG) and left precentral gyrus (PreCG) predicted M100 sensory attenuation. In addition, DCM results indicated that auditory sensory attenuation involved bi-directional information flow between thalamus, IPL, and auditory cortex. In summary, our data show that sensory attenuation is mediated by bottom-up and top-down information flow in a thalamocortical network, providing support for the role of predictive processing in sensory-motor system.

Neuropsychological deficits in participants at clinical high risk for psychosis recruited from the community: relationships to functioning and clinical symptoms.

BACKGROUND: The current study examined the pattern of neurocognitive impairments in a community-recruited sample of clinical high-risk (CHR) participants and established relationships with psychosocial functioning. METHODS: CHR-participants (n = 108), participants who did not fulfil CHR-criteria (CHR-negatives) (n = 42) as well as a group of healthy controls (HCs) (n = 55) were recruited. CHR-status was assessed using the Comprehensive Assessment of At-Risk Mental States (CAARMS) and the Schizophrenia Proneness Instrument, Adult Version (SPI-A). The Brief Assessment of Cognition in Schizophrenia Battery (BACS) as well as tests for emotion recognition, working memory and attention were administered. In addition, role and social functioning as well as premorbid adjustment were assessed. RESULTS: CHR-participants were significantly impaired on the Symbol-Coding and Token-Motor task and showed a reduction in total BACS-scores. Moreover, CHR-participants were characterised by prolonged response times (RTs) in emotion recognition as well as by reductions in both social and role functioning, GAF and premorbid adjustments compared with HCs. Neurocognitive impairments in emotion recognition accuracy, emotion recognition RT, processing speed and motor speed were associated with several aspects of functioning explaining between 4% and 12% of the variance. CONCLUSION: The current data obtained from a community sample of CHR-participants highlight the importance of dysfunctions in motor and processing speed and emotion recognition RT. Moreover, these deficits were found to be related to global, social and role functioning, suggesting that neurocognitive impairments are an important aspect of sub-threshold psychotic experiences and a possible target for therapeutic interventions.

Towards a neurodynamical understanding of the prodrome in schizophrenia.

The identification of biomarkers for the early diagnosis of schizophrenia that could inform novel treatment developments is an important objective of current research. This paper will summarize recent work that has investigated changes in oscillatory activity and event-related potentials with Electro/Magnetoencephalography (EEG/MEG) in participants at high-risk for the development of schizophrenia, highlighting disruptions in sensory and cognitive operations prior to the onset of the syndrome. Changes in EEG/MEG-data are consistent with evidence for alterations in Glutamatergic and GABAergic neurotransmission as disclosed by Magnetic Resonance Spectroscopy and brain stimulation, indicating changes in Excitation/Inhibition balance parameters prior to the onset of psychosis. Together these data emphasize the importance of research into neuronal dynamics as a crucial approach to establish functional relationships between impairments in neural circuits and emerging psychopathology that together could be fundamental for early intervention and the identification of novel treatments for emerging psychosis.

Acute ketamine dysregulates task-related gamma-band oscillations in thalamo-cortical circuits in schizophrenia.

Hypofunction of the N-methyl-d-aspartate receptor (NMDAR) has been implicated as a possible mechanism underlying cognitive deficits and aberrant neuronal dynamics in schizophrenia. To test this hypothesis, we first administered a sub-anaesthetic dose of S-ketamine (0.006 mg/kg/min) or saline in a single-blind crossover design in 14 participants while magnetoencephalographic data were recorded during a visual task. In addition, magnetoencephalographic data were obtained in a sample of unmedicated first-episode psychosis patients (n = 10) and in patients with chronic schizophrenia (n = 16) to allow for comparisons of neuronal dynamics in clinical populations versus NMDAR hypofunctioning. Magnetoencephalographic data were analysed at source-level in the 1-90 Hz frequency range in occipital and thalamic regions of interest. In addition, directed functional connectivity analysis was performed using Granger causality and feedback and feedforward activity was investigated using a directed asymmetry index. Psychopathology was assessed with the Positive and Negative Syndrome Scale. Acute ketamine administration in healthy volunteers led to similar effects on cognition and psychopathology as observed in first-episode and chronic schizophrenia patients. However, the effects of ketamine on high-frequency oscillations and their connectivity profile were not consistent with these observations. Ketamine increased amplitude and frequency of gamma-power (63-80 Hz) in occipital regions and upregulated low frequency (5-28 Hz) activity. Moreover, ketamine disrupted feedforward and feedback signalling at high and low frequencies leading to hypo- and hyper-connectivity in thalamo-cortical networks. In contrast, first-episode and chronic schizophrenia patients showed a different pattern of magnetoencephalographic activity, characterized by decreased task-induced high-gamma band oscillations and predominantly increased feedforward/feedback-mediated Granger causality connectivity. Accordingly, the current data have implications for theories of cognitive dysfunctions and circuit impairments in the disorder, suggesting that acute NMDAR hypofunction does not recreate alterations in neural oscillations during visual processing observed in schizophrenia.

Test-retest reliability of the magnetic mismatch negativity response to sound duration and omission deviants.

Mismatch negativity (MMN) is a neurophysiological measure of auditory novelty detection that could serve as a translational biomarker of psychiatric disorders, such as schizophrenia. However, the replicability of its magnetoencephalographic (MEG) counterpart (MMNm) has been insufficiently addressed. In the current study, test-retest reliability of the MMNm response to both duration and omission deviants was evaluated over two MEG sessions in 16 healthy adults. MMNm amplitudes and latencies were obtained at both sensor- and source-level using a cortically-constrained minimum-norm approach. Intraclass correlations (ICC) were derived to assess stability of MEG responses over time. In addition, signal-to-noise ratios (SNR) and within-subject statistics were obtained in order to determine MMNm detectability in individual participants. ICC revealed robust values at both sensor- and source-level for both duration and omission MMNm amplitudes (ICC = 0.81-0.90), in particular in the right hemisphere, while moderate to strong values were obtained for duration MMNm and omission MMNm peak latencies (ICC = 0.74-0.88). Duration MMNm was robustly identified in individual participants with high SNR, whereas omission MMNm responses were only observed in half of the participants. Our data indicate that MMNm to unexpected duration changes and omitted sounds are highly reproducible, providing support for the use of MEG-parameters in basic and clinical research.

Impairment in predictive processes during auditory mismatch negativity in ScZ: Evidence from event-related fields.

Patients with schizophrenia (ScZ) show pronounced dysfunctions in auditory perception but the underlying mechanisms as well as the localization of the deficit remain unclear. To examine these questions, the current study examined whether alterations in the neuromagnetic mismatch negativity (MMNm) in ScZ-patients could involve an impairment in sensory predictions in local sensory and higher auditory areas. Using a whole-head MEG-approach, we investigated the MMNm as well as P300m and N100m amplitudes during a hierarchical auditory novelty paradigm in 16 medicated ScZ-patients and 16 controls. In addition, responses to omitted sounds were investigated, allowing for a critical test of the predictive coding hypothesis. Source-localization was performed to identify the generators of the MMNm, omission responses as well as the P300m. Clinical symptoms were examined with the positive and negative syndrome scale. Event-related fields (ERFs) to standard sounds were intact in ScZ-patients. However, the ScZ-group showed a reduction in the amplitude of the MMNm during both local (within trials) and global (across trials) conditions as well as an absent P300m at the global level. Importantly, responses to sound omissions were reduced in ScZ-patients which overlapped both in latency and generators with the MMNm sources. Thus, our data suggest that auditory dysfunctions in ScZ involve impaired predictive processes that involve deficits in both automatic and conscious detection of auditory regularities. Hum Brain Mapp 38:5082-5093, 2017. © 2017 Wiley Periodicals, Inc.

The Youth Mental Health Risk and Resilience Study (YouR-Study).

BACKGROUND: The transition from adolescence to adulthood is associated with the emergence of psychosis and other mental health problems, highlighting the importance of this developmental period for the understanding of developing psychopathology and individual differences in risk and resilience. The Youth Mental Health Risk and Resilience Study (YouR-Study) aims to identify neurobiological mechanisms and predictors of psychosis-risk with a state-of-the-art neuroimaging approach (Magnetoencephalography, Magnetic Resonance Spectroscopy, Magnetic Resonance Imaging) in combination with core psychological processes, such as affect regulation and attachment, that have been implicated in the development and maintenance of severe mental health problems. METHODS/DESIGN: One hundred participants meeting clinical high-risk criteria (CHR) for psychosis through the Comprehensive Assessment of At-Risk Mental State and Schizophrenia Proneness Instrument, Adult Version, in the age range from 16 to 35 years of age will be recruited. Mental-state monitoring up to a total of 2 years will be implemented to detect transition to psychosis. In addition, a sample of n = 40 help-seeking participants will be recruited who do not meet CHR-criteria, a group of n = 50 healthy control participants and a sample of n = 25 patients with first-episode psychosis. MEG-activity will be obtained during auditory and visual tasks to examine neural oscillations and event-related fields. In addition, we will obtain estimates of GABA and Glutamate levels through Magnetic Resonance Spectroscopy (MRS) to examine relationships between neural synchrony and excitatory-inhibition (E/I) balance parameters. Neuroimaging will be complemented by detailed neuropsychological assessments as well as psychological measures investigating the impact of childhood abuse, attachment experiences and affect regulation. DISCUSSION: The YouR-study could potentially provide important insights into the neurobiological mechanisms that confer risk for psychosis as well as biomarkers for early diagnosis of severe mental health problems. Moreover, we expect novel data related to the contribution of affect regulation and attachment-processes in the development of mental health problems, leading to an integrative model of early stage psychosis and the factors underlying risk and resilience of emerging psychopathology.

Preferential detachment during human brain development: age- and sex-specific structural connectivity in diffusion tensor imaging (DTI) data.

Human brain maturation is characterized by the prolonged development of structural and functional properties of large-scale networks that extends into adulthood. However, it is not clearly understood which features change and which remain stable over time. Here, we examined structural connectivity based on diffusion tensor imaging (DTI) in 121 participants between 4 and 40 years of age. DTI data were analyzed for small-world parameters, modularity, and the number of fiber tracts at the level of streamlines. First, our findings showed that the number of fiber tracts, small-world topology, and modular organization remained largely stable despite a substantial overall decrease in the number of streamlines with age. Second, this decrease mainly affected fiber tracts that had a large number of streamlines, were short, within modules and within hemispheres; such connections were affected significantly more often than would be expected given their number of occurrences in the network. Third, streamline loss occurred earlier in females than in males. In summary, our findings suggest that core properties of structural brain connectivity, such as the small-world and modular organization, remain stable during brain maturation by focusing streamline loss to specific types of fiber tracts.

Source-reconstruction of event-related fields reveals hyperfunction and hypofunction of cortical circuits in antipsychotic-naive, first-episode schizophrenia patients during Mooney face processing.

Schizophrenia is characterized by dysfunctions in neural circuits that can be investigated with electrophysiological methods, such as EEG and MEG. In the present human study, we examined event-related fields (ERFs), in a sample of medication-naive, first-episode schizophrenia (FE-ScZ) patients (n = 14) and healthy control participants (n = 17) during perception of Mooney faces to investigate the integrity of neuromagnetic responses and their experience-dependent modification. ERF responses were analyzed for M100, M170, and M250 components at the sensor and source levels. In addition, we analyzed peak latency and adaptation effects due to stimulus repetition. FE-ScZ patients were characterized by significantly impaired sensory processing, as indicated by a reduced discrimination index (A'). At the sensor level, M100 and M170 responses in FE-ScZ were within the normal range, whereas the M250 response was impaired. However, source localization revealed widespread elevated activity for M100 and M170 in FE-ScZ and delayed peak latencies for the M100 and M250 responses. In addition, M170 source activity in FE-ScZ was not modulated by stimulus repetitions. The present findings suggest that neural circuits in FE-ScZ may be characterized by a disturbed balance between excitation and inhibition that could lead to a failure to gate information flow and abnormal spreading of activity, which is compatible with dysfunctional glutamatergic neurotransmission.

Abnormal neural oscillations and synchrony in schizophrenia.

Converging evidence from electrophysiological, physiological and anatomical studies suggests that abnormalities in the synchronized oscillatory activity of neurons may have a central role in the pathophysiology of schizophrenia. Neural oscillations are a fundamental mechanism for the establishment of precise temporal relationships between neuronal responses that are in turn relevant for memory, perception and consciousness. In patients with schizophrenia, the synchronization of beta- and gamma-band activity is abnormal, suggesting a crucial role for dysfunctional oscillations in the generation of the cognitive deficits and other symptoms of the disorder. Dysfunctional oscillations may arise owing to anomalies in the brain's rhythm-generating networks of GABA (gamma-aminobutyric acid) interneurons and in cortico-cortical connections.

The phase of thalamic alpha activity modulates cortical gamma-band activity: evidence from resting-state MEG recordings.

Recent findings have implicated thalamic alpha oscillations in the phasic modulation of cortical activity. However, the precise relationship between thalamic alpha oscillations and neocortical activity remains unclear. Here we show in a large sample of healthy human participants (n = 45) using spatial filtering techniques and measures of phase amplitude coupling that the amplitude of gamma-band activity in posterior medial parietal cortex is modulated by the phase of thalamic alpha oscillations during eyes-closed resting-state recordings. In addition, our findings show that gamma-band activity in visual cortex was not modulated by thalamic alpha oscillations but coupled to the phase of strong cortical alpha activity. To overcome the limitations of electromagnetic source localization we estimated conduction delays using transfer entropy and found nonspurious information transfer from thalamus to cortex. The present findings provide novel evidence for magneto-encephalography-measured phase coupling between cortical gamma-band activity and thalamic alpha oscillations, which highlight the role of phasic inhibition in the coordination of cortical activity.

Effects of N-Methyl-d-Aspartate Receptor Antagonists on Gamma-Band Activity During Auditory Stimulation Compared With Electro/Magneto-encephalographic Data in Schizophrenia and Early-Stage Psychosis: A Systematic Review and Perspective.

BACKGROUND AND HYPOTHESIS: N-Methyl-d-aspartate receptor (NMDA-R) hypofunctioning has been hypothesized to be involved in circuit dysfunctions in schizophrenia (ScZ). Yet, it remains to be determined whether the physiological changes observed following NMDA-R antagonist administration are consistent with auditory gamma-band activity in ScZ which is dependent on NMDA-R activity. STUDY DESIGN: This systematic review investigated the effects of NMDA-R antagonists on auditory gamma-band activity in preclinical (n = 15) and human (n = 3) studies and compared these data to electro/magneto-encephalographic measurements in ScZ patients (n = 37) and 9 studies in early-stage psychosis. The following gamma-band parameters were examined: (1) evoked spectral power, (2) intertrial phase coherence (ITPC), (3) induced spectral power, and (4) baseline power. STUDY RESULTS: Animal and human pharmacological data reported a reduction, especially for evoked gamma-band power and ITPC, as well as an increase and biphasic effects of gamma-band activity following NMDA-R antagonist administration. In addition, NMDA-R antagonists increased baseline gamma-band activity in preclinical studies. Reductions in ITPC and evoked gamma-band power were broadly compatible with findings observed in ScZ and early-stage psychosis patients where the majority of studies observed decreased gamma-band spectral power and ITPC. In regard to baseline gamma-band power, there were inconsistent findings. Finally, a publication bias was observed in studies investigating auditory gamma-band activity in ScZ patients. CONCLUSIONS: Our systematic review indicates that NMDA-R antagonists may partially recreate reductions in gamma-band spectral power and ITPC during auditory stimulation in ScZ. These findings are discussed in the context of current theories involving alteration in E/I balance and the role of NMDA hypofunction in the pathophysiology of ScZ.