Background: Transcranial magnetic stimulation can be combined with electromyography (TMS-EMG) and electroencephalography (TMS-EEG) to evaluate the excitatory and inhibitory functions of the cerebral cortex in a standardized manner. It has been postulated that schizophrenia is a disorder of functional neural connectivity underpinned by a relative imbalance of excitation and inhibition. The aim of this review was to provide a comprehensive overview of TMS-EMG and TMS-EEG research in schizophrenia, focused on excitation or inhibition, connectivity, motor cortical plasticity and the effect of antipsychotic medications, symptom severity and illness duration on TMS-EMG and TMS-EEG indices. Methods: We searched PsycINFO, Embase and Medline, from database inception to April 2020, for studies that included TMS outcomes in patients with schizophrenia. We used the following combination of search terms: transcranial magnetic stimulation OR tms AND interneurons OR glutamic acid OR gamma aminobutyric acid OR neural inhibition OR pyramidal neurons OR excita* OR inhibit* OR GABA* OR glutam* OR E-I balance OR excitation-inhibition balance AND schizoaffective disorder* OR Schizophrenia OR schizophreni*. Results: TMS-EMG and TMS-EEG measurements revealed deficits in excitation or inhibition, functional connectivity and motor cortical plasticity in patients with schizophrenia. Increased duration of the cortical silent period (a TMS-EMG marker of γ-aminobutyric acid B receptor activity) with clozapine was a relatively consistent finding. Limitations: Most of the studies used patients with chronic schizophrenia and medicated patients, employed cross-sectional group comparisons and had small sample sizes. Conclusion: TMS-EMG and TMS-EEG offer an opportunity to develop a novel and improved understanding of the physiologic processes that underlie schizophrenia and to assess the therapeutic effect of antipsychotic medications. In the future, these techniques may also help predict disease progression and further our understanding of the excitatory/inhibitory balance and its implications for mechanisms that underlie treatment-resistant schizophrenia.

AimsTranscranial magnetic stimulation (TMS) is a non-invasive brain stimulation tool designed to probe the strength of inhibitory and excitatory neurotransmission in the cortex. Combined with electromyography, paired-pulse TMS paradigms have revealed a deficit in inhibition mediated by GABA-A receptors in patients with schizophrenia. Combined TMS-electroencephalography (TMS-EEG) provides a more detailed examination of cortical excitability and may shed more light into the pathophysiology of schizophrenia. Of the various peaks of the TMS-evoked EEG signal, responses at 45 (N45) and 100 ms (N100) likely reflect GABA-A and GABA-B receptor-mediated inhibition, respectively. Responses at 25 ms (P25) are affected by voltage-gated channel ligands, whereas glutamatergic processes may be related to the P70 component. We here aim to systematically investigate the role of these neural processes in patients with schizophrenia by using TMS-EEG.MethodTMS-evoked EEG potentials (TEPs) were recorded in patients with schizophrenia (n = 19) and in age-matched healthy controls (n = 17). 150 TMS pulses at 90% of resting motor threshold were applied over the left primary motor cortex during EEG recording. Differences in TEPs between the two groups were analysed for all electrodes and for time windows corresponding to each TEP (P25: 0.015-0.035 ms; N45: 0.035-0.06 ms; P70: 0.035-0.06 ms; N100: 0.09-0.14ms) by applying multiple independent sample t-tests. Further, a cluster-based permutation analysis approach was implemented to correct for multiple comparisons.ResultCompared to controls, patients showed amplitude reduction for the P25 (negative and positive cluster; p < 0.001 and p = 0.04, respectively), N45 (negative and positive cluster; p < 0.001 and p = 0.001, respectively) and P70 component (negative and positive cluster; p = 0.04 and p = 0.004, respectively).ConclusionThere results extend on previous literature about impairment of GABA-A receptor mediated inhibition in schizophrenia, as demonstrated by the N45 amplitude reduction, whereas no significant differences in GABA-B index (i.e., N100) were revealed. Our results also showed that, although specific mechanisms underlying P25 and P70 have not been fully elucidated yet, excitatory neurotransmission is altered in this clinical population. To conclude, TMS-EEG may provide a more comprehensive view of the inhibitory and excitatory mechanisms involved in the pathophysiology of schizophrenia.