681. Transcranial magnetic stimulation reveals altered GABAergic and glutamatergic activity in treatment-resistant schizophrenia

Abstract

Abstract Background Treatment-resistant schizophrenia (TRS), affecting roughly one-third of patients, shows poor response to standard antipsychotics and may reflect more severe or distinct neurophysiological disruptions compared to treatment-responsive cases. Prior evidence from imaging and other methods suggested cortical hyperexcitability and plasticity deficits in schizophrenia, but in vivo functional assessments via non-invasive brain stimulation like transcranial magnetic stimulation (TMS) had not fully clarified differences between TRS, non-TRS schizophrenia, and healthy individuals, especially linking these to clinical and cognitive features. Aims & Objectives The primary goal was to evaluate GABA-mediated cortical inhibition and glutamate-related facilitation in TRS patients compared to non-TRS schizophrenia patients and healthy controls, using TMS paradigms. A secondary objective was to assess LTP-like plasticity across groups. Neurophysiological findings were integrated with measures of clinical symptom severity, cognitive performance, and cortical excitability to explore whether TRS shows a distinctive cortical dysfunction profile, consistent with a continuum of impairment within schizophrenia. Method This cross-sectional study recruited participants, including individuals with TRS, non-TRS schizophrenia patients, and matched healthy controls. Neurophysiological assessments employed TMS over the motor cortex, measuring parameters like active motor threshold, short-interval intracortical inhibition (SICI; primarily mediated by GABA-A receptors), intracortical facilitation (ICF; glutamate-related), and an excitation index (EI) reflecting the balance of inhibition and facilitation. Intermittent theta burst stimulation (iTBS) was used to probe cortical plasticity. Clinical evaluations included neurological soft signs, as well as the Positive and Negative Syndrome Scale (PANSS) and the PANSS Autism Severity Score (PANSS-ASS) for symptoms, alongside cognitive testing. Thus, we analyzed group differences and associations between TMS measures and symptom/cognitive domains. Results TRS patients showed significantly elevated active motor thresholds and markedly impaired SICI compared to healthy controls, consistent with reduced GABAergic inhibition. The EI was higher in TRS subjects compared to non-TRS, supporting greater cortical hyperexcitability in TRS. Cortical plasticity (post-iTBS response) was reduced in TRS and non-TRS relative to controls, without a significant difference between TRS and non-TRS. Deficits in SICI correlated positively with more severe negative symptoms (via PANSS negative subscale) and autistic-like features in the patient groups. Overall, the findings suggest a gradient of neurophysiological abnormalities in schizophrenia, with TRS displaying the most prominent hyperexcitability and inhibitory deficits, alongside shared plasticity impairments across schizophrenia subtypes. Discussion & Conclusions We interpret these findings as evidence of a graded, progressive disruption in cortical physiology across schizophrenia. Specifically, TRS is characterized by the most severe impairments in GABA-A receptor-mediated inhibition (evident from reduced SICI) and the highest levels of cortical hyperexcitability (reflected in the elevated EI). Non-TRS patients display intermediate abnormalities, positioned between TRS and healthy controls. This pattern suggests a neurophysiological spectrum rather than discrete categories, where the degree of excitatory-inhibitory imbalance may contribute to varying treatment responsiveness. Reduced cortical plasticity (measured via post-iTBS changes) was observed in TRS compared to controls, indicating that plasticity deficits might represent a resistance substrate. Motor cortex measures may serve as accessible proxies for broader cortical dysfunction, given convergent evidence from other regions (e.g., prefrontal areas) in schizophrenia research.