NEUROPHYSIOLOGICAL SIGNATURES OF CORTICAL EXCITABILITY AND PLASTICITY IN ANTIPSYCHOTIC-REFRACTORY SCHIZOPHRENIA: A TMS-BASED INVESTIGATION

Treatment-resistant schizophrenia (TRS) represents a major clinical challenge, as a substantial proportion of individuals with schizophrenia fail to respond adequately to standard antipsychotic treatments. Despite its prevalence and severe functional impact, the neurobiological mechanisms that differentiate TRS from treatment-responsive schizophrenia remain incompletely understood. In this study, we used transcranial magnetic stimulation (TMS) to investigate cortical excitatory and inhibitory dynamics, along with proxy measures of synaptic plasticity, in patients with TRS, patients with treatment-responsive schizophrenia, and healthy control participants. We assessed indices of intracortical inhibition (including short-interval intracortical inhibition), intracortical facilitation, and overall excitation/inhibition balance within the primary motor cortex. LTP-like cortical plasticity was evaluated using an intermittent theta-burst stimulation (iTBS) protocol applied over the primary motor cortex. Compared with healthy controls, TRS patients demonstrated significantly higher active motor thresholds (p=0.015) and a pronounced reduction in SICI, indicating GABAergic dysfunction (p = 0.001). The excitation index was elevated in TRS relative to both non-TRS patients (p=0.034) and controls (p=0.002), suggesting enhanced cortical excitability. Measures of LTP-like plasticity following iTBS were significantly reduced in both TRS (p=0.008) and non-TRS patients (p = 0.033) compared with controls, although TRS and non-TRS did not differ significantly from each other. Furthermore, impairments in SICI correlated with greater severity of negative symptoms (r = 0.524, adjusted p=0.03) and autistic features (r=0.517, adjusted p=0.03), reflecting clinical relevance of inhibitory intracortical deficits. These results support the notion of a continuum of cortical dysfunction across schizophrenia subtypes.