Loss of regional theta differentiation in TMS-EEG response marks network dysfunction in psychosis risk

The clinical high-risk state for psychosis (CHR-P) aims to identify individuals in a potential prodromal phase of the disorder. Brain network dysconnectivity is believed to underlie psychotic disorders and has been studied using concurrent transcranial magnetic stimulation (TMS) and electroencephalography (EEG). However, such data is not yet available for individuals in the CHR-P state. Single-pulse TMS was applied to the left dorsolateral prefrontal cortex (lDLPFC), left posterior parietal cortex (lPPC), and dorsomedial prefrontal cortex (DMPFC) while measuring EEG. Time-frequency data in the gamma and theta bands were investigated in 58 healthy controls (HC) and 44 CHR-P individuals, testing for differences between stimulations sites and associations with psychopathology and neurocognition. We observed a differentiated response to TMS based on stimulation sites in the theta band in the HC group, with the strongest response being after lDLPFC stimulation, followed by lPPC and DMPFC. This differentiation was absent in CHR-P patients. The increased theta response after lPPC and DMPFC stimulation was negatively correlated with unusual thought content, while the response to lPPC and lDLPFC stimulation was negatively correlated with avolition, decreased experience of emotion, and deterioration in role functioning. Generally, no differences were found for gamma power. The absence of a differentiated theta response to TMS in CHR-P suggests the loss of functional specialization of the stimulated regions and their connections. Because of the inverse relationship between theta oscillations and psychopathological symptoms, we propose that this may represent a compensatory mechanism in the CHR-P state.