Mechanistic clinical trial of individualized tDCS for hallucinations in schizophrenia

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The large majority of patients with schizophrenia (Sz) experience auditory verbal hallucinations (AVH) as a core feature of their disorders. AVH can be associated with increased aggression, distress, suicide rates, and difficulty navigating the social environment. They are refractory to treatment with antipsychotics in ~30% of patients. Physiological dysfunction of posterior auditory/language regions, such as left auditory cortex and temporoparietal junction, and anterior language regions, such as left inferior frontal cortex and anterior insula, is thought to play a major role in generating AVH. Noninvasive brain stimulation (NIBS) approaches such as transcranial magnetic stimulation and transcranial direct current stimulation (tDCS) have shown promise in treating AVH but have been difficult to reproduce often due to lack of individualized targeting and lack of target engagement biomarkers. This project investigates individualized high-definition tDCS (HD-tDCS), a novel technique that produces a more focal electrical field than conventional tDCS, for treatment of AVH. Inhibitory HD-tDCS is used to test hypotheses regarding two targets, posterior (PosT) and anterior (AntT) auditory/language regions, and their role in influencing the sensory features (e.g. loudness) and evaluative features (e.g. salience) of AVH, respectively. Participants are randomized to receive either sham, active conventional, active PosT, or active AntT stimulation. Individualized targeting and standardized dosing is achieved by MR-guided computational modeling of electrical fields produced in each participant’s brain anatomy. Furthermore, functional target engagement is verified by measuring pre/post treatment changes in elevated resting state functional connectivity (rsFC) within and between PosT and AntT. Etiological biomarkers that track source monitoring, prediction error, and neurophysiological abnormalities associated with AVH are also tested pre/post treatment. The project builds on the candidate’s background in basic auditory neurophysiology, clinical expertise in psychotic disorders and noninvasive brain stimulation, and more recent fellowship training in basic neuroimaging and neurophysiology. The application proposes a 5-year career development program which will provide essential and additional training in basic science of AVH, clinical trials design and implementation, translational neuroimaging, translational neurophysiology, noninvasive brain stimulation, and academic career skills. The acquired skills will allow the candidate to transition into an independent patient-oriented researcher investigating individualized noninvasive brain stimulation for treatment of neuropsychiatric symptoms and disorders. During the project he will work directly with experts in Sz, AVH, fMRI, rsFC, aEPs, computational modeling, NIBS, and clinical trial design. The results of the proposed clinical trial will guide future novel interventions for neuropsychiatric disorders using individualized targeting and target engagement biomarkers. In addition the findings will have the potential to relieve the burden of illness imposed by persistent AVH in Sz.