Schizophrenia is a complex neuropsychiatric disorder characterized by delusions, hallucinations, disorganized behavior, and progressive cognitive deficits.  This disorder is ranked among the top ten disabling medical disorders by the World Health Organization. Despite the best of the available treatments, about 25 – 35% of patients with schizophrenia show partial or no clinical improvement and they persist to have symptoms that contribute to a critical component of the disability burden.  In addition, most of the existing antipsychotic medications are associated with intolerable side effects as well. 

Contextually, alterative paradigms that involve neuromodulatory techniques have been gaining increasing significance in treating schizophrenia patients.  Transcranial Direct Current Stimulation [tDCS] has been reported to be useful in treating hallucinations resistant to antipsychotic treatment in schizophrenia patients.  Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulatory technique that delivers low intensity, direct current to cortical areas through the surface application of electrodes on the scalp facilitating or inhibiting spontaneous neuronal activity.  Continuous theta-burst stimulation is a safe and well-tolerated treatment option in auditory hallucinations when applied unilaterally, as well as, bilaterally.  At present, there is no research study that informs whether a schizophrenia patient may differentially respond to one of these two treatments; such information can be very vital in expediting appropriate neuromodulation treatment choice.  This research project addresses this compelling research question. 

Aims and hypothesis:

Primary

The primary aim of this study is to identify resting brain functional connectivity markers of response to continuous Theta Burst Stimulation (cTBS) and cathodal transcranial Direct Current Stimulation (c-tDCS) in schizophrenia patients with persistent auditory hallucinations. We hypothesize that a differential pre-treatment resting brain functional connectivity signal will identify responders to cTBS and c-tDCS

Secondary

To compare the neurobiological profile of schizophrenia patients with persistent auditory hallucinations with matched healthy controls using multi-modal data (brain imaging, Electroencephalography (EEG), TMS-tDCS perturbation study metrics, Heart Rate Variability (HRV), and neuroplastic gene polymorphisms)

To examine the differential effect of cTBS versus c-tDCS on the neurobiological profile of schizophrenia patients with persistent auditory hallucinations using multi-modal data (brain imaging, EEG, TMS-tDCS perturbation study metrics, HRV) and potential interactions with neuroplasticity gene polymorphisms

To evaluate the predictive utility of multi-modal data (brain imaging, EEG, TMS-tDCS perturbation study metrics, HRV, and neuroplastic gene polymorphisms) in identifying clinical response to cTBS or c-tDCS in schizophrenia patients with persistent auditory hallucinations

Study Design

Participants meeting selection criteria will be enrolled in a sequential neuromodulation treatment study. All treatments will be added to ongoing pharmacotherapy. In part-1 (randomized controlled trial), participants will be randomized to receive (a) true cTBS (with sham tDCS) and (b) true c-tDCS (with sham cTBS) to the left TPJ for 15 days. Participants will be blind to the true-sham status of their treatment. An investigator blind to group assignment will assess the change over time in the severity of auditory hallucinations using the Auditory Hallucination Rating Scale (AHRS). Participants with a <30% change in AHRS scores will be considered to be non-responders. In part-2, non-responders to either of the treatments will receive a crossover of the alternative treatment (blinded to the participant and the raters); initiated after a 2-4-week washout period. Treatment response will be reassessed at the end of the cross-over treatment. Study participants will undergo investigations before and after each treatment part to identify biomarkers that predict differential response to these neuromodulatory interventions.