Neurobiological and clinical effects of High-Definition tDCS on persistent auditory hallucinations in schizophrenia: A randomized controlled trial

Abstract Background High-definition transcranial direct current stimulation (HD-tDCS) is a potential add-on treatment for persistent auditory hallucinations (AH). However, the lack of evidence from methodical studies implores the need for a systematic evaluation to ascertain its effectiveness. Aim To examine the clinical and neurobiological role of HD-tDCS in the alleviation of persistent AH and the persistence of its effects in patients with schizophrenia in a double-blinded, sham-controlled study with concurrent resting state fMRI data. Methods Thirty-four patients with persistent AH were randomized into a TRUE or SHAM arm for five days of the RCT phase (with concurrent resting state fMRI imaging data at baseline and post-RCT), followed by an open-label extension phase of 5 days of TRUE HD-tDCS. In the RCT phase, patients received -2mA current in the TRUE arm and feeble current mimicking sensory effects in the SHAM arm using the 4 X 1 montage at the left temporo-parietal junction (l-TPJ) using subject-specific neuro-navigation. AH severity was assessed using the PSYRATS Auditory Hallucination Rating Scale (AHS) at baseline, after RCT, after the end of the open-label, and then by 1st and 3rd-month following the last HD-tDCS session. The electric field (EF) was estimated at the region of interest using a simulation technique to further explore the neurobiological effects between the TRUE versus the SHAM group, Results A significant difference in the neuro-modulatory effect was seen in the neuroimaging analysis at the l-TPJ secondary to the TRUE compared to SHAM HD-tDCS after five days of RCT. At the follow-up, subjects in the SHAM who crossed over to TRUE HD-tDCS significantly improved in AH scores compared to patients who received ten days of TRUE HD-tDCS (T=2.95, p<0.05). However, there was no significant difference in AH scores between the TRUE and SHAM arm at the end of 5 days of RCT and immediately after five days of additional open-label HD-tDCS. In the simulation analysis, differences were noted in the TRUE (EF= 0.22 V/m) versus the feeble current SHAM arm group. It was interesting to observe, that though feeble in magnitude, SHAM current also created a local electric field (EF= 0.007 V/m). Conclusions Five days of TRUE cathodal HD-tDCS administered to alleviate AH causes cortical effects of interest. Neuromodulatory effects preceded by clinical effects suggest possible clinical latency. Significant improvement in SHAM succeeding TRUE HD-tDCS compared to the ten days of TRUE HD-tDCS suggests the possibility of long-term effects of HD-tDCS acting through mechanisms like homeostatic meta-plasticity. Additional evidence in support of the probable priming effects is the ROI-based electric field simulation showing the generation of local electric field secondary to feeble current in the SHAM arm. Hence sham current with low EF when followed by TRUE current with higher magnitude EF showed enhanced inhibition as compared to the group that followed 10 days of TRUE current further supporting homeostatic meta-plasticity mechanisms. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial CTRI/2018/02/012061- Clinical Trial Registry of India ### Funding Statement This work is supported by the Indian Council of Medical Research (HRD/HEADNCS-01-2018) awarded to Dr. Rujuta Parlikar, Department of Science and Technology Grant (Government of India) to Dr. G Venkatasubramanian (DST/SJF/LSA-02/2014-15), DBT-Wellcome Trust India Alliance Grant (IA/CRC/19/1/610005) and by the Department of Biotechnology (BT/HRD-NBA-NWB/38/2019-20(6)) and DBT Wellcome Trust India Alliance Intermediate fellowship grant to Dr. Janardhanan C. Narayanaswamy (IA/CPHI/16/1/502662). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: National Institute of Mental Health And Neurosciences Institute Ethics Committee (Bengaluru, India) approved this research protocol I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors