Schizophrenia is a severe neuropsychiatric disorder of the brain and is also one of the top ten disabling diseases. A common symptom of schizophrenia (SCZ) is hearing voices inside one's heads which others do not. Despite adequate medication, SCZ patients may continue to hear voices that are often rude or unfriendly and cause distress to the patients. Transcranial direct current stimulation (tDCS) is a safe, non-invasive brain stimulation technique that reduces 'hearing voices'. However, how and why add-on tDCS works is unclear. The brain can change itself in response to its environment; this is called neuroplasticity. tDCS possibly changes the brain's environment and/or enhances the brain's ability to respond favourably to its environment. This theory will be examined here by studying changes in brain functions before and after giving tDCS to schizophrenia patients hearing voices. The aim of this study is to examine the brain's neuroplasticity potential as the biological phenomena driving treatment effects of tDCS in Schizophrenia patients with clinically significant and persistent auditory verbal hallucinations. The secondary aims are to answer whether the brain's neuroplasticity potential in schizophrenia patients can predict their responsivity to tDCS treatment for auditory verbal hallucinations, and if chronicity of illness effects tDCS treatment response.

The brain's neuroplasticity potential will be examined using neuroimaging and neurophysiological techniques that give information about the integrity of the brain's signal processing efficiency, the chemical concentration of certain bio-molecules within it, and how well different areas of the brain communicate with each other. With this information, the potential role of the brain's neuroplasticity potential in facilitating treatment effects of tDCS can be better understood. With this knowledge, it could be possible personalize tDCS treatment, profile tDCS responders and non-responders based on demographic and biological factors, and prescribe tDCS at the appropriate time within the illness course for maximal benefit to the SCZ patients.

20-30% schizophrenia (SCZ) patients struggle with auditory verbal hallucinations (AVH) minimally responsive to pharmaceutical treatments. An add-on fronto-temporoparietal transcranial direct current stimulation (tDCS) is suggested to address persistent AVH in SCZ patients. High heterogeneity among existing randomized control trials for AVH treatment in SCZ and the lack of empirical studies investigating the tDCS action mechanism warrants a systematic investigation into the mechanistic basis of tDCS action.

This proposal aims to examine the potential for neuroplasticity modulation as the mechanistic factor behind the therapeutic effects of left fronto-temporo-parietal tDCS for treating clinically significant AVH in early-course and chronic SCZ patients. It has been proposed and demonstrated that more tDCS sessions over a shorter interval lead to rapid plasticity induction. Accelerated tDCS protocol delivers a higher number of tDCS sessions over a shorter duration. Accelerated protocol (5 sessions/day for 2 days, inter-session interval~20 minutes) for the treatment of AVH in SZ showed clinical improvement with concurrent changes in neurophysiological correlates of auditory hallucination pathophysiology. Specifically, this study will examine neuroplasticity potential as a biomarker for tDCS treatment response with an accelerated tDCS (acctDCS) protocol. Using a randomized, double-blind, sham-controlled parallel-arm, pre-post design, changes in neuroplasticity potential with tDCS treatment for AVH in SCZ will be assessed. The four composite primary outcome measures of this study are:

1. changes in N100-derived event-related-potential waveforms (neurophysiological),
2. changes glutamine-glutamate levels (neurochemical),
3. changes in resting-state functional connectivity (neuroimaging), and
4. reduction in AVH severity (clinical).

The secondary objectives of this study are:

1. exploring the correlation between neurobiological measures of neuroplasticity changes induced by tDCS and clinical improvement in AVH to indicate the nature and strength of the relationship between the two;
2. exploring the effect of verum (active) tDCS on early course versus late course SCZ patients will uncover if illness chronicity is a potential barrier to tDCS responsivity; and
3. utilizing disorder-related (age at illness onset, medication, the severity of the symptom, etc.) and biographic (age, sex, years of education, etc.) features of the study sample towards predicting neuroplasticity modulation in the study sample.

INCLUSION CRITERIA

• Diagnosis of schizophrenia or schizoaffective disorder as per DSM-5 (American Psychiatric Association, 2013)
• Clinically Significant Auditory Verbal Hallucinations
• Right-handedness
• Written informed consent

EXCLUSION CRITERIA

• Features suggestive of a psychiatric emergency
• Any contraindication to tDCS procedures
• Pregnancy or post-partum status
• Left/Mixed Handedness

De-identified individual participant data (IPD) that underlie the results reported in specific publication arising out of the trial will be shared with researchers for individual participant data meta-analysis.

IPD will be shared 9 months after the publication of the trial results and will stay available for up to 36 months.

Researchers seeking to access IPD should write to the investigator(s) with a methodologically sound proposal. The investigator(s) will provide the details of further steps.

A computer-generated randomization sequence will be used for random assignment of treatment condition. A tDCS device equipped to deliver verum or sham stimulation upon entering manufacturer-assigned codes will be used for the study. Allocation concealment will be maintained by off-site bio-statistician.