Transcranial Brain Stimulation and Its Underlying Neural Mechanisms as a Novel Treatment for Auditory Hallucinations

Study Overview
=================
Brief Summary
-----------------
The present study aims to investigate whether transcranial direct current stimulation (tDCS) reduces auditory hallucinations in patients with psychosis. In addition, the neuronal changes of tDCS will be examined.

Detailed Description
-----------------
The majority of patients with psychosis experience hallucinations, particularly auditory hallucinations are frequent. The hallucinations often leads to massive distress and impairments in social functioning and sometimes even order patients to commit acts of violence against themselves or others. The standard treatment for auditory hallucinations is antipsychotic medication. However, side-effects can be severe and about 25-30% of the patients do not respond to the medication. Transcranial direct current stimulation is a non-invasive brain stimulation technique, which modulates cortical excitability in a pain-free free with mild transient adverse effects, if any. Typically, cortical excitability underneath the anode is boosted while cathodal stimulation has inhibitory effects. Previous studies found that 2 daily sessions of 20 min tDCS for five subsequent days may reduce auditory hallucinations. Investigators want to further assess the efficacy of tDCS in sample that is large enough to detect medium to large effects. In addition, investigators want to investigate the neural mechanisms that underlie the tDCS treatment by examining various neuroimaging parameters before, immediately after treatment, and 3 months after treatment.

Official Title
-----------------
Transcranial Brain Stimulation and Its Underlying Neural Mechanisms as a Novel Treatment for Auditory Hallucinations

Conditions
-----------------
Psychotic Disorders

Intervention / Treatment
-----------------
* Device: DC Stimulator PLUS (NeuroConn)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosed with schizophrenia spectrum disorder or other psychotic disorder Frequent auditory hallucinations (at least 5 times a week). Patients are on a stable dose of antipsychotic medication (which can also be zero) for at least 2 weeks. Mentally competent for informed consent. Provided informed consent. Exclusion Criteria: Metal objects in or around the head that cannot be removed (i.e. cochlear implant, surgical clips, piercing) History of seizures, or a history of seizures in first-degree relatives. History of eye trauma with a metal object or professional metal workers History of brain surgery, brain infarction, head trauma, cerebrovascular accident, broken skull, brain tumour, heart disease, cardiac pacemaker. Skin disease on the scalp on the position of the tDCS electrodes Coercive treatment based on a judicial ruling Pregnancy in female patients

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: real tDCS<br>DC Stimulator PLUS (NeuroConn) The real tDCS condition comprises two daily sessions of 20 min tDCS, separated by a minimum break of 3h, for five consecutive days. Anodal and cathodal tDCS will be applied with 2mA to the left dorsolateral prefrontal cortex (a point midway between F3 and FP1) and the left peri-Sylvian region (a point midway between T3 and P3), respectively. Electrode size is 7cm x 5cm. | Device: DC Stimulator PLUS (NeuroConn)<br> <br> |
| Sham Comparator: sham tDCS<br>DC Stimulator PLUS (NeuroConn) The sham condition is identical to the real tDCS condition except that after 40s of tDCS stimulation is going to be reduced to a small pulse every 550msec (110 μA over 15 msec) through the remainder of the 20 minute period. | Device: DC Stimulator PLUS (NeuroConn)<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Auditory Hallucination Rating Scale (AHRS) | Measure for severity of hallucinations | Change from Baseline to immediately after treatment and 3 months after treatment | 
| Questionnaire for Psychotic Experiences (QPE) | Measure for severity of hallucinations | Change from Baseline to immediately after treatment and 3 months after treatment | 
| Positive and Negative Syndrome Scale (PANSS) | Measure for positive and negative symptoms in psychotic disorders | Change from Baseline to immediately after treatment and 3 months after treatment | 
| Hallucinations App | iPhone/iPod application for self-ratings of auditory hallucinations | Continuously between baseline and 3 months after treatment | 
| Hallucination Change Scale (HCS) | Measure for changes in severity of auditory hallucinations | Change from Baseline to immediately after treatment and 3 months after treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stroop task | Measure of executive functioning | Change from Baseline to immediately after treatment and 3 months after treatment | 
| Trailmaking test A and B | Measure of visuomotor speed | Change from Baseline to immediately after treatment and 3 months after treatment | 
| Expectations Questionnaire | prior expectations participants have regarding the outcome of the treatment on a scale from 0 (The treatment will have no effect) to 10 (The treatment will make the voices go away entirely.) | Change from Baseline to immediately after treatment and 3 months after treatment | 
| Adverse Effects Questionnaire | The presence and severity of side-effects will be monitored using the tDCS adverse effects questionnaire | The questionnaire is completed after each tDCS session. That is, twice on each day of the five day treatment program | 
| The Clinical Global Impressions Scale - Severity | Measure of global functioning | Change from Baseline to immediately after treatment and 3 months after treatment | 
| Global Assessment of Functioning | Measure of global functioning | Change from Baseline to immediately after treatment and 3 months after treatment | 
| Shape, size, and integrity of gray and white matter structures in the brain | Structural Magnetic Resonance Imaging (MRI) | Change from Baseline to immediately after treatment and 3 months after treatment | 
| GABA and glutamate levels in the dorsolateral prefrontal cortex and peri-Sylvian regions | MR spectroscopy | Change from Baseline to immediately after treatment and 3 months after treatment | 
| BOLD (Blood Oxygenation Level Dependent signal) response during resting state | Resting state functional MRI | Change from Baseline to immediately after treatment and 3 months after treatment | 
| Dichotic listening paradigm | Measure of executive functioning | Change from Baseline to immediately after treatment and 3 months after treatment | 
| Dichotic listening paradigm | Measure of language lateralization | Change from Baseline to immediately after treatment and 3 months after treatment | 
| BOLD response during dichotic listening paradigm | Changes in brain activity in the left dorsolateral prefrontal cortex and the peri-Sylvian language regions | Change from Baseline to immediately after treatment and 3 months after treatment | 
| White matter structure and connectivity | MR Diffusion Tensor Imaging | Change from Baseline to immediately after treatment and 3 months after treatment |