SMA Targeted Magnetic Stimulation Against Auditory Verbal Hallucinations

Study Overview
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Brief Summary
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Auditory verbal hallucinations (AVH) are prevalent among patients with psychiatric disorders. Not only being highly stressful and functionally impairing, AVH often persist despite treatment. Recent attempts to treat AVH with add-on repetitive transcranial magnetic stimulation (rTMS) when targeting the temporoparietal junction (TPJ), a language node in the brain, has gained limited success. The aim of this investigation is to reduce AVH with rTMS using continous theta-burst stimulation over a novel target, the supplementary motor area (SMA), in participants with frequent AVH, while also assessing potential neurophysiological mechanisms underlying the symptom.

Official Title
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SMA Targeted Magnetic Stimulation Against Auditory Verbal Hallucinations

Conditions
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Auditory Hallucination

Intervention / Treatment
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* Device: continuous theta burst stimulation over the SMA
* Device: sham continuous theta burst stimulation over the SMA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inclusion criteria for the AVH group: Reported AVH with a minimum frequency of at least daily occurrence, with onset more than one month ago Stable psychopharmacological treatment past month Inclusion criteria for the non-AVH control group Reporting no occurrences of AVH for the past year Stable psychopharmacological treatment past month Inclusion criteria for the healthy control group No life-time occurrence of AVH No history of psychiatric disorders as assessed with a Mini-International Neuropsychiatric Interview (M.I.N.I.) Exclusion Criteria: Ferromagnetic or electromagnetic implants that may pose a risk during magnetic resonance imaging (MRI) and/or cTBS A history of epilepsy Pregnancy Current substance use disorder or a history of alcohol use disorder as assessed with Alcohol Use Disorders Identification Test (AUDIT), Drug Use Disorders Identification Test (DUDIT), urine samples with test for illicit drugs and Phosphatidylethanol (PEth) Daily benzodiazepine use Factors that make the participant unlikely to be able to complete the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 59 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: First phase is a cross-over with two randomized blinded sessions with either verum cTBS or sham with wash-out, for each participant, and a second open feasibility treatment phase with 5 sessions/day over four days for participants with distressing auditory verbal hallucinations
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open label active cTBS<br>Four consecutive days with 40s cTBS, 100% MT over the SMA, five times a day with 50 minutes between stimulations | Device: continuous theta burst stimulation over the SMA<br>* Each cTBS session consists of bursts of three pulses delivered with a rate of 50 Hz, with bursts repeated at a rate of 5 Hz for a total duration of 40 seconds, summing up to 600 pulses, 100% of motor threshold (MT) and applied over bilateral SMA. The target is located in the anterior-posterior direction over the transition between pre-SMA and SMA proper, (cortical point where a vertical line will pass through the anterior commissure). The center of a figure-of-eight coil will be placed over the target, guided with neuronavigation equipment that utilizes the anatomical brain image from the pre-cTBS scanning session.<br>|
| Experimental: active cTBS<br>One test session with 40s active cTBS, 100% MT, over the SMA in the initial double blind cross-over phase | Device: continuous theta burst stimulation over the SMA<br>* Each cTBS session consists of bursts of three pulses delivered with a rate of 50 Hz, with bursts repeated at a rate of 5 Hz for a total duration of 40 seconds, summing up to 600 pulses, 100% of motor threshold (MT) and applied over bilateral SMA. The target is located in the anterior-posterior direction over the transition between pre-SMA and SMA proper, (cortical point where a vertical line will pass through the anterior commissure). The center of a figure-of-eight coil will be placed over the target, guided with neuronavigation equipment that utilizes the anatomical brain image from the pre-cTBS scanning session.<br>|
| Sham Comparator: Sham cTBS<br>One test session with 40s sham cTBS, 100% MT, over the SMA in the initial double blind cross-over phase with a special sham coil that diverts the magnetic field to be only superficial | Device: sham continuous theta burst stimulation over the SMA<br>* The same stimulation parameters but a concealed sham coil will be used with only superficial magnetic stimulation to mimic the sensation of the active stimulation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Amplitude on EEG in speech-listen task | Neurophysiological outcome of the blinded cross-over phase | 5-30 minutes after intervention | 
| Change on The Psychotic Symptom Rating Scales (PSYRATS) | Auditory Verbal Hallucination symptom interview, total score | 1 day after completion of open treatment phase | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Finger tapping test | Computerized version of the finger tapping test from The Halstead-Reitan Neuropsychological Test Battery, performance | 5-30 minutes after intervention | 
| Double step saccade-task | Performance (Zimmermann et al Sci Rep, 2018). | 20-60 minutes after intervention | 
| Resting state functional magnetic resonance imaging (rsfMRI) | Resting state SMA connectivity change as measured with fMRI | 1 day after completion of open treatment phase | 
| Magnetic resonance spectroscopy (MRS) over the SMA quantifying glutamate and gamma-aminobutyric acid (GABA) and other metabolites | Prefrontal GABA and Glutamate concentration change as measured with a MEGA-PRESS magnetic resonance spectroscopy sequence following intervention. | 1 day after completion of open treatment phase | 
| Brief Psychiatric Rating Scale (BPRS) | Total score | 1 day after completion of open treatment phase | 
| App recorded ratings of auditory verbal hallucinations (AVH) | 5 times a day randomized time points for app ratings of AVH | From first day of open treatment phase, and through one week after completion of treatment |