SMA Targeted Magnetic Stimulation Against Auditory Verbal Hallucinations (SMA-AVH)

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.

Study Overview

• Status: Terminated
• Conditions: Auditory Hallucination
• Intervention / Treatment: Device: continuous theta burst stimulation over the SMA; Device: sham continuous theta burst stimulation over the SMA

• Study Type: Interventional
• Enrollment (Actual): 46
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Sweden
  • Uppsala, Sweden, 751 85
    • Department of neuroscience, psychiatry, unit for Brain Stimulation and psychiatric clinical trials

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 59 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Open label active cTBS; 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; 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.
Experimental: active cTBS; 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; 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.
Sham Comparator: Sham cTBS; 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; 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Uppsala University
• Investigators: Principal Investigator: Robert Boden, MD, Uppsala University

Study record dates

Study Major Dates

• Study Start (Actual): November 2, 2020
• Primary Completion (Actual): February 1, 2024
• Study Completion (Actual): February 8, 2024

Study Registration Dates

• First Submitted: November 6, 2020
• First Submitted That Met QC Criteria: November 25, 2020
• First Posted (Actual): December 3, 2020

Study Record Updates

• Last Update Posted (Actual): July 22, 2024
• Last Update Submitted That Met QC Criteria: July 19, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Perceptual Disorders; Hallucinations
• Other Study ID Numbers: SMA-AVH

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No