Deep TMS of Neural Circuits Associated With Stimulant Use Disorder

Deep TMS Neuromodulation of Neural Circuits Associated With Stimulant Use Disorder

This study aims to evaluate the efficacy of deep transcranial magnetic stimulation (dTMS) as a treatment for Veterans with a methamphetamine use disorder (MUD).

Study Overview

• Status: Recruiting
• Conditions: Transcranial Magnetic Stimulation; Methamphetamine Use Disorder
• Intervention / Treatment: Device: Deep Transcranial Magnetic Stimulation (dTMS) H4 coil - Active; Device: Deep Transcranial Magnetic Stimulation (dTMS) H4 coil - Sham

Detailed Description

To date, TMS has emerged as a promising treatment avenue for addiction and is being tested in clinical trials with some encouraging results. A recent systematic review and meta-analysis highlights that 7/8 (87.5%) studies using TMS for MUD or 38/50 (88%) in addiction more broadly have targeted the left DLPFC alone. While this strategy has been useful in reducing craving, treated individuals resume use shortly after treatment at similar rates to those receiving sham. Here, utilizing a data-driven and innovative approach, the investigators aim to modulate target brain function that has been shown to predict treatment outcomes for individuals with MUD. The literature describes how TMS treatment is associated with physiological changes in the brain at the target area and in remote structurally or functionally connected brain areas. TMS has been associated with changes in long-term potentiation (LTP) or depression (LTD) to increase neuroplasticity through increases in brain-derived neurotrophic factor (BDNF) and implicated in influencing the excitatory/inhibitory balance of GABAergic synapses. H-coil designs have the potential to target deeper regions of the brain as well as multiple downstream, interacting brain networks in a novel manner. For example, insula stimulation has the potential to strengthen the salience network broadly and subsequently ameliorate relapse risk.

An emerging advancement is the use of coils that target deeper regions of the brain and have the potential of targeting multiple, interacting brain networks. The H-coil configuration in this technique stimulates a broader area (e.g., up to 17 cubic centimeters) as well as a deeper area (e.g., up to 4 cm), relative to standard figure-of-eight coils, further enhancing innovation and generalizability. With this coil, the investigators hypothesize modifying the salience network nodes that are otherwise not reached by figure-of-eight coils. Notably, published studies to date that utilize these H-coils for addiction yield promising results. However, whether the proposed stimulation strategies will have objectively measurable impact on their respective brain targets or similar impact in individuals with MUD remains unclear.

The proposed study fills a critical, scientific gap of the need to evaluate a novel, non-invasive brain stimulation technique for MUD.

The investigators believe this proposed work will provide preliminary data for a larger grant submission that could allow for a more complex study design to fully answer gaps in current knowledge about deep TMS H4 coil as a possible treatment approach for MUD.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Samantha Ward, BS; Phone Number: 63840 650-493-5000; Email: samward@stanford.edu
• Study Contact Backup: Name: Eileen G Fischer, BS; Phone Number: 210-993-2065; Email: grace.fischer@stanford.edu

Study Locations

• United States
  • California
    • Palo Alto, California, United States, 94304
      • Recruiting
      • VA Palo Alto Health Care System
      • Contact: Samantha Ward, BS; Phone Number: 63840 650-493-5000; Email: samward@stanford.edu
      • Contact: Eileen Grace Fischer, BS; Phone Number: 210-993-2065; Email: grace.fischer@stanford.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion:

• Must be within the age range of 25-75.
• Participants must meet Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for moderate to severe MUD (≥4 diagnostic symptoms).
• Participants must be able to obtain a Motor Threshold (MT), which will be determined during the screening process.
• Participants must have an adequately stable condition and environment to enable attendance at scheduled clinic visits.
• Participants must be able to read, verbalize, understand, and voluntarily sign the Informed Consent Form prior to participation in study procedures in English.
• If participants are on a medication regimen for comorbid symptoms, that regimen will be stable for the duration of the study and patient will be willing to remain on this regimen during the treatment phase.
• Participants must be fluent in English

Exclusion criteria:

• Transcranial magnetic stimulation (TMS) and magnetic resonance imaging (MRI) contraindications: such as a cardiac pacemaker, cochlear implant, or an implanted device (deep brain stimulation, ferromagnetic metal in the head and body, claustrophobia, pregnant or breastfeeding or other ferromagnetic device/object in the head and body within 30 cm of the treatment coil.
• General medical condition, disease, or neurological disorder that interferes with the assessments or participation.
• Unable to safely withdraw, at least two weeks prior to treatment, from medications that increase seizure risk.
• Current substance abuse as determined by positive toxicology screen
• Have a mass lesion, cerebral infarct, or other active CNS disease, including a seizure disorder.
• A recent suicide attempt (defined as within the last 30 days) or presence of current suicidal plan or intent. Patients at risk for suicide will be required to establish a written safety plan involving their primary therapist before entering the study.
• Severe impediment to vision, hearing and/or hand movement, as this is likely to interfere with the ability to follow study protocols.
• Greater than mild traumatic brain injury (defined as greater than 10 minutes loss of consciousness).
• Taking benzodiazepines or neuroleptic medications, or any medication known to alter seizure threshold.
• Acute or unstable chronic illness.
• Current or lifetime history of bipolar disorder or psychosis.
• Participation in another concurrent intervention-based clinical trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active dTMS; Participants will receive 30 active dTMS treatments, administered 3 times per day over 10 consecutive business days. Each treatment visit will last approximately 30 minutes in total.	Device: Deep Transcranial Magnetic Stimulation (dTMS) H4 coil - Active; The study will utilize the H4 coil to administer active Deep Transcranial Magnetic Stimulation (dTMS) to the bilateral insula, a core salience network node.
Sham Comparator: Sham dTMS; Participants will receive 30 sham dTMS sessions, administered 3 times per day over 10 consecutive business days. Each treatment visit will last approximately 30 minutes in total.	Device: Deep Transcranial Magnetic Stimulation (dTMS) H4 coil - Sham; The study will utilize an identical protocol using the H4 coil to administer a sham condition.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insula Function	The primary measure of SN function will include insula activation during the monetary incentive delay task, anticipation of loss contrasted with no loss	1-4 days post-treatment
Percentage of Days Abstinent	Methamphetamine use outcomes will be assessed using the TimeLine Follow Back (TLFB) Method, which utilizes calendar cue to recall recent, self-reported substance use, combined with objective biomarker data	3 months post-treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Other Salience Network Function	The secondary measures of SN function will include insula to PFC functional connectivity, and dACC to insula functional connectivity using the same task as the primary measure.	1-4 days post-treatment
Resting-State Salience Network	The investigators will also utilize whole-brain, voxel-wise analyses for the task with stringent error correction, as well as insula activation and insula to dACC functional connectivity during resting state fMRI.	1-4 days post-treatment
Binary Relapse	Binary (yes/no) relapse after treatment via self-report	3 months post-treatment

Collaborators and Investigators

• Sponsor: Stanford University
• Collaborators: VA Palo Alto Health Care System
• Investigators: Principal Investigator: Claudia B Padula, PhD, Stanford University; Principal Investigator: Michelle R Madore, PhD, Stanford University

Publications and helpful links

General Publications

• Peters SK, Dunlop K, Downar J. Cortico-Striatal-Thalamic Loop Circuits of the Salience Network: A Central Pathway in Psychiatric Disease and Treatment. Front Syst Neurosci. 2016 Dec 27;10:104. doi: 10.3389/fnsys.2016.00104. eCollection 2016.
• Harel M, Perini I, Kampe R, Alyagon U, Shalev H, Besser I, Sommer WH, Heilig M, Zangen A. Repetitive Transcranial Magnetic Stimulation in Alcohol Dependence: A Randomized, Double-Blind, Sham-Controlled Proof-of-Concept Trial Targeting the Medial Prefrontal and Anterior Cingulate Cortices. Biol Psychiatry. 2022 Jun 15;91(12):1061-1069. doi: 10.1016/j.biopsych.2021.11.020. Epub 2021 Dec 6.
• Gay A, Cabe J, De Chazeron I, Lambert C, Defour M, Bhoowabul V, Charpeaud T, Tremey A, Llorca PM, Pereira B, Brousse G. Repetitive Transcranial Magnetic Stimulation (rTMS) as a Promising Treatment for Craving in Stimulant Drugs and Behavioral Addiction: A Meta-Analysis. J Clin Med. 2022 Jan 26;11(3):624. doi: 10.3390/jcm11030624.
• Koob GF, Volkow ND. Neurocircuitry of addiction. Neuropsychopharmacology. 2010 Jan;35(1):217-38. doi: 10.1038/npp.2009.110.

Study record dates

Study Major Dates

• Study Start (Actual): March 15, 2025
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: August 26, 2024
• First Submitted That Met QC Criteria: August 27, 2024
• First Posted (Actual): August 29, 2024

Study Record Updates

• Last Update Posted (Estimated): September 12, 2025
• Last Update Submitted That Met QC Criteria: September 10, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: Veterans; Neuroimaging; Relapse; Deep Transcranial Magnetic Stimulation (dTMS)
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Pathological Conditions, Signs and Symptoms; Recurrence
• Other Study ID Numbers: 72401

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Any data, specimens, forms, reports, and other records that leave the site will be identified only by a participant ID number to maintain confidentiality. The ID Number will have no relationship to any aspect of identifiable private information. Therefore, the data associated with each participant will be completely de-identified and there will be no mechanism by which users can re-identify participant data (e.g., name, address) with the subject code.
• IPD Sharing Time Frame: Three to twelve months after publication.
• IPD Sharing Access Criteria: Researchers who provide a methodologically sound proposal.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

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