Clinical trial NCT06949423: Assessing the Impact of Deep TMS Neuromodulation on Neural Circuits Associated With Alcohol Use Disorder
Official title: Accessing the Impact of Deep TMS Neuromodulation on Neural Circuits Associated With Alcohol Use Disorder
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: NA
Conditions: Alcohol Use Disorder (AUD)
Transcranial Magnetic Stimilation
Keywords: Veterans
Deep Transcranial Magnetic Stimulation (dTMS)
Neuroimaging
Relapse
Lead sponsor: Stanford University
Sponsor class: OTHER
First posted: 2025-04-29
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 2-arm, 1:1 ratio, randomized, double-blind, sham-controlled
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the efficacy of deep transcranial magnetic stimulation as a treatment for Veterans with Alcohol Use Disorder (AUD) to decrease the exceedingly high rate of relapse associated with this condition.

Detailed description: Alcohol use disorder (AUD) is a highly prevalent disorder with a chronic relapse-remit cycle, and over 60% of individuals relapse within months of treatment. Preclinical and human research over the last several decades have defined AUD as a neural circuit-based disorder, which are driven by changes in salience network (SN) function. Emerging non-invasive neuromodulation techniques, such as deep transcranial magnetic stimulation (dTMS), can directly modify neural targets that are related to AUD relapse risk, including the SN.

Preclinical and clinical studies have shown that manipulation of deep cortical nodes within the salience network (SN), such as the dorsal anterior cingulate cortex (dACC), can reduce compulsive drinking. Our lab has demonstrated that blunted dACC activation to affective cues predicts relapse - identifying dACC as a promising neuromodulation target. A systematic interrogation of salience network neuromodulation bridges preclinical and clinical research and has the potential to revolutionize AUD treatment. Our preliminary data demonstrates 1) feasibility of the proposed dTMS protocol and 2) promising neural and clinical outcomes. Specifically, those who received this innovative intervention demonstrated increased dACC activation to affective cues from pre- to post-treatment, dynamic changes in functional connectivity and 100% abstinence at follow up.

Building on these data and a theory-driven conceptual framework, the current proposal aims to systematically address three remaining scientific gaps: 1) to what extent does dTMS stimulation of the dACC modify drinking rates and neural targets, 2) can target engagement be a marker of early treatment response, and 3) how long do the effects of dTMS last? This research is significant and innovative as it utilizes a novel, neuromodulation technique to directly manipulate neural networks that drive relapse in AUD.

Eligibility criteria: Inclusion Criteria:

* Age 18-75.
* Current DSM-5 diagnosis of moderate to severe AUD (\&#8805;4 diagnostic symptoms).
* Ability to obtain a Motor Threshold (MT) will be determined during the screening process.
* Has an adequately stable condition and environment to enable attendance at scheduled clinic visits.
* Able to read, understand and voluntarily sign the Informed Consent Form prior to participating in any study-specific procedures or assessments.
* If 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.
* Fluency 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, metal in the head, metal in the body, claustrophobia, pregnant or breastfeeding or other ferromagnetic device/objected 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 (except caffeine or nicotine) as determined by positive toxicology screen.
* Have a mass lesion, cerebral infarct, or other active CNS disease, including an alcohol-related seizure or 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, 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 benzodiazepine 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

Primary outcomes:
measure: Change in Dorsal Anterior Cingulate Cortex Function (dACC) Activation During the FACES Task, Measured via fMRI
timeFrame: 1-4 days post treatment
measure: Percentage of Days Abstinent from Alcohol, Assessed by Timeline Followback (TLFB)
timeFrame: 3-months post treatment
measure: Percentage of Heavy Drinking Days, Assessed by Timeline Followback (TLFB)
timeFrame: 3 months post-treatment
Secondary outcomes:
measure: Change in Salience Network Functional Connectivity During FACES Task, Measured via fMRI
timeFrame: 1-4 days post treatment
measure: Change in Resting-State Salience Network Activation, Measured via fMRI
timeFrame: 1-4 days post-treatment
measure: Change in Resting-State Salience Network Functional Connectivity, Measured via fMRI
timeFrame: 1-4 days post treatment
measure: Relapse Status, assessed by Timeline Followback (TLFB)
timeFrame: 3 months post-treatment
measure: Total Number of Alcoholic Drinks Consumed, Assessed by Timeline Followback (TLFB)
timeFrame: 3 months post-treatment
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: VA Palo Alto Health Care System
state: California
Study officials:
affiliation: Stanford University
name: Claudia B Padula, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Stanford University
name: Michelle R Madore, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Padula CB, Tenekedjieva LT, McCalley DM, Al-Dasouqi H, Hanlon CA, Williams LM, Kozel FA, Knutson B, Durazzo TC, Yesavage JA, Madore MR. Targeting the Salience Network: A Mini-Review on a Novel Neuromodulation Approach for Treating Alcohol Use Disorder. Front Psychiatry. 2022 May 17;13:893833. doi: 10.3389/fpsyt.2022.893833. eCollection 2022.
citation: Padula CB, Tenekedjieva LT, McCalley DM, Morales JM, Madore MR. Accelerated deep TMS in alcohol use disorder: A preliminary pilot trial targeting the dorsal anterior cingulate cortex increases neural target engagement and abstinence. Brain Stimul. 2024 Sep-Oct;17(5):1098-1100. doi: 10.1016/j.brs.2024.09.002. Epub 2024 Sep 13. No abstract available.
citation: 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.
citation: 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.
citation: Koob GF, Volkow ND. Neurocircuitry of addiction. Neuropsychopharmacology. 2010 Jan;35(1):217-38. doi: 10.1038/npp.2009.110.