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MPFC Theta Burst Stimulation as a Treatment Tool for Alcohol Use Disorder: Effects on Drinking and Incentive Salience

Primary Purpose

Alcohol Use Disorder, Alcohol Drinking, Substance Use

Status

Recruiting

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

Real TBS to the mPFC

Sham TBS to the mPFC

About this trial

This is an interventional treatment trial for Alcohol Use Disorder focused on measuring Transcranial Magnetic Stimulation, Medial Prefrontal Cortex, Brain Stimulation, Non-invasive, Adult

Eligibility Criteria

21 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Age 21-65 (to maximize participation; note: Scalp-to-Cortex distance will be included as a covariate to calculate adjusted TMS dose given expected cortical atrophy in heavy alcohol users and older adults and the demonstrated effect50 on TMS-fMRI responses in addiction)
Alcohol Use Disorder, determined by DSM-V criteria, using the Structured Clinical Interview for DSM-V
Consumption of more than 14 drinks (women) or 21 drinks (men) per week, with at least 4 heavy drinking days (defined as ≥ 4 drinks for women and ≥ 5 for men) per week during the 30-days prior to enrolling.
Able to read and understand questionnaires and informed consent.

Exclusion Criteria:

Has metal placed above the neck
Is at elevated risk of seizure (i.e., has a history of seizures, is currently prescribed medications known to lower seizure threshold)
Has a history of moderate to severe alcohol withdrawal or medicated alcohol withdrawal
Has a history of claustrophobia
Has a history of chronic migraines
Has a history of traumatic brain injury, including a head injury that resulted in hospitalization, loss of consciousness for more than 10 minutes, or having ever been informed that they have an epidural, subdural, or subarachnoid hemorrhage
Has an unstable medical illness requiring planned medical/surgical intervention (e.g. chemotherapy, surgical procedure)
Medications: Is currently taking or initiates a new prescription for drugs known to improve alcohol drinking treatment outcomes (e.g. naltrexone, acamprosate, topiramate) or taking psychiatric/sleeping medications except for stable (1 month) antidepressants/SSRI's. [Note: this criterion is for scientific rather than safety or patient comfort reasons].
Has a history of substance use disorder (other than nicotine) by DSM-V criteria in the past 6 months
Meets DSM V criteria for panic disorder, bipolar disorder, obsessive-compulsive disorder, schizophrenia, dissociative disorders, eating disorders, and any other psychotic disorder. [Note: The inclusion of participants with other affective and anxiety disorders is essential because of the marked frequency of the co-existence of mood and other anxiety disorders among patients with AUD at large]
Has current suicidal ideation or homicidal ideation
Females of childbearing potential who are pregnant (by urine HCG), nursing, or who are not using a reliable form of birth control.

Sites / Locations

Medical University of South CarolinaRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Sham Comparator

Arm Label

Real TBS to the mPFC

Sham TBS to the mPFC

Arm Description

For continuous theta burst stimulation (cTBS), participants will receive 3 sessions of stimulation per visit over the left medial prefrontal cortex (mPFC) (each train: 3 pulse bursts presented at 5Hz, 15 pulses/sec, 600 pulses/session, 60 sec intertrain interval; 120% RMT, MagPro; 10-15 min inter session interval) using a figure 8 coil (Coil Cool-B65 A/P).

The MagVenture MagPro system has an integrated, active sham which passes current through two surface electrodes placed on the scalp. The electrodes will be placed on the left frontalis muscle for all sessions. A patient identification card will randomize participants to receive either real or sham stimulation. This system maintains blinding by a gyroscope in the coil which indicates to the clinical staff whether the coil should be rotated up or down for this participant once the card is entered into the machine. One side of the coil is active, the other is sham. The integrity of the double-blind procedure will be assessed by asking the patients and study personnel rate their confidence regarding whether they thought they received real or sham (scale 1-10).

Outcomes

Primary Outcome Measures

Change in Percent Heavy Drinking Days (PHDD) from baseline

The primary outcome analysis will examine the TMS treatment effect (active vs. sham) on drinking outcomes-measured as percent heavy drinking days (PHDD) (heavy drinking day defined as 4 or more drinks for women and 5 or more drinks for men)-in the follow-up period beginning after the final treatment session. Collected via timeline follow back (TLFB) in three 28-day (month) intervals, this will be analyzed using multivariate mixture models to consider the effect of time (month after treatment) and the interaction of treatment with time, baseline drinking, number of treatment sessions received, and any other potential covariates (e.g., age, nicotine use, time since last drink). Drinking data will be collected on all randomized participants, irrespective of treatment completion. Lower percentages indicate fewer heavy drinking days in the 28-day interval.

Change in Percent Days Abstinent (PDA) from baseline

The primary outcome analysis will examine the TMS treatment effect (active vs. sham) on drinking outcomes-measured as percent days abstinent (PDA) - in the follow-up period beginning after the final treatment session. Collected via timeline follow back (TLFB) in three 28-day (month) intervals, this will be analyzed using multivariate mixture models to consider the effect of time (month after treatment) and the interaction of treatment with time, baseline drinking, number of treatment sessions received, and any other potential covariates (e.g., age, nicotine use, time since last drink). Drinking data will be collected on all randomized participants, irrespective of treatment completion. Higher percentages indicate increased days abstinent from alcohol in the 28-day interval.

Change in alcohol cue task MRI activation 1-week post treatment from baseline

For the alcohol cue reactivity task, multivariate mixture model analyses will be used to calculate the difference in activation between the ALC and BEV blocks for vmPFC and ventral striatal ROIs, and to analyze maximum likelihood estimates for ALC vs. BEV activation as a function of time, treatment, and the cross-level interactions of these factors. Specifically, the cue task stimuli will be nested within time (post- vs. pre-treatment scan); time will be nested within participant; and participants will be nested within treatment (Sham vs. Active).

Secondary Outcome Measures

Change in anxiety via State-Trait Anxiety Inventory from baseline

As an exploratory analysis, anxiety will be measured using the State-Trait Anxiety Inventory to assess the impact of treatment on self-reported comorbid affective psychopathology. Scoring ranges from 20-80 for each subscale, with higher scores indicating higher anxiety symptoms.

Change in alcohol use via Obsessive-Compulsive Drinking Scale from baseline

As an exploratory analysis, alcohol craving will be measured using the Obsessive-Compulsive Drinking Scale to assess the impact of treatment on self-reported obsessive-compulsive aspects of craving. Scoring ranges from 0-40, with 0 indicating a higher ability to control drinking. This questionnaire also includes an obsessive sub-scale and a compulsive sub-scale each ranging from 0-20, with lower scores indicating lower aspects of alcohol craving and higher ability to control these urges.

Change in depression via Becks Depression Inventory-II from baseline

As an exploratory analysis, depression will be measured using the Becks Depression Inventory-II to assess the impact of treatment on self-reported comorbid affective psychopathology. Scoring ranges from 0-63, with higher scores indicating higher levels of depressive symptoms.

Change in alcohol use via Alcohol Audit from baseline

As an exploratory analysis, alcohol severity will be measured using the Alcohol AUDIT assessment to assess the impact of treatment on self-reported alcohol severity. Scoring ranges from 0-40, with 40 indicating a higher risk of alcohol severity.

Changes in cognitive performance from baseline

Individual domains of the cognitive test battery will be tested as well as a linear composite to ascertain potential effects in specific domains as well as broader cognitive function. The same multivariate mixture model analyses will be performed on a composite measure of neurocognitive behavioral performance (assessed at baseline and end of treatment phase) to assess whether the TMS treatment affects neurocognitive performance.

Changes in Snaith-Hamilton Pleasure Scale from baseline

The same multivariate mixture model analyses will be performed on the Snaith-Hamilton Pleasure Scale assessed weekly during treatment to examine whether hedonic tone/natural reward responsivity is influenced by active TMS.

Full Information

NCT ID

NCT04998916

First Posted

August 3, 2021

Last Updated

November 11, 2022

Sponsor

Medical University of South Carolina

Collaborators

National Institutes of Health (NIH), National Institute on Alcohol Abuse and Alcoholism (NIAAA)

1. Study Identification

Unique Protocol Identification Number

NCT04998916

Brief Title

MPFC Theta Burst Stimulation as a Treatment Tool for Alcohol Use Disorder: Effects on Drinking and Incentive Salience

Official Title

MPFC Theta Burst Stimulation as a Treatment Tool for Alcohol Use Disorder: Effects on Drinking and Incentive Salience

Study Type

Interventional

2. Study Status

Record Verification Date

November 2022

Overall Recruitment Status

Recruiting

Study Start Date

July 6, 2021 (Actual)

Primary Completion Date

December 31, 2026 (Anticipated)

Study Completion Date

December 31, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Medical University of South Carolina

Collaborators

National Institutes of Health (NIH), National Institute on Alcohol Abuse and Alcoholism (NIAAA)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Yes

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of this study is to develop transcranial magnetic stimulation (TMS), specifically TMS at a frequency known as theta burst stimulation (TBS), to see how it affects the brain and changes the brain's response to alcohol-related pictures. TMS and TBS are stimulation techniques that use magnetic pulses to temporarily excite specific brain areas in awake people (without the need for surgery, anesthetic, or other invasive procedures). TBS, which is a form of TMS, will be applied over the medial prefrontal cortex, (MPFC), which has been shown to be involved with drinking patterns and alcohol consumption. This study will test whether TBS can be used as an alternative tool to reduce the desire to use alcohol and reducing the brain's response to alcohol-related pictures.

Detailed Description

With advances in optogenetic stimulation techniques, preclinical studies have demonstrated that activity in frontal-striatal neural circuits has a causal influence on heavy drinking and alcohol reinstatement. Clinically, however, this research has not yet been translated into a neural circuit based therapeutic technique for patients with alcohol use disorder (AUD). The long term goal of this multidisciplinary research study team is to determine the optimal parameters through which non-invasive transcranial magnetic stimulation can be used to improve alcohol drinking outcomes (abstinence, heavy drinking days) among individuals seeking behavioral treatment for AUD. Building on a foundation of several target identification studies and a small double-blinded clinical trial in treatment-engaged AUD patients performed by the study team in the Charleston Alcohol Research Center, here the investigator proposes a double-blind placebo controlled, randomized study to evaluate the efficacy of theta burst stimulation (TBS) to medial prefrontal cortex (mPFC) as a tool to decrease drinking and brain reactivity to alcohol cues among treatment-seeking individuals with AUD. Individuals will be screened initially by the Clinical Intake and Assessment core, then given an opportunity to enroll in this study, provide informed consent, and be randomized to receive real or sham TBS to the mPFC 36 sessions (3x/day on each of 3 days/week over 4 weeks, i.e., 12 days). The scientific premise of this 5 year proposal is that, by modulating the neural circuits that regulate alcohol cue-reactivity it will be possible to increase alcohol abstinence rates and decrease heavy drinking days over a 4 month period. With the combined scientific expertise in brain stimulation, neuroimaging, alcohol use disorder research in the Charleston Alcohol Research Center, and clinical practice at MUSC, the study team is uniquely suited to develop this critical line of research. The outcomes of the proposed Aims will provide an evidence-based foundation for a multisite clinical trial and will hasten progress towards developing a new neural circuit based treatment for patients with AUD.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Alcohol Use Disorder, Alcohol Drinking, Substance Use, Drinking, Alcohol, Alcohol Use Disorder (AUD)

Keywords

Transcranial Magnetic Stimulation, Medial Prefrontal Cortex, Brain Stimulation, Non-invasive, Adult

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderOutcomes Assessor

Masking Description

This study will utilize a double-blind, sham-controlled clinical trial to evaluate the efficacy of the TBS treatment to the vmPFC

Allocation

Randomized

Enrollment

86 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Real TBS to the mPFC

Arm Type

Experimental

Arm Description

Arm Title

Sham TBS to the mPFC

Arm Type

Sham Comparator

Arm Description

Intervention Type

Device

Intervention Name(s)

Real TBS to the mPFC

Intervention Description

This will be delivered with the Magventure Magpro system; 600 pulses of continuous theta burst stimulation with the active sham coil (double blinded using the integrated active sham system).

Intervention Type

Device

Intervention Name(s)

Sham TBS to the mPFC

Intervention Description

This will be delivered with the Magventure Magpro system; 600 pulses with the active sham coil (double blinded using the integrated active sham system). The MagVenture MagPro system has an integrated active sham that passes current through two surface electrodes placed on the scalp. The electrodes are placed on the left frontalis muscle under the coil for both the real and sham stimulation sessions.

Primary Outcome Measure Information:

Title

Change in Percent Heavy Drinking Days (PHDD) from baseline

Description

Time Frame

Baseline (Week 1), Post-treatment (4-weeks from baseline), 1-month post treatment (Follow-up #1), 2-months post treatment (Follow-up #2), 3-months post treatment (Follow-up #3)

Title

Change in Percent Days Abstinent (PDA) from baseline

Description

Time Frame

Baseline (Week 1), Post-treatment (4-weeks from baseline), 1-month post treatment (Follow-up #1), 2-months post treatment (Follow-up #2), 3-months post treatment (Follow-up #3)

Title

Change in alcohol cue task MRI activation 1-week post treatment from baseline

Description

Time Frame

Baseline (Week 1), Post-treatment (4-weeks from baseline)

Secondary Outcome Measure Information:

Title

Change in anxiety via State-Trait Anxiety Inventory from baseline

Description

Time Frame

Baseline (Week 1), Post-treatment (4-weeks from baseline), 1-month post treatment (Follow-up #1), 2-months post treatment (Follow-up #2), 3-months post treatment (Follow-up #3)

Title

Change in alcohol use via Obsessive-Compulsive Drinking Scale from baseline

Description

Time Frame

Baseline (Week 1), Post-treatment (4-weeks from baseline), 1-month post treatment (Follow-up #1), 2-months post treatment (Follow-up #2), 3-months post treatment (Follow-up #3)

Title

Change in depression via Becks Depression Inventory-II from baseline

Description

Time Frame

Baseline (Week 1), Post-treatment (4-weeks from baseline), 1-month post treatment (Follow-up #1), 2-months post treatment (Follow-up #2), 3-months post treatment (Follow-up #3)

Title

Change in alcohol use via Alcohol Audit from baseline

Description

Time Frame

Baseline (Week 1), Post-treatment (4-weeks from baseline), 1-month post treatment (Follow-up #1), 2-months post treatment (Follow-up #2), 3-months post treatment (Follow-up #3)

Title

Changes in cognitive performance from baseline

Description

Time Frame

Baseline (Week 1), Post-treatment (4-weeks from baseline)

Title

Changes in Snaith-Hamilton Pleasure Scale from baseline

Description

Time Frame

Baseline (Week 1), Weekly throughout treatment (Weeks 1-4), Post-treatment (4-weeks from baseline)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

21 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Age 21-65 (to maximize participation; note: Scalp-to-Cortex distance will be included as a covariate to calculate adjusted TMS dose given expected cortical atrophy in heavy alcohol users and older adults and the demonstrated effect50 on TMS-fMRI responses in addiction) Alcohol Use Disorder, determined by DSM-V criteria, using the Structured Clinical Interview for DSM-V Consumption of more than 14 drinks (women) or 21 drinks (men) per week, with at least 4 heavy drinking days (defined as ≥ 4 drinks for women and ≥ 5 for men) per week during the 30-days prior to enrolling. Able to read and understand questionnaires and informed consent. Exclusion Criteria: Has metal placed above the neck Is at elevated risk of seizure (i.e., has a history of seizures, is currently prescribed medications known to lower seizure threshold) Has a history of moderate to severe alcohol withdrawal or medicated alcohol withdrawal Has a history of claustrophobia Has a history of chronic migraines Has a history of traumatic brain injury, including a head injury that resulted in hospitalization, loss of consciousness for more than 10 minutes, or having ever been informed that they have an epidural, subdural, or subarachnoid hemorrhage Has an unstable medical illness requiring planned medical/surgical intervention (e.g. chemotherapy, surgical procedure) Medications: Is currently taking or initiates a new prescription for drugs known to improve alcohol drinking treatment outcomes (e.g. naltrexone, acamprosate, topiramate) or taking psychiatric/sleeping medications except for stable (1 month) antidepressants/SSRI's. [Note: this criterion is for scientific rather than safety or patient comfort reasons]. Has a history of substance use disorder (other than nicotine) by DSM-V criteria in the past 6 months Meets DSM V criteria for panic disorder, bipolar disorder, obsessive-compulsive disorder, schizophrenia, dissociative disorders, eating disorders, and any other psychotic disorder. [Note: The inclusion of participants with other affective and anxiety disorders is essential because of the marked frequency of the co-existence of mood and other anxiety disorders among patients with AUD at large] Has current suicidal ideation or homicidal ideation Females of childbearing potential who are pregnant (by urine HCG), nursing, or who are not using a reliable form of birth control.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Julia Wolf

Phone

843-792-5560

imperato@musc.edu

First Name & Middle Initial & Last Name or Official Title & Degree

Claire Cox

Phone

843-970-2497

coxcl@musc.edu

Facility Information:

Facility Name

Medical University of South Carolina

City

Charleston

State/Province

South Carolina

ZIP/Postal Code

29401

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Julia Wolf

Phone

843-792-5560

imperato@musc.edu

First Name & Middle Initial & Last Name & Degree

James Lopez

lopezja@musc.edu

First Name & Middle Initial & Last Name & Degree

Lisa McTeague, PhD

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

MPFC Theta Burst Stimulation as a Treatment Tool for Alcohol Use Disorder: Effects on Drinking and Incentive Salience

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