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CME / ABIM MOC / CE

Can Transcranial Magnetic Stimulation Help With Alcohol Dependence?

  • Authors: News Author: Pauline Anderson; CME Author: Laurie Barclay, MD
  • CME / ABIM MOC / CE Released: 2/4/2022
  • Valid for credit through: 2/4/2023
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  • Credits Available

    Physicians - maximum of 0.25 AMA PRA Category 1 Credit(s)™

    ABIM Diplomates - maximum of 0.25 ABIM MOC points

    Nurses - 0.25 ANCC Contact Hour(s) (0 contact hours are in the area of pharmacology)

    IPCE - 0.25 Interprofessional Continuing Education (IPCE) credit

    You Are Eligible For

    • Letter of Completion
    • ABIM MOC points

Target Audience and Goal Statement

This activity is intended for psychiatrists, family medicine/primary care clinicians, internists, nurses, and other members of the health care team for patients with alcohol dependence.

The goal of this activity is to describe clinical outcomes, including percentage of heavy drinking days and Penn Alcohol Craving Scale, and neural activity on functional magnetic resonance imaging associated with deep repetitive transcranial magnetic stimulation targeting medial prefrontal cortex and anterior cingulate cortex, based on findings of a proof-of-concept, double-blind, sham-controlled, randomized clinical trial in patients with alcohol addiction.

Upon completion of this activity, participants will:

  • Assess the clinical and functional magnetic resonance imaging outcomes associated with deep repetitive transcranial magnetic stimulation targeting the medial prefrontal cortex and anterior cingulate cortex among patients with alcohol addiction, based on findings of a proof-of-concept randomized clinical trial
  • Evaluate the clinical implications of clinical and functional magnetic resonance imaging outcomes associated with deep repetitive transcranial magnetic stimulation targeting the medial prefrontal cortex and anterior cingulate cortex among patients with alcohol addiction, based on findings of a proof-of-concept randomized clinical trial
  • Outline implications for the healthcare team


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New Author

  • Pauline Anderson

    Freelance writer, Medscape

    Disclosures

    Disclosure: Pauline Anderson has disclosed no relevant financial relationships.

CME Author

  • Laurie Barclay, MD

    Freelance writer and reviewer
    Medscape, LLC

    Disclosures

    Disclosure: Laurie Barclay, MD, has disclosed the following relevant financial relationships:
    Own stock, stock options, or bonds from the following ineligible company(ies): AbbVie (former)

Editor/CME Reviewer

  • Amanda Jett, PharmD, BCACP

    Associate Director, Accreditation and Compliance
    Medscape, LLC

    Disclosures

    Disclosure: Amanda Jett, PharmD, BCACP, has disclosed no relevant financial relationships.

CME/CE Reviewer/Nurse Planner

  • Leigh A. Schmidt, MSN, RN, CMSRN, CNE, CHCP

    Associate Director, Accreditation and Compliance
    Medscape, LLC

    Disclosures

    Disclosure: Leigh A. Schmidt, MSN, RN, CMSRN, CNE, CHCP, has disclosed no relevant financial relationships.


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CME / ABIM MOC / CE

Can Transcranial Magnetic Stimulation Help With Alcohol Dependence?

Authors: News Author: Pauline Anderson; CME Author: Laurie Barclay, MDFaculty and Disclosures

CME / ABIM MOC / CE Released: 2/4/2022

Valid for credit through: 2/4/2023

processing....

Clinical Context

Alcohol addiction has a high disease burden but limited treatment options. Transcranial magnetic stimulation (TMS) noninvasively targets pathological brain circuit activity, rather than individual neurochemical systems.

Study Synopsis and Perspective

Deep, repetitive TMS is safe and effective in decreasing symptoms of alcohol addiction and brain reactivity, new research suggests.

In a randomized, double-blind, sham-controlled trial, participants who received TMS targeting the medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC) for 3 weeks showed significantly reduced heavy drinking days compared with a group who received a sham treatment.

The active treatment group also reported significantly less alcohol craving and showed less functional connectivity on MRI in areas of the brain that can trigger craving and relapse.

Clinicians should "keep their eyes open" in the wake of this phase 2 trial, co-corresponding author Markus Heilig, MD, PhD, professor of psychiatry and director at the Center for Social and Affective Neuroscience, Department of Biomedical and Clinical Sciences, Linköping University, Sweden, told Medscape Medical News.

"If and when this replicates in the equivalent of a phase 3 study, we will actually have a completely novel treatment available for this difficult-to-treat and very impactful disease," Dr Heilig said.

The findings were published online December 5 in Biological Psychiatry.

Proof of Concept

In the proof-of-concept trial, researchers enrolled and randomly assigned 51 treatment-seeking adults with moderate to severe alcohol dependence to receive active or sham treatment. Before treatment, participants completed "craving induction," which included holding and smelling but not consuming an alcoholic beverage.

Dr Heilig noted that before stimulating the brain, "you want to make it as malleable as possible," and brain networks tend to be more malleable when they are active.

During the 3-week treatment phase, active or sham stimulations were delivered in five 30-minute sessions per week. During the sessions, all participants wore a helmet with a deep TMS coil.

In the active stimulation group, each session included 100 trains of 30 pulses at 10 Hz (3 seconds) with 15-second intervals, for a total of 3000 pulses. The sham stimulation produced the same acoustic artifact and generated skin sensations mimicking those of the active stimulation, but it did not involve a magnetic field.

Participants, operators, and raters were blinded to the type of coil used.

Five participants relapsed during the first 3 weeks of treatment and were excluded from the analysis. The mean age of those completing treatment (n=23 in each group) was 43 years, and two thirds were men.

The gender makeup of the study reflects "what a real treatment-seeking group looks like," Dr Heilig said.

During the 12-week follow-up phase, 5 additional participants dropped out.

"Pretty Robust" Treatment Effect

The primary outcome was reduction in percentage of heavy drinking days (pHDD), defined as consuming at least five drinks of 12 g alcohol per day for men and at least 4 such drinks for women.

Initially, pHDD dropped in both groups, which is something generally seen in alcohol studies, said Dr Heilig. "The moment people decide to participate in a study, everybody drops their consumption, [which] biases a study like this against picking up an effect," he added.

However, heavy drinking days increased during follow-up in the sham group but remained low in the active-treatment group. The mean pHDD was significantly lower in the active vs sham groups (2.9% vs 10.6%; P=.037).

"So despite the bias, a treatment effect does emerge" and was "pretty robust," Dr Heilig said.

This was supported by a significant group difference in weekly alcohol consumption and a trend-level difference in percentage of alcohol-positive urine samples.

A secondary outcome was change in alcohol craving, assessed with the Penn Alcohol Craving Scale (PACS). PACS scores decreased in both groups during treatment but were more steeply reduced in the active group. During follow-up, craving levels increased to a lesser extent in the active group.

MRI scans showed reduced connectivity from the mPFC to the subgenual ACC, an area involved in negative emotions that can trigger craving and relapse, said Dr Heilig. There was also reduced connectivity between the dorsal ACC and caudate, a circuit involved in the reward system.

In treatment trials, researchers look for a biomarker of target engagement. However, "to date, there has been no study using TMS that has actually demonstrated the intervention had a measurable effect on brain activity. So to me, this is a biomarker; it did something to the brain," Dr Heilig said.

Delving Deeper Into the Brain

The results underline the importance of stimulating deeper parts of the brain, co-corresponding author Abraham Zangen, PhD, head of the Brain Stimulation and Behavior Lab and chair of the PsychoBiology Brain Program, Ben Gurion University, Israel, told Medscape Medical News.

Early TMS studies, which involved superficial brain stimulation, reduced cigarette consumption but was not associated with quitting, Dr Zangen said. "It was only when we targeted deeper parts of the prefrontal cortex that we were able to induce smoking cessation," he added.

It was this research that led to approval by the US Food and Drug Administration of deep TMS for smoking cessation.

This same deep-brain approach was used in the current study. "So the emphasis on the technology that allows penetration into deeper parts of the brain and targeting the relevant pathological circuitry of addiction is a key complement of the success of this study," Dr Zangen said.

Results also showed no serious adverse events. Only a few participants reported transient headaches, which all resolved spontaneously, and frequency did not differ between groups.

Dr Heilig now hopes to carry out a multisite phase 3 study of the intervention and would suggest it involve 4 (instead of 3) weeks of initial treatment and then a weekly booster session. "There are biological reasons to believe that might be more efficient, although we don't have the data," he said.

In contrast, he noted that the longer the trial, the more difficult it might be to recruit patients.

Clinically Significant?

Commenting for Medscape Medical News, Derek Blevins, MD, assistant professor of clinical psychiatry, Columbia University, and research psychiatrist, Division on Substance Use Disorders, New York State Psychiatric Institute, called the research "really exciting."

To date, most TMS studies have been relatively small and looked at a target such as craving. Although these studies did show some effect, the clinical significance of that effect was unclear, said Dr Blevins, who was not involved with the current research.

"I think this new study actually demonstrated a clinically significant effect of a noninvasive treatment for a disease that's very difficult to treat," he said.

A potential limitation of the study, however, was that it required abstinence, Dr Blevins noted. It would be "really helpful" to understand how TMS might aid individuals such as those who relapsed during the study, "because they're the more treatment-refractory individuals we see in clinical practice," he said.

If a multicenter trial is launched, Dr Blevins said that he would also like it to include an ethnically and racially diverse population.

The study was supported by grants from the European Union's Horizon 2020 research and innovation program and the Swedish Research Council. Dr Heilig reports having received consulting fees, research support, or other compensation from Indivior, Camurus, BrainsWay, Aelis Farma, and Janssen Pharmaceuticals. Dr Zangen is an inventor of deep TMS coils and has financial interest in BrainsWay, which produces and markets these coils. Blevins reported no relevant financial relationships.

Biol Psychiatry. Published online December 5, 2021.[1]

Study Highlights

  • In this double-blind, sham-controlled randomized clinical trial, 51 recently abstinent, treatment-seeking patients with moderate to severe alcohol use disorder were randomly assigned to sham or active dTMS, using an H7 coil targeting midline frontocortical areas (mPFC and ACC).
  • Treatment included 15 sessions, each delivering 100 trains of 30 pulses at 10 Hz over the course of 3 weeks, followed by 5 sessions over the course of 3 months of follow-up.
  • The active group vs the sham control group had significantly lower self-reports of craving after treatment and pHDD during follow-up (pHDD=2.9%±0.8% vs 10.6%±1.9%; P=.037).
  • The active group also had significantly lower weekly alcohol consumption and a trend-level difference in percentage of alcohol-positive urine samples.
  • Active dTMS was associated with decreased resting state functional connectivity of dACC with caudate and decreased connectivity of mPFC to subgenual ACC.
  • Treatment was safe and well-tolerated, with no serious adverse events and only a small proportion of participants reporting transient headaches.
  • The investigators concluded that they provided initial proof-of-concept for dTMS targeting midline frontocortical structures as a treatment for alcohol addiction, which is notoriously difficult to treat.
  • Functional magnetic resonance imaging reflected dTMS-induced reduced connectivity from mPFC to subgenual ACC, an area involved in negative emotions that can trigger craving and relapse, and between dACC and caudate, a reward system circuit.
  • Therapeutic benefits of dTMS appeared to be associated with persistent changes in brain network activity, in a pattern opposite to that reported in heavy alcohol users and in alcohol addiction.
  • Treatment effect detection despite pronounced placebo response, which is routinely observed in clinical alcohol treatment trials, supports the finding's robustness.
  • Although abstinence has historically been considered the only valid regulatory endpoint in studies of alcohol addiction treatments, reduction of drinking risk levels is now also considered a worthwhile indicator of treatment outcome, as lowering alcohol consumption for several weeks is sufficient to initiate recovery of executive and general cognitive functioning and underlying brain changes.
  • The study precludes causal inferences regarding brain activity changes for clinical outcomes, but these provide a biomarker of target engagement consistent with causality.
  • Study limitations include small sample in this proof-of-concept trial and possible lack of generalizability to patients with higher severity.
  • The findings strongly support a full-scale confirmatory multicenter trial.
  • Longer duration of initial treatment might improve efficacy but increase drop-out rates.

Clinical Implications

  • Deep, repetitive TMS safely and effectively reduces alcohol addiction symptoms and brain reactivity in areas triggering craving and relapse.
  • The findings provide initial proof-of-concept for dTMS targeting midline frontocortical structures as an alcohol addiction treatment.
  • Implications for the Health Care Team: dTMS treatment was shown to be safe and well tolerated, with no serious adverse events.

 

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