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

Maayan Harel; Irene Perini; Robin Kämpe; Uri Alyagon; Hadar Shalev; Itay Besser; Wolfgang H Sommer; Markus Heilig; Abraham Zangen

doi:10.1016/j.biopsych.2021.11.020

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.

Authors

Maayan Harel¹, Irene Perini², Robin Kämpe², Uri Alyagon¹, Hadar Shalev³, Itay Besser³, Wolfgang H Sommer⁴, Markus Heilig⁵, Abraham Zangen⁶

Affiliations

¹ Department of Life Sciences, Ben-Gurion University, Beer Sheva, Israel; Zlotowski Center for Neuroscience, Ben-Gurion University, Beer Sheva, Israel.
² Center for Social and Affective Neuroscience, Department of Biomedical and Clinical Sciences, Linköping University Hospital, Linköping, Sweden.
³ Zlotowski Center for Neuroscience, Ben-Gurion University, Beer Sheva, Israel; Department of Psychiatry, Ben-Gurion University and Soroka Medical Center, Beer Sheva, Israel.
⁴ Institute of Psychopharmacology, Central Institute of Mental Health, University of Heidelberg, Medical Faculty Mannheim, Mannheim, Germany; Bethanien Hospital for Psychiatry, Psychosomatics, and Psychotherapy, Greifswald, Germany.
⁵ Center for Social and Affective Neuroscience, Department of Biomedical and Clinical Sciences, Linköping University Hospital, Linköping, Sweden; Department of Psychiatry, Linköping University Hospital, Linköping, Sweden. Electronic address: markus.heilig@liu.se.
⁶ Department of Life Sciences, Ben-Gurion University, Beer Sheva, Israel; Zlotowski Center for Neuroscience, Ben-Gurion University, Beer Sheva, Israel. Electronic address: azangen@bgu.ac.il.

PMID: 35067356
DOI: 10.1016/j.biopsych.2021.11.020

Abstract

Background: Alcohol addiction is associated with a high disease burden, and treatment options are limited. In a proof-of-concept study, we used deep repetitive transcranial magnetic stimulation (dTMS) to target circuitry associated with the pathophysiology of alcohol addiction. We evaluated clinical outcomes and explored associated neural signatures using functional magnetic resonance imaging.

Methods: This was a double-blind, randomized, sham-controlled trial. A total of 51 recently abstinent treatment-seeking patients with alcohol use disorder (moderate to severe) were randomized to sham or active dTMS, using an H7 coil targeting midline frontocortical areas, including the medial prefrontal and anterior cingulate cortices. Treatment included 15 sessions over 3 weeks, followed by five sessions over 3 months of follow-up. Each session delivered 100 trains of 30 pulses at 10 Hz. The primary predefined outcome was reduction in percentage of heavy drinking days, obtained using timeline follow-back interviews. Secondary analyses included self-reports of craving, ethyl glucuronide in urine, and brain imaging measures.

Results: Both craving after treatment and percentage of heavy drinking days during follow-up were significantly lower in the active versus sham control group (percentage of heavy drinking days = 2.9 ± 0.8% vs. 10.6 ± 1.9%, p = .037). Active dTMS was associated with decreased resting-state functional connectivity of the dorsal anterior cingulate cortex with the caudate nucleus and decreased connectivity of the medial prefrontal cortex to the subgenual anterior cingulate cortex.

Conclusions: We provide initial proof-of-concept for dTMS targeting midline frontocortical structures as a treatment for alcohol addiction. These data strongly support a rationale for a full-scale confirmatory multicenter trial. Therapeutic benefits of dTMS appear to be associated with persistent changes in brain network activity.

Keywords: ACC; Alcohol use disorder; Deep rTMS; H7 coil; fMRI; mPFC.

Publication types

Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Alcoholism* / diagnostic imaging
Alcoholism* / therapy
Craving
Double-Blind Method
Gyrus Cinguli
Humans
Prefrontal Cortex
Transcranial Magnetic Stimulation* / methods
Treatment Outcome