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Deep brain stimulation of the nucleus accumbens in the treatment of severe alcohol use disorder: a phase I pilot trial

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Abstract

Alcohol use disorder (AUD) is a highly prevalent, often refractory, medical illness. The symptoms of AUD are driven by dysfunction in several neurocircuits centered on the nucleus accumbens (NAc). Case reports and animal studies suggest NAc-DBS may be an effective harm-reduction treatment in severe AUD. Six patients with severe, refractory AUD underwent NAc-DBS. Safety metrics and clinical outcomes were recorded. Positron emission tomography (FDG-PET) was used to measure glucose metabolism in the NAc at baseline and 6 months. Functional magnetic resonance imaging (fMRI) was used to characterize postoperative changes in NAc functional connectivity to the rest of the brain, as well as NAc and dorsal striatal reactivity to alcoholic visual cues. This study was registered with ClinicalTrials.gov, NCT03660124. All patients experienced a reduction in craving. There was a significant reduction in alcohol consumption, alcohol-related compulsivity, and anxiety at 12 months. There was no significant change in depression. FDG-PET analysis demonstrated reduced NAc metabolism by 6 months, which correlated with improvements in compulsive drinking behaviors. Clinical improvement correlated with reduced functional connectivity between the NAc and the visual association cortex. Active DBS was associated with reduced activation of the dorsal striatum during passive viewing of alcohol-containing pictures. NAc-DBS is feasible and safe in patients with severe, otherwise refractory AUD. It is associated with a reduction in cravings and addictive behavior. A potential mechanism underlying this process is a down-regulation of the NAc, a disruption of its functional connectivity to the visual association cortex, and interference of cue-elicited dorsal striatum reactivity. Trial Registration NCT03660124 (www.clinicaltrials.gov).

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Fig. 1: Summary of electrode locations and clinical outcomes.
Fig. 2: Mean liver function tests preoperatively and at the last available followup.
Fig. 3: Boxplots displaying change in glucose metabolism (SUVR) within the nucleus accumbens.
Fig. 4: Reduced functional connectivity between the nucleus accumbens and the visual association area correlates with improvement in alcohol-related compulsivity (measured with the OCDS).
Fig. 5: Boxplots displaying BOLD activation (measured as a z-statistic) within the dorsal striatum while subjects viewed pictures of alcohol compared to viewing neutral pictures.

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Data availability

The data presented in this article will be available to other researchers upon reasonable request to the corresponding author.

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Acknowledgements

Dr. Josee Lynch made important contributions during early stages of project conception. Dr. Sabine Vollstädt-Klein generously shared the alcohol visual-cue dataset used in the fMRI portion of the study.

Funding

Funding was supplied by internal research funds, as well as support from the Harquail Centre for Neuromodulation, and philanthropic support to the Sunnybrook Foundation—none of whom played any role in the collection or interpretation of data, writing of the manuscript, or the decision to publish.

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Authors and Affiliations

  1. Division of Neurosurgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada

    Benjamin Davidson, Ying Meng, Clement Hamani & Nir Lipsman

  2. Harquail Centre for Neuromodulation, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, ON, Canada

    Benjamin Davidson, Peter Giacobbe, Sean M. Nestor, Jennifer S. Rabin, Maged Goubran, Alexander J. Nyman, Anusha Baskaran, Ying Meng, Christopher B. Pople, Clement Hamani & Nir Lipsman

  3. Sunnybrook Research Institute, Toronto, ON, Canada

    Benjamin Davidson, Peter Giacobbe, Sean M. Nestor, Jennifer S. Rabin, Maged Goubran, Alexander J. Nyman, Anusha Baskaran, Ying Meng, Christopher B. Pople, Clement Hamani & Nir Lipsman

  4. Department of Psychiatry, Sunnybrook Health Sciences Center, Toronto, ON, Canada

    Peter Giacobbe & Sean M. Nestor

  5. Addictions Division, Centre for Complex Interventions, Temerty Centre for Therapeutic Brain Interventions, Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada

    Tony P. George

  6. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    Tony P. George

  7. Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada

    Jennifer S. Rabin

  8. Rehabilitation Sciences Institute, University of Toronto, Toronto, ON, Canada

    Jennifer S. Rabin

  9. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

    Maged Goubran & Simon J. Graham

  10. Physical Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada

    Simon J. Graham & Fred Tam

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  1. Benjamin Davidson
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Contributions

BD made significant contributions to conceptualization, data curation, formal analysis, methodology, validation, visualization, writing (original draft) and writing (review/editing). He verified the underlying data. PG and TPG made significant contributions to conceptualization, funding acquisition, methodology, project administration, resources, supervision, and writing (review/editing). SMN made significant contributions to data curation, methodology, project administration, resources, validation, and writing (review/editing). JSR made significant contributions to data curation, formal analysis, methodology, project administration, resources, supervision, validation, writing (original draft) and writing (review/editing). AJN made significant contributions to data curation, formal analysis, project administration, resources, software, writing (original draft), and writing (review/editing). MG made significant contributions to formal analysis, methodology, project administration, resources, software, supervision, visualization, writing (original draft), and writing (review/editing). AB made significant contributions to conceptualization, data curation, formal analysis, funding acquisition, methodology, project administration, resources, software, supervision, validation, visualization, writing (original draft) and writing (review/editing). She verified the underlying data. YM made significant contributions to conceptualization, data curation, formal analysis, project administration, resources, software, validation, writing (original draft), and writing (review/editing). CBP made significant contributions to data curation, formal analysis project administration, resources, software, validation, and writing (review/editing). SJG made significant contributions to conceptualization, data curation, funding acquisition, methodology, project administration, resources, software, supervision, and writing (review/editing). FT made significant contributions to conceptualization, data curation, formal analysis, methodology, resources, software, validation, and writing (review/editing). CH made significant contributions to conceptualization, funding acquisition, methodology, project administration, resources, software, supervision, validation, visualization, writing (original draft) and writing (review/editing). He verified the underlying data. NL made significant contributions to conceptualization, funding acquisition, methodology, project administration, resources, software, supervision, validation, visualization, writing (original draft) and writing (review/editing). He verified the underlying data.

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Correspondence to Benjamin Davidson or Nir Lipsman.

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Davidson, B., Giacobbe, P., George, T.P. et al. Deep brain stimulation of the nucleus accumbens in the treatment of severe alcohol use disorder: a phase I pilot trial. Mol Psychiatry 27, 3992–4000 (2022). https://doi.org/10.1038/s41380-022-01677-6

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