Deep Brain Stimulation to Understand and Treat Addiction

Official title

Deep Brain Stimulation for Disorders of Addiction: Mechanisms and a Pilot Blinded Randomized Cross-over Placebo Controlled Trial

Overview

This study is testing whether deep brain stimulation (DBS) can safely help people with severe alcohol use disorder who have not improved with standard treatments. DBS uses small electrical signals to change activity in brain areas linked to craving, self-control, and emotion. The study will test whether this treatment can reduce how often people drink and how much they drink each day. Researchers will also record brain activity to better understand how DBS affects craving and relapse.

Detailed description

Alcohol use disorder (AUD) is a leading cause of preventable illness and death worldwide and remains a major public health concern. In the United Kingdom, alcohol misuse is the greatest risk factor for death and disability among adults aged 15-49, yet many people relapse despite standard treatments. Treatment-refractory AUD therefore represents an urgent unmet clinical need. Addiction is increasingly viewed as a disorder of maladaptive brain network activity involving dysregulation of motivation, reward, stress, and executive-control systems.

Deep brain stimulation (DBS) delivers small electrical pulses to targeted brain areas to restore balanced network activity. DBS is established for movement and obsessive-compulsive disorders, and early studies suggest potential benefit for substance addictions.

This pilot trial tests dual-target DBS of the nucleus accumbens and ventral internal capsule to modulate circuits supporting craving, emotion, and self-control. Participants with severe, treatment-resistant AUD will undergo an initial open-label optimization phase followed by a randomized, blinded cross-over comparison of dual, single-site, and sham stimulation. Primary outcomes are changes in drinking frequency and quantity. Intracranial recordings from the implanted device will capture local field potentials to identify brain-signal patterns linked to craving and emotion, helping guide the development of future adaptive neuromodulation approaches for addiction.

Interventions

• Device Dual-Target Deep Brain Stimulation
  A surgically implanted deep brain stimulation (DBS) system delivers active stimulation simultaneously to the nucleus accumbens and the ventral internal capsule. Stimulation parameters are based on individualized optimization performed prior to randomization and remain constant throughout this condition.
• Device Nucleus Accumbens Deep Brain Stimulation
  A surgically implanted deep brain stimulation (DBS) system delivers active stimulation to the nucleus accumbens only. Ventral internal capsule stimulation is inactive. Stimulation parameters are based on individualized optimization performed prior to randomization and remain constant throughout this condition.
• Device Ventral Internal Capsule Deep Brain Stimulation
  A surgically implanted deep brain stimulation (DBS) system delivers active stimulation to the ventral internal capsule only. Nucleus accumbens stimulation is inactive. Stimulation parameters are based on individualized optimization performed prior to randomization and remain constant throughout this condition.
• Device Sham Deep Brain Stimulation
  A surgically implanted deep brain stimulation (DBS) system is present but no therapeutic stimulation is delivered during this condition. All stimulation remains inactive.

Primary outcome measures

• Change in Number of Drinking Days per Week (Timeline Followback) [Time frame: Baseline (6 months pre-surgery), monthly during open-label (Months 1-6) and randomized cross-over (Months 6-10) phases]
• Change in Number of Alcohol Units Consumed per Week (Timeline Followback) [Time frame: Baseline (6 months pre-surgery), monthly during open-label (Months 1-6) and randomized cross-over (Months 6-10) phases]
• Adverse Events Related to Surgery or Stimulation [Time frame: Continuously monitored from surgery (Day 1) through the end of Month 10 (study completion)]

Secondary outcome measures (12)

• Change in Alcohol Craving (Alcohol Urge Questionnaire) [Time frame: Baseline (pre-surgery), daily during open-label (Months 1-6) and randomized cross-over (Months 6-10) phases]
• Quality of Life (Short Form Health Survey) [Time frame: Baseline (pre-surgery), monthly during open-label (Months 1-6) and randomized cross-over (Months 6-10) phases]
• Illness Severity (Clinical Global Impression) [Time frame: Baseline (pre-surgery), monthly during open-label (Months 1-6) and randomized cross-over (Months 6-10) phases]
• Momentary Mood, Craving, Anxiety (0-100 VAS via WebApp) [Time frame: Up to five times daily from Baseline (pre-surgery), during open-label (Months 1-6) and randomized cross-over (Months 6-10) phases]
• Cue-Induced Alcohol Craving (0-100 VAS Following Presentation of Personalized Alcohol Cues) [Time frame: During perioperative laboratory testing (Days 1-7) and monthly laboratory sessions during open-label (Months 1-6) and RCT (Months 6-10) phases]
• Daily Ecological Momentary Assessment of Depressive Symptoms (PHQ-9 Items) [Time frame: Once daily from Baseline (pre-surgery), during the 6-month open-label optimization (Months 1-6) and 4-month RCT (Months 6-10) phases]
• Daily Ecological Momentary Assessment of Anxiety Symptoms (GAD-7 Items) [Time frame: Once daily from Baseline (pre-surgery), during the 6-month open-label optimization (Months 1-6) and 4-month RCT (Months 6-10) phases]
• Daily Ecological Momentary Assessment of Alcohol Urge (AUQ Items) [Time frame: Once daily from Baseline (pre-surgery), during the 6-month open-label optimization (Months 1-6) and 4-month RCT (Months 6-10) phases]
• Daily Assessment of Delay Discounting (Monetary Choice Questionnaire) [Time frame: Once daily from Baseline (pre-surgery), during the 6-month open-label optimization (Months 1-6) and 4-month RCT (Months 6-10) phases]
• Daily Assessment of Risk-Taking Behavior (Mixed Gamble Task) [Time frame: Once daily from Baseline (pre-surgery), during the 6-month open-label optimization (Months 1-6) and 4-month RCT (Months 6-10) phases]
• Compulsive Alcohol-Related Thoughts and Behaviours (Obsessive-Compulsive Drinking Scale) [Time frame: Baseline (pre-surgery) and monthly during open-label (Months 1-6) and randomized cross-over (Months 6-10) phases]
• Local Field Potential (LFP) Activity During Rest and Task Performance [Time frame: During perioperative phase (Days 1-7), and monthly during open-label (Months 1-6) and RCT (Months 6-10) phases]

Eligibility criteria

Inclusion criteria

• Adults aged 18 to 60 years
• Diagnosed with Alcohol Use Disorder (AUD) according to DSM-5 criteria
• Primary diagnosis of treatment-refractory AUD (comorbid nicotine dependence, other psychoactive substance use disorders, moderate major depressive disorder, anxiety disorders or obsessive-compulsive disorder are permissible if AUD is principal)
• Disorder duration of AUD ≥ 5 years
• At least 3 unsuccessful attempts at achieving abstinence
• Failed prior psychotherapy and standard pharmacotherapy for AUD
• Medically and neurologically suitable for surgery and MRI-compatible
• Capable of providing informed consent and willing to comply with study procedures

Exclusion criteria

• Severe psychiatric disorder other than Alcohol Use Disorder (e.g., schizophrenia, schizoaffective disorder, bipolar disorder)
• Severe major depressive disorder (moderate depression acceptable)
• Current active suicidal ideation or history of serious suicide attempts
• Previous treatment with electroconvulsive therapy (ECT)
• Presence of implanted electrical devices, including:
• Cardiac pacemaker or defibrillator (or clinical indication for pacemaker placement)
• Implanted vagus nerve stimulator (VNS)
• Any other chronically implanted neurostimulation device
• Significant neurological history, including prior hemorrhagic or ischemic stroke, subarachnoid hemorrhage, or other major neurological illness
• Any significant medical condition that, in the opinion of the clinical team, would increase surgical or anesthetic risk
• Current pregnancy
• Contraindications to deep brain stimulation or neurosurgery, including:
• Inability to tolerate general anesthesia (as assessed by anesthesiology)
• Increased risk of bleeding (as determined by hepatology/hematology review)
• History of coagulopathy
• Current or previous anticoagulant use
• Uncontrolled hypertension (controlled hypertension with medication is acceptable)
• Stage 4 liver cirrhosis
• History of major cardiac arrhythmia (e.g., atrial fibrillation) or need for anti-arrhythmic medication
• History of requiring cardioversion
• History of repeated falls
• History of major head injury
• Marked cognitive impairment
• Seizure history, including multiple alcohol withdrawal seizures
• Marked cortical atrophy on neuroimaging
• Inadequate logistical or social support that would impair the safe conduct of deep brain stimulation therapy, including inability to reliably attend scheduled visits, lack of reasonable access to the study site, or inadequate home or caregiver support necessary for postoperative care, device management and follow-up.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Crossover

Masking

Double blind

Primary purpose

Treatment

Study locations

United Kingdom · 2 centers

• Cambridge University Hospitals (Addenbrooke's Hospital) — Cambridge
• King's College Hospital — London

Publications

• Rezai AR, Mahoney JJ, Ranjan M, Haut MW, Zheng W, Lander LR, Berry JH, Farmer DL, Marton JL, Tirumalai P, Mears A, Thompson-Lake DGY, Finomore VS, D'Haese PF, Aklin WM, George DT, Corrigan JD, Hodder SL. Safety and feasibility clinical trial of nucleus accumbens deep brain stimulation for treatment-refractory opioid use disorder. J Neurosurg. 2023 Jun 9;140(1):231-239. doi: 10.3171/2023.4.JNS23114 PMID 37329519
• Davidson B, Giacobbe P, George TP, Nestor SM, Rabin JS, Goubran M, Nyman AJ, Baskaran A, Meng Y, Pople CB, Graham SJ, Tam F, Hamani C, Lipsman N. Deep brain stimulation of the nucleus accumbens in the treatment of severe alcohol use disorder: a phase I pilot trial. Mol Psychiatry. 2022 Oct;27(10):3992-4000. doi: 10.1038/s41380-022-01677-6. Epub 2022 Jul 21. PMID 35858989
• Bach P, Luderer M, Muller UJ, Jakobs M, Baldermann JC, Voges J, Kiening K, Lux A, Visser-Vandewalle V; DeBraSTRA study group; Bogerts B, Kuhn J, Mann K. Deep brain stimulation of the nucleus accumbens in treatment-resistant alcohol use disorder: a double-blind randomized controlled multi-center trial. Transl Psychiatry. 2023 Feb 8;13(1):49. doi: 10.1038/s41398-023-02337-1. PMID 36755017
• Chen L, Li N, Ge S, Lozano AM, Lee DJ, Yang C, Li L, Bai Q, Lu H, Wang J, Wang X, Li J, Jing J, Su M, Wei L, Wang X, Gao G. Long-term results after deep brain stimulation of nucleus accumbens and the anterior limb of the internal capsule for preventing heroin relapse: An open-label pilot study. Brain Stimul. 2019 Jan-Feb;12(1):175-183. doi: 10.1016/j.brs.2018.09.006. Epub 2018 Sep 14. PMID 30245163
• Muller UJ, Voges J, Steiner J, Galazky I, Heinze HJ, Moller M, Pisapia J, Halpern C, Caplan A, Bogerts B, Kuhn J. Deep brain stimulation of the nucleus accumbens for the treatment of addiction. Ann N Y Acad Sci. 2013 Apr;1282:119-28. doi: 10.1111/j.1749-6632.2012.06834.x. Epub 2012 Dec 10. PMID 23227826
• Denys D, Mantione M, Figee M, van den Munckhof P, Koerselman F, Westenberg H, Bosch A, Schuurman R. Deep brain stimulation of the nucleus accumbens for treatment-refractory obsessive-compulsive disorder. Arch Gen Psychiatry. 2010 Oct;67(10):1061-8. doi: 10.1001/archgenpsychiatry.2010.122. PMID 20921122
• Deuschl G, Schade-Brittinger C, Krack P, Volkmann J, Schafer H, Botzel K, Daniels C, Deutschlander A, Dillmann U, Eisner W, Gruber D, Hamel W, Herzog J, Hilker R, Klebe S, Kloss M, Koy J, Krause M, Kupsch A, Lorenz D, Lorenzl S, Mehdorn HM, Moringlane JR, Oertel W, Pinsker MO, Reichmann H, Reuss A, Schneider GH, Schnitzler A, Steude U, Sturm V, Timmermann L, Tronnier V, Trottenberg T, Wojtecki L, PMID 16943402
• Voon V, Grodin E, Mandali A, Morris L, Donamayor N, Weidacker K, Kwako L, Goldman D, Koob GF, Momenan R. Addictions NeuroImaging Assessment (ANIA): Towards an integrative framework for alcohol use disorder. Neurosci Biobehav Rev. 2020 Jun;113:492-506. doi: 10.1016/j.neubiorev.2020.04.004. Epub 2020 Apr 13. PMID 32298710

Identifiers

NCT: NCT07341230 · A096527 · MR/W020408/1

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗