Deep Brain Stimulation of the Nucleus Accumbens/Ventral Capsule for Severe and Intractable Opioid and Benzodiazepine Use Disorder

Abstract

Given high relapse rates and the prevalence of overdose deaths, novel treatments for substance use disorder (SUD) are desperately needed for those who are treatment refractory. The objective of this study was to evaluate the safety of deep brain stimulation (DBS) for SUD and the effects of DBS on substance use, substance craving, emotional symptoms, and frontal/executive functions. DBS electrodes were implanted bilaterally within the Nucleus Accumbens/Ventral anterior internal capsule (NAc/VC) of a man in his early 30s with >10-year history of severe treatment refractory opioid and benzodiazepine use disorders. DBS of the NAc/VC was found to be safe with no serious adverse events noted and the participant remained abstinent and engaged in comprehensive treatment at the 12-week endpoint (and 12-month extended follow-up). Using a 0–100 visual analog scale, substance cravings decreased post-DBS implantation; most substantially in benzodiazepine craving following the final DBS titration (1.0 ± 2.2) compared to baseline (53.4 ± 29.5; p < .001). A trend toward improvement in frontal/executive function was observed on the balloon analog risk task performance following the final titration (217.7 ± 76.2) compared to baseline (131.3 ± 28.1, p = .066). FDG PET demonstrated an increase in glucose metabolism in the dorsolateral prefrontal and medial premotor cortices at the 12-week endpoint compared to post-surgery/pre-DBS titration. Heart Rate Variability (HRV) improved following the final titration (rMSSD = 56.0 ± 11.7) compared to baseline (19.2 ± 8.2; p < .001). In a participant with severe, treatment refractory opioid and benzodiazepine use disorder, DBS of the NAc/VC was safe, reduced substance use and craving, and improved frontal and executive functions. Confirmation of these findings with future studies is needed.

In 2019, it was estimated that 10.5 million people in the United States misused opioids and opioid overdoses contributed to 46,800 overdose deaths (Center for Behavioral Health Statistics and Quality, 2020; National Institute on Drug Abuse, 2020). Among persons with opioid use disorder (OUD), co-occurring substance use is prevalent (Hassan & Le Foll, 2019; Mahoney et al., 2020). While treatment including medication for OUD (MOUD) is beneficial, success rates for OUD are low (Weiss et al., 2011) and further complicated by co-occurring substance use disorders (SUDs) for which there are no medication treatments currently available. Thus, new treatment modalities are desperately needed for those with severe, refractory OUD.

The Nucleus Accumbens (NAc) plays a key role in reward neurocircuitry and the neurobiology of addiction (Kalivas & Volkow, 2005; Koob & Volkow, 2010, 2016). The NAc maintains direct and indirect involvement with several brain regions associated with addictive behaviors including the dorsal striatum, amygdala, hippocampus, and prefrontal cortex (Volkow et al., 2016). Over the past 20 years, deep brain stimulation (DBS) of the NAc/VC (ventral anterior internal capsule) has demonstrated safety and efficacy in hundreds of patients with obsessive compulsive disorder (OCD), depression, and other conditions (Greenberg et al., 2010; Kumar et al., 2019; Senova et al., 2019). Given this safety profile, we investigated DBS of the NAc/VC for treatment of severe OUD. Our rationale is that DBS will normalize dopamine, thus decreasing cravings while increasing frontal lobe/executive functions. This rationale is supported by previous studies involving DBS for OUD (Supplementary Table 1). Previously published case reports and pilot studies in individuals with OUD have demonstrated that DBS of the NAc decreased substance use and substance craving, reduced emotional symptoms, improved intellectual/cognitive functioning, and was also associated with changes in brain glucose metabolism (Chen et al., 2019; Ge et al., 2018; Kuhn et al., 2014; Valencia-Alfonso et al., 2012; Zhou et al., 2011).

The overarching goal of this pilot study is to further evaluate the safety, tolerability, and feasibility of NAc/VC DBS for treatment refractory OUD and to assess trends in outcomes, including successful engagement in treatment, decreased substance use and craving, improved emotional/psychiatric symptoms, and increased frontal lobe function. Positive trends in the pilot study would provide the necessary preliminary data to justify a prospective randomized clinical trial of DBS as a treatment for OUD. The current case report includes findings from the initial participant enrolled in this pilot study. While there have been previous reports of DBS for OUD, our report, to our knowledge, is the first to employ an integrated, multi-modal, and comprehensive approach evaluating multiple behavioral (including both cue-induced and non-cue induced substance craving), cognitive, and physiological factors associated with substance use and frontal lobe functions.

Methods

As part of an FDA- and IRB-approved clinical trial (ClinicalTrials.gov Identifier: NCT03950492) funded by the National Institute of Drug Abuse (NIDA), we implanted DBS electrodes bilaterally within the NAc/VC (Supplementary Figure 1a) of the first participant after written informed consent was provided and eligibility criteria was confirmed. The participant is a man in his early 30s with >10-year history of severe, treatment refractory OUD who utilized multiple levels of treatment (including MOUD within outpatient, inpatient, residential settings) without sustained benefit. During these treatment attempts, he frequently relapsed either during or soon after treatment discontinuation, typically being unable to remain drug abstinent for longer than a few days, often resorting to using opioids (including illicit buprenorphine-naloxone when not prescribed) as well as benzodiazepines. The participant had experienced at least 4 overdoses in the year prior to enrollment in the study.

Following the Screening (Phase 1) and Baseline (Phase II) inpatient phases, bilateral quadripolar 3 mm electrodes (DBS lead 3387, Medtronic Inc., Dublin, IE) were implanted during the DBS Surgery and Recovery inpatient phase (Phase III). DBS settings were adjusted during the DBS Stimulation and Titration inpatient phase (Phase IV) followed by discharge to the Outpatient Follow-Up phase (Phase V). During the 12-week outpatient phase, the participant returned for research related assessments and monitoring twice weekly. For optimization, DBS stimulation parameter adjustments were made during Week 7 and remained unchanged throughout the 12-week endpoint (and extended 12-month follow-up) and were as follows: Electrodes: 1−, 9−, 2+, 10+; Frequency: 145 Hz; Pulse Width: 90 μs; Intensity: 6 V. Details regarding specific DBS parameters adjustments are included in Supplementary Table 2. Of note, the final stimulation parameters in the current case (specifically amplitude and, to a lesser extent, frequency) are generally higher than those reported in previous reports of DBS for OUD (Supplementary Table 1), depression (Crowell et al., 2019; Ramasubbu et al., 2018), and OCD (Graat et al., 2020; Vicheva et al., 2020). However, this participant did not have optimal behavioral responses with settings of lower frequency and amplitude. Independent sample t-tests were used to determine differences in behavioral and cognitive measures between phases, specifically comparing responses/performances following stimulation optimization (Phase V: Weeks 8–12) to previous phases (reference groups). Data were analyzed using SPSS 26.0.

Primary Outcome Assessments

Urine Toxicology

Qualitative urine toxicology was performed twice weekly across all study phases and quantitative urine toxicology (gas chromatography–mass spectrometry; GC–MS) was performed during screening intake (Phase I) and during the Phase V 12-week follow-up visit. Toxicology results were obtained for opioids/opioid analogs, cocaine, amphetamine, benzodiazepines, barbiturates, and delta-9-tetrahydrocannabinol.

Cue Reactivity

Craving for opioids and benzodiazepines was assessed at baseline (prior to cue exposure) using a visual analog scale (VAS) where 0 = no craving and 100 = maximum craving. Images of opioids and other substances and substance related cues were presented to the participant for 5 min. Craving was assessed immediately following cue exposure (time point = 0) and +5 and +10 min after cue presentation. Cue Reactivity sessions were conducted approximately five times per week during inpatient Phases I–IV and once weekly during outpatient Phase V. Primary outcome variables of interest included baseline craving (pre-cue exposure) and maximum change in craving post-cue exposure (peak craving rating at timepoint 0, +5, or +10 minus baseline craving rating).

Positron Emission Tomography

¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT was performed by a Siemens Biograph 20 mCT at the conclusion of Phase III (prior to turning the stimulator on) and at the 12-week endpoint. 90-min dynamic scans with 4.5 mm³ resolution were acquired and standard alignment and image analysis methods were used (Cox, 1996; Jenkinson et al., 2002). FDG-PET images were summarized (16–90 min) and normalized by GM to derive standardized uptake value ratio (SUVr) maps. For this initial case report, we chose to focus on those areas of the brain where there was a change of greater than 10% in metabolism from Phase III to Phase V.

Physiological Monitoring

Wearable technology included a Garmin© smartwatch and Oura© smart ring which were used to collect heart rate variability (HRV) throughout the duration of the study.

Cognitive Functioning (Decision-Making)

The Balloon Analogue Risk Task (BART; Lejuez et al., 2002) was administered to assess risk-taking behavior. The BART was administered weekly during Phases I–III and Phase V (the BART was not administered during Phase IV due to time limitations and priority on other assessments/procedures).

Cognitive Functioning (Impulsivity)

The Barratt Impulsiveness Scale (BIS-11; Patton et al., 1995) is a self-report questionnaire designed to assess impulsiveness. The BIS-11 was administered three times per week during Phases I–IV and twice weekly during outpatient Phase V.

Emotional/Psychiatric Functioning

Depression and anxiety were assessed via the Comprehensive Psychopathological Rating Scale (CPRS; Asberg & Schalling, 1979), which includes the Montgomery Asberg Depression Rating Scale (MADRS; Montgomery & Asberg, 1979) and Brief Scale for Anxiety (BSA; Tyrer et al., 1984). The CPRS was administered three times per week during Phases I–IV and twice weekly during outpatient Phase V.

Results

Safety and Tolerability

Through the 12-week endpoint (as well as through the extended 12-month follow-up), DBS was deemed safe and well-tolerated with no serious adverse events and no device or stimulation related adverse events.

Substance Use

The participant self-reported complete abstinence from substance use during Phases I–V and qualitative urine toxicology was consistently negative for all substances except for prescribed buprenorphine-naloxone through the 12-week endpoint (and throughout the extended 12-month follow-up). Quantitative urine toxicology, obtained at the 12-week endpoint, also did not reveal the presence of any illicit substance metabolites.

Baseline Substance Craving Ratings Pre-Cue Exposure

Average baseline craving ratings for opioids and benzodiazepines, prior to cue presentation and across Phases I–V, clearly demonstrate substantial post-surgical reductions in baseline craving, most notably following the final setting adjustment performed during Week 7 (Table 1).

Table 1.

Substance Craving, Physiological Response, Cognitive Functioning, and Emotional Symptoms Across Study Phases

	Phases I and II	Phase III	Phase IV	Phase V: Weeks 1–7	Phase V: Weeks 8–12
	Screening/baseline	DBS surgery and recovery	DBS stimulation and titration	Follow-up and monitoring		Statistical differencef
Baseline craving ratings prior to cue exposurea
Opioid	5.8 ± 12.6	3.5 ± 6.9	2.5 ± 6.2	1.4 ± 3.8	0.0 ± 0.0	—
Benzodiazepine	53.4 ± 29.5	30.0 ± 9.8	29.2 ± 7.6	25.0 ± 15.3	1.0 ± 2.2	a, b, c***; d**
Maximum craving change post cue exposureb
Opioid	17.7 ± 21.7	6.5 ± 8.8	8.8 ± 8.6	2.9 ± 4.9	2.0 ± 2.7	a, c*
Benzodiazepine	32.7 ± 10.7	14.8 ± 9.1	7.1 ± 5.4	7.1 ± 6.4	7.0 ± 8.4	a***
Physiological responsec
HRV (rMSSD)	19.2 ± 8.2	46.8 ± 11.45	40.0 ± 5.4	41.0 ± 4.7	56.0 ± 11.7	a, c, d***
Decision makingc
BART	131.3 ± 28.1	174.3 ± 47.6	NAe	183.6 ± 40.3	217.7 ± 76.3	—
Impulsivityd
BIS-11	89.1 ± 9.8	89.8 ± 7.5	84.2 ± 7.2	81.6 ± 8.9	68.8 ± 4.0	a***
Emotional symptomsd
MADRS	14.0 ± 2.7	8.6 ± 4.3	7.3 ± 3.4	5.6 ± 3.3	0.5 ± 1.1	a, d***; b, c**
BSA	10.8 ± 1.9	6.6 ± 3.7	4.8 ± 2.2	2.5 ± 2.4	0.5 ± 1.1	a***; b, c, d**

Note. HRV = Heart Rate Variability; rMSSD = Root Mean Square of the Successive Differences; BART = Balloon Analogue Risk Task; BIS-11 = Barratt Impulsiveness Scale; MADRS = Montgomery Asberg Depression Rating Scale; BSA = Brief Scale for Anxiety.

^aAssessed using a Visual Analog Scale (VAS) where 0 = “no craving” and 100 = “maximum craving.” Data reflect baseline craving (pre-cue exposure) ratings.

^bData reflect maximum (peak) change in craving [maximum craving rating at time point 0, +5, or +10 minus baseline craving rating].

^cHigher values represent improvements.

^dLower values represent improvements and/or reductions.

^eBART not administered during Phase IV due to focus on Stimulation and Titration assessments/procedures.

^fSignificant difference between Phase V: Weeks 8–12 (following the final optimization of stimulation parameters) and a: Phase I and II; b: Phase III; c: Phase IV; d: Phase V: Weeks 1–7.

^*p < .05.

^**p < .01.

^***p < .001.

Maximum Change in Substance Craving Following Cue Exposure

Average peak change in craving following cue presentation across Phases I–V clearly demonstrates post-surgical reductions in cue-induced craving, most notably during Phase IV (stimulation/titration) and Phase V (follow-up) (Table 1).

Positron Emission Tomography

In examining the subtraction of stimulation “off” from stimulation “on” conditions, we observed an increase in FDG-SUVr in the dorsolateral prefrontal and medial premotor cortices and a decrease in the basal ganglia, thalamus, and cerebellum (Supplementary Figure 1b).

Physiological Response

HRV demonstrated post-surgical improvements following the final setting adjustment performed during Week 7 (Table 1).

Cognitive Functioning (Decision Making and Impulsivity)

BART performance improved post-surgically with a trend toward significance during Phase V following the final adjustment in comparison to Phases I–II (p = .06). Self-reported impulsivity (BIS-11) also improved post-surgically following the final setting adjustment performed during Week 7 (Table 1).

Emotional/Psychiatric Functioning

Reductions in symptoms of depression (MADRS) and anxiety (BSA) were evident post-surgically following the final setting adjustment performed during Week 7 (Table 1).

Discussion

DBS implantation of the NAc/VC in a man in his early 30s with severe, treatment refractory opioid and benzodiazepine use disorder was found to be safe. Furthermore, the participant remained abstinent from illicit substance use according to self-report and confirmed via urine toxicology throughout the 12-month outpatient follow-up. The participant continued to be actively engaged and compliant with comprehensive treatment including MOUD using buprenorphine/naloxone, individual and group therapy, and participation in mutual support groups (AA/NA). This participant’s course supports our hypothesis that DBS is useful in assisting an individual with treatment refractory OUD in succeeding with the standard of care (comprehensive treatment including MOUD).

In this first participant enrolled in a clinical trial, DBS implantation reduced substance craving, improved physiological response (HRV), improved performance on a decision-making task (BART), reduced self-reported impulsivity (BIS-11), and reduced symptoms of depression and anxiety (MADRS/BSA). The results of the FDG PET in this participant are consistent with the results of the behavioral and cognitive data. Specifically, he demonstrated increased frontal lobe metabolism which corresponds to his increased frontal/executive functioning as well as his improved decision making in daily life. This increased frontal metabolism has been observed previously with NAc DBS (Scharre et al., 2018). The mechanisms accounting for the metabolic decreases in subcortical areas are unclear, but may reflect inhibitory effects of DBS in the basal ganglia (Chiken & Nambu, 2016). The findings of improved frontal lobe functioning are also consistent with the positive functional outcomes observed during outpatient follow-up. The participant secured employment and he has demonstrated a high level of dedication and commitment to this position according to the report of coworkers. In addition, he is goal-oriented in his thought processes, reporting interest in pursuing certification to become a peer recovery coach.

This case report provides novel contribution to the literature for the following reasons. While prior reports included individuals who used co-occurring substances in addition to opioids (Kuhn et al., 2014: amphetamine and alcohol or benzodiazepines; Zhu et al., 2020: hypnotics), they do not appear to meet the severity level of the participant’s co-occurring benzodiazepine use disorder in the current case. Given that co-occurring substance use is more the norm rather than the exception (Mahoney et al., 2020), investigation of treatments for SUD in general (rather than substance specific treatments such as MOUD) is of importance. In addition, this case report included a comprehensive approach to outcome assessment focusing on (a) safety/tolerability, (b) substance use, (c) substance craving, both cue induced and non-cue induced, (d) frontal/executive functions, and (e) emotional/psychiatric symptoms. As displayed in Supplementary Table 1, previous reports have included some of these outcomes, but not all. In addition, while other reports include craving measurements, the inclusion of a cue induced craving paradigm with serial assessments adds useful information. Supporting this, in the pilot study mentioned above (Chen et al., 2019), the authors reported that patients who relapsed did so in the context of cues (e.g., “they restarted using drugs when they saw their friends injecting heroin at a party”) thus reinforcing the importance of assessing craving via a cue reactivity paradigm.

While the findings presented in this report are promising, they must be interpreted in the context of the following limitations. As this case report includes one single participant, these findings must be replicated in additional participants and in a controlled trial. By replicating these findings, more substantive conclusions regarding the utility and impact of NAc/VC DBS on frontal lobe functioning, substance use/relapse, and variables associated with substance use/relapse (e.g., craving, cognitive functioning, emotional symptoms, etc.) can be made with greater certainty.

Public Significance Statement.

Given high relapse rates and the prevalence of overdose deaths, novel treatments for substance use disorder (SUD) are desperately needed. In an individual with severe, treatment refractory opioid and benzodiazepine use disorder, deep brain stimulation (DBS) of the Nucleus Accumbens/Ventral Capsule was found to be safe and this participant remained entirely abstinent from illicit substance use throughout the 12-month follow-up. These findings must be replicated so that more substantive conclusions regarding the utility of DBS for SUD can be made.