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
Introduction
Drug addiction is a mental disorder characterized by compulsive drug consumption and seeking, together with difficulty quitting [1]. Currently, the abuse and addiction to opioids, such as prescription pain killers, morphine and especially heroin is a serious global problem. The treatment strategy for addiction generally follows a two-fold approach – promoting detoxification [2] and preventing relapse [3]. The latter is the key for successful treatment. Current treatments for addiction include medical therapies and cognitive behavioral interventions. However, conservative treatments are effective in detoxification but unsuccessful in relapse prevention [4].
The development of an optimal approach for treating addiction is predicated on a detailed understanding of the mechanisms underlying this brain disorder. To date, several theoretical mechanisms [5] have been proposed, and the incentive sensitization theory may address central issues of drug addiction [6]. The core thesis of this theory is that repeated exposure to addictive drugs may render the brain hypersensitive (“sensitized”) in a way that results in pathological levels of incentive salience being attributed to drugs and drug-related stimuli [7]. It has been well established that incentive salience critically relies on dopamine-mediated neurotransmission as one link in a larger chain of mesocorticolimbic circuits and signals [6]. Furthermore, it has been posited that abnormal regulatory effects of mesocorticolimbic circuits due to repeated drug use increases the addicts' craving for drugs, leading to repeated compulsive seeking and consumption of drugs [7].
Based on this theory, direct interventions to regulate the function of mesocorticolimbic circuits, which may help to rectify the drug-induced incentive sensitization process, are believed to be promising approaches for treating drug addiction. Since the 1960s, neurosurgeons have performed brain surgeries to treat addiction that target structures constituting the mesocorticolimbic circuits, i.e. hypothalamotomies [8], cingulotomies [9] and lobotomies [10]. As the nucleus accumbens (NAc), which is situated centrally among the mesocorticolimbic circuits [11], plays a key role in drug-mediated reward and addiction, we first performed stereotactic ablation of the NAc in 2000 [12]. A 5-year follow-up study demonstrated a greater long-term abstinence rate after surgery compared to conservative treatments [13]. However, ablation surgery for addiction remains controversial, as it is destructive, and can lead to irreversible complications [14], such as apathy, motivation decline, and memory deficits.
In recent decades, deep brain stimulation (DBS) has been shown to be effective in treating neurological diseases such as Parkinson's disease, essential tremor and dystonia, as well as some intractable psychiatric disorders, most notably treatment-resistant depression (TRD) and obsessive-compulsive disorder (OCD) [15]. Furthermore, some case reports suggest that DBS can alleviate addiction to alcohol [[16], [17], [18], [19], [20]], nicotine [21,22], amphetamine [23] and heroin [24,25]. Most of these studies have targeted the NAc with outcomes ranging from partial remission to total cessation, while no serious side effects were reported. Taken together, the results indicate that NAc DBS may be a safe and effective option to treat addiction.
In addition to the NAc, which acts as the central node of the reward circuit, there is abundant evidence that the medial forebrain bundle (MFB), which carries ascending dopaminergic projections from the ventral tegmental area (VTA) to numerous limbic forebrain nuclei, acts as another central component of the addiction circuit [26,27]. Consequently, the MFB was also considered to be a promising target for neuromodulation-based addiction therapy [28]. Diffuse tensor image (DTI) analysis confirmed that the human MFB contains two branches: the infero-medial (imMFB) branch and supero-lateral (slMFB) branch. The slMFB subsequently joins the inferior and medial portion of the anterior limb of the internal capsule (ALIC) [29,30], making the ALIC a potential neuromodulation target for addiction treatment. The anatomical proximity of the ALIC with the NAc makes it feasible to stimulate these two structures simultaneously with a single lead. Considering that the NAc and MFB travelling within the ALIC and are both crucial for addiction, we inferred that bilateral stimulation of both structures might be a powerful intervention to prevent heroin addiction relapse. The present preliminary study aimed to assess the outcome of this therapy, while the possible mechanism was tentatively explored as well.
Section snippets
Patients and study design
Eight patients with heroin addiction refractory to medication and conservative treatment received bilateral NAc and ALIC DBS between March 2014 and December 2014. All patients were recruited voluntarily and independently signed the informed consent forms. Patients were eligible for enrollment if they were diagnosed with heroin addiction according to the DSM-V criteria; were 18–50 years of age; had abused heroin for 3 years or more; relapsed at least 3 times after previous conservative treatment
Patients' demographic data
Eight patients (seven male, one female) that met the DSM-V criteria for the diagnosis of drug addiction voluntarily enrolled in this trial (Table 1). All patients had received multiple medical and behavioral treatments, but were not able to maintain long-term abstinence. All of the patients used drugs heavily (mean gram amount of heroin used in a day was 0.51 ± 0.19 g), and all patients repeatedly relapsed (mean number of attempts to abstain was 6.5 ± 2.8, Table 1) after receiving a variety of
Discussion
In this study, we found that bilateral deep brain stimulation of the NAc and the ALIC may be able to help patients remain abstinent from heroin. Five of eight patients maintained abstinence for more than three years, while they had relapsed within 6.5 months after previous treatments. Interestingly, these five patients continued to be abstinent one year after cessation of stimulation. No long-term adverse events occurred during this study. These results indicate that simultaneous DBS of the NAc
Conclusion
Simultaneous DBS of NAc and ALIC appears to be safe, with few side effects, and produces beneficial long-term effects for preventing heroin relapse after detoxification.
Declaration of interests
Dr. Guodong Gao, Dr. Xuelian Wang, and Dr. Nan Li received consulting fee from Suzhou Sceneray Co. Ltd, China. The other authors have no conflicts of interest to declare.
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2022, Brain Research BulletinCitation Excerpt :One patient experienced epileptic seizures who have had epileptic seizures before the surgery (Kuhn et al., 2014). One patient suffered from intracranial bleeding adjacent to the implanted electrode in the right hemisphere but showed no neurological deficit (Chen et al., 2019). Over the DBS treatment course, weight changes happened in some patients (Zhu et al., 2020; Zhou et al., 2011; Zhang et al., 2018; Chen et al., 2019).
Potential brain recovery of frontostriatal circuits in heroin users after prolonged abstinence: A preliminary study
2022, Journal of Psychiatric ResearchCitation Excerpt :Meanwhile, dopamine D2 receptor binding in VS was associated with craving as well as motivation for self-administration (Heinz et al., 2005; Martinez et al., 2005). Deep brain stimulation (DBS) of the NAc was also proved to be effective in reducing subjective craving and abstaining from heroin consumption in heroin users (Chen et al., 2019; Kuhn et al., 2014; Valencia-Alfonso et al., 2012). The OFC plays an important role in craving regulation, decision-making (Bolla et al., 2003), and response inhibition (Goldstein and Volkow, 2011).
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These authors contributed equally to this work.