Researchers co-led by BBRF grantees have conducted a clinical test of a new way to target deep-brain stimulation (DBS)-based treatments to prevent drug craving and relapse in a patient with longstanding and severe opioid use disorder (OUD). The results suggest a new strategy for optimizing and personalizing DBS treatment of persistent and life-threatening opioid addiction and could inform treatments of other disorders involving dysfunction in the brain’s reward system, including other substance-use disorders, eating disorders, and OCD.

The patient, a 25-year-old male, became addicted to opioids when he was only 13, after being treated with opioids in connection with a medical condition. He started to inject them intravenously at age 15, and subsequently suffered a number of overdoses requiring hospitalization. By the time a DBS device was implanted in his brain at age 21, the young man had also been diagnosed with depression, anxiety, and ADHD, and was receiving medications for all three. He had also developed severe tardive dyskinesia (TD), a movement disorder causing involuntary, repetitive, and uncontrollable movements.

To treat his TD, which was severely disabling, his medical team decided to implant a DBS device, to stimulate a brain area called the globus pallidus internus. DBS has been employed only in extremely difficult cases of TD for which conventional therapies are ineffective. DBS devices generate electrical pulses at predetermined regular intervals (like a pacemaker) in particular sites in the brain, and are FDA-approved options for movement disorders like dystonia, essential tremor, and Parkinson’s disease. DBS therapies are thought to reduce circuit imbalances in the brain. In this case, because the young man continued to suffer pronounced drug cravings and other OUD symptoms in addition to severe TD, his multidisciplinary team of doctors decided at the same time to deliver DBS stimulation in a separate brain region, the nucleus accumbens (NAc). The NAc is well known to be involved in regulating reward, is implicated in processing drug cravings, and DBS of the NAc has been reported in various animal experiments to reduce or eliminate drug cravings. It has also been used as a target for DBS in addicted individuals.

The DBS implantation, conducted more than 4 years prior to the current study, did reduce TD and helped the patient control his drug cravings, leading to a multi-year period of remission from OUD. In this unique case, the patient developed an unrelated but serious systemic infection that warranted the removal of his NAc DBS pulse generator. In the period that followed, the patient’s acute drug cravings returned, but the infection continued. To ensure it did not spread to the DBS electrodes and the brain itself, the DBS wire was “externalized,” making possible the recording of brain signals in response to drug cravings. This presented the medical team with an unusual opportunity to study how to optimize DBS effectiveness once the device could be reactivated after the patient’s infection cleared.

The team recently explained this unique clinical scenario in Nature Communications. Team co-leaders were Casey H. Halpern, M.D., and Dr. Anna Rose Childress, both of the University of Pennsylvania. Dr. Halpern received a BBRF Young Investigator grant in 2016. Co-first authors of the team’s paper were Liming Qiu, M.D., and Dr. Young-Hoon Nho, of the same institution. Dr. Qiu’s 2024 BBRF Young Investigator grant directly supported the experiments reported in the new paper. Four other past BBRF grantees were members of the team, including the late Nolan R. Williams, M.D., who originally referred this patient for surgery. Dr. Williams was the 2024 BBRF Colvin Prize winner, 2019 BBRF Klerman Prize winner, and a 2018 and 2016 BBRF Young Investigator.

Before the DBS device was reactivated in the patient, the team was able to conduct tests which enabled them to measure with great precision electrophysiological responses in his brain to drug cues, using computer-generated graphics and videos. This was meant to provoke the patient’s cravings in a controlled manner, to understand hyperreactive brain signals related to drug triggers.

This yielded a distinct pattern of electrical activity in the nucleus accumbens that was linked with sharp increases in his drug cravings in response to the cues. The pattern was seen in intracranial electroencephalogram (iEEG) readouts measured through the DBS electrode already placed in the patient’s NAc when the DBS device was implanted 4 years earlier. The insight the team obtained enabled them to localize a particular EEG-pattern in a low-frequency “band” anatomically focused in what researchers call the “shell” area of the ventral NAc. In patients who do not have already-implanted electrodes (something done only in DBS surgeries, which are very rare) and specifically who don’t have electrodes implanted in the NAc, it previously had been impossible to see this biomarker signal of extreme drug-cue reactivity. In humans, past evaluations of neural activity in the NAc were mainly based on functional MRI scans, which are limited in terms of both spatial and temporal resolution.

The identified wave pattern—a physiological response—was the first electro-cue-reactivity ever reported in the human NAc, the team said. This information, as well as other information gleaned in other tests, some of which involved behavioral methods, provided a basis for the team to reprogram the DBS device at half the dose required previously. The device was reactivated following clearing of the patient’s infection.

One member of the team, 2018 BBRF Young Investigator Katherine W. Scangos, M.D., Ph.D., had conducted similar experiments several years ago with colleagues at the University of California, San Francisco. In a patient with an array of surgically implanted EEG electrodes, they were able to test in real time how a single individual with severe refractory major depression reacted to DBS-delivered electrical stimulation delivered at a wide range of parameters. The objective in that experiment, as in those conducted with the OUD patient described in the new paper, was to find the combination of focal location, electrical frequency, and intensity that had the effect of optimally reducing the patient’s symptoms (in the current case, drug cravings).

In the case of the OUD patient treated in the current paper, reactivation of the DBS signal—at an intensity much lower and presumably more sustainable than that used previously—in the NAc location corresponding with the iEEG-based biomarker, had the effect of suppressing the patient’s drug-related cravings, which was sustained 6 months after reactivation. Along with his continued abstinence from opioid use, this constituted a remission from OUD, as defined by the DSM-5 diagnostic manual.

Interestingly, the patient’s improvement was progressive over time, which to the team “suggests a possible cumulative or time-dependent effect of DBS on craving suppression and behavioral regulation.” They speculate that this improvement trend may reflect improving plasticity in the fronto-striatal part of the brain and/or “gradual behavioral integration of neuromodulatory effects” introduced by DBS.

The electrophysiological signal that led the team to reprogram the DBS device was thought to be specific to drug-related symptoms—in other words, it did not appear to be consistent with a more general reward-blunting effect of the DBS stimulation. The specific focus of the biomarker signal in the shell of the ventral NAc region allowed the team to improve the therapy’s precision, accounting for superior DBS results once the device was reactivated. Its stimulation pulses had formerly been focused in another part of the NAc, possibly accounting for why the intensity of the stimulation originally needed to be much higher to generate a therapeutic response.

The team noted that this study, involving only a single individual, and one with multiple other disorders, cannot be assumed to be generally applicable to other patients without rigorous additional clinical experimentation and testing: “It remains unclear how factors such as age of onset, route of drug administration, prior treatment exposure, and other variables might influence electrophysiological expression of drug-cue reactivity.” The same applies, of course, to cue-reactivity to other addictive substances, as well as to other disorders in which circuit dysfunction involving the NAc is associated with other problems related to reward, such as eating disorders.

What can, however, be said of the current experiments, the team reported, is that they identified the potentially significant utility of using iEEG-based guidance to optimize DBS programming to personalize the therapeutic impact of neurostimulation. Relevance to other SUDs and “reward-related” pathologies will be the subject of future research.

In addition to Drs. Halpern, Qiu, Williams and Scangos, the team also included A. Eden Evins, M.D., MPH, a 1999 and 1996 BBRF Young Investigator; R. Mark Richardson, M.D., Ph.D., 2015 BBRF Young Investigator.