Latest developments in the detection and quantification of adrenaline: advances and clinical applications.

Although effective treatments for opioid use disorder (OUD) exist(), opioid-related overdose deaths in the United States have risen dramatically in recent years(). New treatments are needed to improve OUD outcomes. One avenue for the development of new OUD treatments is neuromodulation, which leverages our growing understanding of the neurobiology of addiction to directly modulate specific brain targets. Through direct neural targeting, neuromodulation offers a novel treatment approach in OUD, and may avoid the off-target adverse effects sometimes seen with medications. Specific neuromodulation approaches tested for OUD include transcranial magnetic stimulation (TMS), deep brain stimulation (DBS), and low intensity focused ultrasound (LIFUS). TMS modulates neuronal function by sending magnetic pulses through the skull into the underlying brain region(). TMS is well studied, has FDA approvals (e.g., for treatment of depression) and is generally well tolerated. However, because TMS coils generally have a penetration depth of a few centimeters(), TMS cannot reach many subcortical brain regions thought to be critical to the neurocircuitry of addiction, such as the nucleus accumbens (NAc). In addition, TMS often requires regular clinic attendance (e.g., treatments 5 days per week for 4–6 weeks). DBS also has FDA approvals (e.g., for treatment of movement disorders) and changes neuronal activity through chronic or adaptive stimulation delivered via implanted electrodes and a programmable stimulator. While DBS allows targeting of subcortical structures, changing stimulation parameters (e.g., frequency, pulse width, and current) based on response, and the opportunity for local field potential recording from the target, it requires an invasive and costly neurosurgical procedure. Finally, LIFUS focuses an array of ultrasound beams on a specific location in the brain, where waves summate to deliver ultrasonic energy. LIFUS can target deep brain structures(), and recent work suggests that specific protocols can have either inhibitory or excitatory effects(). Although in an earlier stage of development than TMS and DBS, and with few human trials to date, early work suggests that LIFUS can modulate subcortical structures like DBS, but without the risks inherent in surgery. To date, two prior studies have examined LIFUS for OUD. Both were conducted by the same research group as the current study(), and both examined LIFUS to the nucleus accumbens (NAc). One was a first-in-humans case report() and the other a dose-finding study among four participants(). In this issue, Rezai et al.() build on their prior work in a single-arm, open-label, study of LIFUS to the bilateral NAc for severe OUD. Seven participants received a single 20-minute session of LIFUS to the bilateral NAc using an ExAblate Neuro Type 2 device (Insightec; Miami, FL). LIFUS was administered as an adjunct to medication for OUD while participants were admitted to residential treatment. An eighth participant received both the original sonication, and a second sonication after day 60 following relapse to opioid use. Participants were followed for 90 days. Primary outcomes were safety, tolerability, and feasibility of bilateral LIFUS to the NAc. Secondary outcomes were effects on craving, substance use, mood, and functional brain connectivity.