Low-intensity focused ultrasound targeting the nucleus accumbens as a potential treatment for substance use disorder: safety and feasibility clinical trial
James J. Mahoney, Marc W. Haut, Jeffrey Carpenter, Manish Ranjan, Daisy G. Y. Thompson-Lake, Jennifer L. Marton, Wanhong Zheng, James H. Berry, Padma Tirumalai, Ashley Mears, Pierre D’Haese, Victor S. Finomore, Sally L. Hodder, Ali R. Rezai
Frontiers in Psychiatry 2023, 14 · 10.3389/fpsyt.2023.1211566
Abstract
Introduction While current treatments for substance use disorder (SUD) are beneficial, success rates remain low and treatment outcomes are complicated by co-occurring SUDs, many of which are without available medication treatments. Research involving neuromodulation for SUD has recently gained momentum. This study evaluated two doses (60 and 90 W) of Low Intensity Focused Ultrasound (LIFU), targeting the bilateral nucleus accumbens (NAc), in individuals with SUD. Methods Four participants (three male), who were receiving comprehensive outpatient treatment for opioid use disorder at the time of enrollment and who also had a history of excessive non-opioid substance use, completed this pilot study. After confirming eligibility, these participants received 10 min sham LIFU followed by 20 min active LIFU (10 min to left then right NAc). Outcomes were the safety, tolerability, and feasibility during the LIFU procedure and throughout the 90-day follow-up. Outcomes also included the impact of LIFU on cue-induced substance craving, assessed via Visual Analog Scale (VAS), both acutely (pre-, during and post-procedure) and during the 90-day follow-up. Daily craving ratings (without cues) were also obtained for one-week prior to and one-week following LIFU. Results Both LIFU doses were safe and well-tolerated based on reported adverse events and MRI scans revealed no structural changes (0 min, 24 h, and 1-week post-procedure). For the two participants receiving "enhanced" (90 W) LIFU, VAS craving ratings revealed active LIFU attenuated craving for participants' primary substances of choice relative to sham sonication. For these participants, reductions were also noted in daily VAS craving ratings (0 = no craving; 10 = most craving ever) across the week following LIFU relative to pre-LIFU; Participant #3 pre- vs. post-LIFU: opioids (3.6 ± 0.6 vs. 1.9 ± 0.4), heroin (4.2 ± 0.8 vs. 1.9 ± 0.4), methamphetamine (3.2 ± 0.4 vs. 0.0 ± 0.0), cocaine (2.4 ± 0.6 vs. 0.0 ± 0.0), benzodiazepines (2.8 ± 0.5 vs. 0.0 ± 0.0), alcohol (6.0 ± 0.7 vs. 2.7 ± 0.8), and nicotine (5.6 ± 1.5 vs. 3.1 ± 0.7); Participant #4: alcohol (3.5 ± 1.3 vs. 0.0 ± 0.0) and nicotine (5.0 ± 1.8 vs. 1.2 ± 0.8) (all p 's Discussion In conclusion, LIFU targeting the NAc was safe and acutely reduced substance craving during the LIFU procedure, and potentially had longer-term impact on craving reductions. While early observations are promising, NAc LIFU requires further investigation in a controlled trial to assess the impact on substance craving and ultimately substance use and relapse.
Abstract via europepmc.
Exposures
Exposure 1: LIFU to bilateral nucleus accumbens (60 W lower dose and 90 W enhanced dose)
Target: nucleus accumbens — “bilateral nucleus accumbens (NAc)”
Device: Insightec · Insightec · ExAblate Neuro Type 2 ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 220 | ✓✓✓ |
| Pulse duration (ms) | 100 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 1 | ✓✓✓⚑ |
| Duty cycle (%) | 3.3pulse duration × PRF gives 10%, which disagrees with the stated value | ✓✓✓⚑ |
| Sonication duration (s) | 300 | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | not reported | |
| In-situ pressure (kPa) | not reported | |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported | |
| Isppa, domain unspecified (W/cm²) | 55, 80swept | ✓✓✓⚑ |
After baseline sham sonication, two 5-min sessions of active sonication were delivered to the left NAc, followed by two 5-min sessions to the right NAc (10 min per hemisphere total). Table 1 gives on/off repetition time of 5 s on/10 s off with pulse duration (on/off) of 100/900 ms and duty cycle 3.3%. The first two participants received the 60 W lower dose at 220 kHz; participants #3 and #4 received the 90 W enhanced dose at 220 kHz.
Flags from extraction
exposures[0].unspecified_domain.isppa_w_cm2— Table 1 lists 'Intensity (watts/cm²)' as ~55 (lower dose) and ~80 (enhanced dose) without specifying whether this is Isppa or Ispta, or the measurement domain (free field vs. in situ); recorded under isppa_w_cm2 as the more likely peak-intensity interpretation and flagged.exposures[0].timing.pulse_repetition_frequency_hz— PRF of 1 Hz was derived by converting the stated pulse period (100 ms on + 900 ms off = 1000 ms) to a rate, per the unit-conversion allowance in the instructions, not from the duty cycle.auditory_control— The paper states sham and active sonication were indistinguishable because 'the ultrasound device made the same sound' in both conditions; this does not map cleanly onto the closed vocabulary and is recorded as 'other'.exposures[0].timing.duty_cycle_pct— Table 1 states duty cycle 3.3%, which is inconsistent with the 100/900 ms on/off pulse pattern alone (which implies 10%); likely reflects an additional nested on/off macro-structure (5 s on/10 s off) not fully described numerically. Recorded as stated in Table 1.