Low-Intensity Transcranial Focused Ultrasound for the Treatment of Obsessive-Compulsive Disorder

The investigational product is the NeuroFUS PRO V2.0 with a DPX-500-4CH transducer and TPO-203 Transducer Power Output. NeuroFUS PRO is a computer system (hardware and software, including in addition to the above: the Brainsight Neuronavigation system manufactured by Rogue Research Inc. Montreal, Canada, and the k-Plan software developed by University College London, United Kingdom). This system delivers low-intensity (nonthermal) focused ultrasound (FUS) for transcranial brain modulation. It is provided and supported by Brainbox Ltd (Cardiff, UK). The TPO-203 (manufactured by Sonic Concepts Inc, Bothell WA, US) is the ultrasound transducer component which converts electrical energy into the sonic energy used in the intervention. The TPO-203 features four channels (to allow for convergent targeted sonication from multiple sources) with a total of 80 watts of power (20w per channel) calibrated to a 50 O load. The device can generate frequencies between 10-kHz and 10MHz in 10Hz increments, with burst lengths of 1µs to 9µs in 1µs steps, and 10µs – 120µs in 10µs steps. The intervention will be delivered to the Nucleus Accumbens (NAcc) and the Basolateral Amygdala via application of the transducer to the participant’s scalp. Trial participants in each group will receive stimulation to both brain regions (crossover design). The sonication will be delivered as theta-burst transcranial ultrasound stimulation (tbTUS). tbTUS will consist of an 80-second train of 20-millisecond ultrasound bursts (0.5MHz) repeated every 200 milliseconds (pulse repetition frequency of 5Hz, duty cycle of 10%, 400 bursts) with an amplifier intensity of 20W. In the first 3 TUS sessions, Group 1 will receive stimulation to the NAcc and Group 2 to the Basolateral Amygdala only. In the second 3 TUS sessions the groups will be reversed and receive stimulation to the other region only. TUS sessions are likely to last approximately 45 minutes each in total, including setting up neuronavigation, administering TUS and completion of the task. The intervention will be administered by the TUS Laboratory Technician at QIMR Berghofer, under the direct supervision of Dr Mosley. The CRF includes questions and checklists to be completed in each session to ensure compliance with the required steps. In addition, all sessions will be completed by the same TUS Technician, supervised by Dr Mosley, both of whom will be extensively trained in the protocol. Each participant will receive one such 80-second train per session, across six sessions. Three task-based sessions will be delivered in one week (Monday, Wednesday, Friday) targeted to the basolateral amygdala in a task state (see below). Three further sessions will be delivered in a subsequent week (following four weeks washout) on Monday, Wednesday and Friday, targeted to the nucleus accumbens in a state of rest. The order of stimulation sites will be counterbalanced amongst the cohort. Stimulation in the task state will be delivered while participants are presented with a set of images drawn from the International Affective Picture System, a database of stimuli designed to elicit attention and emotion. Alongside, positive and neutral pictures, each set of images will contain a number of pictures chosen to provoke discomfort in each participant according to their symptoms (e.g., a person with harm-oriented OCD will be shown images of a knife or blood). Participants will be debriefed by Dr Mosley to ensure that distress returns to baseline levels. Total participation time is expected to be around ten weeks per participant plus 4 weeks follow-up. This includes an initial screening, a targeting session followed by two rounds of clinical assessments, baseline imaging, two five-day TUS interventions, post-intervention imaging and clinical assessments separated by a washout period of four weeks. This is a randomised, single-blind, crossover clinical trial. There will be two active treatment groups who will complete both of two treatment conditions. Fifty percent of participants will be assigned to Group 1, while 50% will be assigned to Group 2. Participant IDs will be assigned by a member of the research team who is not involved in baseline assessments or delivering the TUS intervention. Participants will be randomly assigned. The numbers 1-6 will be generated in a random order using the random number generator function in the software package R. Participants will be allocated these numbers in the order of their participant ID numbers. Those allocated the random numbers 1-3 will be placed in group one, with those allocated 4-6 placed in group two. Each treatment will consist of three sessions of TUS delivered across a period of five days to one of two target brain regions, and there will be a one-month washout period between the treatment conditions. Follow-up clinical and brain imaging assessments will occur for all participants within a week of the completion of their treatment. Follow-up of adverse event diaries will occur at four weeks post-treatment. In total, participants are expected to participate in the trial for a period of approximately ten weeks, plus follow-up. The intervention will be delivered at a single academic centre, QIMR Berghofer Medical Research Institute. Participants will undergo brain imaging at the Herston Imaging Research Facility.