Durable effects of deep brain ultrasonic neuromodulation on major depression: a case report

Abstract

Background Severe forms of depression have been linked to hyperactivity of the subcallosal cingulate cortex. The ability to stimulate the subcallosal cingulate cortex or associated circuits noninvasively and directly would maximize the number of patients who could receive treatment. To this end, we have developed an ultrasound-based device for effective noninvasive modulation of deep brain circuits. Here we describe an application of this tool to an individual with treatment-resistant depression. Case presentation A 30-year-old Caucasian woman with severe treatment-resistant non-psychotic depression was recruited into a clinical study approved by the Institutional Review Board of the University of Utah. The patient had a history of electroconvulsive therapy with full remission but without sustained benefit. Magnetic resonance imaging was used to coregister the ultrasound device to the subject’s brain anatomy and to evaluate neural responses to stimulation. Brief, 30-millisecond pulses of low-intensity ultrasound delivered into the subcallosal cingulate cortex target every 4 seconds caused a robust decrease in functional magnetic resonance imaging blood-oxygen-level-dependent activity within the target. Following repeated stimulation of three anterior cingulate targets, the patient’s depressive symptoms resolved within 24 hours of the stimulation. The patient remained in remission for at least 44 days afterwards. Conclusions This case illustrates the potential for ultrasonic neuromodulation to precisely engage deep neural circuits and to trigger a durable therapeutic reset of those circuits. Trial registration ClinicalTrials.gov, NCT05301036. Registered 29 March 2022, https://clinicaltrials.gov/ct2/show/NCT05301036

Noninvasive modulation of essential tremor with focused ultrasonic waves

“…Further, the skull correction method used here [37] enabled a compensation for the increased attenuation of this relatively high frequency. Previous studies validated the neuromodulatory efficacy of this parameter, being appropriate to modulate fMRI blood oxygenation leveldependent activity at target and to induce mood changes in subjects with major depressive disorder [7,34]. The pulse repetition frequency and duty cycle were chosen to maximize acoustic intensity and acoustic duration to enhance efficacy [48] while minimizing heating.…”

“…Using the same device, we recently delivered a substantial amount of ultrasound energy, for a total duration of 50 min of stimulation, into the subgenual cingulate cortex of a subject with major depression [34]. Following this exposure, we found that the subject's depression symptoms resolved within the first day and the beneficial effects lasted for several weeks [34]. Therefore, there is evidence that the approach reported here, when delivering substantially more ultrasound energy, could also provide therapeutic benefits to patients.…”

“…The ultrasound array system has been described and used previously [7,34]. Briefly, the hardware consisted of two spherically focused phased arrays mounted to a rigid plastic frame such that they were positioned opposite to each other and separated by a distance of 180 mm.…”

Low-intensity focused ultrasound to the insula and dorsal anterior cingulate has site-specific and pressure dependent effects on pain during measures of central sensitization

“…The Institutional Review Board at Virginia Tech approved all experimental procedures (IRB #21-796). N=16 healthy participants (25.7 years ± 3.4 years; range (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34); M/F 5/11), who met all inclusion/exclusion criteria provided written informed consent to all aspects of the study.…”

“…LIFU has been extensively studied in small [3][4][5] and large animals [6][7][8][9] including humans [10][11][12][13]. It has been demonstrated to produce safe [14,15] and reversible inhibition and excitation [8,16] in different parts of the cortex [12,13,17] and subcortical structures [1,18] including emerging clinical applications [19][20][21][22][23]. An additional promising clinical application for LIFU is pain as demonstrated in both primates [8,24] and humans [25,26].…”