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.

Keywords: Depression; Neuromodulation; Ultrasound.

Fig. 1

Approach for effective deep brain ultrasonic neuromodulation in humans. a Application to a patient with major depression. Programmatic electronic focusing is achieved using two sets of 126 individually controlled transducer elements, one over the left and one over the right side of the head. The subject’s head is secured in place using a standard radiological mask. Lateral windows are made within the mask for unobstructed ultrasound propagation. Coupling is mediated using cryogel. b Treatment validation. A standard Siemens flex coil was positioned over the subject’s head. Ultrasound was delivered into the target in 30-millisecond on periods (650 kHz, 1.0 MPa peak pressure) followed by 4-second off periods (0.8% duty). The on and off periods were presented in 1 minute ON blocks, followed by 1 minute OFF blocks of no ultrasound, for a total of up to 10 min (see also c). The MRI scanner acquired fMRI BOLD signals during the stimulation. The colorbar shows the t-statistic associated with the BOLD difference between the ON and OFF blocks. The white circles outline the approximate location of the SCC. c The modulation of the blood-oxygen-level-dependent (BOLD) signal by the ON and OFF ultrasound conditions. The fitted model (red) assumes standard hemodynamic response. d Control stimulation. To control for potential generic artifacts associated with ultrasound, we delivered a stimulus that had the same waveform and pressure amplitude as the stimulus focused into the SCC, but was unfocused (that is, the transducers emitted a plane wave)

Fig. 2

Noninvasive deep brain stimulation is capable of improving mood states in patients with major depression. Following a single treatment session of 64-minutes of active stimulation to three separate targets of the SCC, the subject’s HDRS-6 score fell from 11 to 0. Depression remained in remission for the 44 days while the subject was monitored, with a final HDRS-6 of 0. Inset shows the SCC targets sonicated