Background: This preregistered pilot study (NCT05697172) investigates the impact of low intensity focused ultrasound (LIFU) targeted at the right anterior limb of the internal capsule (rALIC), a well-established psychosurgical target for treatment-resistant depression [1-4] due to involvement in neural circuits important for mood related processing. We used individualized probabilistic tractography to define individual thalamo-orbitofrontal and thalamo-anterior cingulate tracts traversing the rALIC to target these white matter tracts with LIFU. We examined the effects of LIFU on regional functional connectivity, emotional behavior, and peripheral autonomic activity, measured by heart rate variability (HRV), compared with sham sonication.

Methods: In this double-blind (participant and rater), cross-over study, 10 participants (7 females, mean age 36 ± 9 years) diagnosed with Major Depressive Disorder (MDD) received both active and sham LIFU sessions using a Sonic Concepts NeuroFUS Pro® device. Sessions were spaced two weeks apart and the sequence of active or sham treatments was randomized. LIFU was administered following a theta burst pattern as previously described [5] (500 kHz transducer, 80 seconds, 10% duty cycle), achieving an estimated tissue ISPPA of 2.26 Watt/cm2. For sham procedures, a Sorbothane® membrane was placed between the transducer and scalp to attenuate acoustic energy. Each session began with the participants completing the Brief State Rumination Inventory (BRSI) and Positive and Negative Affect Schedule (PANAS) state assessments, followed by a 5-minute pre-stimulus HRV recording, the 80-second LIFU active or sham stimulus, a 5-minute post-stimulus HRV recording, and a repeat of the BRSI and PANAS assessments. Subjects also underwent an MRI session including a 6-minute resting-state functional scan after each LIFU session.

Functional connectivity (ROI-to-ROI of bilateral 48 ROIs located at the thalami and orbitofrontal or anterior cingulate cortices; 1128 connections) was analyzed with SPM-CONN toolbox [6]. ROI-to-ROI connectivity was compared between active and sham LIFU sessions. Cluster-level inferences based on permutation tests were applied (Spatial Pairwise Clustering [7]). Frequency-domain HRV, BSRI, and PANAS scores were evaluated with linear mixed effect models (Session: active vs. sham, Time: pre vs. post, and Session-by-Time interaction).

Results: Participants tolerated the application of LIFU to the rALIC well, with no detectable changes in neurological signs or DWI, FLAIR, or T2 MRI sequences. The correct detection rate for both active and sham sessions in the sample was 60% (X2[1] = 0.20, p = 0.65), indicating successful blinding. There were no significant Session-by-Time interactions for clinical measures. However, there were two clusters of decreased functional connectivity following the active LIFU session compared to the sham session. Cluster 1 consisted of reduced functional connectivity between the right thalamus and bilateral subgenual anterior cingulate cortex (sgACC; Cluster mass index = 253.01, p-FDR = 0.02, Cohen’s d = -1.28), and Cluster 2 consisted of decreased functional connectivity between the left thalamus and bilateral sgACC, as well as bilateral ventral caudate, and between the left thalamus and the right medial orbitofrontal gyrus (Cluster mass index = 205.60, p-FDR = 0.04, Cohen’s d = -0.77). There was a significant Session-by-Time interaction in LF/HF HRV (F [1,27] = 4.24, p = 0.049), with a specific increase in LF/HF observed following the sham session (t [27] = -2.55, p = 0.02, Cohen’s d = 0.81), a change not seen following the active LIFU session (t [27] = 0.36, p = 0.72, Cohen’s d = 0.11).

Conclusions: This preliminary analysis shows that LIFU applied to white matter tracts that are part of a large-scale circuit critical to symptom formation in major depression [1] produces measurable functional changes in such a circuit. In addition, there was a subtle but significant change in cardiac sympatho-vagal balance possibly related to increased arousal in response to sham but not LIFU stimulation. These findings show proof-of-principle that LIFU has neuromodulatory effects when applied to white matter tracts. If confirmed in larger samples, these preliminary findings suggest LIFU can be developed as a neuromodulatory approach for personalized, symptom-specific neuromodulation targets.

References:

1. Lippitz BE, Mindus P, Meyerson BA, Kihlstrom L, Lindquist C. Lesion topography and outcome after thermocapsulotomy or gamma knife capsulotomy for obsessive-compulsive disorder: relevance of the right hemisphere. Neurosurgery. 1999;44(3):452-8; discussion 58-60.

2. Sanchez SM, Tsuchiyagaito A, Kuplicki R, Park H, Postolski I, Rohan M, et al. Repetitive Negative Thinking-Specific and Nonspecific White Matter Tracts Engaged by Historical Psychosurgical Targets for Depression. Biol Psychiatry. 2023.

3. Scangos KW, Khambhati AN, Daly PM, Makhoul GS, Sugrue LP, Zamanian H, et al. Closed-loop neuromodulation in an individual with treatment-resistant depression. Nat Med. 2021;27(10):1696-700.

4. Machado A, Haber S, Sears N, Greenberg B, Malone D, Rezai A. Functional topography of the ventral striatum and anterior limb of the internal capsule determined by electrical stimulation of awake patients. Clin Neurophysiol. 2009;120(11):1941-48.

5. Zeng K, Darmani G, Fomenko A, Xia X, Tran S, Nankoo J-F, Oghli YS, Wang Y, Lozano AM, Chen R (2022): Induction of human motor cortex plasticity by theta burst transcranial ultrasound stimulation. Ann Neurol, in press. https://doi.org/10.1002/ana.26294.

6. Whitfield-Gabrieli S, Nieto-Castanon A. Conn: a functional connectivity toolbox for correlated and anticorrelated brain networks. Brain Connect. 2012;2(3):125-41.

7. Zalesky A, Cocchi L, Fornito A, Murray MM, Bullmore E. Connectivity differences in brain networks. Neuroimage. 2012;60(2):1055-62.

Keywords: Depression, Focused Ultrasound, Non-Invasive Neuromodulation, Functional Connectivity, Negative Affect

Disclosure: Nothing to disclose.