Background & Aims

Our interdisciplinary team is working to develop a focused ultrasound neuromodulation device, called the MR-guided focused ultrasound (MRgFUS) neuromodulation system, for non-invasive and non-addictive treatment of chronic pain. Our innovative device combines MRI and functional MRI (fMRI) with low-intensity transcranial focused ultrasound (FUS). This integration ensures accurate and reliable modulation of specific pain targets by visualizing FUS beam via magnetic resonance acoustic radiation force imaging (MR-ARFI) and provides novel insights into the mechanistic underpinnings of FUS modulation through whole-brain functional monitoring. Our cutting-edge MRgFUS neuromodulation system boasts the ability to modulate pain regions and circuits reversibly and bidirectionally with unparalleled precision and real-time monitoring capabilities.

Methods

Six adult macaque monkeys were included in the study. All MRI scans were conducted using Philips 3T Ingenia CX scanner, equipped with a pair of FLEX surface coils (inner diameter = 12 cm) positioned on both sides of the head. Whole-brain high-resolution T1-weighted structural images and fMRI data were obtained. Each fMRI run contained 337 imaging volumes. During a typical fMRI session, four runs of resting state fMRI data were acquired, two before and two after FUS stimulation of the thalamus. Standard fMRI pre-processing steps were applied. Inter-ROI correlation coefficients between brain regions that showed BOLD signal changes to 47 oC stimulation were computed and compared before and after FUS exposure. Pulsed ultrasound at 650 kHz frequency with an intensity of 550 kPa intensity was delivered using a 128-element transducer array to target the thalamus. Group-level fMRI analysis was conducted using the macaque monkey brain template.

Results

Our recent preclinical fMRI studies in nonhuman primates unveiled pronounced suppressive effects of 650 kHz pulsed FUS on thermal painful stimulus-evoked fMRI responses across diverse brain targets such as the thalamic VPL nucleus, ACC, and the periaqueductal gray (PAG), supporting its ability to reach targets residing in various parts of the brain. We have previously shown that the FUS-induced suppression of nociceptive heat-evoked fMRI responses at thalamic VPL drastically reconfigured the heat-nociceptive information processing flow and the organization of the thalamocortical effective connectivity network. Here, we present data demonstrating that FUS exposure significantly weakened the overall strengths of inter-regional resting state functional connectivity (rsFC) within the heat nociception network, with a small number of brain regions exhibiting strengthened rsFC. FUS exposure also drastically altered the organization of the resting-state nociceptive network.

Conclusions

Low-intensity focused ultrasound robustly modulates heat-evoked fMRI responses in the thalamus, ACC, and PAG, subsequently altering the organization of the resting state nociceptive network.

References

Mishra A,Yang P-F, Manuel TJ, Newton AT, Phipps MA, Luo H, Sigona MK, Reed, JL, Gore JC, Grissom WA, Caskey CF, Chen LM. Disrupting Nociceptive Information Processing Flow through Transcranial Focused Ultrasound Neuromodulation of Thalamic Nuclei. Brain Stimul 2023 Sept 21; 16(5):1430-1444. PMID: 37741439 DOI: 10.1016/j.brs.2023.09.013
Yang P-F, Phipps MA, Newton AT, Jonathan S, Manuel TJ, Gore JC, Grissom WA, Caskey CF, Chen LM. Differential dose responses of transcranial focused ultrasound at brain regions indicate causal interactions. 2022 Brain stimul. Nov-Dec; 15(6):1552-1564. PMID:36496128. PMCID:PMC9806861.
Phipps MA, Sumeeth J, Yang P-F, Chen LM, Grissom WA, Caskey CF. A reduced aperture allows for transcranial focus localization at lower pressure. 2022 JASA Express Letter. 2(6):062001. PMCID: PMC9245740
Yang P-F, Phipps MA, Jonathan S, Newton AT, Byun N, Gore JC, Grissom WA, Caskey CF, Chen LM. Bidirectional and neuron-selective modulation of brain activity by transcranial focused ultrasound in non-human primates. Brain stimulation. 2021 Mar-Apr;14(2):261-272. PMID: 31069643

Presenting Author

Li Min Chen

Poster Authors

Li Chen

MD, PhD

Vanderbilt University Medical Center

Lead Author

Arabinda Mishra

Vanderbilt University Medical Center

Lead Author

M Anthony Phipps

Vanderbilt University Medical Center

Lead Author

Allen Newton

Vanderbilt University Medical Center

Lead Author

Pai-Feng Yang

Vanderbilt University Medical Center

Lead Author

Michelle Sigona

Vanderbilt University

Lead Author

Charles Caskey

Vanderbilt University Medical Center

Lead Author

Topics

  • Treatment/Management: Interventional Therapies – Neuromodulation