Low-intensity transcranial focused ultrasound suppresses pain by modulating pain processing brain circuits

Abstract

Despite enormous efforts made in clinical pain research, there is still a need to identify a novel non-pharmacological solution due to critical side-effects. Low-intensity transcranial focused ultrasound (tFUS) is an emerging non-invasive neuromodulation technology with high spatial specificity and deep brain penetration. Here, we demonstrate that tFUS stimulation at pain processing brain circuits significantly affects behavioral responses to noxious stimuli in in vivo mouse models. We developed a tightly-focused 128-element random array ultrasound transducer with a dynamic focus steering for targeting small mice brains, and found that a single-session tFUS to the primary somatosensory cortex (S1) attenuates heat pain sensitivity in wild-type mice, bidirectionally modulate thermal and mechanical hyperalgesia in humanized mouse model of sickle cell disease as a function of ultrasound pulse repetition frequency (PRF), and targeting deeper cortical structure (e.g., insula) led to a sustained behavioral change associated with heat hyperalgesia. Furthermore, we found that multi-session tFUS to S1 and insula resulted in a long-lasting suppression of heat pain-associated behaviors in older sickle mice and confirmed the safety of the tFUS protocol. These profound experimental evidence of tFUS-induced non-invasive modulation of pain-related behaviors from short- to long-term effects may facilitate the next-generation chronic pain treatment.

An Investigation of Parameter-Dependent Cell-Type Specific Effects of Transcranial Focused Ultrasound Stimulation Using an Awake Head-Fixed Rodent Model

“…Ultrasound has been tested in awake rodents before, but most commonly it is delivered under anesthesia and effects tested after awakening, which only allows for testing of long-term effects (M. G. Kim et al, 2022). Wearable transducers for rodents have been developed, but generally only allow for EEG recordings to be taken due to the higher noise levels from movement, and these transducers are not capable of as high precision or as wide a range of parameters (Di Ianni et al, 2023;Hou et al, 2024;Jo et al, 2022;Piech et al, 2017).…”

Single cell RNA-sequencing reveals GINIP-expressing neurons as the main targets of focused ultrasound

“…Transcranial FUS has been used to treat pain by targeting specific brain circuits. FUS stimulation of the periaqueductal grey (PAG) effectively suppresses formalin-evoked pain in rats (4), and stimulation of the primary somatosensory cortex (S1) significantly attenuates heat pain sensitivity in wild type mice, and modulates injury-induced thermal and mechanical hyperalgesia in a mouse model of sickle cell disease (5). Although very encouraging, these attempts mainly focused on modulation of the activity of central but not peripheral nervous system.…”