Low-intensity transcranial focused ultrasound changes pain-associated behaviors by modulating pain processing brain circuits

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.