Low-intensity focused ultrasound to the insula and dorsal anterior cingulate has site-specific and pressure dependent effects on pain during measures of central sensitization

Abstract

Background: The insula and dorsal anterior cingulate cortex (dACC) are core brain regions involved in pain processing and central sensitization, a shared mechanism across various chronic pain conditions. Methods to modulate these regions may serve to reduce central sensitization, though it is unclear which target may be most efficacious for different measures of central sensitization. Objective/Hypothesis: Investigate the effect of low-intensity focused ultrasound (LIFU) pressure to the anterior insula (AI), posterior insula (PI) or dACC on conditioned pain modulation (CPM) and temporal summation of pain (TSP). Methods: N = 16 volunteers underwent TSP and CPM pain tasks pre/post a 10 minute LIFU intervention to either the AI, PI, dACC or Sham stimulation. Pain ratings were collected pre/post LIFU. Results: LIFU to the PI significantly attenuated pain ratings in both TSP and the CPM protocols. LIFU to the dACC only affected TSP pain ratings. LIFU to AI had no effect on either TSP or CPM pain ratings. LIFU pressure modulated group means but did not affect overall group differences. Conclusions: LIFU to the PI and dACC differentially affected central sensitization. This may, in part, be due to dosing (pressure) of LIFU. Inhibition of the PI with LIFU may be a future potential therapy in chronic pain populations demonstrating central sensitization. The minimal effective dose of LIFU for efficacious neuromodulation will help to translate LIFU for therapeutic options.

Low-intensity focused ultrasound to the human insular cortex differentially modulates the heartbeat-evoked potential: a proof-of-concept study

“…Prior in-vitro and animal work has consistently shown dose-response relationships with LIFU where more energy produces stronger effects on the outcome of interest [83–86]. While previous human studies have reported estimated intracranial energy [41,87–89], the present investigation along with its companion behavioral study [42] provide early evidence of a dose-response to LIFU in humans on measures ranging from pain perception to neurophysiologic responses. Interestingly, in the present study the observed effects of pressure on HEP amplitudes were the same for both PI and dACC conditions, but not for AI.…”

“…2024 [42]), LIFU was stereotaxically targeted to either the AI, PI, dACC or Sham. For Sham, the transducer was randomly positioned at one of those sites within and between participants.…”

“…On each formal testing day, participants were seated in a comfortable chair and connected to continuous EEG and ECG (see above). After the initial set of tasks prior to LIFU (see In et al, 2024 [42]), LIFU was stereotaxically targeted to either the AI, PI, dACC or Sham. For Sham, the transducer was randomly positioned at one of those sites within and between participants.…”

“…These results demonstrate the ability to modulate HEP amplitudes via noninvasive targeting of key interoceptive brain regions. Our findings have implications for the causal role of these areas in bottom-up heart-brain communication that could guide future work investigating the HEP as a marker of interoceptive processing in healthy and clinical populations.2024 [42]), LIFU was stereotaxically targeted to either the AI, PI, dACC or Sham. For Sham, the transducer was randomly positioned at one of those sites within and between participants.Participants were also given headphones to play the masking auditory stimulus throughout the entire LIFU application period (Figure 1A).…”

“…LIFU has been demonstrated to affect electrophysiologic, bold oxygen-level dependent (BOLD), and neurotransmitter activity for both superficial and deep structures in humans that translates to behavior changes [33][34][35][36][37][38][39]. More specifically, recent work from our lab demonstrates LIFU can specifically target the PI, AI, and dACC with differential effects on subjective report of pain, pain-evoked electrophysiologic potentials, and heart rate variability [40][41][42].…”