Lowering pain with LIFU

In this issue of Blood, Kim et al¹ demonstrate that focal delivery of low-intensity focused ultrasound (LIFU) to known “pain centers” in the brain can reduce pain-related behaviors (hyperalgesia) in a humanized mouse model of sickle cell pain.

LIFU is a burgeoning field, with early results^2-4 blossoming into a variety of demonstrations of its ability to focally and noninvasively modulate brain function⁵ and with an increasingly impressive movement toward treating human maladies.⁶ A relevant example is the work of Legon and colleagues,⁷ who reduced acute pain experienced by healthy test subjects through temporary modification of the anterior and posterior portions of the insula. These and other studies sought to modify a single node (or adjacent structures within a node) that lies in the brain circuits that contribute to painful experiences. In their work, Kim et al separately reduced the function of 2, anatomically distant “pain-related” nodes as described by Labrakakis.⁸ One was the sensory cortex, hence they reduced its “sensory-discriminative” contribution. The other was the insula, hence they reduced one of several contributors to the “affective-motivational” dimension of pain.⁸ This yielded a transient reduction of multimodal hyperalgesia. Extensive supplementary controls clearly demonstrated the focal nature of the brain modulation they created as well as the safety of their approach. Finally, by testing different LIFU protocols that produced different results, they defined boundaries to help the search in future work to optimize LIFU-based strategies for pain.

I commend Kim et al for focusing on sickle cell pain, which is highly relevant epidemiologically and has insufficient specific clinical options for amelioration. Addressing pain is a longstanding unmet need for patients with sickle cell anemia and for the field of hematology. However, the treatment approach presented goes beyond this painful disorder, given the universal nature of the focal nodes modified by their LIFU and the other nodes reachable by LIFU.⁹ As such, the work lends hope for reduction of chronic pain in other conditions.

Kim et al found that the quantitative reduction in hyperalgesia was quite modest, however, as a single session of LIFU yielded 30 minutes of reduced hyperalgesia and 14 days of 1-hour sessions resulted in only 2 hours of reduced hyperalgesia. Although not a clinically relevant protocol, this is one of only a few studies to show persistent behavioral vs electrophysiological changes in brain function.⁹ Moreover, Kim et al demonstrated the proof of concept of this approach that future work will likely optimize, namely the induction of longer lasting neuroplasticity that supports a reduction in painful experiences. Encouragingly, Riis and colleagues⁶ recently showed that 1 hour of multifocal LIFU within the subcallosal cingulate cortex could produce 44 days of significantly reduced depression in a patient with severe depression.

Beyond this proof of concept, the critical contribution by Kim and colleagues is that it points toward novel strategy of pain reduction: modulation of 2 pain centers, potentially quite distant anatomically, and likely in coordination. Specifically, one may consider reduction in nociceptive afferent signals (or amplified nonnoxious afferent signals due to central sensitization of the spinal cord) by reducing the function of the sensory cortex while also reducing the affective response to those sensations by decreasing the function of the insula. Future work may consider this multifocal modulatory strategy with a timed delay¹⁰ in delivery of LIFU to the insula relative to the sensory cortex, given that the former is downstream of the latter.

Kim et al also highlighted the technological means of embodying this strategy for human use---not quite novel, but effectively motivated and demonstrated by their work. The implanted device they used (see Figure 2 in the article by Kim et al) allowed LIFU treatment of the sensory cortex and, separately, the insula, in the same animal. Although implantation was used in this case, their impressive LIFU technology (a minuscule collection of 128 randomly distributed transducer elements deployed on a spherical section) is a model for a human-sized, noninvasive device that could someday treat pain by coordinated modulation of 2 or more distant nodes within the brain.

Conflict-of-interest disclosure: P.D.M. declares no competing financial interests.