Sensations generated by intense focused ultrasound (iFU) can occur cutaneously and/or at depth, in contrast to other forms of stimulation (heat, electricity) whose action usually occurs only at the skin surface or mechanical stimulation (von Frey hairs, calibrated forceps, tourniquets) that compress, hence stimulate all tissue. Previous work on iFU stimulation has led to the hypothesis that the tactile basis of iFU stimulation should correlate with the density of mechanoreceptors at the site of iFU stimulation. Here we tested that hypothesis, correlating a ‘two-point’ neurological exam, a standard measure of superficial mechanoreceptor density, with the intensity of superficially applied iFU necessary to generate sensations with high sensitivity and specificity. We applied iFU at 1.1 MHz for a 0.1 second to the fingertip pads of seventeen test subjects in a blinded fashion and escalating intensities until they consistently observed iFU-induced sensations. Most test subjects achieved high values of sensitivity and specificity, doing so at values of spatially and temporally averaged intensity measuring less than 100 W/cm^2. Moreover, the test subject’s sensitivity to iFU stimulation correlated with the density of mechanoreceptors as determined by a standard two-point discrimination neurological exam, consistent with earlier hypotheses.

We tested the hypothesis that neuropathic tissue is more sensitive to stimulation by intense focused ultrasound (iFU) than control tissue. We created a diffusely neuropathic paw in rats via partial ligation of the sciatic nerve, whose sensitivity to iFU stimulation we compared with sham-surgery and normal control paws. We then applied increasing amounts of iFU (individual 0.2 second pulses at 1.15 MHz) to the rats’ paws, assaying for their reliable withdrawal from that stimulation. Neuropathic rats preferentially withdrew their injured paw from iFU at smaller values of iFU intensity (176 W/cmˆ2 +/- 56) than did sham surgery (217 W/cmˆ2 +/- 25) and normal control (>280 W/cmˆ2) animals, with greater sensitivity and specificity (85% for neuropathic rats and 50% each of sham surgery and normal control rats). These results directly support our hypothesis as well as Gavrilov’s idea that doctors may some day use iFU stimulation to diagnose patients with neuropathies.

BackgroundPotential peripheral sources of deep pain can require invasive evocative tests for their assessment. Here we perform research whose ultimate goal is development of a non-invasive evocative test for deep painful tissue.MethodsWe used a rat model of inflammation to show that intense focused ultrasound (iFU) differentially stimulates inflamed versus control tissue and can identify allodynia. To do so we applied iFU to inflamed and normal tissue below the skin of rats’ hind paws and measured the amount of ultrasound necessary to induce paw withdrawal.ResultsiFU of sufficient strength (spatial and temporal average intensities ranged from 100–350 W/cm2) caused the rat to withdraw its inflamed paw, while the same iFU applied to the contralateral paw failed to induce withdrawal, with sensitivity and specificity generally greater than 90%. iFU stimulation of normal tissue required twice the amount of ultrasound to generate a withdrawal than did inflamed tissue, thereby assessing allodynia. Finally, we verified in a preliminary way the safety of iFU stimulation with acute histological studies coupled with mathematical simulations.ConclusionsGiven that there exist systems to guide iFU deep to the skin, image-guided iFU may one day allow assessment of patient’s deep, peripheral pain generators.