Pain relief is usually achieved using over-the-counter painkillers such as paracetamol or anti-inflammatory drugs; more severe pain may require opioids, which can have side effects and lead to addiction. Researchers at Virginia Tech are investigating another approach to pain management that doesn’t use drugs at all, but instead targets a specific point in the brain with focused ultrasound.

The insula is a region in the brain associated with the perception of pain. Its location deep in the folds of the cerebral cortex, however, makes it hard to access. Low-intensity focused ultrasound (LIFU), in which ultrasound beams are converged to a tiny spot, could provide a way to target such deep structures non-invasively with high spatial resolution.

In a double-blind clinical study, led by Wynn Legon from the Fralin Biomedical Research Institute at VTC, the team examined whether using LIFU to non-surgically alter neuronal activity can reduce both the perception of pain and the body’s reaction to a painful stimulus, such as changes in heart rate.

“LIFU provides high spatial specificity combined with the ability to focus to varying depths,” Legon explains. “Thus, this provides access to several hard-to-target brain regions without surgery. It also has the benefit – as do all device-based options – of being non-addictive.”

Legon and colleagues studied 23 healthy volunteers, using the contact heat–evoked potential (CHEP) method to assess pain processing. CHEP works by delivering brief heat stimuli to the hand, to a level judged to be moderately painful (around five on a pain response scale of zero to nine). The heat stimulus generates a CHEP waveform, which can be measured via an electroencephalography (EEG) electrode on the scalp.

Each participant attended four sessions, the first comprising anatomical MRI and CT scanning plus baseline questionnaires. In the other three sessions, volunteers were subjected to 40 CHEP stimuli (300 ms each) during delivery of LIFU (for 1 s) to either the anterior insula (AI) or the posterior insula (PI), or an inert sham exposure.

The researchers used an ultrasound transducer coupled to the head with conventional gel to deliver focused ultrasound with millimetre resolution. They also employed a custom coupling puck designed using each individual’s MRI scans to place the focal spot exactly on the insular targets.

The main goal of the study, reported in the journal PAIN, was to determine whether LIFU to the AI or PI could inhibit pain, as rated by participants during each CHEP session. The researchers also used electrocardiography (ECG) to examine how LIFU affected heart rate and heart-rate variability, and assessed its impact on the CHEP waveform.

The team found that LIFU to both the AI and PI reduced pain ratings. Averaging responses to the 40 CHEP stimuli for each subject resulted in mean pain ratings of 3.03±1.42, 2.77±1.28 and 3.39±1.09 for AI, PI and sham exposure, respectively. The difference observed between PI and sham stimulation was statistically significant, while differences between AI and sham or AI and PI were not.

Legon notes that although this reduction of roughly three-quarters of a point on the pain scale may seem quite small, once this reaches a full point, it verges on being clinically meaningful. “It could make a significant difference in quality-of-life, or being able to manage chronic pain with over-the-counter medicines instead of prescription opioids,” he explains in a press statement.

To assess the impact of LIFU of the CHEP waveform, the researchers measured the peak-to-peak amplitude from the first large negative (N1) to the first large positive (P1) deflection in the EEG. The peak-to-peak amplitudes were 23.35±11.58, 22.90±12.35 and 27.79±10.78 mV for AI, PI and sham exposure, respectively. Analysis revealed a significant difference between sham and AI, and sham and PI, but not between AI and PI.

The team observed that delivering focused ultrasound to the AI or the PI impacted the CHEP trace in distinct ways. LIFU to the PI affected earlier EEG amplitudes, while LIFU to the AI affected later EEG amplitudes, implying that modulating the PI and the AI cause different physical effects.

Legon tells Physics World that, before this study, it was not possible to non-surgically investigate how different regions of the insula contribute to the pain experience or how nociceptive (pain-related) information is relayed from one area to the other. The millimetre resolution of LIFU, however, enables specific targeting of closely located regions to look for specific effects.

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“Previous invasive depth-electrode recordings had demonstrated that nociceptive information was relayed in space and time from PI to AI,” he says. “Our results recapitulated this non-invasively, which is an important finding.”

LIFU did not affect participants’ mean heart rate during CHEP stimuli. The researchers did, however, see a significant difference in heart-rate variability between sham and AI exposure. LIFU to the AI increased heart-rate variability, which is associated with better overall health.

The team is now examining the delivery of LIFU to different brain areas as a potential pain therapeutic. “We do not yet know what dosing is appropriate or what specific parameters may lead to clinically meaningful results,” Legon explains. “Thus, we are beginning to test LIFU for pain relief in chronic pain populations. We are also investigating the utility of LIFU for other clinical indications such as anxiety and addiction.”