Ultrasound Shows Promise As New Pain Treatment, Targeting A Specific Brain Region

                                                          By L. Joseph Parker, MD

A recent study documented a possible new treatment for pain. Something most physicians would be surprised to hear. Ultrasound. That’s right, low-frequency ultrasound waves, when directed to a specific area of the brain called the insula, have been shown to give some pain relief to persons who were being subjected to a standard contact heat evoked potential (CHEP). In this test, brief pulses of heat are applied to the skin using a standardized thermal stimulator. These pulses have been found to register as moderate pain or level five out of ten in most subjects. The pulses for this study lasted 300 milliseconds (ms), according to the article, without describing the pauses, though these can be up to 3000 ms. Both pulse and pause lengths can vary depending on the protocol.

Neural responses to this stimulation can be recorded with an electroencephalograph (EEG) or magnetoencephalograph (MEG) and then analyzed for components such as the N2-P2 complex. This is a negative deflection on the graph that typically bottoms out 200 to 400 ms after the stimulus is applied, followed by a positive deflection that peaks around 300 to 500 ms after the stimulus. P2 is believed to be associated with cognitive and emotional processing responses to pain. The N2-P2 complex has been correlated with pain intensity and gives a more subjective measure of physiological pain perception than self-reporting, which can be influenced by many psychological factors.

The insula is an area of the cortex between the frontal, parietal, and temporal lobes that is recessed in the lateral sulcus, separating those lobes, and is covered by cortical extensions from them called opercula. The insula is connected to multiple brain regions, including the prefrontal or executive cortex, the limbic system, the thalamus, and sensory cortices. The insula appears to integrate sensory information with the emotional processing of pain perception and awareness, as well as the processing of empathy, compassion, guilt, and embarrassment. It does this for the internal organs also, processing temperature, heart rate, and, to a degree, blood pressure. This area seems to inform the decision-making executive centers about threats to our well-being, including pain. Dysfunction in this area has been related to anxiety, schizophrenia, chronic pain, and even addiction.

The researchers at the Falin Biomedical Research Institute at Virginia Technical University then applied low-intensity focused ultrasound (LIFU) to either the anterior insula (AI) or the posterior insula (PI) for one second or used a sham procedure. This process was repeated on twenty-three healthy volunteers, each of whom was subjected to forty CHEP stimulations. The researchers then measured the EEG deflections associated with the stimulation and found a significant difference between sham and AI or PI LIFU but not between AI and PI, indicating that activation of either the anterior or posterior insula affected the recorded waveforms. They then asked the volunteers to rate their level of pain experience. The results showed 3.03+/-1.42 for the anterior insula, 2.77+/-1.28 for the posterior insula, and 3.39+/-1.09 for the sham stimulation. This showed a statistically significant difference between PI and sham that was not present between AI and PI or AI and sham. The difference was small, but with refinement could be clinically significant.

There was an interesting difference between targeting the anterior or posterior insula wherein LIFU to the PI seemed to affect early EEG deflections, while LIFU to the AI affected late EEG deflections. This study was the first to investigate how these different regions of the insula process the experience of pain. This is possible because LIFU is non-invasive and extremely precise, allowing the ultrasound waves to be focused to the millimeter. Previous invasive electrode measurements during neurosurgery had shown that the posterior insular received pain stimulation signals first and then passed the processed information on to the anterior insular. The LIFU study was the first to support this observation.

In another study published in the Journal of Neuroscience, the same researchers targeted the dorsal anterior cingulate cortex (ACC). This area is part of the cingulate cortex just below and posterior to the frontal cortex on the medial aspect of the brain just above the corpus callosum. The dACC is associated with cognitive processes such as attention, executive function, impulse inhibition, conflict monitoring, and error detection. This is crucial for emotional regulation and integrating emotional and cognitive information, pain processing, pain anticipation, and affective responses. This area is also related to the “theory of mind,” where we can strive to understand the thought processes of another. This is mapped onto our own bodily sense by the insula through what are called “mirror neurons” that generate painful or uncomfortable feelings in us when we see someone suffering. One theory of psychopathy is that they lack this ability.

Ultrasound is considered a benign imaging modality, but when it comes to the brain, there are a few concerns I have. From what I can gather, acoustic cavitation and thermal transfer have been considered and ruled out as safety concerns, but I didn’t find any long-term studies. If this is ever to be a pain treatment, it would probably need to be administered repeatedly over a significant period of time. The exact mechanism by which the neurons are affected by the ultrasound waves was not elucidated by the articles I could find, but we can assume that they alter the ionic permeability of the cell membrane is altered changing the polarization of the membrane. The crux of this research is that we might be able to reach deep into the brain and alter neuronal processing.

Here’s a question for you. Could this technology be used against a person? By stimulating the amygdala and generating feelings of terror by some unscrupulous interrogator? Before you say “we” would never do that, I refer you to the retired Air Force psychologists Bruce Jessen and James Mitchell who helped develop torture protocols for the CIA and even took part in some of the interrogations. Or could it be used for a better purpose? To stimulate areas of the brain that are dormant or hypoactive in some mental conditions, allowing psychopaths to feel empathy for the first time for instance? I think it is safe to say that this is an amazing technology with both great and terrible potential.

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