Targeted manipulation of pain neural networks: The potential of focused ultrasound for treatment of chronic pain

Abstract

Focused ultrasound (FUS) is a promising technology for facilitating treatment of brain diseases including chronic pain. Focused ultrasound is a unique modality for delivering therapeutic levels of energy into the body, including the central nervous system (CNS). It is non-invasive and can target spatially localized effects through the intact skull to cortical or subcortical regions of the brain. FUS can achieve three different mechanisms of action in the brain that are relevant for chronic pain treatment: (1) localized thermal ablation of neural tissue; (2) localized and transient disruption of the blood-brain barrier for targeted drug delivery to CNS structures; and (3) inhibition or stimulation of neuronal activity in targeted regions. This review provides an in-depth look at the technology of FUS with emphasis placed on applications to CNS-based treatments of chronic pain. While still in the early stages of clinical translation and with some technical challenges remaining, we suggest that FUS has great potential as a novel approach for manipulating CNS networks involved in pain treatment.

Keywords: Analgesia; Brain; Focused ultrasound; Neural circuits; Neuromodulation; Neurosurgical ablation; Pain; Targeted drug delivery.

Figure 1:

Thematic overview of focused ultrasound treatments for chronic pain. Chronic pain can result in aberrant activity within, and connections between, brain regions that collectively give rise to the experience of pain. Focused ultrasound is uniquely suited to selectively target any of these pain network nodes to deliver a therapy with the goal of normalizing the network back to the pre-pain state.

Figure 2:

Brain regions and pathways involved in the perception and experience of pain. Nociceptive signals from the periphery travel from the spinal cord into the brain along pathways that include the spinothalamic, spinoparabrachio–amygdaloid and spinoreticulo–thalamic tracts. Information entering the thalamus is relayed to cortical areas that include the primary somatosensory cortex, insula and cingulate cortex. Further connections within the brain to regions such as prefrontal cortex and the amygdala allow for attentional and emotional factors to be incorporated in the experience of pain. Integrated signals from various higher order areas of the brain are transmitted via the periaqueductal gray to the spinal cord to act as descending modulatory influences on the incoming nociceptive signals. Figure adapted from (Simons et al., 2014).

Figure 3:

A conceptual demonstration of ultrasound focusing in the brain. The ultrasound energy should be considered along concentric hemispheric surfaces starting at the transducer face and propagating with decreasing radius towards the focus. The first plot shows the total power (W) on these surfaces as a function of radial distance from the transducer where the power gets attenuated sharply by the skull and mildly by the brain tissue. The second plot shows the corresponding surface areas (cm²) of the hemispheres. The bottom plot of ultrasound intensity is obtained by taking the ratio of the power over the area (W/cm²).

Figure 4.

Elements of a modern MR-guided focused ultrasound brain tissue ablation procedure. A) The FDA-approved ExAblate Neuro MR-guided transcranial focused ultrasound system from InSightec. B) Treatment planning step using patient-specific CT for skull aberration correction. C) Real-time temperature mapping during the treatment. D) T2-weighted MRI evaluation of lesion at one day post-treatment.

Figure 5.

Focused ultrasound BBB opening. A) Pre-clinical MRI-compatible focused ultrasound system. B) Schematic of microbubbles undergoing stable cavitation within blood vessel to induce disruption of the blood-brain barrier. C) Gadolinium-based contrast MRI imaging for characterization of location and extent of BBB opening.