Deep Brain Stimulation, Stereotactic Radiosurgery and High-Intensity Focused Ultrasound Targeting the Limbic Pain Matrix: A Comprehensive Review

Abstract

Chronic pain (CP) represents a socio-economic burden for affected patients along with therapeutic challenges for currently available therapies. When conventional therapies fail, modulation of the affective pain matrix using reversible deep brain stimulation (DBS) or targeted irreversible thalamotomy by stereotactic radiosurgery (SRS) and magnetic resonance (MR)-guided focused ultrasound (MRgFUS) appear to be considerable treatment options. We performed a literature search for clinical trials targeting the affective pain circuits (thalamus, anterior cingulate cortex [ACC], ventral striatum [VS]/internal capsule [IC]). PubMed, Ovid, MEDLINE and Scopus were searched (1990-2021) using the terms "chronic pain", "deep brain stimulation", "stereotactic radiosurgery", "radioneuromodulation", "MR-guided focused ultrasound", "affective pain modulation", "pain attention". In patients with CP treated with DBS, SRS or MRgFUS the somatosensory thalamus and periventricular/periaquaeductal grey was the target of choice in most treated subjects, while affective pain transmission was targeted in a considerably lower number (DBS, SRS) consisting of the following nodi of the limbic pain matrix: the anterior cingulate cortex; centromedian-parafascicularis of the thalamus, pars posterior of the central lateral nucleus and internal capsule/ventral striatum. Although DBS, SRS and MRgFUS promoted a meaningful and sustained pain relief, an effective, evidence-based comparative analysis is biased by heterogeneity of the observation period varying between 3 months and 5 years with different stimulation patterns (monopolar/bipolar contact configuration; frequency 10-130 Hz; intensity 0.8-5 V; amplitude 90-330 μs), source and occurrence of lesioning (radiation versus ultrasound) and chronic pain ethology (poststroke pain, plexus injury, facial pain, phantom limb pain, back pain). The advancement of neurotherapeutics (MRgFUS) and novel DBS targets (ACC, IC/VS), along with established and effective stereotactic therapies (DBS-SRS), increases therapeutic options to impact CP by modulating affective, pain-attentional neural transmission. Differences in trial concept, outcome measures, targets and applied technique promote conflicting findings and limited evidence. Hence, we advocate to raise awareness of the potential therapeutic usefulness of each approach covering their advantages and disadvantages, including such parameters as invasiveness, risk-benefit ratio, reversibility and responsiveness.

Keywords: Anterior cingulate cortex; Central lateral nucleus of the thalamus; Centromedian-parafascicular; Chronic pain; Deep brain stimulation; Limbic pain network; Magnetic resonance-guided focussed ultrasound; Stereotactic radiosurgery; Ventral striatum/anterior limb of the internal capsule.

Fig. 1

a Somatosensory and affective nuclei of the thalamus. Schematic diagram depicting the location and composition of the thalamic nuclei. The somatosensory thalamus includes the nuclei ventromedialis (VPM) and ventrolateralis (VPL); (yellow), and the centromedian-parafascicular complex of the thalamus (CmPf), which is located in internal medullary lamina (grey). b Projections of the somatosensory and affective pain circuits of the thalamus. Pain processing pathways are highlighted within the cerebral tissue. The somatosensory process and pain memory pathway originate from the brainstem and spinal cord via ascending fibres and project to the thalamic nuclei, which are found in the centre of the brain above the brainstem. Signals from the VPL project to the somatosensory cortex, located in the parietal lobe, and these signals are further exchanged between the primary (S1) and secondary (S2) regions. The affective pain processing pathway originates from the CmPF and is projected to the insula, located within the lateral sulcus, and is then transmitted to the anterior cingulate cortex (ACC) and prefrontal cortex (PFC). Finally, this signal is sent back to the brainstem and spinal cord via descending fibres. Currently available interventions, namely deep brain stimulation (DBS), stereotactic radiosurgery (SRS) and magnetic resonance-guided focused ultrasound (MRgFUS), targeting the different regions (CmPf, ACC, VS/ALIC, CLT) of the brain for the treatment of chronic pain are depicted