Reducing Pain in CRPS Using Personalized Brain Stimulation: A Feasibility Study

Complex regional pain syndrome (CRPS) is a chronic pain condition that is debilitating and dramatically decreases the quality of life. CRPS is characterized by a constellation of sensory, motor, and autonomic dysfunction. CRPS patients present with allodynia and hyperalgesia. There are also trophic changes of the affected limb, changes in skin colour and temperature, alterations in motor control, the presence of tremors, dystonia and edema, and feelings of hate towards the CRPS affected limb. Cortical representations of the affected limb in the somatosensory cortex are smaller and possess greater overlap with adjacent areas. This is speculated to be a result of a decrease in afferent input originating from the periphery. Additionally, this reorganization is reinforced by the minimal usage of the affected limb by patients in order to avoid pain. The worldwide incidence of CRPS is 26.2 per 100,000 people per year and is 3 to 4 times more prevalent in females. Based on these reports, it is estimated that Canada will experience ~10,000 new cases of CRPS each year. CRPS creates an economic burden; healthcare costs are increased by ~20% and two-thirds of individuals diagnosed with CRPS will not return to work. Taken together, these findings demonstrate the existing impact and increasing burden of CRPS on the Canadian workforce, economy, and healthcare. Pain relief is an unmet need in patients with CRPS. Options for medical management of CRPS include medications such as opioids, anticonvulsants, antidepressants, sympathetic blockade and invasive spinal cord stimulation (SCS). However, evidence for these treatments come from medium to low quality randomized control trials (RCTs). SCS, though effective for many patients with CRPS, is associated with significant complications and costs. At present, CRPS is managed through continued physiotherapy with supportive treatment for pain and mental health . However, this method does not effectively alleviate pain in CRPS.

Repetitive transcranial magnetic stimulation (rTMS) applied to the motor cortex has been shown to effectively alleviate pain in CRPS along with several other pain conditions. However, rTMS does not effectively alleviate pain for all individuals and there exists a large degree of interindividual variability in the efficacy of rTMS as a treatment for pain. This interindividual variability is thought to be a result of individual differences in patterns of brain activity. Indeed, in depression, tailoring rTMS to individual differences in depression-related brain activity recorded non-invasively via electroencephalography (EEG) resulted in more consistent and enhanced improvements in depression symptoms. Specifically, altering the frequency and location of rTMS according to alpha, beta, and theta power enhanced improvements in depression symptoms. In CRPS, one promising EEG marker is the movement-related cortical potential (MRCP) and is generated by real or imagined movement. Nerve stimulation delivered at the peak-negativity of the MRCP generated by attempted dorsiflexions in stroke patients resulted in improvements in a 10-meter walking task but not in a finger tapping task. Further, these patients had enhanced excitability of the cortical representation of the stimulated muscle. This is thought to have occurred because nerve stimulation caused cortical activity via afferent feedback within a couple hundred milliseconds of movement intention. Additionally, the peak-negativity of the MRCP is closely timed to alpha desynchronization, an EEG marker of cortical excitability.

MRCPs occur in paraplegic individuals, individuals suffering from stroke, individuals with amyotrophic lateral sclerosis, and Parkinson's disease. Given that MRCPs persist in a variety of conditions whereby movement is limited or even abolished, it is probable that MRCPs are quantifiable in CRPS. Using the MRCP in CRPS, one can theoretically reinforce connections used in sensorimotor control of the affected limb and the sensorimotor cortex. In addition to pain, CRPS is associated with structural and functional changes of the somatosensory, primary motor, and supplementary motor areas. MRCPs which are obtained from the sensorimotor cortices will provide a window into the movement planning processes that can be enhanced through MRCP tailored brain stimulation. Further, even if an individual cannot move, imagined movements that are furnished by the same sensorimotor cortices can be used to tailor brain stimulation.

To the best of the investigator's knowledge, MRCPs have not been used to trigger TMS by a real-time brain-computer interface (BCI) in healthy controls or in patient populations. The investigator's lab has developed a BCI that accurately detects MRCPs in healthy controls (Appendix Figure 1) with its best performance being an accuracy of 92%, true-positive-rate of 80% and a false-positive-rate of 7%. These results are comparable to other BCIs that detect MRCPs. Additionally, the investigator's lab has developed and validated a closed-loop EEG-triggered TMS framework that is compatible with the investigator's BCI (Appendix Figure 2). Ultimately, it is feasible for the investigator's lab to accurately tailor rTMS timing to MRCPs in healthy controls. However, the feasibility of doing so in a pain population and specifically in CRPS has yet to be determined. To the best of the investigator's knowledge MRCP morphology has not been studied in CRPS. However, MRCPs have been characterized in paraplegic individuals, individuals suffering from stroke, individuals with amyotrophic lateral sclerosis, and Parkinson's disease. Therefore, the feasibility of real-time MRCP tailored rTMS needs to be established in CRPS. Further, the effect of this approach on subjective and neurophysiological measures of pain have yet to be determined. Understanding the short-term effects of this novel approach would inform a future real-time MRCP tailored rTMS intervention for CRPS. The goal of the research is to determine the feasibility and effects of a novel BCI approach to delivering rTMS in individuals suffering from complex regional pain syndrome.

The goals of this study are to: