The Feasibility of rTMS and Sensorimotor Training Task for the Treatment of Complex Regional Pain Syndrome: A Pilot Study

Background: Complex regional pain syndrome (CRPS) is a chronic pain condition characterized by a constellation of sensory, motor and autonomic dysfunction (Gierthmühlen et al., 2014). CRPS can be a debilitating disorder that drastically impacts quality of life. There are two types of CRPS; type 1 in which there is no identifiable nerve injury but occurs after a known noxious event and commonly involves immobilization, and type 2 in which there is a distinct nerve injury. There are challenges in the diagnosis of CRPS and presently the Budapest criteria are modified for the relevant context of research or practice. For this study the investigators plan to use the Budapest modified research criteria as suggested (Harden et al., 2013). CRPS differs from other chronic pain conditions; neuropathic-such as radicular pain or postherpetic neuralgia, or generalized non-specific pain conditions-such as fibromyalgia; in that, pain is associated with obvious and distinct alterations in sensory processing, sympathetic nervous involvement, and motor dysfunction. Limited treatment options for these individuals currently exist, and guidelines are based on expert consensus (Goebel et al, 2019). Existing knowledge suggests that continued physiotherapy with supportive pain control and psychological treatment is the most important strategy to manage CRPS (Goebel et al, 2019).

Repetitive transcranial magnetic stimulation (rTMS) offers a potential opportunity to noninvasively treat pain in patients with CRPS. Some studies have illustrated the analgesic effects of rTMS in patients with CRPS. Gaertner et al. (2018) delivered 10 Hz stimulation to the motor cortex in patients with CRPS. Patients were able to choose between one (n= 6) or five (n= 15) sessions of treatment. A significant reduction in pain was demonstrated in both groups one week following the last treatment session. There were no group differences in changes in pain. Two patients from each group maintained a >50% reduction in pain relief beyond 6 weeks post treatment. Further, Piceralli et al. (2010) observed a reduction in pain following 10 sessions of 10 Hz rTMS applied to the motor cortex in a group of 12 patients with CRPS. Additionally, Pleger et al. (2004) found that one session of rTMS applied to the motor cortex was sufficient to cause pain relief, however the duration of relief was experienced for only 45 minutes after stimulation. rTMS has been also used in other chronic pain conditions such as neuropathic pain (NP). Sham controlled studies have demonstrated the analgesic effects of rTMS applied to the primary motor cortex on NP symptoms in patients with spinal cord injury (Defrin et al., 2007; Jette et al., 2013; Yilmaz et al., 2014; Sun et al., 2019). These latter effects occur immediately following treatment (Jette et al., 2013) and persist up to six-weeks post-treatment (Yilmaz et al., 2014).

Although the chronic pain condition may vary, analgesic effects of rTMS are suggested to be a result of modulation of nociceptive inhibitory circuits from stimulation of the motor cortex (Lefaucheur et al., 2008; Nizard et al., 2012). This stimulation may cause changes in glutamatergic or GABAergic neurotransmitter pathways leading to a suppression of pain sensation (Lefaucheur et al., 2008; Ciampi De Andrade et al., 2014). Additionally, rTMS facilities neuroplasticity and the retraining of cortical circuits. This can be used to restore cortical activity that is altered in patients with CRPS (León et al., 2018).

Unlike other chronic pain conditions, the aim of CRPS treatment includes halting the progression of the disease early and thereby decreasing pain, rather than targeting pain alone. One approach is to reinforce afferent connections between the affected limb and the somatosensory cortex. In addition to pain, CRPS is associated with structural and functional changes of the somatosensory, primary motor, and supplementary motor areas (Urits et al., 2018; Echalier et al., 2020). Specifically, cortical representations of the affected limb in the somatosensory cortex are smaller and possess greater overlap with adjacent areas (Swart et al., 2009; Pietro et al., 2013). This is speculated to be a result of a decrease in afferent input originating from the periphery (Legrain et al., 2011; Moseley et al., 2012). Additionally, this reorganization is reinforced by the minimal usage of the affected limb by patients in order to avoid pain (Echalier et al., 2020). As such, this begins to raise the question, as to whether a sensorimotor task that stimulates afferent input originating from the periphery may aid in reinstating somatosensory cortical territory and ultimately aid in pain relief in these patients.

The objective of this study is to investigate the feasibility of the study procedures in a feasibility study involving 18 patients. In addition, the use of rTMS paired with a sensorimotor training task will be investigated in CRPS I patients, to induce positive neuroplastic changes so as to effect temporary and long-term pain relief. rTMS will be delivered to the primary motor cortex controlling the hand to create an environment within the sensory motor cortex that promotes neuroplasticity. This is accomplished through high frequency rTMS which increases cortical excitability (León et al., 2018). This in turn promotes intraneuronal connectivity and reorganization achieved through sensorimotor integration provided by the sensorimotor training task. In this task, digits two through five and the wrist on the affected hand will be non-invasively stimulated individually and require the participant to make a movement with that digit or wrist.