Background: Diabetic neuropathy is one of the most common complications of diabetes occurring in \~50% of patients \[1, 2\]. Of these individuals, \~20% will develop painful diabetic neuropathy (pDN) \[3\] as a consequence of abnormal changes in the peripheral somatosensory system \[4\]. pDN is characterized by sensory changes including hyperalgesia, allodynia, paresthesia, and burning, shooting, and electric shock-like pain affecting lower and upper extremities \[4-6\]. pDN is a result of high glucose concentrations that damages peripheral nerves \[7\] resulting in hyperexcitability of nociceptive neurons in the dorsal horn and central sensitization \[8\]. pDN is also marked by alterations in the central nervous system \[6\] including the descending modulatory system \[9\] and maladaptive changes to somatosensory and motor areas \[10\]. pDN is associated with decreased quality of life, anxiety, and depression \[5\]. The treatment of pDN currently involves opioid agonist, antidepressants, and anticonvulsants however, these drugs are associated with undesired side effects \[11\] and only achieve a 50% reduction in pain with delayed onset \[12\]. Importantly, the prevalence of pDN is increasing \[13\] and given the limited effectiveness of pharmacological interventions, pDN represents a major healthcare crisis.

Repetitive transcranial magnetic stimulation (rTMS) may be a beneficial therapy for patients with pDN. Sham controlled studies \[14-19\] and meta-analyses \[20-23\] have demonstrated that high frequency rTMS stimulation applied to the primary motor cortex reduces symptoms of neuropathic pain in heterogenous groups of patients \[24\]. Our lab recently demonstrated that rTMS is effective at alleviating electric attacks in an individual with NP following SCI \[25\]. rTMS is also effective in pDN. Yang \[26\] found analgesic relief one day following stimulation to the hand representation of the primary motor cortex that persisted for 1 week. rTMS was also associated with significant improvements in physical and mental health measured using the SF-36 physical component score and mental component score respectively \[26\]. Abdelkader \[27\] indicated pain relief at 3 weeks post rTMS in patients with insulin-dependent and non-insulin-dependent pDN as well as improvements in lower limb nerve conduction latency and velocity. Comparatively, Onesti \[8\] targeted the leg representation in the primary motor cortex. rTMS reduced pain compared to sham immediately post stimulation but did not persist at three weeks \[8\]. rTMS also produced a depression of spinal nociceptive neurons as indicated through a decrease in the area of nociceptive flexion RIII reflex \[8\]. This finding suggests that rTMS increases the firing rates of cells in motor cortex and increases corticospinal excitability and neuroplasticity. These changes are thought to modulate descending inhibitory pain pathways through spinal interneural networks producing hypoexcitability of spinal nociceptive neurons \[8\]. Although the few studies in pDN demonstrate promise, it is important to note that rTMS is effective for \~50% of patients with neuropathic pain \[24, 28\] leaving much room for further improvement.

Recent advancements in rTMS technology have created the opportunity for remarkable strides in neuroplasticity. This new development called controlled pulse parameter TMS (cTMS) increases the magnitude and longevity of rTMS induced plasticity in humans \[29, 30\]. Fundamental to previous (i.e. traditional) rTMS is the biphasic pulse shape that are used during stimulation. In cTMS, pulses are monophasic and modifiable, and can be delivered at high rates used in rTMS \[31, 32\]. Although not tested in chronic pain, cTMS possess the power to make transformative changes in pDN, potentially yielding greater and widespread improvements in pain. The overarching goal of the proposed research is to assess the effects of a 10-day cTMS stimulation protocol on measures of pain, neuroplasticity, and somatosensory function in individuals with pDN.

How is cTMS thought to induce neuroplasticity and reduce pain? The primary motor cortex (M1) is directly implicated in modulating pain signals \[33\] through descending inhibitory control to thalamus \[34, 35\] and its connections with pain processing areas \[36\] including somatosensory \[37\] anterior cingulate cortex and prefrontal cortices \[38, 39\]. The analgesic effect of rTMS is suggested to occur by re-establishing both intracortical inhibition \[40\], GABAergic inhibition \[41, 43\], and descending inhibitory control \[34, 35\]. cTMS may more readily activate and cause change in the circuits projecting to these areas. Specifically, monophasic pulses delivered with repetitive cTMS produce larger and more long-lasting changes in cortical excitability \[29\] and greater depths of inhibition compared to traditional biphasic rTMS \[30\]. Monophasic pulses also produce more reliable cortical responses in cortical excitability, intracortical and GABAergic inhibition \[44\]. These findings have been suggested to occur as a result of the uniform pattern of cortical activation from monophasic pulses. Monophasic pulses produce greater global mean field power (GMFP) measured through electroencephalography (EEG) compared to biphasic \[31\]. Specifically, biphasic pulses may activate populations of both excitatory and inhibitory neurons which may dampen the overall effects of the stimulation protocol \[29\]. Taken together, cTMS may facilitate a greater propensity for change in these circuits and ultimately pain relief when applied to individuals with NP. The specific aims of this study in pDN are to:

1. Investigate the effects of a 10-day cTMS intervention on pain symptoms. The investigators hypothesize that cTMS will produce analgesic relief that will be associated with changes in neuroplasticity and somatosensory function compared to sham. Importantly, the effect of real and sham cTMS will be explored within individuals.
2. To explore the feasibility of the 10-day cTMS intervention. This will inform the utility of cTMS interventions in future treatments studies. In addition, the patient perceived change from the intervention will be assessed to improve the patient experience for future studies.
3. To assess the effects of the 10-day cTMS intervention on neurophysiology and somatosensory function. It is hypothesized that cTMS will produce neuromodulatory effects associated with increased cortical excitability, GABAergic inhibition, neuroplasticity, and improve somatosensory function compared to sham.