Diabetic neuropathy (DN) is one of the most common complications of diabetes, occurring in \~50% of patients. DN results from damage to the peripheral and autonomic nervous systems. Due to the damage to small peripheral nerve fibers, patients often do not properly perceive local traumas because of the absence of pain perception and vibration perception. The upper and lower limbs are the most commonly affected areas among individuals with DN, putting patients at a higher risk of developing skin ulcerations and undergoing amputations. DN is characterized by various symptoms including numbness, loss of sensation, tingling, weakness, pain, unsteadiness, loss of vibration sense and abnormal temperature (often cold). DN is associated with decreased quality of life, depression, sleep disturbance and anxiety. It is currently managed by the control of blood glucose levels, medications to relieve pain and symptoms, physical therapy and lifestyle modifications. The global prevalence of DN is increasing, leading to a high incidence of lower limp amputations in the DN population, which accounts for approximately 70% of non-traumatic amputations worldwide. DN is also correlated with increased risk of cardiovascular disease and leads to an increase in mortality of diabetic patients. Therefore, it is crucial to find new ways to improve neuropathy in patients living with DN.

A novel approach to treating neuropathy is through the induction of neuroplasticity. Neuroplasticity refers to the ability of the brain to change, either through structural reorganization or functional changes in brain activation. Neuroplasticity can be induced non-invasively with a form of brain stimulation known as repetitive Transcranial Magnetic Stimulation (rTMS). rTMS involves an electromagnetic coil placed against the scalp that generates magnetic pulses to induce electric fields in the brain. By delivering these electric fields in rapid succession and at low intensity, functional changes in the brain (i.e. neuroplasticity) can be evoked. rTMS can be used to treat neurodegeneration, blood flow change, autonomic nervous disorders, depression, and vascular endothelial injury. rTMS can produce inhibitory or excitatory stimulation of the cerebral cortex or specific areas, leading to remodeling of the nervous system. This makes it a promising application for promoting nerve regeneration, neuroprotection, and localization of injuries. DN is closely related to cardiovascular disease as DN damages the autonomic nervous system (ANS), which controls heart rate (HR) and blood pressure (BP). With rTMS, this damage in ANS, specifically, HR and BP, can be improved. Inhibitory stimulation can lower HR while excitatory stimulation can enhance heart rate variability. Both inhibitory and excitatory stimulation can lower BP. Thus, the use of rTMS can improve a variety of functions that could prevent further complications and possibly improve neuropathy, as well.

Inflammation is a crucial factor in the progression of DN, as it involves an increase in chemokine production, inflammatory cell infiltration in the kidney, tissue damage, and production of pro-inflammatory cytokines. Infiltration of inflammatory cells into the kidney can lead to diabetic kidney disease, which is the most prevalent cause of terminal renal failure globally with suboptimal treatment options. Due to the close link between DN and inflammation, reducing inflammation has been suggested as a possible therapeutic option for this population. Additionally, diabetic wounds and inflammation are also associated, therefore controlling inflammation may improve wound management and healing rates. Researchers have recently discovered that rTMS can impact the levels of inflammatory markers (such as IL-1B, IL-6, IL-10, TNF-α, TGF-β, CRP, SP, and BDNF) in other conditions such as depression, post-stroke, and Alzheimer's. The study by Zhao et al. investigated the effects of 20 sessions of rTMS intervention on 29 individuals diagnosed with refractory depression. Significant increases in serum BDNF levels and decreases in IL-1β and TNF-α levels were noted after one week of intervention, compared to healthy individuals, and this trend continued over the 4-week stimulation period. However, there was no change noted in the sham group. Cha et al. conducted a post-stroke study measuring the effects of 10 sessions of rTMS intervention on 10 individuals with post-stroke cognitive impairment. Following the intervention, levels of IL-1β, IL-6, TNF-α, and TGF-β mRNA decreased. Velioglu et al. explored the effects of 10 sessions of rTMS intervention on 15 individuals with Alzheimer's Disease. An increase in BDNF levels was noted following the conclusion of the intervention. Although no studies have been done in the DN population, the use of rTMS to examine changes in these levels is promising.

The goal of the proposed research is to investigate the use of rTMS to improve the symptoms of neuropathy in patients living with diabetic neuropathy.