Hoffmann reflex rate-dependent depression as a biomarker of spinally driven pain in diabetes

• Main Author: Worthington, Anne
• Format: Dissertation
• Language: English
• Published: University of Manchester 2022
• Subjects: Biomarker; Diabetes; H-reflex; Neuropathy; Pain; Phenotype; QST; Rate Dependent Depression; Spinal Disinhibition

Neuropathic pain is a frequent and disabling complication of diabetic polyneuropathy (DPN). However, it is not known why some patients develop painful DPN (pDPN) while others do not suffer pain. Although DPN is a primary disorder of the peripheral nerves it is increasingly recognised that processes in the central nervous system, including the spinal cord, are involved in generating neuropathic pain in DPN. One potential pain generating mechanism is spinal disinhibition whereby a loss of spinal inhibition leads to increased ascending nociceptive drive due to amplification of, or a failure to suppress, incoming signals from the periphery. Investigations in diabetic rodents implicate spinal disinhibition as a major mechanism of pain generation. A biomarker of spinal disinhibition in rodents is impaired rate dependent depression of the H-reflex (HRDD). The H-reflex is easily measured in humans and preliminary studies in patients have shown that HRDD is also impaired in pDPN associated with type 1 diabetes. This thesis aims to further investigate the role of HRDD as a biomarker of spinal disinhibition in pDPN in a larger sample size, including patients with type 2 diabetes, by deeply phenotyping neuropathy and pain using quantitative sensory testing, questionnaires, conditioned pain modulation and tests of neuropathy severity. The work establishes that HRDD is impaired in a larger cohort of patients with pDPN, including those with type 2 diabetes. It also shows that HRDD is enhanced in patients with painless DPN. By using receiver operator characteristic analysis the optimal HRDD parameters which delineate patients with pDPN from those without pain are defined. To aid transferability of H-reflex testing into the clinic a simple clinical scale, the Neuropathy Disability Score, is defined as a predictor of H-reflex amplitude. Finally, the work shows that increasing impairment abnormal HRDD, and by inference spinal disinhibition, is associated with a distinct pain phenotype characterised by a relative gain of function that would be expected to enhance ascending mechanical and thermal nociceptive drive despite sensory loss.