Current Diabetes Reports

, 18:1 | Cite as

The H-Reflex as a Biomarker for Spinal Disinhibition in Painful Diabetic Neuropathy

  • Corinne Lee-Kubli
  • Andrew G. Marshall
  • Rayaz A. Malik
  • Nigel A. Calcutt
Microvascular Complications—Neuropathy (R Pop-Busui, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Microvascular Complications—Neuropathy


Purpose of Review

Neuropathic pain may arise from multiple mechanisms and locations. Efficacy of current treatments for painful diabetic neuropathy is limited to an unpredictable subset of patients, possibly reflecting diversity of pain generator mechanisms, and there is a lack of targeted treatments for individual patients. This review summarizes preclinical evidence supporting a role for spinal disinhibition in painful diabetic neuropathy, the physiology and pharmacology of rate-dependent depression (RDD) of the spinal H-reflex and the translational potential of using RDD as a biomarker of spinally mediated pain.

Recent Findings

Impaired RDD occurs in animal models of diabetes and was also detected in diabetic patients with painful vs painless neuropathy.


RDD status can be determined using standard neurophysiological equipment. Loss of RDD may provide a clinical biomarker of spinal disinhibition, thereby enabling a personalized medicine approach to selection of current treatment options and enrichment of future clinical trial populations.


Rate-dependent depression Spinal disinhibition Neuropathic pain Diabetic neuropathy H-reflex KCC2 



This study is supported by National Institutes for Health awards DK057629 (NAC), DP3DK108245 (NAC), and DK081082 (NAC and RAM) and American Diabetes Association Award 1-17-ICTS-062 (AGM, NAC).

Compliance with Ethical Standards

Conflict of Interest

Corinne Lee-Kubli, Andrew G. Marshall, Rayaz A. Malik, and Nigel A. Calcutt declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

Previously unpublished data (Fig. 1) was collected by Corinne Lee-Kubli and Nigel Calcutt using the UCSD IACUC-approved protocol S-02059R.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Corinne Lee-Kubli
    • 1
  • Andrew G. Marshall
    • 2
    • 3
  • Rayaz A. Malik
    • 2
    • 4
  • Nigel A. Calcutt
    • 5
  1. 1.The Salk Institute for Biological SciencesLa JollaUSA
  2. 2.Faculty of Medical and Human Sciences, Institute of Cardiovascular SciencesUniversity of Manchester and National Institute for Healthy Research/Wellcome Trust Clinical Research FacilityManchesterUK
  3. 3.Department of Clinical Neurophysiology, Salford Royal Hospital, National Health Service Foundation TrustManchester Academic Health Science CentreManchesterUK
  4. 4.Department of MedicineWeill Cornell Medicine-QatarDohaQatar
  5. 5.Department of PathologyUniversity of California San DiegoLa JollaUSA

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