Optimizing Hoffmann reflex rate-dependent depression recording: Toward a standardized biomarker for spinal disinhibition in neuropathic pain

Abstract

Introduction: Spinal disinhibition is increasingly recognized as a key mechanism underlying neuropathic pain, including painful diabetic neuropathy and other central sensitization syndromes. The rate-dependent depression of the Hoffmann reflex (RDD-HR), a neurophysiological phenomenon reflecting inhibitory function in spinal circuits, is impaired in several pain-related conditions, such as painful diabetic neuropathy, spinal cord injury, multiple sclerosis, amyotrophic lateral sclerosis, and Parkinson’s disease. However, the lack of standardized methods for its assessment has limited its clinical adoption as a biomarker of spinal inhibition.

Objective: To define and validate a standardized, time-efficient, and clinically feasible protocol for measuring RDD-HR in upper and lower limbs of healthy individuals, with a view toward its future application as a diagnostic tool in pain and neuroinflammation-related conditions involving spinal disinhibition.

Methodology: We recorded bilateral Hoffmann reflexes from the flexor carpi radialis and soleus muscles in healthy adults. Electrical stimulation at seven frequencies (0.1–5 Hz) was delivered in three 10-pulse trains per frequency. Reflex amplitude was quantified using the area under the curve (AUC), and RDD-HR was calculated as the median percentage decrease in AUC relative to the first pulse. Sigmoid curve fitting identified the stimulation frequency at which 50% of maximum depression occurred (S₅₀). Additional analyses determined the minimal number of stimuli required for reliable estimation of RDD-HR using a bootstrapping approach based on confidence interval inclusion, and assessed whether averaging across multiple trains improved measurement reliability through two-way ANOVA.

Results: RDD-HR was recorded in 21 healthy volunteers (13 women, 24–47 years, BMI 18.8–27.0) and exhibited a consistent sigmoidal pattern across all limbs. Depression was similar at 1, 2, and 5 Hz, at which maximal depression was reached, supporting 1 Hz as optimal, along with the S₅₀ frequency. Maximum depression was greater in lower limbs (~70%) than in upper limbs (~53%). S₅₀ was also slightly higher in lower limbs (0.6 Hz vs. 0.3 Hz), suggesting limb-specific differences in spinal inhibitory mechanisms. Reliable RDD-HR estimation was achieved with only seven stimuli and a single train. Upper limb testing required lower stimulation intensities, offering a practical alternative to lower limb recordings, particularly in populations where pain or mobility limitations make lower limb assessment difficult.

Conclusions: This study establishes a standardized protocol for RDD-HR assessment using a single seven-pulse train at just two stimulation frequencies, applicable to both upper and lower limbs. By simplifying and validating this method, we provide a feasible approach for integrating RDD-HR into clinical practice as a non-invasive biomarker of spinal inhibitory dysfunction. This has particular relevance for the diagnosis and monitoring of pain conditions associated with spinal disinhibition. Future work should validate this protocol in clinical populations and explore its utility in evaluating treatment response in pain rehabilitation.