Diabetes Metab J.  2024 Nov;48(6):1029-1046. 10.4093/dmj.2024.0614.

Rate-Dependent Depression of the Hoffmann Reflex: Practical Applications in Painful Diabetic Neuropathy

• Han L
• Calcutt NA
• Zhou X

• KMID: 2561787
• DOI: http://doi.org/10.4093/dmj.2024.0614

Abstract

Measurement of the rate-dependent depression (RDD) of the Hoffmann (H) reflex, a technique developed over half a century ago, is founded on repeated stimulation of the H-reflex with tracking of sequentially evoked H-wave amplitudes in the resulting electromyogram. RDD offers insight into the integrity of spinal reflex pathways and spinal inhibitory regulation. Initially, RDD was predominantly utilized in the mechanistic exploration and evaluation of movement disorders characterized by spasticity symptoms, as may occur following spinal cord injury. However, there is increasing recognition that sensory input from the periphery is modified at the spinal level before ascending to the higher central nervous system and that some pain states can arise from, or be exaggerated by, disruption of spinal processing via a mechanism termed spinal disinhibition. This, along with the urgent clinical need to identify biological markers of pain generator and/or amplifier sites to facilitate targeted pain therapies, has prompted interest in RDD as a biomarker for the contribution of spinal disinhibition to neuropathic pain states. Current research in animals and humans with diabetes has revealed specific disorders of spinal GABAergic function associated with impaired RDD. Future investigations on RDD aim to further elucidate its underlying pathways and enhance its clinical applications.

Keyword

Diabetic neuropathies; Electrophysiology; H-reflex; Neuralgia; Neural inhibition

Figure

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  Fig. 1. The pathway and electrophysiological waveform of the H-reflex. Stimulation of large motor neurons directly excites the soleus muscle, resulting in the recording of the M-component. Excitation of the sciatic nerve is also relayed by type Ia afferent fibers through the dorsal root ganglion. Subsequently, it enters the spinal cord via the posterior root and posterior horn, establishes synapses with α motor neurons, and is propagated through their axons to evoke excitation in the soleus muscle, thereby generating the H-component.

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  Fig. 2. Schematic diagram of waveforms during normal and impaired rate-dependent depression (RDD). Following administration of a series of five consecutive H-stimulations (H1 to H5), a distinct attenuation of the amplitude of H2 and subsequent waves compared to H1 becomes evident. This phenomenon is referred to as RDD. In certain pathological conditions, this attenuation disappears.

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  Fig. 3. Critical membrane proteins and ion flows of GABAergic synaptic modulation. Potassium-chloride-cotransporter 2 (KCC2), responsible for mediating chlorine (Cl)– efflux, and sodium-potassium-chloride-cotransporter 1 (NKCC1), mediating Cl– influx, jointly maintain the Cl– balance of the cell membrane. γ-Aminobutyric acid receptor A (GABAAR), serving as a Cl– channel, when interacts with GABA in a healthy state, leading to Cl– influx and subsequent cellular hyperpolarization. The inhibitory regulation of this ensemble of membrane proteins is hypothesized to be a key mechanism underlying rate-dependent depression (RDD). In pathological conditions, the downregulation of KCC2 expression induced by brain-derived neurotrophic factor (BDNF) alters the intracellular and extracellular [Cl–], while the function of GABAAR relies on [Cl–], leading to the efflux of Cl– and tending to depolarization, thus intensifying pain. The impairment in this regulatory system alters the postsynaptic currents, ultimately manifesting as the absence of RDD. TrkB, tyrosine kinase receptor B.

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  Fig. 4. The correlation between the inhibitory regulatory dysfunction of the ascending sensory pathway at the spinal cord level and the rate-dependent depression (RDD) output. This exploration illustrates the scientific hypothesis of the normal ascending sensory pathway through the spinal cord (green arrows) and the ascending sensory pathway during pain conditions (red arrows). It is postulated that the original afferent inputs and activated glial cells may jointly contribute to the abnormal increase in brainderived neurotrophic factor (BDNF), which subsequently leads to the downregulation of potassium-chloride-cotransporter 2 (KCC2) and the conversion of γ-aminobutyric acid receptor A (GABAAR) into excitatory. This process results in the disinhibition of the spinal cord, manifesting phenotypically as pain and hyperalgesia, and electrophysiologically as impairments in RDD.

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  Fig. 5. Objective strategy for the analgesic prescription for patients with painful diabetic peripheral neuropathy (DPN). When individuals seek treatment, rate-dependent depression (RDD) is first assessed. Depending on whether RDD is impaired—indicating that the pain may be due to spinal target mechanisms—different medications can be selected accordingly. Unlike strategies based on anecdotal evidence, using RDD in painful DPN aims to create an objective, criterion-based targeting approach. This method detects spinal-mediated inhibitory modulation in patients with pain, allowing for the administration of tailored analgesic drugs. As a result, it enables personalized and precise analgesic therapy.

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