Impaired rate-dependent depression of the H-reflex in type-2 diabetes, prediabetes, overweight and obesity: A cross-sectional study

Abstract

Type-2 diabetes is a chronic metabolic disorder characterized by hyperglycemia, resulting from deficits in insulin secretion or insulin resistance. According to the International Diabetes Federation, approximately 463 million people suffered from this condition in 2019, with a rapidly increasing impact in low-and middle-income countries. Obesity is a well-known risk factor for diabetes, and current data project a continuous increase in diabetes prevalence worldwide in obese individuals. Among the common complications, diabetic peripheral neuropathy (DPN) causes sensory symptoms, including pain that contributes to foot ulceration, and if not controlled, limb amputation may occur. The diagnosis of DPN is a clinical problem. Rate-dependent depression (RDD) of the Hoffmann reflex in the lower limbs has been proposed as a test to determine the presence of neuropathic pain in subjects with type-1 and type-2 diabetes. Recently, impaired RDD has been described in obese and diabetic rodent models. In this study, we characterized the RDD by evaluating the H-reflex at 0.2, 1, 2, 5, and 10 Hz in 39 patients with type-2 Diabetes mellitus (T2DM) and 42 controls without diabetes, subsequently classified as overweight/obese and prediabetic. A significant decrease in the RDD of the H-reflex was found in T2DM subjects at 1, 2, 5, and 10 Hz (P < .001) stimulation frequencies compared to controls, but not at 0.2 Hz (P = .48). A major finding of this study is that impaired RDD was also found in 11/25 overweight and obese subjects in at least 2 stimulation frequencies, being 10 of those classified in prediabetic levels according to their HbA1C values. The RDD of the H-reflex could be used as a quantitative and sensitive tool to study T2DM subpopulations with peripheral neuropathy. RDD could be used as a screening tool in combination with clinical tests to diagnose DPN and evaluate the progression of this condition.

Post-activation depression of the Hoffman reflex is not altered by galvanic vestibular stimulation in healthy subjects

“…Overall, our results confirm previous findings indicating that GVS increases the excitability at the neural elements involved in the H-reflex ( Lowrey and Bent, 2009 ; Okada et al, 2018 ; Nakamura et al, 2021 ); however, this increase in excitability did not affect the P-AD in healthy individuals, suggesting preservation of inhibitory spinal mechanisms. In this context, it has been described that a reduction or loss of the P-AD in pathological conditions occurs, such as in multiple sclerosis ( Cantrell et al, 2022 ), spinal cord injury ( Nielsen et al, 1995 ; Knikou and Murray, 2019 ), and recently, in diabetic neuropathy ( Lee-Kubli and Calcutt, 2014 ; Marshall et al, 2017 ; Worthington et al, 2021 ) and prediabetic, overweight and obese subjects ( Salinas et al, 2022 ).…”

Evidence of impaired H-reflex and H-reflex rate-dependent depression in diabetes, prediabetes and obesity: a mini-review

“…Salinas et al. ( 29 ), reported that the T2DM group presented a significantly increased latency compared to the control group (p < 0.001), and when subgroups were analyzed for p-DPN and p+DPN, latencies were significantly prolonged in the non-painful group at all stimulation frequencies. Also, Marshall et al.…”

“…In the same study, it is reported an improvement of 7.5% in the RDD after 2 weeks of gabapentin treatment ( 34 ). Nevertheless, Salinas et al., reported that although there is greater impairment of RDD in subjects with painful neuropathy, RDD is also impaired in subjects with non-painful diabetic neuropathy and they did not find enhanced RDD in any subpopulation of T2DM subjects ( 29 ). A common observation between both research groups is that H-reflex might be absent or severely attenuated in some patients, specifically in those with severe DSPN, so this test may not be suitable for all subjects, being limited to mild and moderate neuropathy ( 26 , 29 , 31 ).…”

“…In addition to the H-reflex test, electrophysiological studies such as nerve conduction velocity (NCV), help to diagnose large fiber neuropathy but are less specific for small fibers, so, small fiber neuropathy could be underdiagnosed ( 20 ), thus, other tests have been proposed such as the RDD which has been suggested as a biomarker of spinal disinhibition associated with pain in DSPN and which does not assess large or small fibers, but rather somatosensory dysfunction ( 29 ). Interestingly, it has been observed that the RDD is not only impaired in DSPN but also in overweight and obesity with metabolic syndrome ( 29 ). Therefore, this test may be helpful as a complementary tool when searching for DSPN even in the absence of pain or a diabetes diagnosis ( 13 ).…”

“…On the other hand, the Rate-Dependent Depression of the H-reflex (RDD hereinafter) is observed when the amplitude of the H-wave over paired or consecutive stimulations at frequencies > 1 Hz decreases compared to the first evoked response ( 25 ). Recently, the use of the RDD has been proposed to evaluate somatosensory processing in the spinal cord since its impairment is associated with diabetic neuropathy in animal models ( 26 – 28 ) and patients with type 1 and 2 diabetes ( 26 , 29 – 31 ).…”