Background & Aims

Painful diabetic neuropathy (PDN) is a significant complication arising in approximately 20% of individuals with diabetes mellitus. A recent randomized controlled clinical trial demonstrated the potential efficacy of 10kHz spinal cord stimulation (SCS) as a promising therapy for PDN, showing both pain reduction and potential neurological improvements (Petersen et al., 2023). In earlier preclinical investigations, we reported the selective activation of the thigh muscle by 10kHz SCS, with minimal activation observed through single-pulse (low frequency) SCS. Our paired pulse study revealed inhibition of the compound muscle action potential (CMAP) from the second pulse when the delay was less than 1000ms. Impaired Rate-Dependent Depression (RDD) is known in diabetic rodents (Marshall et al), and our study focused on examining changes in RDD from electromyography (EMG) evoked by implanted SCS.

Methods

We applied SCS via a micro-sized, in-line quadripolar electrode array positioned epidurally over the L5-L6 dorsal spinal segments (innervating the left hind paw) of 7-week-old Sprague-Dawley rats. A paired pulse protocol of 10kHz SCS was employed, with variable delays (20, 200, and 500ms). Needle electromyograms (EMG) captured CMAPs from the hindlimb thigh (biceps femoris). We compared the amplitudes of the first (R1) and second (R2) responses in CMAPs evoked during paired pulses by 10kHz SCS. The RDD study was conducted during diabetic pain development (on day 0, 7, and 14 after STZ injection).

Results

Throughout the progression of pain, the RDD expressed as the R2/R1 ratio showed an increasing trend with time across all delays in paired pulses. Specifically, on days 0, 7, and 14, the R2/R1 ratios were as follows: 0.52±0.28, 0.62±0.34, and 0.66±0.32 for a 20 ms delay; 0.51±0.11, 0.93±0.08, and 0.76±0.25 for a 200 ms delay; and 0.62±0.2, 0.95±0.09, and 0.82±0.22 for a 500 ms delay between paired pulses. In the comparison of ratios on day 14 against their respective baseline (day 0), only the RDD with a 200 ms delay exhibited statistical significance (p<0.05 in t-test).

Conclusions

Our study utilized EMG to investigate the spinal reflex evoked by paired pulse stimulation from implanted SCS during the development of PDN-model rats. The observed RDD patterns may reflect the change in spinal circuitry in PDN . When paired pulses were delivered with a 200ms delay, the second response exhibited significantly impaired depression, corresponding to dysfunction of presynaptic inhibition associated with GABA release in spinal cord inhibitory neurons. This protocol might be beneficial for investigating the mechanisms of PDN symptom improvement with 10kHz SCS.

References

Marshall AG, Lee-Kubli C, Azmi S, Zhang M, Ferdousi M, Mixcoatl-Zecuatl T, Petropoulos IN, Ponirakis G, Fineman MS, Fadavi H, Frizzi K, Tavakoli M, Jeziorska M, Jolivalt CG, Boulton AJM, Efron N, Calcutt NA, Malik RA. Spinal Disinhibition in Experimental and Clinical Painful Diabetic Neuropathy. Diabetes. 2017 May;66(5):1380-1390. doi: 10.2337/db16-1181. Epub 2017 Feb 15. PMID: 28202580; PMCID: PMC5399611.

Presenting Author

Dongchul Lee

Poster Authors

Dongchul Lee

PhD

Nevro Corp

Lead Author

Topics

  • Models: Chronic Pain - Neuropathic