Spinal cord stimulation for postural abnormalities in Parkinson's disease: 1-year prospective pilot study.

BACKGROUND: Postural abnormalities (PA) are common in the advanced stages of Parkinson's disease (PD), but effective therapies are lacking. A few studies suggested that spinal cord stimulation (SCS) could be a potential therapy whereas its effect is still uncertain. We aimed to investigate whether SCS had potential for benefiting PD patients with PA. METHODS: T8-12 SCS was operated on six PD patients with PA and all patients were followed for one year. Evaluations were made before and after SCS. Moreover, three patients were tested separately with SCS on-state and off-state to confirm the efficacy of SCS. RESULTS: Improvements in lateral trunk flexion degree, anterior thoracolumbar flexion degree and motor function were found after SCS. The improvements diminished while SCS was turned off. CONCLUSIONS: Lower thoracic SCS may be effective for improving PA in PD patients, but further studies are needed to confirm this conclusion. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1900024326, Registered on 6th July 2019; https://www.chictr.org.cn/showproj.aspx?proj=40835 .

Non-invasive spinal cord electrical stimulation for arm and hand function in chronic tetraplegia: a safety and efficacy trial.

Cervical spinal cord injury (SCI) leads to permanent impairment of arm and hand functions. Here we conducted a prospective, single-arm, multicenter, open-label, non-significant risk trial that evaluated the safety and efficacy of ARCEX Therapy to improve arm and hand functions in people with chronic SCI. ARCEX Therapy involves the delivery of externally applied electrical stimulation over the cervical spinal cord during structured rehabilitation. The primary endpoints were safety and efficacy as measured by whether the majority of participants exhibited significant improvement in both strength and functional performance in response to ARCEX Therapy compared to the end of an equivalent period of rehabilitation alone. Sixty participants completed the protocol. No serious adverse events related to ARCEX Therapy were reported, and the primary effectiveness endpoint was met. Seventy-two percent of participants demonstrated improvements greater than the minimally important difference criteria for both strength and functional domains. Secondary endpoint analysis revealed significant improvements in fingertip pinch force, hand prehension and strength, upper extremity motor and sensory abilities and self-reported increases in quality of life. These results demonstrate the safety and efficacy of ARCEX Therapy to improve hand and arm functions in people living with cervical SCI. ClinicalTrials.gov identifier: NCT04697472 .

Reciprocal inhibition of the thigh muscles in humans: A study using transcutaneous spinal cord stimulation.

Evaluating reciprocal inhibition of the thigh muscles is important to investigate the neural circuits of locomotor behaviors. However, measurements of reciprocal inhibition of thigh muscles using spinal reflex, such as H-reflex, have never been systematically established owing to methodological limitations. The present study aimed to clarify the existence of reciprocal inhibition in the thigh muscles using transcutaneous spinal cord stimulation (tSCS). Twenty able-bodied male individuals were enrolled. We evoked spinal reflex from the biceps femoris muscle (BF) by tSCS on the lumber posterior root. We examined whether the tSCS-evoked BF reflex was reciprocally inhibited by the following conditionings: (1) single-pulse electrical stimulation on the femoral nerve innervating the rectus femoris muscle (RF) at various inter-stimulus intervals in the resting condition; (2) voluntary contraction of the RF; and (3) vibration stimulus on the RF. The BF reflex was significantly inhibited when the conditioning electrical stimulation was delivered at 10 and 20 ms prior to tSCS, during voluntary contraction of the RF, and during vibration on the RF. These data suggested a piece of evidence of the existence of reciprocal inhibition from the RF to the BF muscle in humans and highlighted the utility of methods for evaluating reciprocal inhibition of the thigh muscles using tSCS.

Functional mapping of the lower urinary tract by epidural electrical stimulation of the spinal cord in decerebrated cat model.

Several neurologic diseases including spinal cord injury, Parkinson's disease or multiple sclerosis are accompanied by disturbances of the lower urinary tract functions. Clinical data indicates that chronic spinal cord stimulation can improve not only motor function but also ability to store urine and control micturition. Decoding the spinal mechanisms that regulate the functioning of detrusor (Detr) and external urethral sphincter (EUS) muscles is essential for effective neuromodulation therapy in patients with disturbances of micturition. In the present work we performed a mapping of Detr and EUS activity by applying epidural electrical stimulation (EES) at different levels of the spinal cord in decerebrated cat model. The study was performed in 5 adult male cats, evoked potentials were generated by EES aiming to recruit various spinal pathways responsible for LUT and hindlimbs control. Recruitment of Detr occurred mainly with stimulation of the lower thoracic and upper lumbar spinal cord (T13-L1 spinal segments). Responses in the EUS, in general, occurred with stimulation of all the studied sites of the spinal cord, however, a pronounced specificity was noted for the lower lumbar/upper sacral sections (L7-S1 spinal segments). These features were confirmed by comparing the normalized values of the slope angles used to approximate the recruitment curve data by the linear regression method. Thus, these findings are in accordance with our previous data obtained in rats and could be used for development of novel site-specific neuromodulation therapeutic approaches.

Improvement in Motor and Walking Capacity during Multisegmental Transcutaneous Spinal Stimulation in Individuals with Incomplete Spinal Cord Injury.

Transcutaneous multisegmental spinal cord stimulation (tSCS) has shown superior efficacy in modulating spinal locomotor circuits compared to single-site stimulation in individuals with spinal cord injury (SCI). Building on these findings, we hypothesized that administering a single session of tSCS at multiple spinal segments may yield greater enhancements in muscle strength and gait function during stimulation compared to tSCS at only one or two segments. In our study, tSCS was applied at single segments (C5, L1, and Coc1), two segments (C5-L1, C5-Coc1, and L1-Coc1), or multisegments (C5-L1-Coc1) in a randomized order. We evaluated the 6-m walking test (6MWT) and maximum voluntary contraction (MVC) and assessed the Hmax/Mmax ratio during stimulation in ten individuals with incomplete motor SCI. Our findings indicate that multisegmental tSCS improved walking time and reduced spinal cord excitability, as measured by the Hmax/Mmax ratio, similar to some single or two-site tSCS interventions. However, only multisegmental tSCS resulted in increased tibialis anterior (TA) muscle strength. These results suggest that multisegmental tSCS holds promise for enhancing walking capacity, increasing muscle strength, and altering spinal cord excitability in individuals with incomplete SCI.

[Neurosurgical treatment of postherpetic neuralgia]. / Neirokhirurgicheskoe lechenie postgerpeticheskoi nevralgii.

Postherpetic neuralgia is a chronic and debilitating condition that can occur following an episode of herpes zoster (shingles). It is characterized by severe, persistent pain in the area where the shingles rash occurred. While various treatment approaches exist, including medications and non-invasive therapies, some cases of postherpetic neuralgia may require neurosurgical intervention. Neurosurgical treatment options for postherpetic neuralgia aim to alleviate the pain by targeting the affected nerves or neural pathways. One common approach is spinal cord stimulation (SCS). In SCS, electrodes are implanted along the spinal cord, and electrical impulses are delivered to interfere with the transmission of pain signals. This technique can modulate pain perception and significantly reduce the intensity and frequency of postherpetic neuralgia symptoms. Neurosurgical treatment of postherpetic neuralgia is typically considered when conservative measures have failed to provide sufficient relief. However, it is crucial for patients to undergo a comprehensive evaluation and consultation with a neurosurgeon to determine the most appropriate treatment approach based on their specific condition and medical history. The risks, benefits, and potential outcomes of neurosurgical interventions should be carefully discussed between the patient and their healthcare provider to make an informed decision.

Study protocol for a prospective, randomized, multicenter trial to investigate the influence of peripheral nerve stimulation on patients with chronic sacroiliac joint syndrome (SILENCING).

BACKGROUND: The prevalence of sacroiliac joint pain (SIJP) is estimated to be 10-30% in patients with chronic low back pain. Numerous conservative and surgical treatment modalities for SIJP have been described with limited evidence regarding long-term pain relief. Spinal cord stimulation (SCS) is a well-established technique to treat patients with chronic low back pain. However, the effect on patients with SIJP is not consistent. Therefore, peripheral nerve stimulation (PNS) for chronic SIJP was implemented in experimental trials. Clinical data on PNS for SIJP is still lacking. The authors present a case series and a protocol for a prospective, multicenter study to determine the effect of PNS in patients with chronic intractable SIJP. METHOD: A multicenter, prospective randomized controlled trial was designed. Patients with chronic intractable SIJP will be recruited and randomized in a 4:3 ratio to either the peripheral nerve stimulation group or to the best medical treatment group. A total of 90 patients are planned to be enrolled (52 in the PNS group and 38 in the BMT group). Patients in the intervention group receive a percutaneous implantation of a unilateral or bilateral lead which is externalized for a trial phase for 3-14 days. After trial phase only patients with at least 50% reduction of pain receive an impulse generator for permanent stimulation. Regular visits for participants are planned on day 0, after 3 months (± 30 days), 6 months (± 30 days), and 12 months (± 60 days). The primary outcome measurements is the difference in Numeric Pain Rating Scale (NRS) between baseline and after 6 months. Secondary outcomes is improvement of pain associated disability (ODI) and improvement of health-related quality of life after 6 and 12 months. DISCUSSION: We have described the protocol for a prospective, multicenter, randomized trial evaluating the influence of PNS on patients with chronic sacroiliac joint syndrome. We believe that PNS on patients with chronic sacroiliac joint syndrome will show promising results regarding pain relief and quality of life in comparison to BMT after 12 months. The design of this trial promises high evidence in comparison to the data to date. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05357300. Registered on April 26, 2022.

Spinal Cord Stimulation for Poststroke Hemiparesis: A Scoping Review.

IMPORTANCE: Spinal cord stimulation (SCS) is a neuromodulation technique that can improve paresis in individuals with spinal cord injury. SCS is emerging as a technique that can address upper and lower limb hemiparesis. Little is understood about its effectiveness with the poststroke population. OBJECTIVE: To summarize the evidence for SCS after stroke and any changes in upper extremity and lower extremity motor function. DATA SOURCES: PubMed, Web of Science, Embase, and CINAHL. The reviewers used hand searches and reference searches of retrieved articles. There were no limitations regarding publication year. STUDY SELECTION AND DATA COLLECTION: This review followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist. The inclusion and exclusion criteria included a broad range of study characteristics. Studies were excluded if the intervention did not meet the definition of SCS intervention, used only animals or healthy participants, did not address upper or lower limb motor function, or examined neurological conditions other than stroke. FINDINGS: Fourteen articles met the criteria for this review. Seven studies found a significant improvement in motor function in groups receiving SCS. CONCLUSIONS AND RELEVANCE: Results indicate that SCS may provide an alternative means to improve motor function in the poststroke population. Plain-Language Summary: The results of this study show that spinal cord stimulation may provide an alternative way to improve motor function after stroke. Previous neuromodulation methods have targeted the impaired supraspinal circuitry after stroke. Although downregulated, spinal cord circuitry is largely intact and offers new possibilities for motor recovery.

Use of a Sheath and Stylet for a Difficult Dorsal Root Ganglion Stimulation Lead Extraction: A Case Report.

Dorsal root ganglion stimulation (DRG-S) is a relatively new neuromodulation technique that has shown promising results in the treatment of chronic pain conditions. We present a case of a difficult lead extraction during the explantation of a DRG-S device. The lead was unable to be removed despite multiple attempts until a sheath and stylet were used to facilitate extraction. As DRG-S utilization becomes more widespread, DRG-S device explantation will inevitably become more common. The technique described in this report may be beneficial in certain cases of difficult DRG-S lead extraction.

Multi-session transcutaneous spinal cord stimulation prevents chloride homeostasis imbalance and the development of hyperreflexia after spinal cord injury in rat.

Spasticity is a complex and multidimensional disorder that impacts nearly 75% of individuals with spinal cord injury (SCI) and currently lacks adequate treatment options. This sensorimotor condition is burdensome as hyperexcitability of reflex pathways result in exacerbated reflex responses, co-contractions of antagonistic muscles, and involuntary movements. Transcutaneous spinal cord stimulation (tSCS) has become a popular tool in the human SCI research field. The likeliness for this intervention to be successful as a noninvasive anti-spastic therapy after SCI is suggested by a mild and transitory improvement in spastic symptoms following a single stimulation session, but it remains to be determined if repeated tSCS over the course of weeks can produce more profound effects. Despite its popularity, the neuroplasticity induced by tSCS also remains widely unexplored, particularly due to the lack of suitable animal models to investigate this intervention. Thus, the basis of this work was to use tSCS over multiple sessions (multi-session tSCS) in a rat model to target spasticity after SCI and identify the long-term physiological improvements and anatomical neuroplasticity occurring in the spinal cord. Here, we show that multi-session tSCS in rats with an incomplete (severe T9 contusion) SCI (1) decreases hyperreflexia, (2) increases the low frequency-dependent modulation of the H-reflex, (3) prevents potassium-chloride cotransporter isoform 2 (KCC2) membrane downregulation in lumbar motoneurons, and (4) generally augments motor output, i.e., EMG amplitude in response to single pulses of tSCS, particularly in extensor muscles. Together, this work displays that multi-session tSCS can target and diminish spasticity after SCI as an alternative to pharmacological interventions and begins to highlight the underlying neuroplasticity contributing to its success in improving functional recovery.

Use of an Antibacterial Envelope in Spinal Cord Stimulation Reduces the Rate and Severity of Iatrogenic Infections.

OBJECTIVE: To examine if the use of an antibacterial envelope (TYRX) decreases the rate of postoperative infection in chronic pain patients undergoing treatment with spinal cord stimulation (SCS) involving device implantation. METHODS: Single-center retrospective cohort study comparing postoperative infections rates in non-TYRX recipients from 2018 to 2020 with recipients of a TYRX antibacterial envelope from 2020 to 2021. Infection was registered if a patient received any form of antibiotic treatment after hospital discharge within a follow-up period of 100 days. RESULTS: A total of 198 patients were included: 100 in the TYRX group and 98 in the non-TYRX group. There were no significant differences between the 2 groups regarding age, body mass index (BMI), smoking, diabetes, and use of immunosuppression. The overall infection rate was 5.6%. The infection rate was 4% in the TYRX group and 7.1% in the non-TYRX group (P = 0.6). However, the 4 cases of postoperative infection in the TYRX group could be effectively managed with oral antibiotics alone, whereas 6 out of the 7 patients in the non-TYRX group required intravenous antibiotics. Moreover, device explantation was necessary in 3 of these patients suggesting the event of more severe infections in the non-TYRX group (P = 0.014). CONCLUSIONS: The TYRX antibacterial envelope displayed infection rates reducing capabilities, along with a clear tendency to reduce revision surgeries and system removals due to infections.

High-Frequency Spinal Stimulation Suppresses Microglial Kaiso-P2X7 Receptor Axis-Induced Inflammation to Alleviate Neuropathic Pain in Rats.

OBJECTIVE: Neuropathic pain poses a persistent challenge in clinical management. Neuromodulation has emerged as a last-resort therapy. Conventional spinal cord stimulation (Con SCS) often causes abnormal sensations and provides short analgesia, whereas high-frequency spinal cord stimulation (HF SCS) is a newer therapy that effectively alleviates pain without paresthesia. However, the modes of action of 10kHz HF SCS (HF10 SCS) in pain relief remain unclear. To bridge this knowledge gap, we employed preclinical models that mimic certain features of clinical SCS to explore the underlying mechanisms of HF10 SCS. Addressing these issues would provide the scientific basis for improving and evaluating the effectiveness, reliability, and practicality of different frequency SCS in clinical settings. METHODS: We established a preclinical SCS model to examine its effects in a neuropathic pain rat model. We conducted bulk and single-cell RNA sequencing in the spinal dorsal horn (SDH) to examine cellular and molecular changes under different treatments. We employed genetic manipulations through intrathecal injection of a lentiviral system to explore the SCS-mediated signaling axis in pain. Various behavioral tests were performed to evaluate pain conditions under different treatments. RESULTS: We found that HF10 SCS significantly reduces immune responses in the SDH by inactivating the Kaiso-P2X7R pathological axis in microglia, promoting long-lasting pain relief. Targeting Kaiso-P2X7R in microglia dramatically improved efficacy of Con SCS treatment, leading to reduced neuroinflammation and long-lasting pain relief. INTERPRETATION: HF10 SCS could improve the immunopathologic state in the SDH, extending its benefits beyond symptom relief. Targeting the Kaiso-P2X7R axis may enhance Con SCS therapy and offer a new strategy for pain management. ANN NEUROL 2024;95:966-983.

Neuropathic Pain Medication and Antidepressant Use after Disability Pension in Patients with Spinal Cord Stimulation for Persistent Spinal Pain Syndrome.

Background: Treatment of persistent spinal pain syndrome (PSPS) is challenging. Chronic pain associated with PSPS can lead to an impaired ability to work. Objective: To obtain information on whether receiving a disability pension (DP) affects pain and pain treatments in retiring working-age PSPS patients. Neuropathic pain medication and antidepressant use were considered as an indicator of neuropathic pain. Methods: The study group comprised 129 consecutive PSPS patients with spinal cord stimulation (SCS) devices implanted at Kuopio University Hospital Neurosurgery between January 1, 1996, and December 31, 2014. Purchase data of gabapentinoids, tricyclic antidepressants, and serotonin-norepinephrine reuptake inhibitors from January 1995 to March 2016, as well as the data on working ability, were retrieved from national registries. Results: The data showed that 28 of 129 (21.7%) SCS permanent patients had a DP, and 27 had a sufficient follow-up time (two years before and one year after DP). Most patients (61%) used neuropathic pain medications during the follow-up, while 44% used antidepressants. Most patients (70%, n = 19) retired because of dorsopathies. The dose of gabapentinoids started to increase before the DP; after the DP, the doses started to increase again after the decrease but remained at a lower level. Conclusions: Neuropathic pain medication and antidepressant use suggest that pain continues after the DP-that is, pensioners continue to experience inconvenient chronic pain. Resources for patient care are therefore needed after the DP. However, the DP reduces the dose increase of gabapentinoids; the dose is higher immediately before retirement than at the end of the follow-up.

Web-Based Information on Spinal Cord Stimulation: Qualitative Assessment of Publicly Accessible Online Resources.

BACKGROUND: Despite the growing accessibility of web-based information related to spinal cord stimulation (SCS), the content and quality of commonly encountered websites remain unknown. OBJECTIVE: This study aimed to assess the content and quality of web-based information on SCS. METHODS: This qualitative study was prospectively registered in Open Science Framework. Google Trends was used to identify the top trending, SCS-related search queries from 2012 to 2022. Top queried terms were then entered into separate search engines. Information found on websites within the first 2 pages of results was extracted and assessed for quality using the DISCERN instrument, the Journal of the American Medical Association benchmark criteria, and the Health on the Net Foundation code of conduct certification. Website readability and SCS-related information were also assessed. RESULTS: After exclusions, 42 unique sites were identified (scientific resources: n=6, nonprofit: n=12, for-profit: n=20, news or media: n=2, and personal or blog: n=2). Overall, information quality was moderate (DISCERN). Few sites met all the Journal of the American Medical Association benchmark criteria (n=3, 7%) or had Health on the Net Foundation certification (n=7, 16%). On average, information was difficult to read, requiring a 9th- to 10th-grade level of reading comprehension. Sites described SCS subcategories (n=14, 33%), indications (n=38, 90%), contraindications (n=14, 33%), side effects or risks (n=28, 66%), device considerations (n=25, 59%), follow-up (n=22, 52%), expected outcomes (n=31, 73%), provided authorship details (n=20, 47%), and publication dates (n=19, 45%). The proportion of for-profit sites reporting authorship information was comparatively less than other site types (n=3, 15%). Almost all sites focused on surgically implanted SCS (n=37, 88%). On average, nonprofit sites contained the greatest number of peer-reviewed reference citations (n=6, 50%). For-profit sites showed the highest proportion of physician or clinical referrals among site types (n=17, 85%) indicating implicit bias (ie, auto-referral). CONCLUSIONS: Overall, our findings suggest the public may be exposed to incomplete or dated information from unidentifiable sources that could put consumers and patient groups at risk.

The role of stimulus periodicity on spinal cord stimulation-induced artificial sensations in rodents.

Objective.Sensory feedback is critical for effectively controlling brain-machine interfaces and neuroprosthetic devices. Spinal cord stimulation (SCS) is proposed as a technique to induce artificial sensory perceptions in rodents, monkeys, and humans. However, to realize the full potential of SCS as a sensory neuroprosthetic technology, a better understanding of the effect of SCS pulse train parameter changes on sensory detection and discrimination thresholds is necessary.Approach.Here we investigated whether stimulation periodicity impacts rats' ability to detect and discriminate SCS-induced perceptions at different frequencies.Main results.By varying the coefficient of variation (CV) of interstimulus pulse interval, we showed that at lower frequencies, rats could detect highly aperiodic SCS pulse trains at lower amplitudes (i.e. decreased detection thresholds). Furthermore, rats learned to discriminate stimuli with subtle differences in periodicity, and the just-noticeable differences from a highly aperiodic stimulus were smaller than those from a periodic stimulus.Significance.These results demonstrate that the temporal structure of an SCS pulse train is an integral parameter for modulating sensory feedback in neuroprosthetic applications.

Enhancing spinal cord stimulation-induced pain inhibition by augmenting endogenous adenosine signalling after nerve injury in rats.

BACKGROUND: The mechanisms for spinal cord stimulation (SCS) to alleviate chronic pain are only partially known. We aimed to elucidate the roles of adenosine A1 and A3 receptors (A1R, A3R) in the inhibition of spinal nociceptive transmission by SCS, and further explored whether 2'-deoxycoformycin (dCF), an inhibitor of adenosine deaminase, can potentiate SCS-induced analgesia. METHODS: We used RNAscope and immunoblotting to examine the distributions of adora1 and adora3 expression, and levels of A1R and A3R proteins in the spinal cord of rats after tibial-spared nerve injury (SNI-t). Electrophysiology recording was conducted to examine how adenosine receptor antagonists, virus-mediated adora3 knockdown, and dCF affect SCS-induced inhibition of C-fibre-evoked spinal local field potential (C-LFP). RESULTS: Adora1 was predominantly expressed in neurones, whereas adora3 is highly expressed in microglial cells in the rat spinal cord. Spinal application of antagonists (100 µl) of A1R (8-cyclopentyl-1,3-dipropylxanthine [DPCPX], 50 µM) and A3R (MRS1523, 200 nM) augmented C-LFP in SNI-t rats (DPCPX: 1.39 [0.18] vs vehicle: 0.98 [0.05], P=0.046; MRS1523: 1.21 [0.07] vs vehicle: 0.91 [0.03], P=0.002). Both drugs also blocked inhibition of C-LFP by SCS. Conversely, dCF (0.1 mM) enhanced SCS-induced C-LFP inhibition (dCF: 0.60 [0.04] vs vehicle: 0.85 [0.02], P<0.001). In the behaviour study, dCF (100 nmol 15 µl-1, intrathecal) also enhanced inhibition of mechanical hypersensitivity by SCS in SNI-t rats. CONCLUSIONS: Spinal A1R and A3R signalling can exert tonic suppression and also contribute to SCS-induced inhibition of spinal nociceptive transmission after nerve injury. Inhibition of adenosine deaminase may represent a novel adjuvant pharmacotherapy to enhance SCS-induced analgesia.

Distinguishing reflex from non-reflex responses elicited by transcutaneous spinal stimulation targeting the lumbosacral cord in healthy individuals.

Transcutaneous spinal stimulation (TSS) studies rely on the depolarization of afferent fibers to provide input to the spinal cord; however, this has not been routinely ascertained. Thus, we aimed to characterize the types of responses evoked by TSS and establish paired-pulse ratio cutoffs that distinguish posterior root reflexes, evoked by stimulation of afferent nerve fibers, from motor responses, evoked by stimulation of efferent nerve fibers. Twelve neurologically intact participants (six women) underwent unipolar TSS (cathode over T11-12 spinal processes, anode paraumbilically) while resting supine. In six participants, unipolar TSS was repeated 2-3 months later and also compared to a bipolar TSS configuration (cathode 2.5 cm below T11-12, anode 5 cm above cathode). EMG signals were recorded from 16 leg muscles. A paired-pulse paradigm was applied at interstimulus intervals (ISIs) of 25, 50, 100, 200, and 400 ms. Responses were categorized by three assessors into reflexes, motor responses, or their combination (mixed responses) based on the visual presence/absence of paired-pulse suppression across ISIs. The paired-pulse ratio that best discriminated between response types was derived for each ISI. These cutoffs were validated by repeating unipolar TSS 2-3 months later and with bipolar TSS. Unipolar TSS evoked only reflexes (90%) and mixed responses (10%), which were mainly recorded in the quadriceps muscles (25-42%). Paired-pulse ratios of 0.51 (25-ms ISI) and 0.47 (50-ms ISI) best distinguished reflexes from mixed responses (100% sensitivity, > 99.2% specificity). These cutoffs performed well in the repeated unipolar TSS session (100% sensitivity, > 89% specificity). Bipolar TSS exclusively elicited reflexes which were all correctly classified. These results can be utilized in future studies to ensure that the input to the spinal cord originates from the depolarization of large afferents. This knowledge can be applied to improve the design of future neurophysiological studies and increase the fidelity of neuromodulation interventions.