Somatosensory burst peripheral nerve stimulation focally upregulates corticospinal and spinal excitability in the upper limb: a randomized crossover pilot study

Somatosensory burst peripheral nerve stimulation focally upregulates corticospinal and spinal excitability in the upper limb: a randomized crossover pilot study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Somatosensory burst peripheral nerve stimulation focally upregulates corticospinal and spinal excitability in the upper limb: a randomized crossover pilot study Nish Mohith Kurukuti, Hamidollah Hassanlouei, Xin Sienna Yu, Jose Louis Pons This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6728178/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Peripheral nerve stimulation (PNS) is commonly used in research and clinical settings for pain management and for augmenting somatosensory inputs for motor recovery. Its functional effects are dependent on stimulation parameters such as frequency, intensity, and duration of stimulation. Recently, interest in temporally modulated PNS (burst PNS), where high-frequency carrier pulses are demodulated to low-frequency bursts, has increased. Burst PNS applied below the motor threshold (sensory) have been used for pain and tremor suppression. However, the effects of burst sensory PNS (sPNS) on corticospinal and spinal excitability are unknown, limiting their application. Methods We evaluated the impact of a session of burst sPNS on corticospinal excitability through motor-evoked potentials (MEPs) and on spinal excitability through F-wave and H-reflex assessments targeting the first dorsal interosseous (FDI) and flexor carpi radialis (FCR) muscles. Ten healthy participants underwent a randomized crossover study with two experimental visits, where corticospinal and spinal excitability were evaluated before and after a session (40 min) of burst sPNS at the wrist or no stimulation (control). Results Compared with the control condition, burst sPNS resulted in a focal increase in MEP amplitudes (p < 0.001) in the FDI muscle but not in the FCR muscle (p = 0.26). Similarly, only the F-wave amplitude increased following burst sPNS (p = 0.008) for the FDI muscle compared with the control condition, but no differences were observed in the H-reflex amplitude (p = 0.33) in the FCR muscle between the burst sPNS and the control condition. Conclusion Our findings suggest that burst sPNS might modulate spinal and/or cortical excitability in the short term (5–10 min in this study). However, the relative changes in cortical and spinal levels due to burst sPNS are unknown, and the timeline for these continued aftereffects needs further investigation. Trial registration NCT04501133 Transcutaneous electrical nerve stimulation burst stimulation corticospinal excitability spinal excitability motor-evoked potentials F-wave H-reflex Figures Figure 1 Figure 2 Figure 3 Figure 4 BACKGROUND Peripheral nerve stimulation (PNS) is a common rehabilitation technique widely used to enhance motor function by modulating neuronal excitability. Clinically, it is employed to alleviate chronic pain symptoms ( 1 ), enhance somatosensory input to improve motor recovery in stroke ( 2 ) and spinal cord injury ( 3 ), and suppress tremors in movement disorders ( 4 ). PNS provides differential effects depending on the stimulation parameters. The two common parameters that vary in the clinical setting are the frequency and intensity of stimulation. The motor PNS (mPNS), which is delivered above the motor threshold to evoke extra torque/force, has been used to augment motor rehabilitation and/or assist in generating functional movements (gait) in individuals with stroke and incomplete spinal cord injury ( 5 , 6 ). Alternatively, sensory PNS (sPNS), with a stimulation intensity below the sensory threshold, when delivered at high frequencies (> 90 Hz), is used for suppressing pain ( 1 ) and tremor ( 4 ), whereas at low frequencies (< 30 Hz) in combination with target-oriented training, it is used for rehabilitating hand function in stroke ( 7 ). Mechanistically, the PNS evokes artificial volleys that propagate orthodromically and antidromically along the recruited afferent and/or efferent fibers. Orthodromic afferent volleys travel to the spinal cord and brain, where they modulate corticospinal (CS) excitability. This modulation has been shown to persist for up to 2 hours post-stimulation ( 8 ). Studies using transcranial magnetic stimulation (TMS) have shown that modulation of motor evoked potentials (MEPs), a measure of CS excitability, is dependent on PNS parameters such as frequency ( 9 , 10 ), intensity ( 11 ), duration ( 12 ), and even the pattern or waveform of delivery ( 13 ). Recently, interest in temporally patterned sPNS to improve the effectiveness of sPNS in rehabilitation has increased. Burst sPNS, where high-frequency carrier pulses are demodulated to low-frequency bursts, has shown promise in suppressing symptoms such as pain ( 14 ) and tremors ( 15 ). However, the impact of such burst-modulated sPNS on CS and spinal excitability remains largely unexplored, despite evidence suggesting that the pattern of stimulation delivery plays a critical role in neuroplasticity. Emerging data suggest that the temporal structure of afferent input, not just the total pulse count or intensity, can shape neurophysiological outcomes. In a recent study, Ishibashi et al. ( 13 ) reported that intermittent (burst-like) sPNS increased MEP amplitudes—an indicator of enhanced corticospinal excitability—whereas continuous sPNS at the same frequency and duration decreased excitability. This underscores the unique neuroplastic potential of burst-patterned input, potentially owing to its resemblance to natural afferent firing patterns and its ability to prevent synaptic fatigue. Understanding how this specific PNS protocol of burst sPNS affects CS and spinal excitability could have significant clinical implications, potentially enhancing rehabilitation strategies. Modulation of MEP amplitudes has been largely attributed to changes in cortical excitability ( 16 ). Following short-term (1–2 h) high-frequency PNS, somatosensory cortical representation of the muscles innervated by the stimulated nerve increases ( 17 ). Similar increases in corticomotor representation in the motor cortex following high-frequency PNS have also been reported. Imaging studies have also shown that the PNS induces cortical and subcortical excitability changes in sensorimotor regions ( 18 ). These findings highlight the importance of proprioceptive afferent engagement in modulating sensorimotor circuits. However, the involvement of spinal mechanisms in modulating CS excitability remains unclear. While studies using H-reflex and F-waves have shown no changes in spinal excitability following PNS ( 11 , 13 ), recent findings suggest an increase in spinal excitability following high-frequency PNS when it is delivered with wide pulse widths ( 19 ). These inconsistencies regarding the effects of the PNS on spinal excitability highlight the need for further research. In this study, we investigated the effect of burst sPNS using a wide pulse width targeting the median, radial and ulnar nerves at the wrist and compared it to that of a control condition (no stimulation) by examining CS and spinal excitability in the first dorsal interosseous (FDI) and flexor carpi radialis (FCR) muscles. We hypothesized that MEPs are evoked by TMS over the motor cortex and that the F-wave amplitude evoked by ulnar nerve stimulation increases after burst sPNS in the FDI. We also hypothesized that the increase in corticospinal and spinal excitability would only be present in the FDI but not in the FCR muscle because of the focal effect of burst sPNS ( 20 ). By evaluating these expected changes, we aim to contribute to the growing body of knowledge on how afferent volleys generated during burst sPNS alter CS and spinal excitability in humans, which could inform the development of more effective rehabilitation protocols. METHODS Participants Ten healthy adults (mean age: 33.7 ± 13.0 years; 5 females) volunteered to participate in this randomized crossover study. The participants did not have a history of neuromuscular disorders, sensory deficits, or previous upper limb surgery. Written informed consent was obtained from all participants before testing. The study was approved by the Northwestern University IRB committee (IRB: STU00211930), and all methods conformed to the standards of the Declaration of Helsinki (2004). All the subjects participated in 2 separate ~3-h testing visits at least 72 h apart in which burst sPNS was applied to the median, radial and ulnar nerves at one visit and no stimulation (control) at the other visit. The order of the visits was randomized for each participant through block randomization. The random allocation sequence based on participant IDs was generated via R. The time of day of each session was the same for each subject to reduce the potential confounding effect of diurnal changes in CNS excitability (21). The subjects were instructed to avoid the consumption of caffeine 12 h prior to the testing sessions and during a session to eliminate its influence on CNS excitability (22) and to refrain from intense physical activity 12 h prior to the testing sessions. Following the first visit, participants had a 3-day washout period before participating in the second visit. Motor - evoked potentials and recruitment curves Motor-evoked potentials (MEPs) were recorded from the FDI and FCR muscles via surface electrodes on the dominant arm. The EMG signal was pre-amplified and digitized at 2048 Hz. Relaxation was defined as EMG activity at baseline < 20 µV peak-to-peak amplitude for at least 1 s. During the setup, the optimal scalp positions (contralateral motor cortex to the dominant hand) to elicit reliable MEPs (at least 5 out of 10 attempts) for the FDI and FCR muscles were mapped. For the remainder of the visit, TMS was delivered to the determined optimal scalp positions to stimulate the FDI and FCR muscles. TMS was delivered through a figure-of-eight shaped magnetic coil (outside diameter of 8.7 cm) connected to a MagPro X100 stimulator (MagVenture, Denmark). The magnetic coil was placed tangentially to the scalp, with the intersection of both wings at a 45 deg angle with the midline to optimally stimulate the motor cortex (Brasil-Neto et al. 1992; Mills et al. 1992). The stimulation location was marked on a TMS cap secured on the participant’s head to ensure the repeatability of coil placement throughout the experiment. Along with mapping the optimal scalp position, the resting motor threshold (rMT), defined as the minimum TMS intensity (measured to the nearest 1% of the maximum output of the magnetic stimulator) required to elicit at least five out of ten MEPs ≥ 50 µV in consecutive trials (23), was also determined for the FDI and FCR muscles. For the remainder of the visit, TMS was delivered at intensities expressed relative to the rMT measured from the muscles. The mean MEP amplitudes were obtained in response to 10 TMS stimuli delivered at each of six stimulus intensities: 90%, 100%, 110%, 120%, 130% and 140% of the rMT for each muscle, with the order of intensities randomized. Maximal M-waves (M-max) To determine M-max for the FDI and FCR muscles, the stimulation intensity was increased over several stimuli from below the motor threshold to 1.5–2 times the minimum current required to evoke M-max (20). M-max was calculated as the largest M-wave evoked in the muscles of 3 trials. The amplitude of M-max from each muscle was tested on two occasions: before and after delivery of the burst sPNS or in the control condition. F-waves F-waves were evoked to examine motor neuron excitability for the FDI muscle by using supramaximal stimulus intensity to the ulnar nerve (200-μs pulse duration; DS5; Digitimer). Sixty stimuli were delivered at 1 Hz at an intensity of 150% of the M-max (24). For each stimulus, the peak-to-peak amplitude and persistence (i.e., the percentage of stimuli evoking a response) of the F-waves were measured. F-wave trials were filtered via a second-order Bessel high-pass filter (200 Hz) to “flatten the tail of the M-wave” (25). An F wave was considered to be present if a response with a proper latency (minimum of 30 ms after the stimulus artifact) had an amplitude >=20 µV. H-reflex H-reflexes were elicited to examine spinal excitability for the FCR muscle by stimulating the median nerve (1-ms pulse duration; DS5; Digitimer) near the elbow. The response was identified as an H-reflex if it had a latency between 12 and 25 ms. The intensity to elicit H-max was determined by systematically increasing the intensity and quantifying the H-reflex and M-wave amplitudes (H-M curve). The intensity at which the amplitude of the H-reflex was the maximum with the minimal M-wave was considered the H-max intensity (25). Ten stimuli were delivered approximately 5 seconds apart at the H-max intensity to record the H-reflex at H-max. For each stimulus, the peak-to-peak amplitude of the H-reflex was measured. Burst sPNS During the experimental session with burst sPNS, electrical stimuli were delivered to the nerves at the wrist. A bipolar constant current stimulator (Digitimer DS5, Digitimer, UK) was used along with conductive surface electrodes (2 cm diameter; Axelgaard, Denmark) to deliver electrical current. Two anodes were placed over the median nerve at the flexor retinaculum of the palmar side and over the radial nerve at the distal radius of the wrist. A common cathode was placed over the distal end of the ulna. Burst sPNS involves trains of rectangular biphasic wave pulses with 800 µs duration at a carrier frequency of 100 Hz, which are applied at 5 Hz (100 ms on and then switched off for 100 ms) and delivered for 40 minutes. The stimulus intensity was adjusted to not evoke a visible contraction from the hand muscles while providing paresthesia but not being painful or uncomfortable. This low-intensity stimulation and the stimulus duration preferentially activate large cutaneous and proprioceptive sensory fibers (26). The participants were instructed to refrain from moving the stimulated arm during the administration of burst sPNS. Data analysis Changes in CS excitability induced by burst sPNS were determined by quantifying and comparing the group averages of the 10 MEPs evoked before and after burst sPNS or the control condition. To ensure that all MEPs were obtained at rest, MEP data were inspected post hoc and discarded if the EMG during the 1 s before the TMS exceeded 2 standard deviations of the average baseline signal recorded at rest before the stimulation. Of the 2,350 MEPs evoked from 10 subjects, 19 MEPs (~1% of the total responses) were removed from the analyses on the basis of this criterion. To compare the change in CS excitability, the average MEP amplitude from 10 trials in post assessments for each muscle was normalized to the average MEP amplitude in the pre assessments via Equation (1). Changes in spinal excitability induced by burst sPNS were determined by quantifying and comparing the average peak-to-peak amplitude of the F-waves evoked in the 60 trials and the H-reflex from the 10 trials before and after the burst sPNS or control condition. The percentage occurrence of the F-waves was also computed before and after the burst sPNS or control condition. To compare the changes in spinal excitability, the percent changes in the average peak-to-peak amplitudes of the F-wave, H-reflex, and F-wave persistence were computed via Equation (1). Percent change = (Post/Pre) * 100 Eq 1 Statistical analysis All the statistical analyses were performed with R. The normality of the data distribution was checked via quantile‒quantile plots and histograms. Analyses were performed via linear mixed effect models implemented in the lme4 function with the Kenward-Roger method to estimate the denominator degrees of freedom and the p values. This method considers the dependence of data points within each participant and accounts for them. When necessary, multiple comparisons were performed via the package emmeans , which adjusts the p value for multiple comparisons via the Tukey method. The significance level was set at p = 0.05. The values are reported as the means ± standard deviations. To evaluate the effect of burst sPNS on CS excitability across muscles, percent changes in MEPs for the FDI and FCR were compared via linear mixed effect models with muscle (FDI, FCR) and condition (control, burst sPNS) as fixed effects and participants as random effects. To evaluate the effect of burst sPNS on spinal excitability, we compared the percent change in F-wave amplitude, percent change in H-reflex amplitude, and percent change in F-wave persistence via linear mixed effect models with condition (control, burst sPNS) as a fixed effect and participants as a random effect. To examine the effect of burst sPNS on the M-max for each muscle, we also compared the M-max amplitudes via a linear mixed effect model with condition (control, burst sPNS) and time (Pre, Post) as fixed effects and participants as random effects. RESULTS Maximal M-waves (M-max): The maximal M-wave amplitudes for the FCR muscle did not significantly affect time (F = 0.42, p = 0.52) or condition (F = 0.042, p =0.83). Similarly, the maximal M-wave amplitudes for the FDI muscle did not significantly affect time (F = 0.45, p =0.51) or condition (F = 2.50, p =0.18). These findings suggest that the Mmax did not differ due to burst sPNS or the control conditions for both the FDI and FCR muscles. Motor evoked potentials Significant effects of condition (F = 10.38, p = 0.002), muscle (F = 16.37, p < 0.001), and the interaction between condition and muscle (F = 38.02, p < 0.001) were observed for the percent change in MEP amplitudes for the FDI and FCR muscles. Post hoc analyses revealed that the percent change in MEPs increased for the FDI muscle due to burst sPNS compared with the control condition (137.4 ± 39.8% for burst sPNS vs 97.6 ± 15.9% for the control; p < 0.001; Fig 2D). However, there was no difference in MEPs for the FCR muscle due to burst sPNS compared with the control condition (94.2 ± 21.6% for burst sPNS vs 106.5 ± 30.8% for the control; p = 0.26; Fig 2E). This suggests that burst sPNS had a focal increase in MEP amplitude on the FDI muscle but not on the FCR muscle. Furthermore, the increase in MEP amplitudes following burst sPNS suggests an increase in corticospinal excitability in the FDI due to burst sPNS. F-waves A significant effect of condition (F = 12.7, p = 0.008) was observed for the percent change in F-wave amplitudes for the FDI muscle. Post hoc analysis revealed an increase in the F-wave amplitude following burst sPNS compared with the control condition (120.1 ± 17.1 for burst sPNS vs 103.2 ± 16.84 for control; p = 0.008). However, no significant effect of condition (F = 2.74, p = 0.13) was observed for the percent change in F-wave persistence for the FDI muscle (Fig 3). This suggests that burst sPNS increased motoneuronal excitability but did not impact the persistence of the F wave between the two conditions. H-reflex No significant effect of condition (F = 1.15, p = 0.332) was observed for the percent change in H-reflex amplitudes for the FCR muscle, suggesting that burst sPNS did not modulate the spinal excitability of the FCR muscle (Fig 3). DISCUSSION The aim of the present study was to examine the effects of burst sPNS on corticospinal and spinal excitability and whether these effects were focused on the muscle innervated by the stimulated nerve. Our findings revealed that burst sPNS uniquely increased corticospinal and spinal excitability in the muscle distal to the stimulation site but had no significant effect on the muscle proximal to it. Specifically, we observed that MEPs and F-wave amplitudes increased for the FDI (distal muscle), but neither MEPs nor H-reflex amplitudes were modulated for the FCR (proximal muscle) muscle following burst sPNS. In this study, we demonstrated that burst-modulated subthreshold stimulation can increase MEPs and F-waves, suggesting that burst delivery may mimic or amplify proprioceptive engagement typically associated with contraction, possibly by more effectively synchronizing afferent volleys and modulating corticospinal and spinal excitability in the targeted muscle. It is well documented that the PNS, which is agnostic of stimulation parameters, modulates CS excitability for the muscle innervated by the stimulated nerve in the upper limb ( 20 , 27 – 29 ). Our findings corroborate the hypothesis of region-specific effects due to PNS. The differences observed between the FDI and FCR muscles indicate that afferent volleys elicited by burst sPNS predominantly modulate the neural pathways of muscles distal to the site of the stimulated nerves, underscoring its potential for precise motor rehabilitation. However, to our knowledge, this is the first study showing that burst sPNS, where bursts of high-frequency stimulation are delivered, increases corticospinal and spinal excitability in the target muscle. Corticospinal excitability with burst sPNS Several studies have demonstrated that the PNS modulates CS excitability ( 18 ). This modulation has been attributed to changes in the somatosensory cortex and consequently in the motor cortex due to the direct somatotopically organized corticocortical connections between the somatosensory and motor cortices ( 18 ). Similarly, the observed increase in corticospinal excitability in the FDI muscle following burst sPNS can be attributed to the repetitive activation of afferent pathways from the ulnar nerve-innervated muscles distal to the stimulation site, producing convergent input to the sensorimotor cortex. Furthermore, the findings from this study further extend the knowledge by showing that burst timing, even in the absence of overt muscle contraction, can facilitate excitability—echoing findings from Ishibashi et al. ( 13 ). who reported that intermittent (burst) PNS increased MEPs, whereas continuous PNS of equivalent intensity and frequency decreased them. This finding suggests that the temporal structure of afferent input plays a critical role in facilitating plasticity mechanisms, potentially through Hebbian-like processes, where afferent input strengthens corticospinal connections specific to the FDI. In support of this, previous studies in animal models ( 17 ) and humans ( 30 , 31 ) have demonstrated the role of afferent stimulation in reorganizing cortical circuits and increasing motor cortical excitability. Functional imaging studies corroborate our findings, showing that sPNS enhances cortical excitability in both healthy individuals ( 31 ) and stroke patients with corticospinal tract damage ( 32 ). sPNS increases the signal intensity and the number of activated voxels in the primary motor cortex (M1) during motor tasks, as observed through blood oxygen level-dependent (BOLD)-based fMRI. Additionally, arterial spin labeling revealed increased perfusion in M1 at rest following sPNS in healthy individuals, likely driven by increased neuronal activity and associated blood flow ( 33 ). Together, these findings reinforce the hypothesis that burst sPNS promotes plastic changes in sensorimotor cortical circuits, underscoring the ability of burst sPNS to support motor function improvement. Spinal excitability with burst sPNS Our observation of increased F-wave amplitude without changes in M-max or H-reflex amplitude supports the interpretation that burst sPNS enhances spinal motoneuron excitability, particularly at the postsynaptic level. In our findings, M-max did not change due to burst sPNS, which is consistent with previous findings ( 11 , 13 ). Many prior studies using tonic or continuous PNS protocols failed to show spinal changes ( 10 , 34 ). Studies that used intermittent mPNS ( 11 , 13 ), where twitches were observed in the target muscle during stimulation (above motor threshold intensity), were stimulated with a 30 Hz frequency and a narrow pulse width of 0.2 ms. In the present study, we used a higher carrier frequency (100 Hz), which was demodulated to a much lower frequency (5 Hz), delivered at an intensity set below the motor threshold, with a wide pulse width of 0.8 ms. Similar to our PNS protocol, Vitry et al. used a wide pulse (1 ms) stimulation at 100 Hz and demonstrated increases in thoracic-evoked MEPs ( 19 ). A narrow pulse width has been shown to predominantly facilitate direct peripheral motor recruitment with less contribution through central mechanisms. In contrast, a wider pulse width preferentially engages proprioceptive and large-diameter cutaneous afferents, which may more effectively influence central circuits and evoke motor recruitment with relatively greater central pathways ( 35 ). This could explain the disparity in the results of spinal excitability. Modulation of spinal excitability at rest can be achieved through either presynaptic inhibitory mechanisms or changes in the intrinsic properties of motoneurons ( 36 – 38 ). An increase in the spinal excitability of the FDI muscle can include compensatory mechanisms at the presynaptic and/or postsynaptic levels that compensate for the inhibitory effect of repetitive afferent stimulation. At the presynaptic level, a potential reduction in the sensitivity of Ia afferents to presynaptic inhibition can be proposed as a possible mechanism. In an anesthetized cat, repetitive high-frequency activation of Ia afferents leads to increased calcium accumulation in Ia terminals and consequently an increased probability of neurotransmitter release ( 39 ), which lasts up to several minutes following sustained high-frequency stimulation ( 40 ). At the postsynaptic level, changes in intrinsic motoneuron properties can explain the increased spinal excitability at rest, as observed following burst sPNS. Persistent inward current (PIC) activation is a plausible mechanism, as it is sensitive to neuromodulatory inputs originating from the brainstem’s caudal raphe nucleus and locus coeruleus ( 41 ). These brainstem regions respond to electrical stimulation applied to a nerve ( 42 ), suggesting that the volleys from the burst sPNS may reach the brainstem and regulate descending neuromodulatory input. When the raphe spinal pathway is stimulated, the synaptic release of serotonin on dendritic and somatic 5-HT2 receptors promotes Ca + 2 PICs ( 43 ). Hence, these presynaptic and/or postsynaptic mechanisms may contribute to changes in spinal excitability. Clinical and mechanistic implications Together, these findings support the use of burst sPNS as a targeted, noninvasive strategy for priming corticospinal and spinal circuits. In contrast to conventional TENS or continuous sPNS, burst-modulated protocols offer a temporally structured afferent signal that may better mimic natural sensory input and avoid habituation. Similarly, previous studies by Jadidi et al. ( 44 ) reported that burst and PWM-modulated TENS enhanced motor cortical excitability, suggesting that patterned stimulation protocols may induce more robust and spatially selective plasticity than traditional methods. Given the focal effects observed in the FDI muscle and the lack of change in the FCR muscle, our results highlight the spatial specificity of burst sPNS, which may be a valuable characteristic for applications in stroke, spinal cord injury, and movement disorders where regional modulation is essential. Furthermore, the ability to increase excitability without requiring volitional effort or overt contraction opens doors for early intervention in severely impaired individuals. Future work Earlier investigations utilized a diverse range of stimulation parameters, including variations in intensity, frequency, pulse widths, patterns, and electrode placement. While many studies have focused predominantly on either spinal or corticospinal circuits [e.g., ( 34 , 44 )], recent investigations have evaluated both corticospinal and spinal circuits together, emphasizing the need for a deeper exploration of these mechanisms ( 19 , 45 ). While burst sPNS enhances both corticospinal and spinal excitability through potentially distinct yet complementary mechanisms, the relative contributions of these pathways cannot be distinguished from the current experimental design. Future studies should be structured to specifically isolate and quantify the contribution of each site to the resulting increase in motor output. A clear understanding of these contributions could inform the development of targeted rehabilitation strategies for neurological disorders involving dysfunction in corticospinal or spinal pathways. Longitudinal studies are also needed to determine whether these acute excitability changes translate into sustained functional improvements when paired with training. Additionally, optimizing burst parameters (e.g., carrier frequency, burst duration, duty cycle) is crucial for clinical translation. CONCLUSION Our findings underscore the potential of burst sPNS as a non-invasive and adaptable tool for enhancing motor recovery in neurological disorders. By increasing both corticospinal and spinal excitability, burst sPNS could serve as a “priming” technique and may support functional improvements when combined with physical therapy, personalized neuromodulation, or diagnostic applications. This innovative approach not only offers a promising avenue for motor rehabilitation but also paves the way for its application in performance enhancement and broader neuromodulatory strategies. Abbreviations PNS: Peripheral nerve stimulation mPNS: Motor PNS sPNS: Sensory PNS CS: corticospinal FDI: First Dorsal Interosseous FCR: Flexor carpi radialis TMS: Transcranial magnetic stimulation MEPs: Motor-evoked potentials rMT: resting Motor threshold M-max: Maximal M-waves BOLD: Blood oxygen level-dependent Declarations Ethics approval and consent to participate: Written informed consent was obtained from all the participants before testing. The study was approved by the Northwestern University IRB committee (IRB: STU00211930), and all methods conformed to the standards of the Declaration of Helsinki (2004). Consent for publication: Not applicable Availability of data and materials: Raw data were generated at the Legs + Walking Lab at Shirley Ryan Abilitylab. Derived data supporting the findings of this study are available from the corresponding author (JLP) upon request. Competing interests: All the authors (NMK, HH, XSY, and JLP) declare that they have no competing interests. Funding : This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Authors’ contributions: Conceptualization: NMK, JLP; Data curation: NMK, HH, XSY; Formal analysis: NMK, HH; Funding acquisition: JLP; Investigation: NMK, HH, XSY, JLP; Methodology: NMK, HH; Project administration: NMK, JLP; Resources: JLP; Software: NMK; Supervision: JLP; Validation: NMK, HH; Visualization: NMK, HH; Writing - original draft: NMK, HH; Writing – review and editing: NMK, HH, XSY, JLP. Acknowledgments : The authors would like to thank Grace W. Hoo for helping with subject enrollment and study management. References Vance CG, Dailey DL, Rakel BA, Sluka KA. Using TENS for pain control: the state of the evidence. 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Mang CS, Clair JM, Collins DF. Neuromuscular electrical stimulation has a global effect on corticospinal excitability for leg muscles and a focused effect for hand muscles. Exp Brain Res. 2011;209(3):355-63. Lagerquist O, Zehr EP, Baldwin ER, Klakowicz PM, Collins DF. Diurnal changes in the amplitude of the Hoffmann reflex in the human soleus but not in the flexor carpi radialis muscle. Experimental brain research. 2006;170:1-6. Walton C, Kalmar J, Cafarelli E. Caffeine increases spinal excitability in humans. Muscle & Nerve: Official Journal of the American Association of Electrodiagnostic Medicine. 2003;28(3):359-64. Rossini PM, Barker A, Berardelli A, Caramia M, Caruso G, Cracco R, et al. Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application. Report of an IFCN committee. Electroencephalography and clinical neurophysiology. 1994;91(2):79-92. Vastano R, Perez MA. Changes in motoneuron excitability during voluntary muscle activity in humans with spinal cord injury. J Neurophysiol. 2020;123(2):454-61. Pascual-Valdunciel A, Kurukuti NM, Montero-Pardo C, Barroso FO, Pons JL. Modulation of spinal circuits following phase-dependent electrical stimulation of afferent pathways. J Neural Eng. 2023;20(1). Kurukuti NM, Avrillon S, Pons JL. A session of transcutaneous electrical nerve stimulation changes the input-output function of motoneurons and alters the sense of force. Journal of Neurophysiology.0(0):null. Ridding MC, McKay DR, Thompson PD, Miles TS. Changes in corticomotor representations induced by prolonged peripheral nerve stimulation in humans. Clin Neurophysiol. 2001;112(8):1461-9. Ridding M, Brouwer B, Miles T, Pitcher J, Thompson P. Changes in muscle responses to stimulation of the motor cortex induced by peripheral nerve stimulation in human subjects. Experimental brain research. 2000;131:135-43. Kaelin‐Lang A, Luft AR, Sawaki L, Burstein AH, Sohn YH, Cohen LG. Modulation of human corticomotor excitability by somatosensory input. The Journal of physiology. 2002;540(2):623-33. Ridding M, Rothwell J. Reorganisation in human motor cortex. Canadian journal of physiology and pharmacology. 1995;73(2):218-22. Hamdy S, Rothwell JC, Aziz Q, Singh KD, Thompson DG. Long-term reorganization of human motor cortex driven by short-term sensory stimulation. Nature Neuroscience. 1998;1(1):64-8. Grefkes C, Nowak DA, Eickhoff SB, Dafotakis M, Küst J, Karbe H, et al. Cortical connectivity after subcortical stroke assessed with functional magnetic resonance imaging. Annals of neurology. 2008;63(2):236-46. Wu T, Hallett M. A functional MRI study of automatic movements in patients with Parkinson's disease. Brain. 2005;128(10):2250-9. Mang CS, Lagerquist O, Collins DF. Changes in corticospinal excitability evoked by common peroneal nerve stimulation depend on stimulation frequency. Exp Brain Res. 2010;203(1):11-20. Lagerquist O, Collins DF. Influence of stimulus pulse width on M-waves, H-reflexes, and torque during tetanic low-intensity neuromuscular stimulation. Muscle & Nerve. 2010;42(6):886-93. Hultborn H, Meunier S, Morin C, Pierrot‐Deseilligny E. Assessing changes in presynaptic inhibition of I a fibres: a study in man and the cat. The Journal of physiology. 1987;389(1):729-56. Rudomin P. Selectivity of presynaptic inhibition: a mechanism for independent control of information flow through individual collaterals of single muscle spindle afferents. Progress in Brain Research. 1999;123:109-17. Pierrot-Deseilligny E, Burke D. The circuitry of the human spinal cord: its role in motor control and movement disorders: Cambridge university press; 2005. Enriquez-Denton M, Morita H, Christensen L, Petersen N, Sinkjaer T, Nielsen J. Interaction between peripheral afferent activity and presynaptic inhibition of Ia afferents in the cat. Journal of neurophysiology. 2002;88(4):1664-74. Best AR, Regehr WG. Inhibitory regulation of electrically coupled neurons in the inferior olive is mediated by asynchronous release of GABA. Neuron. 2009;62(4):555-65. Heckman C, Mottram C, Quinlan K, Theiss R, Schuster J. Motoneuron excitability: the importance of neuromodulatory inputs. Clinical Neurophysiology. 2009;120(12):2040-54. Moolenaar G-M, Holloway JA, Trouth C. Responses of caudal raphe neurons to peripheral somatic stimulation. Experimental neurology. 1976;53(2):304-13. Perrier J-F. Modulation of motoneuron activity by serotonin. Curr Pharm Des. 2013;19:4371-84. Jadidi AF, Stevenson AJT, Zarei AA, Jensen W, Lontis R. Effect of modulated TENS on corticospinal excitability in healthy subjects. Neuroscience. 2022;485:53-64. Eginyan G, Zhou X, Williams AM, Lam T. Effects of motor stimulation of the tibial nerve on corticospinal excitability of abductor hallucis and pelvic floor muscles. Frontiers in Rehabilitation Sciences. 2023;3:1089223. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6728178","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":461791728,"identity":"843a3de8-a2d7-4bce-b82b-672832a0cb79","order_by":0,"name":"Nish Mohith Kurukuti","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7UlEQVRIiWNgGAWjYDACZgY2BoYDQAYPECdUgESYG4jWwtiQcAYkwkhACwOyFsY2kAABLebs7M8eMJw5nG9w5oz5g4fzaqP524FaflRsw6nFspnH3IDhxmHLDWd7DBsStx3PnXEYaFvPmds4tRgc5mGTYPhw2MDgPA9Iy7HcBqAWZsY2fFrYnyFpmXMsdz5hLQxmEkCHGRiAHdZQk7uBsBYeM4mEM+kGkmeOFc5IOHYgdyNQy0G8fjl//JnEh2PWBnxnkjd8/FFTlzvv/OGDD35U4NYCBgkI5mEweQC/elRQR4riUTAKRsEoGCEAAKJ4X2/fZfG/AAAAAElFTkSuQmCC","orcid":"","institution":"Department of Biomedical Engineering, McCromick School of Engineering, Northwestern University","correspondingAuthor":true,"prefix":"","firstName":"Nish","middleName":"Mohith","lastName":"Kurukuti","suffix":""},{"id":461791729,"identity":"28811b72-2622-4204-b26f-80e504075701","order_by":1,"name":"Hamidollah Hassanlouei","email":"","orcid":"","institution":"Legs + Walking lab, Shirley Ryan Abilitylab","correspondingAuthor":false,"prefix":"","firstName":"Hamidollah","middleName":"","lastName":"Hassanlouei","suffix":""},{"id":461791730,"identity":"834b8db4-4b38-4e35-bce9-23edb542bc1a","order_by":2,"name":"Xin Sienna Yu","email":"","orcid":"","institution":"Legs + Walking lab, Shirley Ryan Abilitylab","correspondingAuthor":false,"prefix":"","firstName":"Xin","middleName":"Sienna","lastName":"Yu","suffix":""},{"id":461791731,"identity":"da74b48a-8053-411c-99a6-2f955b02ad96","order_by":3,"name":"Jose Louis Pons","email":"","orcid":"","institution":"Legs + Walking lab, Shirley Ryan Abilitylab","correspondingAuthor":false,"prefix":"","firstName":"Jose","middleName":"Louis","lastName":"Pons","suffix":""}],"badges":[],"createdAt":"2025-05-23 00:23:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6728178/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6728178/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":83596330,"identity":"d0d9451e-a498-4e10-928e-d30768482378","added_by":"auto","created_at":"2025-05-29 07:58:23","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":74859,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eExperimental paradigm\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e. The participants underwent two experimental visits, one with burst sPNS and the other with control stimulation. The order of experimental visits was randomized across participants. In the setup session, the cortical hotspots for eliciting motor-evoked potentials (MEPs) and the resting motor thresholds for the FDI and FCR muscles were determined. The Hreflex-Mwave curve was also mapped during the setup session to determine the H-max and M-max for the FCR and FDI muscles. Electrophysiological outcomes such as the MEP input‒output curve (FDI and FCR), H-reflex (FCR), F-wave (FDI), and M-max (FDI and FCR) were measured before (Pre) and after (Post) the intervention session (burst sPNS or control). The intervention session lasted for 40 minutes.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6728178/v1/ab85434bb703309fd2e6f001.png"},{"id":83596335,"identity":"4b8ba0bf-d25a-43d4-9b3a-4d87729765f1","added_by":"auto","created_at":"2025-05-29 07:58:23","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":308694,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eCorticospinal excitability\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e. (A) MEPs were evoked in the FDI and FCR muscles in the dominant hand via TMS targeting the hotspots for the respective muscles from the contralateral cerebral cortex. Once the resting motor threshold (RMT) was determined for each muscle (FDI and FCR), six intensities from 90% - 140% of the RMT were recorded before and after the bust sPNS or control condition. The burst sPNS was delivered to the nerve at the wrist, with the anodes on the radial and median nerves and a common cathode on the ulnar nerve. The peak-to-peak amplitude was quantified to compute the MEPs at each intensity to map the input‒output curve of the MEP. An example of a participant’s MEP responses at various intensities tested and the input‒output curve is shown in B and C. Changes in MEP amplitude werequantified via the average MEP amplitude from the PRE and POST sessions to evaluate the impact of burst sPNS compared with the control (no stimulation) condition. The change in MEP amplitude increased for the FDI muscle (D) following burst sPNS compared with the control condition across all intensities. However, no differences were observed in the MEP amplitudes for the FCR muscle (E) due to burst sPNS. The scale bars shown represent the means, and the error bars indicate SDs; *P \u0026lt; 0.05.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6728178/v1/64d9b07c84646f48848f6483.png"},{"id":83596333,"identity":"5a6f064c-e1f4-48af-a463-debb830b4b4f","added_by":"auto","created_at":"2025-05-29 07:58:23","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":128614,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eSpinal excitability at the FDI muscle\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e. Spinal excitability at the FDI muscle was measured through F-waves by stimulating the ulnar nerve at 150% of the M-max (A). An example of the change in the F-wave due to burst sPNS is illustrated (A, bottom panel). Changes in F-wave amplitude (B) and F-wave persistence (the ratio of trials that evoked F-waves to total trials, C) were quantified across the interventions. The percentage change in F-wave amplitude increased due to burst sPNS compared with the control condition, but no difference was observed in F-wave persistence. The scale bars shown represent the means, and the error bars indicate SDs; *P \u0026lt; 0.05.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6728178/v1/b897634a9bc38ac4714e67f4.png"},{"id":83596336,"identity":"801a615c-c834-4de5-9b94-c3b8c61e296f","added_by":"auto","created_at":"2025-05-29 07:58:23","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":134634,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eSpinal excitability at the FCR muscle\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e. H-reflexes were evoked from the FCR muscle by stimulating the median nerve near the elbow (A). An example of a change in the H-reflex due to burst sPNS is illustrated (B). The percentage change in the H-reflex did not significantly differ between the burst sPNS condition and the control condition (C). The scale bars shown represent the means, and the error bars indicate the SDs.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6728178/v1/f1671df4d13709d64a32394a.png"},{"id":83597707,"identity":"de2c210f-1d6c-47da-885a-efe7e210de08","added_by":"auto","created_at":"2025-05-29 08:22:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1259309,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6728178/v1/d7e4421a-3adf-4175-8cea-291cf1883ca9.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Somatosensory burst peripheral nerve stimulation focally upregulates corticospinal and spinal excitability in the upper limb: a randomized crossover pilot study","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003ePeripheral nerve stimulation (PNS) is a common rehabilitation technique widely used to enhance motor function by modulating neuronal excitability. Clinically, it is employed to alleviate chronic pain symptoms (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e), enhance somatosensory input to improve motor recovery in stroke (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) and spinal cord injury (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e), and suppress tremors in movement disorders (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). PNS provides differential effects depending on the stimulation parameters. The two common parameters that vary in the clinical setting are the frequency and intensity of stimulation. The motor PNS (mPNS), which is delivered above the motor threshold to evoke extra torque/force, has been used to augment motor rehabilitation and/or assist in generating functional movements (gait) in individuals with stroke and incomplete spinal cord injury (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Alternatively, sensory PNS (sPNS), with a stimulation intensity below the sensory threshold, when delivered at high frequencies (\u0026gt;\u0026thinsp;90 Hz), is used for suppressing pain (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) and tremor (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e), whereas at low frequencies (\u0026lt;\u0026thinsp;30 Hz) in combination with target-oriented training, it is used for rehabilitating hand function in stroke (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eMechanistically, the PNS evokes artificial volleys that propagate orthodromically and antidromically along the recruited afferent and/or efferent fibers. Orthodromic afferent volleys travel to the spinal cord and brain, where they modulate corticospinal (CS) excitability. This modulation has been shown to persist for up to 2 hours post-stimulation (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Studies using transcranial magnetic stimulation (TMS) have shown that modulation of motor evoked potentials (MEPs), a measure of CS excitability, is dependent on PNS parameters such as frequency (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e), intensity (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e), duration (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e), and even the pattern or waveform of delivery (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Recently, interest in temporally patterned sPNS to improve the effectiveness of sPNS in rehabilitation has increased. Burst sPNS, where high-frequency carrier pulses are demodulated to low-frequency bursts, has shown promise in suppressing symptoms such as pain (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) and tremors (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). However, the impact of such burst-modulated sPNS on CS and spinal excitability remains largely unexplored, despite evidence suggesting that the pattern of stimulation delivery plays a critical role in neuroplasticity.\u003c/p\u003e \u003cp\u003eEmerging data suggest that the temporal structure of afferent input, not just the total pulse count or intensity, can shape neurophysiological outcomes. In a recent study, Ishibashi et al. (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) reported that intermittent (burst-like) sPNS increased MEP amplitudes\u0026mdash;an indicator of enhanced corticospinal excitability\u0026mdash;whereas continuous sPNS at the same frequency and duration decreased excitability. This underscores the unique neuroplastic potential of burst-patterned input, potentially owing to its resemblance to natural afferent firing patterns and its ability to prevent synaptic fatigue. Understanding how this specific PNS protocol of burst sPNS affects CS and spinal excitability could have significant clinical implications, potentially enhancing rehabilitation strategies.\u003c/p\u003e \u003cp\u003eModulation of MEP amplitudes has been largely attributed to changes in cortical excitability (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Following short-term (1\u0026ndash;2 h) high-frequency PNS, somatosensory cortical representation of the muscles innervated by the stimulated nerve increases (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Similar increases in corticomotor representation in the motor cortex following high-frequency PNS have also been reported. Imaging studies have also shown that the PNS induces cortical and subcortical excitability changes in sensorimotor regions (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). These findings highlight the importance of proprioceptive afferent engagement in modulating sensorimotor circuits. However, the involvement of spinal mechanisms in modulating CS excitability remains unclear. While studies using H-reflex and F-waves have shown no changes in spinal excitability following PNS (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e), recent findings suggest an increase in spinal excitability following high-frequency PNS when it is delivered with wide pulse widths (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). These inconsistencies regarding the effects of the PNS on spinal excitability highlight the need for further research.\u003c/p\u003e \u003cp\u003eIn this study, we investigated the effect of burst sPNS using a wide pulse width targeting the median, radial and ulnar nerves at the wrist and compared it to that of a control condition (no stimulation) by examining CS and spinal excitability in the first dorsal interosseous (FDI) and flexor carpi radialis (FCR) muscles. We hypothesized that MEPs are evoked by TMS over the motor cortex and that the F-wave amplitude evoked by ulnar nerve stimulation increases after burst sPNS in the FDI. We also hypothesized that the increase in corticospinal and spinal excitability would only be present in the FDI but not in the FCR muscle because of the focal effect of burst sPNS (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). By evaluating these expected changes, we aim to contribute to the growing body of knowledge on how afferent volleys generated during burst sPNS alter CS and spinal excitability in humans, which could inform the development of more effective rehabilitation protocols.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003e\u003cstrong\u003eParticipants\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTen healthy adults (mean age: 33.7 \u0026plusmn; 13.0 years; 5 females) volunteered to participate in this randomized crossover study. The participants did not have a history of neuromuscular disorders, sensory deficits, or previous upper limb surgery. Written informed consent was obtained from all participants before testing. The study was approved by the Northwestern University IRB committee (IRB: STU00211930), and all methods conformed to the standards of the Declaration of Helsinki (2004). All the subjects participated in 2 separate ~3-h testing visits at least 72 h apart in which burst sPNS was applied to the median, radial and ulnar nerves at one visit and no stimulation (control) at the other visit. The order of the visits was randomized for each participant through block randomization. The random allocation sequence based on participant IDs was generated via R. The time of day of each session was the same for each subject to reduce the potential confounding effect of diurnal changes in CNS excitability (21). The subjects were instructed to avoid the consumption of caffeine 12 h prior to the testing sessions and during a session to eliminate its influence on CNS excitability (22) and to refrain from intense physical activity 12 h prior to the testing sessions. Following the first visit, participants had a 3-day washout period before participating in the second visit.\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMotor\u003c/strong\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003cstrong\u003eevoked potentials and\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003erecruitment\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;curves\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMotor-evoked potentials (MEPs) were recorded from the FDI and FCR muscles via surface electrodes on the dominant arm. The EMG signal was pre-amplified and digitized at 2048 Hz. Relaxation was defined as EMG activity at baseline \u0026lt; 20 \u0026micro;V peak-to-peak amplitude for at least 1 s. During the setup, the optimal scalp positions (contralateral motor cortex to the dominant hand) to elicit reliable MEPs (at least 5 out of 10 attempts) for the FDI and FCR muscles were mapped. For the remainder of the visit, TMS was delivered to the determined optimal scalp positions to stimulate the FDI and FCR muscles. TMS was delivered through a figure-of-eight shaped magnetic coil (outside diameter of 8.7 cm) connected to a MagPro X100 stimulator (MagVenture, Denmark). The magnetic coil was placed tangentially to the scalp, with the intersection of both wings at a 45 deg angle with the midline to optimally stimulate the motor cortex (Brasil-Neto et al. 1992; Mills et al. 1992). The stimulation location was marked on a TMS cap secured on the participant\u0026rsquo;s head to ensure the repeatability of coil placement throughout the experiment.\u003c/p\u003e\n\u003cp\u003eAlong with mapping the optimal scalp position, the resting motor threshold (rMT), defined as the minimum TMS intensity (measured to the nearest 1% of the maximum output of the magnetic stimulator) required to elicit at least five out of ten MEPs \u0026ge; 50 \u0026micro;V in consecutive trials (23), was also determined for the FDI and FCR muscles. For the remainder of the visit, TMS was delivered at intensities expressed relative to the rMT measured from the muscles. The mean MEP amplitudes were obtained in response to 10 TMS stimuli delivered at each of six stimulus intensities: 90%, 100%, 110%, 120%, 130% and 140% of the rMT for each muscle, with the order of intensities randomized.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMaximal M-waves (M-max)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo determine M-max for the FDI and FCR muscles, the stimulation intensity was increased over several stimuli from below the motor threshold to 1.5\u0026ndash;2 times the minimum current required to evoke M-max (20). M-max was calculated as the largest M-wave evoked in the muscles of 3 trials. The amplitude of M-max from each muscle was tested on two occasions: before and after delivery of the burst sPNS or in the control condition.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eF-waves\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eF-waves were evoked to examine motor neuron excitability for the FDI muscle by using supramaximal stimulus intensity to the ulnar nerve (200-\u0026mu;s pulse duration; DS5; Digitimer). Sixty stimuli were delivered at 1 Hz at an intensity of 150% of the M-max (24). For each stimulus, the peak-to-peak amplitude and persistence (i.e., the percentage of stimuli evoking a response) of the F-waves were measured. F-wave trials were filtered via a second-order Bessel high-pass filter (200 Hz) to \u0026ldquo;flatten the tail of the M-wave\u0026rdquo; (25). An F wave was considered to be present if a response with a proper latency (minimum of 30 ms after the stimulus artifact) had an amplitude \u0026gt;=20 \u0026micro;V.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eH-reflex\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eH-reflexes were elicited to examine spinal excitability for the FCR muscle by stimulating the median nerve (1-ms pulse duration; DS5; Digitimer) near the elbow. The response was identified as an H-reflex if it had a latency between 12 and 25 ms. The intensity to elicit H-max was determined by systematically increasing the intensity and quantifying the H-reflex and M-wave amplitudes (H-M curve). The intensity at which the amplitude of the H-reflex was the maximum with the minimal M-wave was considered the H-max intensity (25). Ten stimuli were delivered approximately 5 seconds apart at the H-max intensity to record the H-reflex at H-max. For each stimulus, the peak-to-peak amplitude of the H-reflex was measured.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBurst sPNS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring the experimental session with burst sPNS, electrical stimuli were delivered to the nerves at the wrist. A bipolar constant current stimulator (Digitimer DS5, Digitimer, UK) was used along with conductive surface electrodes (2 cm diameter; Axelgaard, Denmark) to deliver electrical current. Two anodes were placed over the median nerve at the flexor retinaculum of the palmar side and over the radial nerve at the distal radius of the wrist. A common cathode was placed over the distal end of the ulna. Burst sPNS involves trains of rectangular biphasic wave pulses with 800 \u0026micro;s duration at a carrier frequency of 100 Hz, which are applied at 5 Hz (100 ms on and then switched off for 100 ms) and delivered for 40 minutes. The stimulus intensity was adjusted to not evoke a visible contraction from the hand muscles while providing paresthesia but not being painful or uncomfortable. This low-intensity stimulation and the stimulus duration preferentially activate large cutaneous and proprioceptive sensory fibers (26). The participants were instructed to refrain from moving the stimulated arm during the administration of burst sPNS.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eanalysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eChanges in CS excitability induced by burst sPNS were determined by quantifying and comparing the group averages of the 10 MEPs evoked before and after burst sPNS or the control condition. To ensure that all MEPs were obtained at rest, MEP data were inspected post hoc and discarded if the EMG during the 1 s before the TMS exceeded 2 standard deviations of the average baseline signal recorded at rest before the stimulation. Of the 2,350 MEPs evoked from 10 subjects, 19 MEPs (~1% of the total responses) were removed from the analyses on the basis of this criterion. To compare the change in CS excitability, the average MEP amplitude from 10 trials in post assessments for each muscle was normalized to the average MEP amplitude in the pre assessments via Equation (1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eChanges in spinal excitability induced by burst sPNS were determined by quantifying and comparing the average peak-to-peak amplitude of the F-waves evoked in the 60 trials and the H-reflex from the 10 trials before and after the burst sPNS or control condition. The percentage occurrence of the F-waves was also computed before and after the burst sPNS or control condition. To compare the changes in spinal excitability, the percent changes in the average peak-to-peak amplitudes of the F-wave, H-reflex, and F-wave persistence were computed via Equation (1).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePercent change = (Post/Pre) * 100 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Eq 1\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the statistical analyses were performed with R. The normality of the data distribution was checked via quantile‒quantile plots and histograms. Analyses were performed via linear mixed effect models implemented in the \u003cem\u003elme4\u003c/em\u003e function with the Kenward-Roger method to estimate the denominator degrees of freedom and the p values. This method considers the dependence of data points within each participant and accounts for them. When necessary, multiple comparisons were performed via the package \u003cem\u003eemmeans\u003c/em\u003e, which adjusts the p value for multiple comparisons via the Tukey method. The significance level was set at p = 0.05. The values are reported as the means \u0026plusmn; standard deviations.\u003c/p\u003e\n\u003cp\u003eTo evaluate the effect of burst sPNS on CS excitability across muscles, percent changes in MEPs for the FDI and FCR were compared via linear mixed effect models with muscle (FDI, FCR) and condition (control, burst sPNS) as fixed effects and participants as random effects. To evaluate the effect of burst sPNS on spinal excitability, we compared the percent change in F-wave amplitude, percent change in H-reflex amplitude, and percent change in F-wave persistence via linear mixed effect models with condition (control, burst sPNS) as a fixed effect and participants as a random effect. To examine the effect of burst sPNS on the M-max for each muscle, we also compared the M-max amplitudes via a linear mixed effect model with condition (control, burst sPNS) and time (Pre, Post) as fixed effects and participants as random effects.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003eMaximal M-waves (M-max):\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe maximal M-wave amplitudes for the FCR muscle did not significantly affect time (F = 0.42, p = 0.52) or condition (F = 0.042, p =0.83). Similarly, the maximal M-wave amplitudes for the FDI muscle did not significantly affect time (F = 0.45, p =0.51) or condition (F = 2.50, p =0.18). These findings suggest that the Mmax did not differ due to burst sPNS or the control conditions for both the FDI and FCR muscles.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMotor evoked potentials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSignificant effects of condition (F = 10.38, p = 0.002), muscle (F = 16.37, p \u0026lt; 0.001), and the interaction between condition and muscle (F = 38.02, p \u0026lt; 0.001) were observed for the percent change in MEP amplitudes for the FDI and FCR muscles. Post hoc analyses revealed that the percent change in MEPs increased for the FDI muscle due to burst sPNS compared with the control condition (137.4 \u0026plusmn; 39.8% for burst sPNS vs 97.6 \u0026plusmn; 15.9% for the control; p \u0026lt; 0.001; Fig 2D). However, there was no difference in MEPs for the FCR muscle due to burst sPNS compared with the control condition (94.2 \u0026plusmn; 21.6% for burst sPNS vs 106.5 \u0026plusmn; 30.8% for the control; p = 0.26; Fig 2E). This suggests that burst sPNS had a focal increase in MEP amplitude on the FDI muscle but not on the FCR muscle. Furthermore, the increase in MEP amplitudes following burst sPNS suggests an increase in corticospinal excitability in the FDI due to burst sPNS.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eF-waves\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA significant effect of condition (F = 12.7, p = 0.008) was observed for the percent change in F-wave amplitudes for the FDI muscle. Post hoc analysis revealed an increase in the F-wave amplitude following burst sPNS compared with the control condition (120.1 \u0026plusmn; 17.1 for burst sPNS vs 103.2 \u0026plusmn; 16.84 for control; p = 0.008). However, no significant effect of condition (F = 2.74, p = 0.13) was observed for the percent change in F-wave persistence for the FDI muscle (Fig 3). This suggests that burst sPNS increased motoneuronal excitability but did not impact the persistence of the F wave between the two conditions.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eH-reflex\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo significant effect of condition (F = 1.15, p = 0.332) was observed for the percent change in H-reflex amplitudes for the FCR muscle, suggesting that burst sPNS did not modulate the spinal excitability of the FCR muscle (Fig 3).\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe aim of the present study was to examine the effects of burst sPNS on corticospinal and spinal excitability and whether these effects were focused on the muscle innervated by the stimulated nerve. Our findings revealed that burst sPNS uniquely increased corticospinal and spinal excitability in the muscle distal to the stimulation site but had no significant effect on the muscle proximal to it. Specifically, we observed that MEPs and F-wave amplitudes increased for the FDI (distal muscle), but neither MEPs nor H-reflex amplitudes were modulated for the FCR (proximal muscle) muscle following burst sPNS. In this study, we demonstrated that burst-modulated subthreshold stimulation can increase MEPs and F-waves, suggesting that burst delivery may mimic or amplify proprioceptive engagement typically associated with contraction, possibly by more effectively synchronizing afferent volleys and modulating corticospinal and spinal excitability in the targeted muscle.\u003c/p\u003e \u003cp\u003eIt is well documented that the PNS, which is agnostic of stimulation parameters, modulates CS excitability for the muscle innervated by the stimulated nerve in the upper limb (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). Our findings corroborate the hypothesis of region-specific effects due to PNS. The differences observed between the FDI and FCR muscles indicate that afferent volleys elicited by burst sPNS predominantly modulate the neural pathways of muscles distal to the site of the stimulated nerves, underscoring its potential for precise motor rehabilitation. However, to our knowledge, this is the first study showing that burst sPNS, where bursts of high-frequency stimulation are delivered, increases corticospinal and spinal excitability in the target muscle.\u003c/p\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eCorticospinal excitability with burst sPNS\u003c/h2\u003e \u003cp\u003eSeveral studies have demonstrated that the PNS modulates CS excitability (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). This modulation has been attributed to changes in the somatosensory cortex and consequently in the motor cortex due to the direct somatotopically organized corticocortical connections between the somatosensory and motor cortices (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Similarly, the observed increase in corticospinal excitability in the FDI muscle following burst sPNS can be attributed to the repetitive activation of afferent pathways from the ulnar nerve-innervated muscles distal to the stimulation site, producing convergent input to the sensorimotor cortex. Furthermore, the findings from this study further extend the knowledge by showing that burst timing, even in the absence of overt muscle contraction, can facilitate excitability\u0026mdash;echoing findings from Ishibashi et al. (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). who reported that intermittent (burst) PNS increased MEPs, whereas continuous PNS of equivalent intensity and frequency decreased them. This finding suggests that the temporal structure of afferent input plays a critical role in facilitating plasticity mechanisms, potentially through Hebbian-like processes, where afferent input strengthens corticospinal connections specific to the FDI. In support of this, previous studies in animal models (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) and humans (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e) have demonstrated the role of afferent stimulation in reorganizing cortical circuits and increasing motor cortical excitability.\u003c/p\u003e \u003cp\u003eFunctional imaging studies corroborate our findings, showing that sPNS enhances cortical excitability in both healthy individuals (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e) and stroke patients with corticospinal tract damage (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). sPNS increases the signal intensity and the number of activated voxels in the primary motor cortex (M1) during motor tasks, as observed through blood oxygen level-dependent (BOLD)-based fMRI. Additionally, arterial spin labeling revealed increased perfusion in M1 at rest following sPNS in healthy individuals, likely driven by increased neuronal activity and associated blood flow (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). Together, these findings reinforce the hypothesis that burst sPNS promotes plastic changes in sensorimotor cortical circuits, underscoring the ability of burst sPNS to support motor function improvement.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eSpinal excitability with burst sPNS\u003c/h2\u003e \u003cp\u003eOur observation of increased F-wave amplitude without changes in M-max or H-reflex amplitude supports the interpretation that burst sPNS enhances spinal motoneuron excitability, particularly at the postsynaptic level. In our findings, M-max did not change due to burst sPNS, which is consistent with previous findings (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Many prior studies using tonic or continuous PNS protocols failed to show spinal changes (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). Studies that used intermittent mPNS (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e), where twitches were observed in the target muscle during stimulation (above motor threshold intensity), were stimulated with a 30 Hz frequency and a narrow pulse width of 0.2 ms. In the present study, we used a higher carrier frequency (100 Hz), which was demodulated to a much lower frequency (5 Hz), delivered at an intensity set below the motor threshold, with a wide pulse width of 0.8 ms. Similar to our PNS protocol, Vitry et al. used a wide pulse (1 ms) stimulation at 100 Hz and demonstrated increases in thoracic-evoked MEPs (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). A narrow pulse width has been shown to predominantly facilitate direct peripheral motor recruitment with less contribution through central mechanisms. In contrast, a wider pulse width preferentially engages proprioceptive and large-diameter cutaneous afferents, which may more effectively influence central circuits and evoke motor recruitment with relatively greater central pathways (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). This could explain the disparity in the results of spinal excitability.\u003c/p\u003e \u003cp\u003eModulation of spinal excitability at rest can be achieved through either presynaptic inhibitory mechanisms or changes in the intrinsic properties of motoneurons (\u003cspan additionalcitationids=\"CR37\" citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e). An increase in the spinal excitability of the FDI muscle can include compensatory mechanisms at the presynaptic and/or postsynaptic levels that compensate for the inhibitory effect of repetitive afferent stimulation. At the presynaptic level, a potential reduction in the sensitivity of Ia afferents to presynaptic inhibition can be proposed as a possible mechanism. In an anesthetized cat, repetitive high-frequency activation of Ia afferents leads to increased calcium accumulation in Ia terminals and consequently an increased probability of neurotransmitter release (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e), which lasts up to several minutes following sustained high-frequency stimulation (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e). At the postsynaptic level, changes in intrinsic motoneuron properties can explain the increased spinal excitability at rest, as observed following burst sPNS. Persistent inward current (PIC) activation is a plausible mechanism, as it is sensitive to neuromodulatory inputs originating from the brainstem\u0026rsquo;s caudal raphe nucleus and locus coeruleus (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e). These brainstem regions respond to electrical stimulation applied to a nerve (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e), suggesting that the volleys from the burst sPNS may reach the brainstem and regulate descending neuromodulatory input. When the raphe spinal pathway is stimulated, the synaptic release of serotonin on dendritic and somatic 5-HT2 receptors promotes Ca\u0026thinsp;+\u0026thinsp;2 PICs (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e). Hence, these presynaptic and/or postsynaptic mechanisms may contribute to changes in spinal excitability.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eClinical and mechanistic implications\u003c/h2\u003e \u003cp\u003eTogether, these findings support the use of burst sPNS as a targeted, noninvasive strategy for priming corticospinal and spinal circuits. In contrast to conventional TENS or continuous sPNS, burst-modulated protocols offer a temporally structured afferent signal that may better mimic natural sensory input and avoid habituation. Similarly, previous studies by Jadidi et al. (\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e) reported that burst and PWM-modulated TENS enhanced motor cortical excitability, suggesting that patterned stimulation protocols may induce more robust and spatially selective plasticity than traditional methods. Given the focal effects observed in the FDI muscle and the lack of change in the FCR muscle, our results highlight the spatial specificity of burst sPNS, which may be a valuable characteristic for applications in stroke, spinal cord injury, and movement disorders where regional modulation is essential. Furthermore, the ability to increase excitability without requiring volitional effort or overt contraction opens doors for early intervention in severely impaired individuals.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eFuture work\u003c/h2\u003e \u003cp\u003eEarlier investigations utilized a diverse range of stimulation parameters, including variations in intensity, frequency, pulse widths, patterns, and electrode placement. While many studies have focused predominantly on either spinal or corticospinal circuits [e.g., (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e)], recent investigations have evaluated both corticospinal and spinal circuits together, emphasizing the need for a deeper exploration of these mechanisms (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e). While burst sPNS enhances both corticospinal and spinal excitability through potentially distinct yet complementary mechanisms, the relative contributions of these pathways cannot be distinguished from the current experimental design. Future studies should be structured to specifically isolate and quantify the contribution of each site to the resulting increase in motor output. A clear understanding of these contributions could inform the development of targeted rehabilitation strategies for neurological disorders involving dysfunction in corticospinal or spinal pathways. Longitudinal studies are also needed to determine whether these acute excitability changes translate into sustained functional improvements when paired with training. Additionally, optimizing burst parameters (e.g., carrier frequency, burst duration, duty cycle) is crucial for clinical translation.\u003c/p\u003e \u003c/div\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eOur findings underscore the potential of burst sPNS as a non-invasive and adaptable tool for enhancing motor recovery in neurological disorders. By increasing both corticospinal and spinal excitability, burst sPNS could serve as a \u0026ldquo;priming\u0026rdquo; technique and may support functional improvements when combined with physical therapy, personalized neuromodulation, or diagnostic applications. This innovative approach not only offers a promising avenue for motor rehabilitation but also paves the way for its application in performance enhancement and broader neuromodulatory strategies.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003ePNS: Peripheral nerve stimulation\u003c/p\u003e\n\u003cp\u003emPNS: Motor PNS\u003c/p\u003e\n\u003cp\u003esPNS: Sensory PNS\u003c/p\u003e\n\u003cp\u003eCS: corticospinal\u003c/p\u003e\n\u003cp\u003eFDI: First Dorsal Interosseous\u003c/p\u003e\n\u003cp\u003eFCR: Flexor carpi radialis\u003c/p\u003e\n\u003cp\u003eTMS: Transcranial magnetic stimulation\u003c/p\u003e\n\u003cp\u003eMEPs: Motor-evoked potentials\u003c/p\u003e\n\u003cp\u003erMT: resting Motor threshold\u003c/p\u003e\n\u003cp\u003eM-max: Maximal M-waves\u003c/p\u003e\n\u003cp\u003eBOLD: Blood oxygen level-dependent\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eWritten informed consent was obtained from all the participants before testing. The study was approved by the Northwestern University IRB committee (IRB: STU00211930), and all methods conformed to the standards of the Declaration of Helsinki (2004).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e Not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eRaw data were generated at the Legs + Walking Lab at Shirley Ryan Abilitylab. Derived data supporting the findings of this study are available from the corresponding author (JLP) upon request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e All the authors (NMK, HH, XSY, and JLP) declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions:\u003c/strong\u003e Conceptualization: NMK, JLP; Data curation: NMK, HH, XSY; Formal analysis: NMK, HH; Funding acquisition: JLP; Investigation: NMK, HH, XSY, JLP; Methodology: NMK, HH; Project administration: NMK, JLP; Resources: JLP; Software: NMK; Supervision: JLP; Validation: NMK, HH; Visualization: NMK, HH; Writing - original draft: NMK, HH; Writing \u0026ndash; review and editing: NMK, HH, XSY, JLP.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e: The authors would like to thank Grace W. Hoo for helping with subject enrollment and study management.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eVance CG, Dailey DL, Rakel BA, Sluka KA. Using TENS for pain control: the state of the evidence. Pain Manag. 2014;4(3):197-209.\u003c/li\u003e\n\u003cli\u003eBao SC, Khan A, Song R, Kai-Yu Tong R. Rewiring the Lesioned Brain: Electrical Stimulation for Post-Stroke Motor Restoration. J Stroke. 2020;22(1):47-63.\u003c/li\u003e\n\u003cli\u003eKaramian BA, Siegel N, Nourie B, Serruya MD, Heary RF, Harrop JS, et al. The role of electrical stimulation for rehabilitation and regeneration after spinal cord injury. Journal of Orthopaedics and Traumatology. 2022;23(1):2.\u003c/li\u003e\n\u003cli\u003ePascual-Valdunciel A, Rajagopal A, Pons JL, Delp S. Non-invasive electrical stimulation of peripheral nerves for the management of tremor. 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Frontiers in Rehabilitation Sciences. 2023;3:1089223.\u003cstrong\u003e\u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Transcutaneous electrical nerve stimulation, burst stimulation, corticospinal excitability, spinal excitability, motor-evoked potentials, F-wave, H-reflex","lastPublishedDoi":"10.21203/rs.3.rs-6728178/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6728178/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003ePeripheral nerve stimulation (PNS) is commonly used in research and clinical settings for pain management and for augmenting somatosensory inputs for motor recovery. Its functional effects are dependent on stimulation parameters such as frequency, intensity, and duration of stimulation. Recently, interest in temporally modulated PNS (burst PNS), where high-frequency carrier pulses are demodulated to low-frequency bursts, has increased. Burst PNS applied below the motor threshold (sensory) have been used for pain and tremor suppression. However, the effects of burst sensory PNS (sPNS) on corticospinal and spinal excitability are unknown, limiting their application.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe evaluated the impact of a session of burst sPNS on corticospinal excitability through motor-evoked potentials (MEPs) and on spinal excitability through F-wave and H-reflex assessments targeting the first dorsal interosseous (FDI) and flexor carpi radialis (FCR) muscles. Ten healthy participants underwent a randomized crossover study with two experimental visits, where corticospinal and spinal excitability were evaluated before and after a session (40 min) of burst sPNS at the wrist or no stimulation (control).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eCompared with the control condition, burst sPNS resulted in a focal increase in MEP amplitudes (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) in the FDI muscle but not in the FCR muscle (p\u0026thinsp;=\u0026thinsp;0.26). Similarly, only the F-wave amplitude increased following burst sPNS (p\u0026thinsp;=\u0026thinsp;0.008) for the FDI muscle compared with the control condition, but no differences were observed in the H-reflex amplitude (p\u0026thinsp;=\u0026thinsp;0.33) in the FCR muscle between the burst sPNS and the control condition.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eOur findings suggest that burst sPNS might modulate spinal and/or cortical excitability in the short term (5\u0026ndash;10 min in this study). However, the relative changes in cortical and spinal levels due to burst sPNS are unknown, and the timeline for these continued aftereffects needs further investigation.\u003c/p\u003e\u003ch2\u003eTrial registration\u003c/h2\u003e \u003cp\u003eNCT04501133\u003c/p\u003e","manuscriptTitle":"Somatosensory burst peripheral nerve stimulation focally upregulates corticospinal and spinal excitability in the upper limb: a randomized crossover pilot study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-29 07:58:18","doi":"10.21203/rs.3.rs-6728178/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6e44edac-75e6-404f-800e-6cf8d4ad2602","owner":[],"postedDate":"May 29th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-05-29T07:58:21+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-29 07:58:18","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6728178","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6728178","identity":"rs-6728178","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}