Interlimb Coordination Selectively Modulates Short-Interval Intracortical Inhibition During Arm Cycling

Interlimb Coordination Selectively Modulates Short-Interval Intracortical Inhibition During Arm Cycling | 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 Interlimb Coordination Selectively Modulates Short-Interval Intracortical Inhibition During Arm Cycling Alysha Wira, Ibrahim Refai, Kevin Power This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8823638/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 Corticospinal excitability is greater during synchronous than asynchronous arm cycling; however, potential cortical mechanisms underlying this coordination-dependent modulation remain unclear. The purpose of this study was to examine whether short-interval intracortical inhibition (SICI) and long-interval intracortical inhibition (LICI) differ between synchronous and asynchronous arm cycling. We hypothesized that both forms of intracortical inhibition would be greater during asynchronous cycling. Paired-pulse transcranial magnetic stimulation (TMS) was used to assess SICI and LICI in healthy adults during arm cycling at a fixed cadence and workload. SICI was assessed using a conditioning stimulus at 80% active motor threshold and a test stimulus at 120% active motor threshold with a 3-ms interstimulus interval. For LICI, suprathreshold paired-pulses were delivered with a 100-ms interstimulus interval and timed to the ascending phase of biceps brachii activation. Motor evoked potentials were quantified using peak-to-peak amplitude and expressed as paired-pulse to single-pulse ratios. SICI was significantly greater during synchronous compared with asynchronous arm cycling, whereas LICI did not differ between cycling modes. Background muscle activity was comparable across conditions. These findings indicate that interlimb coordination selectively modulates fast-acting intracortical inhibitory mechanisms during rhythmic arm cycling and provide mechanistic insight into coordination-dependent modulation of corticospinal excitability during locomotor-like movement. cortical corticospinal locomotion exercise movement Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Rhythmic motor behaviors such as locomotion and arm cycling emerge from interactions between spinal and supraspinal neural mechanisms. At the spinal level, central pattern generators (CPGs) provide a foundational framework for producing rhythmic motor output, a principle well established in non-human animals (Brown and Sherrington 1911; Grillner 1981). In humans, however, rhythmic locomotor output is strongly shaped by descending input from the motor cortex, reflecting a greater reliance on supraspinal control (Petersen et al. 2001). Consistent with this view, supraspinal contributions to rhythmic movement have been demonstrated across a range of tasks, including walking and running (Barthelemy and Nielsen 2010; Capaday et al. 1999; Christensen et al. 2001), lower-limb cycling (Christensen et al. 2000; Pyndt and Nielsen 2003; Sidhu et al. 2012), and upper-limb cycling (Forman et al. 2014, 2015, 2016; Lockyer et al. 2018; Power et al. 2018; Spence et al. 2016). Although extensive work has characterized task-dependent modulation of corticospinal and spinal excitability during locomotor activities (Klarner and Zehr 2018; Lockyer et al. 2021), comparatively fewer studies have directly examined how cortical circuits are modulated during rhythmic movement, despite growing interest in this area (Alcock et al. 2019; Benson et al. 2021; Compton et al. 2022; Sidhu et al. 2013, 2018; Wira et al. 2026). An important advantage of arm cycling as a model for examining the cortical control of locomotor output is that bilateral coordination can be systematically manipulated without altering the fundamental rhythmic nature of the task. Specifically, arm cycling can be performed in a synchronous (in-phase) or asynchronous (anti-phase) cycling mode, allowing interlimb coupling to be varied while controlling cadence, power output, and background muscle activation. Using this approach, we recently demonstrated greater corticospinal excitability during synchronous compared with asynchronous arm cycling, despite equivalent mechanical and electromyographic conditions (Ogolo et al. 2025); cortical circuit excitability nor spinal excitability were assessed, however. Although cortical excitability is beginning to be examined during asynchronous locomotor outputs, the mechanisms underlying coordination-dependent modulation of corticospinal excitability remain poorly understood. In particular, the neural basis for the enhanced corticospinal excitability observed during synchronous cycling is unknown. To date, no study has directly assessed cortical excitability during synchronous arm cycling, nor systematically compared cortical excitability between synchronous and asynchronous cycling modes during rhythmic locomotor-like movement. Paired-pulse transcranial magnetic stimulation (TMS) provides a means of addressing this limitation by probing distinct intracortical inhibitory mechanisms within primary motor cortex. Specifically, short-interval intracortical inhibition (SICI) is commonly interpreted as reflecting GABA A -mediated inhibition (Ziemann et al. 1996), whereas long-interval intracortical inhibition (LICI) is associated with GABA B -mediated inhibitory processes (McDonnell et al. 2006). Assessing SICI and LICI during synchronous and asynchronous arm cycling therefore offers a mechanistic approach to determining whether cycling mode alters the balance of intracortical inhibition underlying task-dependent modulation of corticospinal excitability. Therefore, the purpose of the present study was to assess SICI and LICI during arm cycling in order to gain mechanistic insight into the task-dependent modulation of corticospinal excitability observed between cycling modes. Based on prior evidence of enhanced corticospinal excitability during synchronous compared to asynchronous arm cycling, we hypothesized that SICI and LICI would be greater during asynchronous arm cycling. Methods Participants Twelve healthy adults ages ranging from 20-34 participated in this study (age 25.21 ± 4.68 years; height 175.14 ± 10.09 cm; weight 80.07 ± 12.27 kg). Each participant filled out 2 safety check lists including the magnetic stimulation safety checklist (Rossini et al. 2015), a Canadian Society for Exercise Physiology Get Active Questionnaire. The Edinburgh handedness questionnaire (Veale 2014) was also filled out to determine hand dominance of each participant. Participants were allowed to complete the experiment if they had no history of neurological disease or upper-body musculoskeletal injury. Written consent was obtained from each participant after the experiment was verbally explained, and all risks were outlined and explained. The study's experimental procedure was in accordance with the Helsinki Declaration, and all protocols were approved by the Interdisciplinary Committee on Ethics in Human Research at Memorial University of Newfoundland (ICEHR no. 20241603). All procedures were in accordance with the Tri-Council guideline in Canada. Experimental Set-up An arm-cycle ergometer was used for all experimental trials (SCIFIT ergometer, model PRO2 Total Body, Tulsa, OK, USA). Participants were seated in a neutral, comfortable position at a distance that minimized trunk rotation and excessive reaching during arm cycling with forearms in a neutral position. Seat height was individually adjusted so that the shoulders were aligned with the arm-crank shaft, ensuring neutral forearm positioning throughout the cycling motion (Lockyer et al. 2021). To minimize wrist flexion and extension and reduce potential heteronymous reflex contributions arising from connections between wrist flexors and the biceps brachii (Manning and Bawa 2011), wrist braces were worn during all trials. Arm-cycling positions were defined relative to a clock face, consistent with prior work (Chaytor et al. 2020; Lockyer et al. 2021), with 12 o’clock corresponding to top dead center and 6 o’clock to bottom dead center. During arm cycling, elbow flexion occurs between 3 and 9 o’clock, with biceps brachii activation peaking at or near the 6 o’clock position (Chaytor et al. 2020). All participants cycled at a fixed cadence of 60 rpm, corresponding to a cycle duration of 1,000 ms and an interval of 83.33 ms between successive clock-face positions. The experiment was conducted over two separate testing days: one dedicated to SICI and one to LICI. The order of testing days was randomized across participants. Within each session, participants performed synchronous and asynchronous arm-cycling conditions (Figure 1), with condition order randomized. Each cycling trial lasted 2 minutes, with TMS delivered approximately every 7 seconds. For each trial, 15 TMS stimulations, 5 blank trials, and 2 supramaximal Mmax stimulations were administered. Surface Electromyography Surface electromyography (EMG) was recorded from the biceps brachii and triceps brachii muscles of the dominant arm using Ag–AgCl surface electrodes (Kendall™ 130 Foam Electrodes with conductive adhesive hydrogel; Covidien IIC, Massachusetts, USA). Electrodes were placed over the muscle belly, parallel to the muscle fibers, with an interelectrode distance of 2 cm. A ground electrode was placed over the lateral epicondyle of the dominant humerus. Prior to electrode placement, the skin was shaved, lightly abraded with NuPrep, and cleansed with a 70% isopropyl alcohol swab. Interelectrode impedance was verified to be <5 kΩ before data collection. EMG signals were collected online and analog-to-digitally converted using a CED 1401 interface and Signal software (version 5.12; Cambridge Electronic Design Ltd., Cambridge, UK). Signals were sampled at 5,000 Hz, amplified (gain = 300), and band-pass filtered using a 3-pole Butterworth filter with cut-off frequencies of 10–1,000 Hz. Transcranial magnetic stimulation Transcranial magnetic stimulation was delivered to the motor cortex using a BiStim module connected to two Magstim 200 stimulators (Magstim, Whitland, Dyfed, UK) and a circular coil (13.5-cm outer diameter). The vertex was identified as the intersection between the midpoint of the tragus-to-tragus line and the midpoint of the nasion-to-inion line and marked on the scalp (Copithorne et al. 2015). The coil was positioned firmly on the participant’s head, parallel to the ground, with orientation chosen to preferentially activate the dominant motor cortex. Short-interval intracortical inhibition During the SICI session, active motor threshold (AMT) was determined separately for synchronous and asynchronous cycling. AMT was defined as the lowest maximum stimulator output (MSO) that elicited a discernible MEP in the biceps brachii in at least 50% of trials while participants were actively cycling. For single-pulse (SP) trials, stimulation intensity was set at 120% AMT. For paired-pulse (PP) trials, conditioning and test stimuli were delivered at 80% and 120% AMT, respectively, with an interstimulus interval of 3 ms. During SICI trials, TMS was automatically triggered when the dominant arm passed the 6 o’clock position (Alcock et al. 2019) Long-interval intracortical inhibition During the LICI session we followed the same procedures as in our recent study (Wira et al. 2026) and in line with others during cycling movements (Sidhu et al. 2018). Stimulation intensity was first determined separately for each cycling condition. Participants began cycling, and stimulation intensity was initially set at 50% of MSO and progressively increased until a cortical silent period of at least 150 ms following the MEP was elicited. Silent periods exceeding ~100 ms are predominantly mediated by GABA B receptor–dependent intracortical inhibition (Inghilleri et al. 1993). The stimulation intensity was defined once six consecutive stimulations produced an MEP followed by a silent period of ≥150 ms and was held constant for both SP and PP trials within that cycling condition. For PP trials, an interstimulus interval of 100 ms was used. The first stimulus was delivered as the crank passed the 4 o’clock position, with the second stimulus occurring between the 5 and 6 o’clock positions (Figure 2), coinciding with near-peak biceps brachii activation (Chaytor et al. 2020; Forman et al. 2014). Nerve stimulation Brachial plexus stimulation at Erb’s point was used to evoke the maximal compound muscle action potential (Mmax) of the biceps brachii. Ag–AgCl pellet electrodes (Meditrace; disc-shaped, 10-mm diameter; Graphic Controls Ltd., Buffalo, NY, USA) were used, with the cathode positioned over the supraclavicular fossa and the anode placed over the acromion process. Electrical stimuli were delivered as single square-wave pulses (200 μs duration, 100–300 mA) using a constant-current stimulator (model DS7AH; Digitimer Ltd., Welwyn Garden City, UK). Participants cycled at 60 rpm at a constant workload of 30W. Stimulation intensity was incrementally increased until M-wave amplitude plateaued, indicating attainment of Mmax, and the final stimulation intensity was set at 120% of Mmax to ensure supramaximal activation (Lockyer et al. 2021). Data Analysis For both SICI and LICI MEPs were analyzed using the peak-to-peak amplitude of the average MEP from the dominant biceps brachii for each trial. The peak-to-peak amplitude of the MEP was measured using cursers on the Signal 5.12 software (CED) placed after the stimulus artifact and near the return of the voltage trace to baseline levels. The peak-to-peak amplitude of Mmax was assessed to give indications of muscle fatigue and peripheral nerve excitability. MEPs were made into ratios to assess if inhibition was present. For both LICI and SICI ratios were paired-pulse test MEP/ single-pulse test MEP. Background EMG (bEMG) was assessed for both the triceps and biceps brachii of the mean smooth and rectified EMG 50ms immediately prior to the stimulation artifact. Statistical Analysis All statistical analyses were performed using standard parametric procedures. For each participant, MEPs were averaged within each condition prior to statistical testing. SICI and LICI were quantified as the ratio of the paired-pulse test MEP to the corresponding single-pulse test MEP, with values <1 indicating the presence of intracortical inhibition. Background EMG was quantified as the mean amplitude of the rectified and low-pass filtered linear envelope recorded from the biceps and triceps brachii during the 50 ms immediately preceding TMS delivery. Normality of the data distributions was assessed using Shapiro–Wilk tests. Because all variables met assumptions of normality, paired-samples t-tests were used to compare synchronous and asynchronous arm-cycling conditions for each dependent variable. One-tailed tests were selected a priori based on directional hypotheses derived from our previous work demonstrating greater corticospinal excitability during synchronous compared with asynchronous arm cycling, and the specific prediction that both measures of intracortical, SICI and LICI, would be greater during asynchronous cycling. Effect sizes were calculated using Cohen’s d for paired comparisons. Statistical significance was set a priori at p < 0.05. Data are reported as mean ± standard deviation unless otherwise stated. All statistical analyses were performed using Prism software, version 10.0.3. Results Short-interval intracortical inhibition Figure 3 illustrates representative MEP traces from a single participant during synchronous and asynchronous cycling. Traces are shown for each task and represent the average of 15 MEPs per condition. In this example, MEP amplitude differed across task conditions, with smaller responses observed at the during synchronous cycling, indicating higher degree of SICI. SICI differed between cycling modes (Figure 4A). A paired-samples t-test showed that SICI was significantly greater during synchronous arm cycling compared with asynchronous arm cycling (t(10) = 2.03, p = 0.035, one-tailed). The mean difference in SICI between conditions was 8.0% (SD = 13.1), corresponding to a moderate effect size (Cohen’s d = 0.61). This effect was consistent across participants and occurred despite equivalent cycling cadence and background EMG between conditions. Background muscle activity Background EMG activity of the biceps brachii was assessed across the four experimental conditions using a one-way repeated-measures ANOVA. Because the assumption of sphericity was violated, Greenhouse–Geisser corrections were applied (ε = 0.43). The analysis showed no main effect of condition on background biceps brachii EMG (F(1.29, 15.48) = 0.24, p = 0.69), indicating that biceps brachii activation was effectively matched across all four conditions (Figure 4B) and that any observed differences in neurophysiological outcomes cannot be attributed to differences in baseline muscle activity. Background EMG activity of the triceps brachii was assessed across the four experimental conditions using a one-way repeated-measures ANOVA. Because the assumption of sphericity was not met, Greenhouse–Geisser corrections were applied (ε = 0.75). The analysis revealed no main effect of condition on background triceps brachii EMG (F(2.26, 24.09) = 0.64, p = 0.55) (Figure 4C). Long-interval intracortical inhibition Figure 5 illustrates representative MEP traces from a single participant during synchronous and asynchronous cycling. Traces are shown for each task and represent the average of 15 MEPs per condition. In this example, MEP amplitudes did not differ significantly between conditions, though LICI was present. LICI did not differ between cycling modes (Figure 6A). A paired-samples t-test showed that SICI was significantly greater during synchronous arm cycling compared with asynchronous arm cycling (t(10) = 0.411, p = 0.344, one-tailed). The mean difference in LICI between conditions was -2.3% (SD = 19.6), with a very small effect size (Cohen’s d = 0.12). Background muscle activity Paired-samples t-tests (two-tailed) were conducted for both biceps and triceps brachii based on cycling mode and whether the condition was a single- or paired-pulse. Paired t-tests were necessary for LICI bEMG measurements as compared to a one-way ANOVA for SICI because the TMS induced silent period significantly reduced the EMG prior to the second pulse in the paired-pulse condition. The analysis showed no significant difference in biceps brachii bEMG between single-pulse (t(11) = 0.91, p = 0.38) or paired-pulse (t(11) = 0.78, p = 0.45) conditions; Figure 6B and C, respectively. Similarly, bEMG recorded from the triceps brachii did not differ between synchronous and asynchronous conditions. The analysis showed no significant difference between single-pulse (t(11) = 1.63, p = 0.13) or paired-pulse (t(11) = 2.15, p = 0.54) conditions; Figure 6D and E, respectively. Summary of results Paired-samples t -tests demonstrated that cycling mode selectively modulated intracortical inhibition during rhythmic arm cycling. Synchronous cycling was associated with significantly greater SICI, whereas LICI did not differ between cycling modes. Importantly, all effects occurred in the absence of differences in cycling cadence or background muscle activity, indicating that coordination-dependent changes in intracortical inhibition were not attributable to differences in task execution. Discussion Main findings The purpose of this study was to determine whether task-dependent differences in corticospinal excitability between synchronous and asynchronous arm cycling are accompanied by changes in intracortical inhibitory mechanisms. The primary finding was that short-interval intracortical inhibition (SICI) was greater during synchronous compared with asynchronous arm cycling, whereas long-interval intracortical inhibition (LICI) did not differ between cycling modes. These findings indicate that GABA A -mediated inhibitory circuits are selectively modulated by cycling mode during rhythmic arm cycling, whereas GABA B -mediated mechanisms appear relatively insensitive to these task demands. SICI is higher during synchronous arm cycling Recent work from our lab showed that corticospinal excitability to the biceps brachii was higher during synchronous arm cycling than asynchronous arm cycling (Ogolo et al. 2025) but we did not assess cortical or spinal excitability. We suggested that differences between the cycling tasks could be mediated, in part, by task-dependent modulation of cortical excitability. In the current study, we show that SICI was higher during synchronous compared to asynchronous arm cycling (i.e., task-dependent changes). Task-dependent differences in SICI have been previously reported during non-locomotor tasks (Opie et al. 2015). Opie et al. (2015) reported reduced SICI during a gripping task relative to finger abduction, potentially given the force gripping could be organized through efficient, task-appropriate synergies. Asynchronous cycling represents a more natural locomotor coordination pattern and may therefore require less intracortical constraint, resulting in lower SICI compared with synchronous cycling, which likely demands greater inhibitory control to stabilize bilateral output. When compared to studies involving locomotor outputs, we showed that SICI was present during arm cycling but not different than an intensity-matched tonic contraction (Alcock et al. 2019). However, Sidhu and colleagues demonstrated that SICI is phase-dependent during leg cycling with reduced SICI during activation and enhanced SICI during inaction phases of vastus lateralis muscle activity (Sidhu et al. 2013). The finding of higher SICI, a GABA A -mediated cortical inhibition (Ziemann et al. 1996), during synchronous arm cycling suggests that in-phase bilateral coordination is associated with increased recruitment of fast-acting intracortical inhibitory circuits within primary motor cortex. Synchronous arm cycling requires simultaneous activation of homologous muscles across the upper limbs, a coordination pattern that may necessitate enhanced inhibitory regulation to constrain excitatory drive and maintain stable bilateral output. Increased SICI during synchronous cycling may therefore serve to sharpen cortical motor commands, prevent excessive facilitation, and ensure coordinated timing between the two hemispheres. In contrast, asynchronous cycling involves alternating limb activation, which may reduce the need for rapid and strong, simultaneous inhibitory control within each motor cortex. Importantly, the presence of greater SICI during synchronous cycling does not contradict prior reports of higher corticospinal excitability under the same cycling mode (Ogolo et al. 2025). Rather, these findings suggest that increased net corticospinal output during synchronous cycling occurs in the context of heightened inhibitory regulation, potentially reflecting a more tightly controlled cortical state rather than simple disinhibition. LICI is not cycling-task dependent In contrast to SICI, LICI did not differ between synchronous and asynchronous arm cycling. LICI is commonly associated with slower, GABA B -mediated inhibitory processes and is thought to reflect more tonic or global inhibitory control within motor cortex. The absence of LICI modulation suggests that cycling mode selectively influences fast, phasic inhibitory circuits without substantially altering slower inhibitory mechanisms during rhythmic arm cycling. While we previously showed that SICI and LICI are preserved during arm cycling and do not differ from tonic contraction (Alcock et al. 2019; Wira et al. 2026), the current findings reveal that interlimb coordination selectively modulates SICI, supporting a role for SICI in constraining coordination rather than generating rhythmic output. This dissociation also highlights an important functional distinction between intracortical inhibitory systems. While SICI appears sensitive to the temporal and coordination demands of the task, LICI may reflect a background inhibitory tone that remains relatively stable across cycling modes (McDonnell et al. 2006). Alternatively, modulation of GABA B -mediated inhibition may occur under different task constraints, such as higher force levels, fatigue, or during transitions between coordination patterns. These results also provide important context for previous work demonstrating interhemispheric interactions during arm cycling. Although interhemispheric inhibition (IHI) was not directly assessed in the present study, the elevated SICI during synchronous cycling is consistent with increased inhibitory control within motor cortex when homologous representations are co-activated. This finding indicates that enhanced corticospinal excitability during synchronous coordination can coexist with, and may even depend upon, increased intracortical inhibition. Future work will compare IHI between these cycling modes to gain further mechanistic insight into their neural control. Methodological considerations and future directions Several considerations should be acknowledged in the interpretation of the results presented. First, we consider that both forms of cycling used in the present study are partially generated by spinal CPGs. Extensive work by Zehr and colleagues over the course of decades has shown, quite convincingly, that asynchronous arm cycling involved spinal CPG activation. Although alternating coordination is the most commonly expressed locomotor pattern, converging evidence from developmental (Dominici et al. 2011; Thelen 1985), spinal cord injury (Courtine et al. 2009), and reflex modulation studies (Zehr et al. 2007; Zehr and Stein 1999) indicates that human spinal CPGs can generate synchronous rhythmic output. Accordingly, synchronous cycling likely reflects engagement of spinal locomotor circuitry operating under altered supraspinal constraints, rather than a rhythm generated exclusively at the cortical level. However, if synchronous cycling were purely cortically driven, you would expect reflex modulation to collapse or lose phase structure, which it does not. Second, measurements were obtained at a single phase of the cycling modes corresponding to peak, or near peak, biceps brachii activity (Chaytor et al. 2020). Intracortical inhibition may vary across movement phases as previously demonstrated (Sidhu et al. 2013) or between flexor and extensor muscles (Spence et al. 2016). In addition, paired-pulse TMS does not directly assess spinal or subcortical contributions, which may also differ between cycling modes and has not yet been examined. Finally, future studies should combine measures of intracortical inhibition with assessments of interhemispheric inhibition and spinal excitability to more fully characterize the multilevel neural mechanisms underlying coordinated locomotor-like movement. Examining how SICI and LICI change during transitions between cycling modes or under increased task demands may further clarify their functional roles. Conclusion In summary, synchronous arm cycling is associated with greater SICI but unchanged LICI compared with asynchronous cycling, indicating enhanced GABA A -mediated intracortical inhibitory regulation during in-phase bilateral coordination. These findings provide mechanistic insight into task-dependent modulation of corticospinal excitability during arm cycling and highlight the role of fast-acting intracortical inhibitory circuits in shaping coordinated locomotor-like motor output. Declarations Funding This work was supported by an NSERC Discovery Grant to Dr. Kevin Power. Author Contribution KP conceived of the study and all authors were involved in the experimental design. AW and IR were responsible for data collection and analysis. All authors contributed to the interpretation of the data, manuscript preparation, and approved the final version of the manuscript. Data Availability The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request. References Alcock LR , Spence AJ , Lockyer EJ , Button DC , Power KE . 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Developmental origins of motor coordination: leg movements in human infants. Dev Psychobiol 18: 1–22, 1985. Veale JF . Edinburgh Handedness Inventory – Short Form: A revised version based on confirmatory factor analysis. Laterality 19: 164–177, 2014. Wira AD , Refai I , Lockyer EJ , Power KE . Long-interval intracortical inhibition to the biceps brachii is present during arm cycling but is not different than a position-matched tonic contraction. Appl Physiol Nutr Metab , 2026. doi:10.1139/apnm-2025-0297. Zehr EP , Balter JE , Ferris DP , Hundza SR , Loadman PM , Stoloff RH . Neural regulation of rhythmic arm and leg movement is conserved across human locomotor tasks: Common neural control of rhythmic human limb movement. The Journal of Physiology 582: 209–227, 2007. Zehr EP , Stein RB . What functions do reflexes serve during human locomotion? Progress in Neurobiology 58: 185–205, 1999. Ziemann U , Lönnecker S , Steinhoff BJ , Paulus W . The effect of lorazepam on the motor cortical excitability in man. Exp Brain Res 109: 127–135, 1996. 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-8823638","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":590591193,"identity":"17cea2fe-a7bc-4702-acdc-71d1754cf7e3","order_by":0,"name":"Alysha Wira","email":"","orcid":"","institution":"Memorial University of Newfoundland","correspondingAuthor":false,"prefix":"","firstName":"Alysha","middleName":"","lastName":"Wira","suffix":""},{"id":590591194,"identity":"34ad96e0-112c-4638-a5e1-fab8f50f2bf3","order_by":1,"name":"Ibrahim Refai","email":"","orcid":"","institution":"Memorial University of Newfoundland","correspondingAuthor":false,"prefix":"","firstName":"Ibrahim","middleName":"","lastName":"Refai","suffix":""},{"id":590591195,"identity":"45796612-c359-468c-b6ed-3aa3a53730b7","order_by":2,"name":"Kevin Power","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAy0lEQVRIiWNgGAWjYBACCSA+AGUzPiBZC7MB0VpggE0CpzJkINneY3i4gOGOnMHx3mdVN9vuMPC3H8CvRZrnjMHhGQzPjA3OHDe7ndv2jEHiTAJ+LXISaQmHeRgOJ267kcYG1HKYwYCBkBb5Z1At95+xFYO18D8g4DAJ5gNQW9jYmMFaJAjYItmTDNRi8MzY/kwas3TOucM8EjcI2CJx/GDzZ56KO3KS7ccYP+eUHZbj7ydgCwQYHIAzeYhRDwIHCKoYBaNgFIyCEQwAWJpDYheEE+kAAAAASUVORK5CYII=","orcid":"","institution":"Memorial University of Newfoundland","correspondingAuthor":true,"prefix":"","firstName":"Kevin","middleName":"","lastName":"Power","suffix":""}],"badges":[],"createdAt":"2026-02-08 18:38:27","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8823638/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8823638/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102962994,"identity":"1d368b96-c681-450c-9a5d-02027e4a13ad","added_by":"auto","created_at":"2026-02-19 04:12:42","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":456918,"visible":true,"origin":"","legend":"\u003cp\u003e\u0026nbsp;See image above for figure legend.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"SICILICIFigures20261.png","url":"https://assets-eu.researchsquare.com/files/rs-8823638/v1/f38a95b0b0d910d2df7ad69b.png"},{"id":102795261,"identity":"48c09acb-2e17-4299-86f8-f7fc3a8b803a","added_by":"auto","created_at":"2026-02-16 18:52:00","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":200129,"visible":true,"origin":"","legend":"\u003cp\u003e\u0026nbsp;See image above for figure legend.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"SICILICIFigures20262.png","url":"https://assets-eu.researchsquare.com/files/rs-8823638/v1/f3142ee40697f323a6c4a8ed.png"},{"id":102795263,"identity":"c6f6a17b-7609-43bb-981e-3214e8a0881c","added_by":"auto","created_at":"2026-02-16 18:52:00","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":67520,"visible":true,"origin":"","legend":"\u003cp\u003e\u0026nbsp;See image above for figure 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5","display":"","copyAsset":false,"role":"figure","size":67455,"visible":true,"origin":"","legend":"\u003cp\u003e\u0026nbsp;See image above for figure legend.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"SICILICIFigures20265.png","url":"https://assets-eu.researchsquare.com/files/rs-8823638/v1/a7d428eb13eaae4a7ab57a7b.png"},{"id":102963026,"identity":"7816f25c-b7f4-4b13-9df0-d42718a0a05a","added_by":"auto","created_at":"2026-02-19 04:12:54","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":79326,"visible":true,"origin":"","legend":"\u003cp\u003e\u0026nbsp;See image above for figure legend.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"SICILICIFigures20266.png","url":"https://assets-eu.researchsquare.com/files/rs-8823638/v1/9049c6d37fa1cd7d1c1334a5.png"},{"id":102965022,"identity":"b95c6cf1-17cb-4bd2-9324-25738486844a","added_by":"auto","created_at":"2026-02-19 04:30:01","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1958951,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8823638/v1/6c6e7de2-18e8-4021-89c9-b9d5a6d211a3.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Interlimb Coordination Selectively Modulates Short-Interval Intracortical Inhibition During Arm Cycling","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRhythmic motor behaviors such as locomotion and arm cycling emerge from interactions between spinal and supraspinal neural mechanisms. At the spinal level, central pattern generators (CPGs) provide a foundational framework for producing rhythmic motor output, a principle well established in non-human animals (Brown and Sherrington 1911; Grillner 1981). In humans, however, rhythmic locomotor output is strongly shaped by descending input from the motor cortex, reflecting a greater reliance on supraspinal control (Petersen et al. 2001). Consistent with this view, supraspinal contributions to rhythmic movement have been demonstrated across a range of tasks, including walking and running (Barthelemy and Nielsen 2010; Capaday et al. 1999; Christensen et al. 2001), lower-limb cycling (Christensen et al. 2000; Pyndt and Nielsen 2003; Sidhu et al. 2012), and upper-limb cycling (Forman et al. 2014, 2015, 2016; Lockyer et al. 2018; Power et al. 2018; Spence et al. 2016). Although extensive work has characterized task-dependent modulation of corticospinal and spinal excitability during locomotor activities (Klarner and Zehr 2018; Lockyer et al. 2021), comparatively fewer studies have directly examined how cortical circuits are modulated during rhythmic movement, despite growing interest in this area (Alcock et al. 2019; Benson et al. 2021; Compton et al. 2022; Sidhu et al. 2013, 2018; Wira et al. 2026).\u003c/p\u003e\n\u003cp\u003eAn important advantage of arm cycling as a model for examining the cortical control of locomotor output is that bilateral coordination can be systematically manipulated without altering the fundamental rhythmic nature of the task. Specifically, arm cycling can be performed in a synchronous (in-phase) or asynchronous (anti-phase) cycling mode, allowing interlimb coupling to be varied while controlling cadence, power output, and background muscle activation. Using this approach, we recently demonstrated greater corticospinal excitability during synchronous compared with asynchronous arm cycling, despite equivalent mechanical and electromyographic conditions (Ogolo et al. 2025); cortical circuit excitability nor spinal excitability were assessed, however. Although cortical excitability is beginning to be examined during asynchronous locomotor outputs, the mechanisms underlying coordination-dependent modulation of corticospinal excitability remain poorly understood. In particular, the neural basis for the enhanced corticospinal excitability observed during synchronous cycling is unknown. To date, no study has directly assessed cortical excitability during synchronous arm cycling, nor systematically compared cortical excitability between synchronous and asynchronous cycling modes during rhythmic locomotor-like movement.\u003c/p\u003e\n\u003cp\u003ePaired-pulse transcranial magnetic stimulation (TMS) provides a means of addressing this limitation by probing distinct intracortical inhibitory mechanisms within primary motor cortex. Specifically, short-interval intracortical inhibition (SICI) is commonly interpreted as reflecting GABA\u003csub\u003eA\u003c/sub\u003e-mediated inhibition (Ziemann et al. 1996), whereas long-interval intracortical inhibition (LICI) is associated with GABA\u003csub\u003eB\u003c/sub\u003e-mediated inhibitory processes (McDonnell et al. 2006). Assessing SICI and LICI during synchronous and asynchronous arm cycling therefore offers a mechanistic approach to determining whether cycling mode alters the balance of intracortical inhibition underlying task-dependent modulation of corticospinal excitability.\u003c/p\u003e\n\u003cp\u003eTherefore, the purpose of the present study was to assess SICI and LICI during arm cycling in order to gain mechanistic insight into the task-dependent modulation of corticospinal excitability observed between cycling modes. Based on prior evidence of enhanced corticospinal excitability during synchronous compared to asynchronous arm cycling, we hypothesized that SICI and LICI would be greater during asynchronous arm cycling.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cem\u003eParticipants\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eTwelve healthy adults ages ranging from 20-34 participated in this study (age 25.21 \u0026plusmn; 4.68 years; height 175.14 \u0026plusmn; 10.09 cm; weight 80.07 \u0026plusmn; 12.27 kg). Each participant filled out 2 safety check lists including the magnetic stimulation safety checklist (Rossini et al. 2015), a Canadian Society for Exercise Physiology Get Active Questionnaire. The Edinburgh handedness questionnaire (Veale 2014) was also filled out to determine hand dominance of each participant. Participants were allowed to complete the experiment if they had no history of neurological disease or upper-body musculoskeletal injury. Written consent was obtained from each participant after the experiment was verbally explained, and all risks were outlined and explained. The study\u0026apos;s experimental procedure was in accordance with the Helsinki Declaration, and all protocols were approved by the Interdisciplinary Committee on Ethics in Human Research at Memorial University of Newfoundland (ICEHR no. 20241603). All procedures were in accordance with the Tri-Council guideline in Canada. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eExperimental Set-up\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAn arm-cycle ergometer was used for all experimental trials (SCIFIT ergometer, model PRO2 Total Body, Tulsa, OK, USA). Participants were seated in a neutral, comfortable position at a distance that minimized trunk rotation and excessive reaching during arm cycling with forearms in a neutral position. Seat height was individually adjusted so that the shoulders were aligned with the arm-crank shaft, ensuring neutral forearm positioning throughout the cycling motion (Lockyer et al. 2021). To minimize wrist flexion and extension and reduce potential heteronymous reflex contributions arising from connections between wrist flexors and the biceps brachii (Manning and Bawa 2011), wrist braces were worn during all trials.\u003c/p\u003e\n\u003cp\u003eArm-cycling positions were defined relative to a clock face, consistent with prior work (Chaytor et al. 2020; Lockyer et al. 2021), with 12 o\u0026rsquo;clock corresponding to top dead center and 6 o\u0026rsquo;clock to bottom dead center. During arm cycling, elbow flexion occurs between 3 and 9 o\u0026rsquo;clock, with biceps brachii activation peaking at or near the 6 o\u0026rsquo;clock position (Chaytor et al. 2020). All participants cycled at a fixed cadence of 60 rpm, corresponding to a cycle duration of 1,000 ms and an interval of 83.33 ms between successive clock-face positions.\u003c/p\u003e\n\u003cp\u003eThe experiment was conducted over two separate testing days: one dedicated to SICI and one to LICI. The order of testing days was randomized across participants. Within each session, participants performed synchronous and asynchronous arm-cycling conditions (Figure 1), with condition order randomized. Each cycling trial lasted 2 minutes, with TMS delivered approximately every 7 seconds. For each trial, 15 TMS stimulations, 5 blank trials, and 2 supramaximal Mmax stimulations were administered.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSurface Electromyography\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eSurface electromyography (EMG) was recorded from the biceps brachii and triceps brachii muscles of the dominant arm using Ag\u0026ndash;AgCl surface electrodes (Kendall\u0026trade; 130 Foam Electrodes with conductive adhesive hydrogel; Covidien IIC, Massachusetts, USA). Electrodes were placed over the muscle belly, parallel to the muscle fibers, with an interelectrode distance of 2 cm. A ground electrode was placed over the lateral epicondyle of the dominant humerus. Prior to electrode placement, the skin was shaved, lightly abraded with NuPrep, and cleansed with a 70% isopropyl alcohol swab. Interelectrode impedance was verified to be \u0026lt;5 k\u0026Omega; before data collection. EMG signals were collected online and analog-to-digitally converted using a CED 1401 interface and Signal software (version 5.12; Cambridge Electronic Design Ltd., Cambridge, UK). Signals were sampled at 5,000 Hz, amplified (gain = 300), and band-pass filtered using a 3-pole Butterworth filter with cut-off frequencies of 10\u0026ndash;1,000 Hz.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eTranscranial magnetic stimulation\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eTranscranial magnetic stimulation was delivered to the motor cortex using a BiStim module connected to two Magstim 200 stimulators (Magstim, Whitland, Dyfed, UK) and a circular coil (13.5-cm outer diameter). The vertex was identified as the intersection between the midpoint of the tragus-to-tragus line and the midpoint of the nasion-to-inion line and marked on the scalp (Copithorne et al. 2015). The coil was positioned firmly on the participant\u0026rsquo;s head, parallel to the ground, with orientation chosen to preferentially activate the dominant motor cortex.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eShort-interval intracortical inhibition\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDuring the SICI session, active motor threshold (AMT) was determined separately for synchronous and asynchronous cycling. AMT was defined as the lowest maximum stimulator output (MSO) that elicited a discernible MEP in the biceps brachii in at least 50% of trials while participants were actively cycling. For single-pulse (SP) trials, stimulation intensity was set at 120% AMT. For paired-pulse (PP) trials, conditioning and test stimuli were delivered at 80% and 120% AMT, respectively, with an interstimulus interval of 3 ms. During SICI trials, TMS was automatically triggered when the dominant arm passed the 6 o\u0026rsquo;clock position (Alcock et al. 2019)\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eLong-interval intracortical inhibition\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDuring the LICI session we followed the same procedures as in our recent study (Wira et al. 2026) and in line with others during cycling movements (Sidhu et al. 2018). Stimulation intensity was first determined separately for each cycling condition. Participants began cycling, and stimulation intensity was initially set at 50% of MSO and progressively increased until a cortical silent period of at least 150 ms following the MEP was elicited. Silent periods exceeding ~100 ms are predominantly mediated by GABA\u003csub\u003eB\u0026nbsp;\u003c/sub\u003ereceptor\u0026ndash;dependent intracortical inhibition (Inghilleri et al. 1993). The stimulation intensity was defined once six consecutive stimulations produced an MEP followed by a silent period of \u0026ge;150 ms and was held constant for both SP and PP trials within that cycling condition. For PP trials, an interstimulus interval of 100 ms was used. The first stimulus was delivered as the crank passed the 4 o\u0026rsquo;clock position, with the second stimulus occurring between the 5 and 6 o\u0026rsquo;clock positions (Figure 2), coinciding with near-peak biceps brachii activation (Chaytor et al. 2020; Forman et al. 2014).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eNerve stimulation\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eBrachial plexus stimulation at Erb\u0026rsquo;s point was used to evoke the maximal compound muscle action potential (Mmax) of the biceps brachii. Ag\u0026ndash;AgCl pellet electrodes (Meditrace; disc-shaped, 10-mm diameter; Graphic Controls Ltd., Buffalo, NY, USA) were used, with the cathode positioned over the supraclavicular fossa and the anode placed over the acromion process. Electrical stimuli were delivered as single square-wave pulses (200 \u0026mu;s duration, 100\u0026ndash;300 mA) using a constant-current stimulator (model DS7AH; Digitimer Ltd., Welwyn Garden City, UK). Participants cycled at 60 rpm at a constant workload of 30W. Stimulation intensity was incrementally increased until M-wave amplitude plateaued, indicating attainment of Mmax, and the final stimulation intensity was set at 120% of Mmax to ensure supramaximal activation (Lockyer et al. 2021).\u003c/p\u003e\n\u003cp id=\"_Toc161586843\"\u003e\u003cstrong\u003eData Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor both SICI and LICI MEPs were analyzed using the peak-to-peak amplitude of the average MEP from the dominant biceps brachii for each trial. The peak-to-peak amplitude of the MEP was measured using cursers on the Signal 5.12 software (CED) placed after the stimulus artifact and near the return of the voltage trace to baseline levels. The peak-to-peak amplitude of Mmax was assessed to give indications of muscle fatigue and peripheral nerve excitability. MEPs were made into ratios to assess if inhibition was present. For both LICI and SICI ratios were paired-pulse test MEP/ single-pulse test MEP. Background EMG (bEMG) was assessed for both the triceps and biceps brachii of the mean smooth and rectified EMG 50ms immediately prior to the stimulation artifact.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll statistical analyses were performed using standard parametric procedures. For each participant, MEPs were averaged within each condition prior to statistical testing. SICI and LICI were quantified as the ratio of the paired-pulse test MEP to the corresponding single-pulse test MEP, with values \u0026lt;1 indicating the presence of intracortical inhibition. Background EMG was quantified as the mean amplitude of the rectified and low-pass filtered linear envelope recorded from the biceps and triceps brachii during the 50 ms immediately preceding TMS delivery.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNormality of the data distributions was assessed using Shapiro\u0026ndash;Wilk tests. Because all variables met assumptions of normality, paired-samples t-tests were used to compare synchronous and asynchronous arm-cycling conditions for each dependent variable. One-tailed tests were selected a priori based on directional hypotheses derived from our previous work demonstrating greater corticospinal excitability during synchronous compared with asynchronous arm cycling, and the specific prediction that both measures of intracortical, SICI and LICI, would be greater during asynchronous cycling.\u003c/p\u003e\n\u003cp\u003eEffect sizes were calculated using Cohen\u0026rsquo;s d for paired comparisons. Statistical significance was set a priori at p \u0026lt; 0.05. Data are reported as mean \u0026plusmn; standard deviation unless otherwise stated. All statistical analyses were performed using Prism software, version 10.0.3.\u0026nbsp;\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eShort-interval intracortical inhibition\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFigure 3 illustrates representative MEP traces from a single participant during synchronous and asynchronous cycling. Traces are shown for each task and represent the average of 15 MEPs per condition. In this example, MEP amplitude differed across task conditions, with smaller responses observed at the during synchronous cycling, indicating higher degree of SICI.\u003c/p\u003e\n\u003cp\u003eSICI differed between cycling modes (Figure 4A). A paired-samples t-test showed that SICI was significantly greater during synchronous arm cycling compared with asynchronous arm cycling (t(10) = 2.03, p = 0.035, one-tailed). The mean difference in SICI between conditions was 8.0% (SD = 13.1), corresponding to a moderate effect size (Cohen\u0026rsquo;s d = 0.61). This effect was consistent across participants and occurred despite equivalent cycling cadence and background EMG between conditions.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eBackground muscle activity\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eBackground EMG activity of the biceps brachii was assessed across the four experimental conditions using a one-way repeated-measures ANOVA. Because the assumption of sphericity was violated, Greenhouse\u0026ndash;Geisser corrections were applied (\u0026epsilon; = 0.43). The analysis showed no main effect of condition on background biceps brachii EMG (F(1.29, 15.48) = 0.24, p = 0.69), indicating that biceps brachii activation was effectively matched across all four conditions (Figure 4B) and that any observed differences in neurophysiological outcomes cannot be attributed to differences in baseline muscle activity.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBackground EMG activity of the triceps brachii was assessed across the four experimental conditions using a one-way repeated-measures ANOVA. Because the assumption of sphericity was not met, Greenhouse\u0026ndash;Geisser corrections were applied (\u0026epsilon; = 0.75). The analysis revealed no main effect of condition on background triceps brachii EMG (F(2.26, 24.09) = 0.64, p = 0.55) (Figure 4C).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLong-interval intracortical inhibition\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFigure 5 illustrates representative MEP traces from a single participant during synchronous and asynchronous cycling. Traces are shown for each task and represent the average of 15 MEPs per condition. In this example, MEP amplitudes did not differ significantly between conditions, though LICI was present. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLICI did not differ between cycling modes (Figure 6A). A paired-samples t-test showed that SICI was significantly greater during synchronous arm cycling compared with asynchronous arm cycling (t(10) = 0.411, p = 0.344, one-tailed). The mean difference in LICI between conditions was -2.3% (SD = 19.6), with a very small effect size (Cohen\u0026rsquo;s d = 0.12).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eBackground muscle activity\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003ePaired-samples t-tests (two-tailed) were conducted for both biceps and triceps brachii based on cycling mode and whether the condition was a single- or paired-pulse. Paired t-tests were necessary for LICI bEMG measurements as compared to a one-way ANOVA for SICI because the TMS induced silent period significantly reduced the EMG prior to the second pulse in the paired-pulse condition. The analysis showed no significant difference in biceps brachii bEMG between single-pulse (t(11) = 0.91, p = 0.38) or paired-pulse (t(11) = 0.78, p = 0.45) conditions; Figure 6B and C, respectively. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSimilarly, bEMG recorded from the triceps brachii did not differ between synchronous and asynchronous conditions. The analysis showed no significant difference between single-pulse (t(11) = 1.63, p = 0.13) or paired-pulse (t(11) = 2.15, p = 0.54) conditions; Figure 6D and E, respectively.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSummary of results\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003ePaired-samples \u003cem\u003et\u003c/em\u003e-tests demonstrated that cycling mode selectively modulated intracortical inhibition during rhythmic arm cycling. Synchronous cycling was associated with significantly greater SICI, whereas LICI did not differ between cycling modes. Importantly, all effects occurred in the absence of differences in cycling cadence or background muscle activity, indicating that coordination-dependent changes in intracortical inhibition were not attributable to differences in task execution.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003e\u003cstrong\u003eMain findings\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe purpose of this study was to determine whether task-dependent differences in corticospinal excitability between synchronous and asynchronous arm cycling are accompanied by changes in intracortical inhibitory mechanisms. The primary finding was that short-interval intracortical inhibition (SICI) was greater during synchronous compared with asynchronous arm cycling, whereas long-interval intracortical inhibition (LICI) did not differ between cycling modes. These findings indicate that GABA\u003csub\u003eA\u003c/sub\u003e-mediated inhibitory circuits are selectively modulated by cycling mode during rhythmic arm cycling, whereas GABA\u003csub\u003eB\u003c/sub\u003e-mediated mechanisms appear relatively insensitive to these task demands.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSICI is higher during synchronous arm cycling\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRecent work from our lab showed that corticospinal excitability to the biceps brachii was higher during synchronous arm cycling than asynchronous arm cycling (Ogolo et al. 2025) but we did not assess cortical or spinal excitability. We suggested that differences between the cycling tasks could be mediated, in part, by task-dependent modulation of cortical excitability. In the current study, we show that SICI was higher during synchronous compared to asynchronous arm cycling (i.e., task-dependent changes). Task-dependent differences in SICI have been previously reported during non-locomotor tasks (Opie et al. 2015). Opie et al. (2015) reported reduced SICI during a gripping task relative to finger abduction, potentially given the force gripping could be organized through efficient, task-appropriate synergies. Asynchronous cycling represents a more natural locomotor coordination pattern and may therefore require less intracortical constraint, resulting in lower SICI compared with synchronous cycling, which likely demands greater inhibitory control to stabilize bilateral output. When compared to studies involving locomotor outputs, we showed that SICI was present during arm cycling but not different than an intensity-matched tonic contraction (Alcock et al. 2019). However, Sidhu and colleagues demonstrated that SICI is phase-dependent during leg cycling with reduced SICI during activation and enhanced SICI during inaction phases of vastus lateralis muscle activity (Sidhu et al. 2013).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe finding of higher SICI, a GABA\u003csub\u003eA\u003c/sub\u003e-mediated cortical inhibition (Ziemann et al. 1996), during synchronous arm cycling suggests that in-phase bilateral coordination is associated with increased recruitment of fast-acting intracortical inhibitory circuits within primary motor cortex. Synchronous arm cycling requires simultaneous activation of homologous muscles across the upper limbs, a coordination pattern that may necessitate enhanced inhibitory regulation to constrain excitatory drive and maintain stable bilateral output. Increased SICI during synchronous cycling may therefore serve to sharpen cortical motor commands, prevent excessive facilitation, and ensure coordinated timing between the two hemispheres. In contrast, asynchronous cycling involves alternating limb activation, which may reduce the need for rapid and strong, simultaneous inhibitory control within each motor cortex. Importantly, the presence of greater SICI during synchronous cycling does not contradict prior reports of higher corticospinal excitability under the same cycling mode (Ogolo et al. 2025). Rather, these findings suggest that increased net corticospinal output during synchronous cycling occurs in the context of heightened inhibitory regulation, potentially reflecting a more tightly controlled cortical state rather than simple disinhibition.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLICI is not cycling-task dependent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn contrast to SICI, LICI did not differ between synchronous and asynchronous arm cycling. LICI is commonly associated with slower, GABA\u003csub\u003eB\u003c/sub\u003e-mediated inhibitory processes and is thought to reflect more tonic or global inhibitory control within motor cortex. The absence of LICI modulation suggests that cycling mode selectively influences fast, phasic inhibitory circuits without substantially altering slower inhibitory mechanisms during rhythmic arm cycling.\u003c/p\u003e\n\u003cp\u003eWhile we previously showed that SICI and LICI are preserved during arm cycling and do not differ from tonic contraction (Alcock et al. 2019; Wira et al. 2026), the current findings reveal that interlimb coordination selectively modulates SICI, supporting a role for SICI in constraining coordination rather than generating rhythmic output. This dissociation also highlights an important functional distinction between intracortical inhibitory systems. While SICI appears sensitive to the temporal and coordination demands of the task, LICI may reflect a background inhibitory tone that remains relatively stable across cycling modes (McDonnell et al. 2006). Alternatively, modulation of GABA\u003csub\u003eB\u003c/sub\u003e-mediated inhibition may occur under different task constraints, such as higher force levels, fatigue, or during transitions between coordination patterns.\u003c/p\u003e\n\u003cp\u003eThese results also provide important context for previous work demonstrating interhemispheric interactions during arm cycling. Although interhemispheric inhibition (IHI) was not directly assessed in the present study, the elevated SICI during synchronous cycling is consistent with increased inhibitory control within motor cortex when homologous representations are co-activated. This finding indicates that enhanced corticospinal excitability during synchronous coordination can coexist with, and may even depend upon, increased intracortical inhibition. Future work will compare IHI between these cycling modes to gain further mechanistic insight into their neural control.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethodological considerations and future directions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSeveral considerations should be acknowledged in the interpretation of the results presented. First, we consider that both forms of cycling used in the present study are partially generated by spinal CPGs. Extensive work by Zehr and colleagues over the course of decades has shown, quite convincingly, that asynchronous arm cycling involved spinal CPG activation. Although alternating coordination is the most commonly expressed locomotor pattern, converging evidence from developmental (Dominici et al. 2011; Thelen 1985), spinal cord injury (Courtine et al. 2009), and reflex modulation studies (Zehr et al. 2007; Zehr and Stein 1999) indicates that human spinal CPGs can generate synchronous rhythmic output. Accordingly, synchronous cycling likely reflects engagement of spinal locomotor circuitry operating under altered supraspinal constraints, rather than a rhythm generated exclusively at the cortical level. However, if synchronous cycling were purely cortically driven, you would expect reflex modulation to collapse or lose phase structure, which it does not.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSecond, measurements were obtained at a single phase of the cycling modes corresponding to peak, or near peak, biceps brachii activity (Chaytor et al. 2020). Intracortical inhibition may vary across movement phases as previously demonstrated (Sidhu et al. 2013) or between flexor and extensor muscles (Spence et al. 2016). In addition, paired-pulse TMS does not directly assess spinal or subcortical contributions, which may also differ between cycling modes and has not yet been examined. Finally, future studies should combine measures of intracortical inhibition with assessments of interhemispheric inhibition and spinal excitability to more fully characterize the multilevel neural mechanisms underlying coordinated locomotor-like movement. Examining how SICI and LICI change during transitions between cycling modes or under increased task demands may further clarify their functional roles.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, synchronous arm cycling is associated with greater SICI but unchanged LICI compared with asynchronous cycling, indicating enhanced GABA\u003csub\u003eA\u003c/sub\u003e-mediated intracortical inhibitory regulation during in-phase bilateral coordination. These findings provide mechanistic insight into task-dependent modulation of corticospinal excitability during arm cycling and highlight the role of fast-acting intracortical inhibitory circuits in shaping coordinated locomotor-like motor output.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis work was supported by an NSERC Discovery Grant to Dr. Kevin Power.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eKP conceived of the study and all authors were involved in the experimental design. AW and IR were responsible for data collection and analysis. All authors contributed to the interpretation of the data, manuscript preparation, and approved the final version of the manuscript.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003e\u003cstrong\u003eAlcock LR\u003c/strong\u003e, \u003cstrong\u003eSpence AJ\u003c/strong\u003e, \u003cstrong\u003eLockyer EJ\u003c/strong\u003e, \u003cstrong\u003eButton DC\u003c/strong\u003e, \u003cstrong\u003ePower KE\u003c/strong\u003e. 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The effect of lorazepam on the motor cortical excitability in man. \u003cem\u003eExp Brain Res\u003c/em\u003e 109: 127\u0026ndash;135, 1996.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"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":"cortical, corticospinal, locomotion, exercise, movement","lastPublishedDoi":"10.21203/rs.3.rs-8823638/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8823638/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eCorticospinal excitability is greater during synchronous than asynchronous arm cycling; however, potential cortical mechanisms underlying this coordination-dependent modulation remain unclear. The purpose of this study was to examine whether short-interval intracortical inhibition (SICI) and long-interval intracortical inhibition (LICI) differ between synchronous and asynchronous arm cycling. We hypothesized that both forms of intracortical inhibition would be greater during asynchronous cycling. Paired-pulse transcranial magnetic stimulation (TMS) was used to assess SICI and LICI in healthy adults during arm cycling at a fixed cadence and workload. SICI was assessed using a conditioning stimulus at 80% active motor threshold and a test stimulus at 120% active motor threshold with a 3-ms interstimulus interval. For LICI, suprathreshold paired-pulses were delivered with a 100-ms interstimulus interval and timed to the ascending phase of biceps brachii activation. Motor evoked potentials were quantified using peak-to-peak amplitude and expressed as paired-pulse to single-pulse ratios. SICI was significantly greater during synchronous compared with asynchronous arm cycling, whereas LICI did not differ between cycling modes. Background muscle activity was comparable across conditions. These findings indicate that interlimb coordination selectively modulates fast-acting intracortical inhibitory mechanisms during rhythmic arm cycling and provide mechanistic insight into coordination-dependent modulation of corticospinal excitability during locomotor-like movement.\u003c/p\u003e","manuscriptTitle":"Interlimb Coordination Selectively Modulates Short-Interval Intracortical Inhibition During Arm Cycling","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-16 18:51:55","doi":"10.21203/rs.3.rs-8823638/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":"f7670f85-522f-4e04-95f4-1261ab002eaa","owner":[],"postedDate":"February 16th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-18T04:25:46+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-16 18:51:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8823638","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8823638","identity":"rs-8823638","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}