Interaction of corticospinal and dorsal root inputs to human leg muscles
Transcription
Interaction of corticospinal and dorsal root inputs to human leg muscles
Interaction of corticospinal and dorsal root inputs to human leg muscles François D. Roy1, Grady Gibson2, Richard B. Stein2 Departments of Surgery1 and Physiology2, University of Alberta, Edmonton, Canada Abstract Spinal cord stimulation is a technique that has been introduced to monitor and study spinal cord circuitry and potentially to improve function after spinal cord injury. In this study we have examined the interaction between spinal cord and motor cortex stimulation. EMG was recorded from the tibialis anterior (TA) and soleus muscles under conditions of rest and weak voluntary contraction. When the cortical stimulation occurred about 15 ms before the spinal stimulation, the soleus EMG response was facilitated. This was more dramatic with doublets applied to the spinal cord at 50 ms intervals. Normally, the second response would be almost completely suppressed (homosynaptic depression), but motor cortex stimulation in 4 of 6 subjects showed a marked facilitation of the depressed response. In the TA muscle the most marked facilitation occurred when a spinal stimulation was delivered 80-200 ms before a cortical stimulation. This is probably because of rebound excitation after the post-spike hyperpolarization, but was observed in both the resting (no EMG) and weakly contracted TA muscle. Keywords: spinal root stimulation, transcranial magnetic stimulation, dorsal roots, corticospinal tract Introduction Spinal root stimulation has shown some promise to improve motor function after injury to the central nervous system (CNS). Two individuals with a chronic spinal cord injury showed motor benefits that were unachievable when the stimulation was turned off [1, 2]. Epidural stimulation can preferentially target dorsal roots to elicit a monosynaptic reflex response [3]. However, surgical implantation is required, which limits applicability. A non-invasive percutaneous approach is also available [3, 4]. This technique has been useful for studying spinal circuitry during locomotion [5, 6], though to our knowledge, little is known about how it interacts with corticospinal neurons to facilitate movement. We and others have shown that sensory input from the legs can modify corticospinal excitability, both transiently [7-9] and chronically [10]. Activation of the corticospinal tract using transcranial magnetic stimulation (TMS) elicits motor evoked potentials (MEPs). The size of the MEP is correlated with motor function [11, 12] and a sustained increase provides evidence for stronger pathways [10, 13]. In the present study, we characterized the interaction of the MEP with dorsal root inputs activated using percutaneous spinal stimulation. We show that spinal root inputs regulate descending motor pathways, and describe the nature of the interaction. Materials and Methods Eight able-bodied volunteers participated in the study. Subjects gave informed consent for the protocol which was approved by the Health Research Ethics Board at the University of Alberta. Subjects were screened for potential contraindications to the stimulations, which included: back pain, spine surgery, metal implants in the head and history of seizures. Recording and stimulation: Subjects were comfortably seated with the left leg secured to a metal brace that maintained the ankle and knee at angles of 100°. Electromyography (EMG) was recorded from the tibialis anterior (TA) and soleus muscles (Sol) using Ag-AgCl electrodes (3.52.2 cm; Vermont Medical Inc., Bellow Falls VT). The EMG was amplified (1000 times; Octopus, Bortec Technologies, Calgary, Canada) and digitized (5 kHz using Axoscope hardware and software (DigiData 1200 series, Axon Instruments, Union City CA). EMG from the target muscle was also full-wave rectified, smoothed using a 3-Hz first-order low-pass filter and displayed on an oscilloscope so the subjects could monitor their activity. The spinal levels were marked following palpation by a physiotherapist. The cathode (5 x 5 cm; WalkAide premium electrode; Innovative Neurotronics, Austin TX) was placed over the midline of the vertebral column. The site was identified as the position that produced a large, low-threshold reflex response. This root evoked potential (REP) has also been referred to as a multisegmental monosynaptic response (MMR [5]) and a posterior root-muscle reflex (PRM [14, 15]). The anode (7.5 x 13 cm; Axelgaard Manufacturing Co., Fallbrook, California) was placed on the ipsilateral anterior superior iliac spine [3]. Electrical stimulation (1-ms pulse) was provided with a constant current stimulator (Digitimer DS7A). The corticospinal tract was activated using TMS over the motor cortex (MagStim, Dyfed, UK). Pulses were delivered using a double cone coil connected to a MagStim2 stimulator. The coil was orientated to induce postero-anterior currents in the brain and the optimal site was identified during voluntary contraction: 15-20% of the maximum voluntary contraction (MVC). Experimentation Experiments targeted either the TA or the Sol muscle. Six subjects participated in each experiment, and data were collected both at rest and during a tonic contraction (i.e. dorsiflexion or plantarflexion at 1520% MVC). For each condition, the intensity of the spinal stimulation and TMS were set to produce half maximal responses. The intensities were determined after performing recruitment curves. The interaction of spinal stimulation on the motor evoked potential (MEP) produced by a TMS pulse was examined at selected inter-stimulus intervals (-35 to 200 ms). At intervals of 35 to -20 the TMS pulse will reach the spinal cord before the spinal stimulation (TMS conditions spinal stimulation). At intervals of -15 to -10 the two stimuli will sum at the spinal cord (spinal summation). Finally, at intervals of -5 to 200 ms spinal stimulation occurs before the TMS pulse reaches the spinal cord (spinal stimulation conditions TMS). Four responses were collected at each interval, intermixed with 12 responses with TMS alone and 12 with spinal stimulation alone. Since homosynaptic depression is known to suppress a second reflex response [5, 15, 16], we also examined the interactions in the presence of this suppression. This was done by combining TMS with a pair of spinal stimuli delivered 50 ms apart. The TMS pulse was timed with respect to the second REP, which was suppressed by homosynaptic depression. Analysis The REP traces collected with only spinal stimulation were averaged, shifted according to the various interstimulus intervals and subtracted from the MEP traces (see Fig. 1). This ensured that the contribution of the REP and/or the background EMG was removed from the interaction. The onset and offset of the MEP was determined by visual inspection of the data collected from the recruitment curves. The MEP was then quantified as the mean rectified EMG over this interval. This same interval was used to evaluate the trials in which the MEP immediately preceded the REP (see Fig. 1). Values were considered statistically significant if P<0.05 using a t-test. Results The soleus muscle produced a large REP, but a small MEP (Fig. 1A; MEP scaled 20x). The opposite was true in the TA muscle (Fig. 1C; REP scaled 10x). Corticospinal and afferent inputs arriving at the motoneurons pool within a few milliseconds of each other produced a net increase to the MEP (see Combined trace in Fig. 1A). The summation was more than linear, since subtracting the REP (C-B) and the MEP (C-B-A) still leaves a substantial positive response. During voluntary plantarflexion, the interaction increased the Sol MEP by 206 ± 131% (mean ± S.D.) at grouped intervals of -10 to -15 ms (symbol in region of Fig. 2A between vertical dashed lines; P = 0.003). Some temporal facilitation was observed in the TA Figure 1. Average rectified traces showing three distinct interactions. A, Spinal summation of the REP and the MEP at the spinal cord. B, Interaction when the MEP immediate precedes the second REP. On its own, the second REP (i.e. see #2) was greatly suppressed, but the response is markedly enhanced when combined with an MEP. Both (A&B) are from the Sol muscle during a tonic contraction. C, Facilitation of the TA MEP when the spinal stimulus was delivered 100 ms before the TMS pulse. Traces in (C) were collected during dorsiflexion to highlight the recovery of the EMG following the spinal stimulation. Five traces are shown for each condition: 1) A = MEP alone, 2) B = REP alone (shifted according to the time interval), 3) measured interaction C = MEP+REP, 4) difference of the measured interaction after subtracting the REP (C B), and 5) also subtracting the MEP ( C - B - A). An increase in the bottom traces indicates that the interaction is greater than the linear sum. Three traces have been amplified (10x or 20x) to show the small Sol MEP and the level of background EMG. muscle, though the effects did not reach statistical significance. When the Sol MEP arrived before the REP (e.g., -25 ms interval), the motor response was facilitated (Fig. 1B). This interaction was only evident in the Sol muscle and was most striking during spinal doublets. The first REP is large (#1 in Fig. 1B) while the second REP 50 ms later is almost abolished (#2), presumably by homosynaptic depression. However when the MEP is timed to coincide with the second REP at the spinal cord, the second REP is not abolished and is actually considerably larger than the first (see Combined trace in Fig. 1B). Again, subtracting the REP alone (C-B) and the MEP alone (C-B-A) leaves a large positive response, indicating a much greater than linear summation. In this study, 4 out of the 6 subjects produced marked facilitation (i.e. 46 to 460%) of the motor response. The shape of the waveform is consistent with an abolition or even reversal in homosynaptic depression. The interaction was specific to the Sol muscle and was most prominent during tonic plantarflexion (compare symbols in Fig. 2C). In contrast to the mechanisms in the Sol muscle, the interactions in the TA muscle were dominated by resetting motoneuronal activity following the REP. Conditioning motoneurons with a spinal stimulus 80200 ms before TMS markedly increased the MEP. The facilitation was similar in both resting and active states, and paralleled the rebound excitation observed in the contracted muscle. When the muscle was at rest, the rebound excitation of the motoneurons remained below firing threshold as evidenced by the absence of spontaneous EMG. Given that the spinal doublets tended to produce increases over a larger range of intervals, greater activation of dorsal root inputs may add to the overall rebound effect. This late-interval facilitation tended to be weaker in the Sol muscle, and may be related to the stronger period of post-activation inhibition that follows the large Sol REP or because its smaller MEP. When the motoneuron pool was refractory, the MEP tended to be suppressed. This occurred as the MEP trailed the REP and was most pronounced in the Sol muscle. During contraction, the effect was significant for grouped intervals of 0 to 40 ms ( symbols in Fig. 2A&C; P < 0.05). In the TA muscle, the most dominant interaction was seen at longer intervals. An REP, generated 80-200 ms before an MEP, could greatly facilitate the MEP in both relaxed and contracted muscles (Fig. 2B&D P<0.05). During contraction the preceding stimulus evoked a period of rebound excitation that mirrored the profile of facilitation (see B = REP 100ms trace in Fig. 1C). However, the facilitation was still evident when no spontaneous EMG was generated in the resting muscle (see symbols in Fig. 2B&D). Discussion The present study investigated the interaction of dorsal root and corticospinal responses in human leg muscles. Facilitation of the Sol MEP was largest when the two inputs arrived at the spinal cord at nearly the same time. Two specific interactions were noted: 1) the summation of EPSPs at the motoneuron pool (-10 to -15 ms intervals), and 2) removal of the homosynaptic depression caused by successive spinal stimuli (intervals near -20 ms). We have previously shown that heterosynaptic inputs from corticospinal neurons and Ia muscle afferents can sum at the motoneurons to facilitate the Sol MEP [17]; the present results confirm and extend these findings. With electrical stimulation of the tibial nerve in the popliteal fossa, several studies have shown that corticospinal excitation can reduce homosynaptic depression of Ia fibres [18, 19]. The effect is strongest during a plantarflexion [20] and is therefore reminiscent of the current findings done with spinal stimulation. The effect has been attributed to presynaptic disinhibition. Figure 2. Conditioning of the MEP by spinal root stimulation. Responses are from the Sol (A&C) and TA muscles (B&D), each in 6 subjects. Data is shown at rest ( symbols) and during a voluntary contraction ( symbols). Points show the size of the mean rectified MEP collected at the different interstimulus intervals from -35 to 200 ms. Negative intervals indicate that the TMS pulse was delivered before the conditioning spinal stimulus. The interactions are shown for single pulse (A&B) and double pulse spinal stimulation (50 ms interpulse interval; C&D). The horizontal dotted lines represent the size of the unconditioned MEP. The vertical dashed lines show the period when the TMS and spinal stimulation produce responses that should sum at the spinal cord. Conclusions Increasing corticospinal excitability may improve motor function after injury to the CNS, and may also facilitate MEP generation during general anesthesia, as routinely administered during human spine surgery. The present study was aimed at characterizing the interaction of corticospinal and dorsal root inputs to human leg muscles. Here, we show that percutaneous spinal stimulation modulates the MEP in a manner that is partly muscle and task specific. Future work will be done investigating whether the profiles are maintained in individuals with a chronic CNS injury. [11] [12] [13] References [1] S. Harkema, Y. Gerasimenko, J. Hodes, J. Burdick, C. Angeli, Y. Chen, C. Ferreira, A. Willhite, E. Rejc, R. G. Grossman, and V. R. Edgerton, "Effect of epidural stimulation of the lumbosacral spinal cord on voluntary movement, standing, and assisted stepping after motor complete paraplegia: a case study," Lancet, vol. 377, pp. 1938-47, Jun 4 2011. [2] R. Herman, J. He, S. D'Luzansky, W. Willis, and S. Dilli, "Spinal cord stimulation facilitates functional walking in a chronic, incomplete spinal cord injured," Spinal Cord, vol. 40, pp. 65-8, Feb 2002. [3] A. Maertens de Noordhout, J. C. Rothwell, P. D. Thompson, B. L. Day, and C. D. Marsden, "Percutaneous electrical stimulation of lumbosacral roots in man," J Neurol Neurosurg Psychiatry, vol. 51, pp. 174-81, Feb 1988. [4] P. A. Merton, D. K. Hill, H. B. Morton, and C. D. Marsden, "Scope of a technique for electrical stimulation of human brain, spinal cord, and muscle," Lancet, vol. 2, pp. 597-600, Sep 11 1982. [5] G. Courtine, S. J. Harkema, C. J. Dy, Y. P. Gerasimenko, and P. Dyhre-Poulsen, "Modulation of multisegmental monosynaptic responses in a variety of leg muscles during walking and running in humans," J Physiol, vol. 582, pp. 1125-39, 2007. [6] C. J. Dy, Y. P. Gerasimenko, V. R. Edgerton, P. Dyhre-Poulsen, G. Courtine, and S. J. Harkema, "Phase-dependent modulation of percutaneously elicited multisegmental muscle responses after spinal cord injury," J Neurophysiol, vol. 103, pp. 2808-20, May 2010. [7] S. Khaslavskaia and T. Sinkjaer, "Motor cortex excitability following repetitive electrical stimulation of the common peroneal nerve depends on the voluntary drive," Exp Brain Res, vol. 162, pp. 497502, May 2005. [8] M. E. Knash, A. Kido, M. Gorassini, K. M. Chan, and R. B. Stein, "Electrical stimulation of the human common peroneal nerve elicits lasting facilitation of cortical motor-evoked potentials," Exp Brain Res, vol. 153, pp. 366-77, Dec 2003. [9] F. D. Roy and M. A. Gorassini, "Peripheral sensory activation of cortical circuits in the leg motor cortex of man," J Physiol, vol. 586, pp. 4091-105, Sep 1 2008. [10] D. G. Everaert, A. K. Thompson, S. L. Chong, and R. B. Stein, "Does functional electrical stimulation for foot drop strengthen corticospinal connections?," [14] [15] [16] [17] [18] [19] [20] Neurorehabil Neural Repair, vol. 24, pp. 168-77, Feb 2010. D. Barthelemy, M. Willerslev-Olsen, H. Lundell, B. A. Conway, H. Knudsen, F. Biering-Sorensen, and J. B. Nielsen, "Impaired transmission in the corticospinal tract and gait disability in spinal cord injured persons," J Neurophysiol, vol. 104, pp. 116776, Aug 2010. F. D. Roy, J. F. Yang, and M. A. Gorassini, "Afferent regulation of leg motor cortex excitability after incomplete spinal cord injury," J Neurophysiol, vol. 103, pp. 2222-33, Apr 2010. S. L. Thomas and M. A. Gorassini, "Increases in corticospinal tract function by treadmill training after incomplete spinal cord injury," J Neurophysiol, vol. 94, pp. 2844-55, Oct 2005. K. Minassian, B. Jilge, F. Rattay, M. M. Pinter, H. Binder, F. Gerstenbrand, and M. R. Dimitrijevic, "Stepping-like movements in humans with complete spinal cord injury induced by epidural stimulation of the lumbar cord: electromyographic study of compound muscle action potentials," Spinal Cord, vol. 42, pp. 401-16, Jul 2004. K. Minassian, I. Persy, F. Rattay, M. R. Dimitrijevic, C. Hofer, and H. Kern, "Posterior root-muscle reflexes elicited by transcutaneous stimulation of the human lumbosacral cord," Muscle Nerve, vol. 35, pp. 327-36, Mar 2007. U. S. Hofstoetter, K. Minassian, C. Hofer, W. Mayr, F. Rattay, and M. R. Dimitrijevic, "Modification of reflex responses to lumbar posterior root stimulation by motor tasks in healthy subjects," Artif Organs, vol. 32, pp. 644-8, Aug 2008. D. E. Poon, F. D. Roy, M. A. Gorassini, and R. B. Stein, "Interaction of paired cortical and peripheral nerve stimulation on human motor neurons," Exp Brain Res, vol. 188, pp. 13-21, Jun 2008. S. Meunier, "Modulation by corticospinal volleys of presynaptic inhibition to Ia afferents in man," J Physiol Paris, vol. 93, pp. 387-94, Sep-Oct 1999. J. Valls-Sole, R. Alvarez, and E. S. Tolosa, "Vibration-induced presynaptic inhibition of the soleus H reflex is temporarily reduced by cortical magnetic stimulation in human subjects," Neurosci Lett, vol. 170, pp. 149-52, Mar 28 1994. J. F. Iles, "Evidence for cutaneous and corticospinal modulation of presynaptic inhibition of Ia afferents from the human lower limb," J Physiol, vol. 491 ( Pt 1), pp. 197-207, Feb 15 1996. Acknowledgements This research was supported in part by the Canadian Institutes for Health Research. We thank Dr. Monica Gorassini for the loan of some equipment. Author’s Address François D. Roy Neurophysiologist & Assistant Adjunct Professor Department of Surgery, University of Alberta 3B5.02 WMC, 8440 112 St Edmonton, AB T6G 2B7 E-mail: [email protected]