Journal of Electromyography and Kinesiology 25 (2015) 438–443
Contents lists available at ScienceDirect
Journal of Electromyography and Kinesiology journal homepage: www.elsevier.com/locate/jelekin
Acute changes in soleus H-reflex facilitation and central motor conduction after targeted physical exercises Noam Y. Harel a,b,c,⇑, Stephanie A. Martinez a, Steven Knezevic a, Pierre K. Asselin a, Ann M. Spungen a,c,d a
RR&D National Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peters VA Medical Center, Bronx, NY, United States Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States c Department of Rehabilitation Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States d Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States b
a r t i c l e
i n f o
Article history: Received 3 August 2014 Received in revised form 24 January 2015 Accepted 17 February 2015
Keywords: H-reflex facilitation Transcranial magnetic stimulation Corticospinal Reticulospinal Balance exercise
a b s t r a c t We tested the acute effect of exercises targeted simultaneously at cortical and brainstem circuits on neural transmission through corticobulbar connections. Corticobulbar pathways represent a potential target for rehabilitation after spinal cord injury (SCI), which tends to spare brainstem circuits to a greater degree than cortical circuits. To explore this concept, able-bodied volunteers (n = 20) underwent one session each of three exercises targeted at different nervous system components: treadmill walking (spinal locomotor circuits), isolated balance exercise (brainstem and other pathways), and multimodal balance plus skilled hand exercise (hand motor cortex and corticospinal tract). We found that short-interval soleus H-reflex facilitation increased after one session of balance and multimodal exercise by 13.2 ± 4.0% and 8.3 ± 4.7%, and slightly decreased by 1.9 ± 4.4% after treadmill exercise (p = 0.042 on ANOVA across exercise type). Increases in long-interval H-reflex facilitation were not significantly different between exercises. Both balance and multimodal exercise increased central motor conduction velocity by 4.3 ± 2.6% and 4.5 ± 2.8%, whereas velocity decreased by 4.3 ± 2.7% after treadmill exercise (p = 0.045 on ANOVA across exercise type). In conclusion, electrophysiological transmission between the motor cortex and spinal motor neurons in able-bodied subjects increased more following one session of balance exercise than treadmill exercise. Published by Elsevier Ltd.
1. Introduction After contusive spinal cord injury (SCI), spared circuits often consist predominantly of brainstem pathways (Nathan et al., 1996; Jankowska and Edgley, 2006). Descending brainstem pathways connect to many of the same spinal motor neurons to which volitional corticospinal circuits connect (Sasaki et al., 2004; Riddle et al., 2009). Therefore, in the context of SCI, strengthened connections between cortical and brainstem circuits above the injury could provide detour pathways for cortical signals to reach spinal motor neurons below the injury. Previous experiments in animals have demonstrated the potential for detour connections to mediate cortical signals after SCI (Bareyre et al., 2004; Courtine et al., 2008). Our group has applied targeted exercises designed to repetitively and simultaneously
⇑ Corresponding author at: 130 West Kingsbridge Rd, Bronx, NY 10468, United States. Tel.: +1 718 584 9000x1742; fax: +1 718 741 4675. E-mail address: [email protected] (N.Y. Harel). http://dx.doi.org/10.1016/j.jelekin.2015.02.009 1050-6411/Published by Elsevier Ltd.
stimulate cortical and brainstem circuits in animal models to maximize the potential of this mechanism (Harel et al., 2010, 2013). The current report was designed as a proof-of-principle study in able-bodied subjects prior to initiating a trial in individuals with chronic SCI. The goals were to (1) determine the preliminary sensitivity of electrophysiological parameters to detect acute change in response to single sessions of targeted physical exercises; and (2) to test how the addition of exercises stimulating cortical circuits involved in hand control would affect the response to exercises stimulating brainstem and spinal circuits involved in leg control. Volunteers underwent one session each of three different types of exercise – treadmill walking (targeted at spinal locomotor circuits); balance exercise (requiring integrated activation of multiple neural circuit types); or multimodal exercises incorporating balance and simultaneous skilled hand exercises (to activate corticospinal circuits). The main outcome measures were electrophysiological parameters of neural transmission between cortical and spinal motor centers: tibialis anterior motor evoked potentials (MEP), tibialis anterior central motor conduction time, and soleus H-reflex facilitation by subthreshold transcranial magnetic stimulation (TMS).
N.Y. Harel et al. / Journal of Electromyography and Kinesiology 25 (2015) 438–443
The latter technique, soleus H-reflex facilitation, reflects both direct and indirect cortical–spinal transmission. The spinal synapse mediating the H-reflex is subject to influence and modulation by multiple intraspinal and supraspinal inputs (Chen et al., 2010; Thompson et al., 2013; Thompson and Wolpaw, 2014). Even when a TMS pulse is subthreshold for eliciting an evoked potential directly from the target muscle, it can still alter excitability of multiple pathways that lead to modulation of the ensuing H-reflex (Wolfe et al., 1996; Cortes et al., 2011). Varying the interstimulus interval (ISI) between TMS and H-reflex pulses results in different degrees of facilitation and inhibition over different ISI (Nielsen and Petersen, 1995; Wolfe et al., 1996; Serranova et al., 2008; Benito Penalva et al., 2010). One interpretation of these phases posits that they reveal the influence of direct and indirect supraspinal pathways – modulation at short ISI between 0 and 20 ms likely reflects direct pathways, whereas modulation at longer ISI of 60 or more ms may reflect a combination of indirect pathways (Wolfe et al., 1996; Serranova et al., 2008; Benito Penalva et al., 2010). We therefore measured the acute effect of different exercises on H-reflex facilitation in both direct and indirect interval periods. 2. Methods 2.1. Participants Able-bodied volunteers between the age of 21 and 55 years were recruited. Exclusion criteria included significant neurological disease or excessive risk of TMS: history of seizures, medications that increase seizure risk, or implanted electrical or ferromagnetic devices (Rossi et al., 2009). Data were entirely excluded from four of the 24 originally enrolled participants: two did not a have reliable soleus H-reflex response, one did not have reliable tibialis anterior motor evoked potential, and one did not tolerate testing. The remaining 20 subjects had a mean age of 30.8 ± 8.8 years. 10 were female. Technical artifacts prevented complete data analysis for several other sessions as follows: for H-reflex facilitation, the numbers analyzed by exercise were 16 treadmill, 20 balance, and 14 multimodal; for MEPs, 17 treadmill, 16 balance, and 17 multimodal; and for central conduction time 16 treadmill, 17 balance, and 14 multimodal. All procedures were approved by the Institutional Review Board of the James J. Peters VA Medical Center, Bronx, NY. We certify that all applicable institutional and governmental regulations concerning the ethical use of human volunteers were followed during the course of this research. 2.2. Design Subjects underwent electrophysiological testing immediately before and after one 30-min exercise session on three separate days. Post-session testing began within 2 min after exercise termination and took approximately 15–20 min to complete. Exercises were scheduled in random order for each subject. Sessions were separated by at least three days to allow for washout of acute effects. Individual subjects had sessions at roughly the same time of day (morning or afternoon) to control for potential diurnal variation. All results are expressed as percentage change of post-session parameters compared to pre-session parameters. 2.3. Exercises (Fig. 1) Each 30-min session was broken down into 10 periods of 2min ‘on’ and 1-min ‘off’. Subjects did not receive any weight support.
439
2.3.1. Treadmill walking Subjects walked comfortably on a treadmill at 3.2 km/h (except for the initial 2-min period at 2.0 km/h). Subjects were encouraged to swing the arms while walking. 2.3.2. Balance exercise Subjects stood with feet shoulder-width apart on a Bosu™ platform (approximately 63.5 cm diameter, 23 cm height). Subjects were instructed to maintain balance without using the handrails except when needed for safety. To augment task variability, the flat and convex surfaces of the Bosu™ ball were alternated during 10 successive 2-min periods. Subjects were able to maintain balance with minimal or no use of handrails. 2.3.3. Multimodal exercise While performing balance exercises exactly as described above, subjects were asked to type a series of 9-digit numbers into a numerical keypad using one hand. Equal amounts of numbers were directed toward the subject’s left and right hand. Each subject received the same set of randomly generated numbers. To maximize motor cortex activation through fractionated finger use, subjects were instructed to use multiple fingers to type in the numbers (Lemon, 2008). To keep postural task difficulty similar to the balance-only exercise session, care was taken to avoid bearing any weight on the hand in use. 2.4. Testing All electrophysiological assessments were performed in the supine position with knees resting on a foam roll and ankles placed in passive neutral position using a footrest. Surface Ag–AgCl electrodes (Natus) were applied to the bellies of the dominant (based on side of hand used for writing) tibialis anterior and soleus muscles according to SENIAM recommendations (Hermens et al., 2000) (http://seniam.org/sensor_location.htm). Another pair of Ag–AgCl surface electrodes was placed over the tibial nerve in the popliteal fossa to be used for electrical stimulation. The positioning of the stimulating electrode was determined by response to electrical stimulation using a handheld probe (Natus). Recordings were collected with a Viking Select electromyography system (Natus) at a bandwidth of 10–1000 Hz and a sample rate of 5000 Hz. Peripheral responses – The peroneal nerve was stimulated with 0.1 ms pulses at supramaximal intensity to define the tibialis anterior maximal compound motor action potential (Mmax) as well as to elicit F-waves in the antidromic orientation. The tibial nerve was stimulated with 1.0 ms pulses at a range of intensities to determine the threshold and slope of the H-reflex recruitment curve, and the soleus Mmax. For measuring H-reflex facilitation (described below), unconditioned stimulation intensity was set to elicit an H-reflex of 10–20% of Mmax (Serranova et al., 2008). Transcranial magnetic stimulation – A MagPro R30 with MagOption system (MagVenture) was used. The first 12 subjects tested received stimulation with a 70 mm figure-of-eight coil (MC-B70), whereas the last 12 subjects received stimulation with an 80 mm winged coil (D-B80). The TMS coil was centered over the leg motor cortex hotspot for maximal tibialis anterior response. Resting motor threshold was determined as the percent of maximal stimulator output required to elicit a potential of at least 25 lV in 5 out of 10 repetitions. MEP amplitudes were measured over a range of stimulator intensities, with an average of 5 repetitions per intensity. To account for changes in electrode placement and electrode–skin impedance between testing sessions, all MEP amplitudes were normalized to each session’s peripherally evoked Mmax. Central motor conduction time (CMCT) was calculated using M- and F-wave latencies obtained from supramaximal stimulation of the peroneal nerve:
440
N.Y. Harel et al. / Journal of Electromyography and Kinesiology 25 (2015) 438–443
Fig. 1. Exercise paradigms. Treadmill walking (targeted at spinal locomotor central pattern generator (CPG)); balance exercise (targeted at brainstem and other pathways); and multimodal exercise (balance exercises plus fractionated hand exercises targeted at the corticospinal tract (CST)).
CMCT = MEP latency et al., 1988).
[(F latency + M latency
1)/2] (Robinson
2.5. Soleus H-reflex facilitation by transcranial magnetic stimulation TMS pulses (at 80% of tibialis anterior resting motor threshold) were delivered prior to tibial nerve pulses at interstimulus intervals (ISI) of 0–80 ms in pseudorandom order. A minimum of 10 s elapsed between each pulse. TMS-conditioned soleus H-reflex amplitude (average over 5 repetitions) was compared to unconditioned H-reflex amplitude to determine the percent facilitation at each ISI (Wolfe et al., 1996).
At long ISI between 60 and 80 ms, balance, multimodal, and treadmill exercise acutely increased facilitation by 14.2 ± 6.1%, 5.5 ± 6.7%, and 5.7 ± 7.2%, respectively (ns). Isolated balance exercise was the only modality to demonstrate 95% confidence interval of the percent change greater than zero for both short (95%CI 5.28– 21.05) and long (95%CI 2.16–26.30) ISI. 3.2. Tibialis anterior MEPs All exercises acutely increased tibialis anterior MEP amplitude to a similar degree. At 110% of resting motor threshold, post-session MEP amplitude increased by 71 ± 40% for treadmill, 63 ± 42% for balance, and 59 ± 41% for multimodal exercise (ns, not shown).
2.6. Statistics 3.3. Central motor conduction time (CMCT) (Fig. 3) For each exercise condition, the main variable was percent change from baseline pre-session testing. There were no significant effects of intervention order on any of the outcomes. The most rigorous method of analyzing data from crossover studies involves the use of independent-sample rather than repeated-measures tests (Wellek and Blettner, 2012). One-way analysis of variance (ANOVA) was conducted to compare the three exercise interventions on percent change from baseline. Significance was accepted at values of p = 0.05 or less. ANOVA models with statistically significant main effects were further tested by post hoc pairwise ttests. No correction was made for multiple comparisons among outcome measures. Microsoft Excel and SAS JMP 8.0 were used to perform all analyses. 3. Results 3.1. H-reflex facilitation (Fig. 2) Pre-exercise facilitation at short interstimulus intervals (ISI) was 115 ± 2%, whereas at long ISI it was 122 ± 3%. At ISI between 0 and 10 ms, one session of balance, multimodal, or treadmill exercise changed facilitation by +13.2 ± 4.0%, +8.3 ± 4.7%, or 1.9 ± 4.4%, respectively (F = 3.24, 2 df, p = 0.042; on post hoc pairwise testing, p = 0.013 for balance versus treadmill exercise, ns for other pairs). A similar trend toward significance was noted at ISI between 0 and 20 ms, with facilitation changing by +11.4 ± 3.4%, +6.2 ± 4.0%, or 1.4 ± 3.8%, respectively (F = 1.95, 2 df, p = 0.145).
Central conduction time between leg motor cortex and tibialis anterior motor neurons was 14.0 ± 0.4 ms at baseline. After one exercise session, both balance ( 4.3 ± 2.6%) and multimodal exercise ( 4.5 ± 2.8%) demonstrated a reduction in CMCT, whereas treadmill exercise increased CMCT by +4.3 ± 2.7% (F = 3.33, 2 df, p = 0.045). Post hoc pairwise testing revealed significant differences between multimodal and treadmill exercise (p = 0.032), and between balance and treadmill exercise (p = 0.029). 4. Discussion The corticospinal tract (CST) mediates volitional muscle control mostly through direct connections between the motor cortex and spinal cord. Additionally, the CST emits collateral branches as it passes through the brainstem. These corticobulbar fibers mediate indirect connections between the motor cortex and spinal motor neurons (Jankowska et al., 2003; Riddle et al., 2009; Isa et al., 2013). We are interested in using targeted exercises to exploit the potential of corticobulbar circuits to indirectly mediate cortical signals through residual nerve fibers after SCI. Short-term neurophysiological endpoints are needed to better predict clinical responses to longer courses of neurorehabilitation therapy (Lammertse et al., 2007). One goal of this study was therefore to determine whether the acute neurophysiological effects of exercises designed to increase neural transmission between the motor cortex and spinal motor neurons could be measured after
N.Y. Harel et al. / Journal of Electromyography and Kinesiology 25 (2015) 438–443
441
Fig. 2. Soleus H-reflex facilitation. (A) Tibial nerve stimulation is given at varying intervals after a subthreshold TMS pulse over the corresponding leg motor cortex. The first trace is the unconditioned H-reflex baseline. The second trace confirms that the TMS pulse is subthreshold. Other traces show varying amounts of H-reflex facilitation at different interstimulus intervals. Traces are averages of five repetitions. (B and C) Change in H-reflex facilitation after undergoing one session each of three different exercise paradigms. (B) Short-interval facilitation (0–10 ms). (C) Long-interval facilitation (60–80 ms). Balance exercise, and to a lesser degree, multimodal exercise, tend to result in greater increase in post-session facilitation than treadmill exercise. ⁄p = 0.013 for balance versus treadmill exercise on post hoc testing.
just one session of a given exercise. Using this approach, we found that in able-bodied subjects, one session of balance exercise transiently increased soleus H-reflex facilitation and central motor conduction velocity more than one session of treadmill exercise. One session of multimodal exercise combining skilled hand with balance tasks increased central motor conduction velocity but did not significantly increase H-reflex facilitation. Physical exercise represents an accessible albeit non-specific method to activate different combinations of neural circuits. Postural adaptation requires integration of proprioceptive, visual, and vestibular sensory inputs with largely axial muscle outputs (Seelen et al., 1997; Lalonde and Strazielle, 2007). Therefore, balance exercises likely activate multiple subcortical circuits, including reticulospinal and vestibulospinal pathways, spinal, basal ganglia, and cerebellar centers (Drew et al., 2004; Iles et al., 2004; Lalonde and Strazielle, 2007). The balance tasks used in this study focused on maintaining posture on an unstable platform.
This involves axial postural adjustments rather than reaching maneuvers or agility skills. We speculate that this type of balance exercise activates brainstem and spinal sensory circuits to a relatively greater degree than visual and basal ganglia centers (Boutilier et al., 2012). The multimodal exercise regimen was designed to simultaneously stimulate cortical and brainstem circuits: balance exercise was combined with a skilled typing task requiring fractionated finger movements, which are known to activate corticospinal circuits (Lemon, 2008; Rothwell, 2012). A hand motor cortex task was chosen because volitional skilled foot tasks would not be feasible in subjects with SCI, especially while performing concurrent upright balance exercises. To our knowledge, the specific combination of balance and simultaneous skilled hand exercises used in this multimodal program has not previously been used in humans (Harel et al., 2010, 2013). We hypothesized that multimodal balance plus hand exercises would strengthen polysynaptic cortico-bulbo-spinal circuits to a
442
N.Y. Harel et al. / Journal of Electromyography and Kinesiology 25 (2015) 438–443
Fig. 3. Central motor conduction time. Baseline conduction time between leg motor cortex and tibialis anterior motor neurons was 14.0 ± 0.4 ms. Conduction time decreased (velocity increased) significantly after either balance or multimodal exercise, whereas it increased (velocity decreased) after treadmill exercise (⁄, on post hoc testing, p = 0.032 for multimodal versus treadmill exercise, p = 0.029 for balance versus treadmill exercise).
greater degree than treadmill or isolated balance exercise, reflected by increased long-interval H-reflex facilitation. Contrary to our hypothesis, multimodal exercise tended to affect H-reflex facilitation to a lesser degree than isolated balance exercise. This might be explained by several non-exclusive possibilities: The numerical typing task may have excessively stimulated non-motor areas (for example, visual or language cortex) rather than motor cortical areas (Stefan et al., 2004). The use of hand exercises activates hand motor cortex, whereas the goal of the multimodal approach is to improve transmission to the legs. Therefore, simultaneous subcortical and hand motor cortex activation could interfere with corticobulbar signaling to leg circuits. However, the balance exercises used in this study had effects that were relatively robust to potential interference from hand tasks. No standardized, non-invasive method currently exists to measure the strength of indirect corticobulbar connections. The technique used in this study, soleus H-reflex facilitation by subthreshold TMS, may provide greater insight on corticobulbar transmission than commonly used electrophysiological measures such as MEPs and central motor conduction time. ‘Indirect’ H-reflex facilitation (at interstimulus intervals between 60 and 80 ms) may result from polysynaptic routes that involve both intraspinal (Guzman-Lopez et al., 2012) and supraspinal circuits (Wolfe et al., 1996; Iles et al., 2004; Ahmed, 2013). ‘Direct’ H-reflex facilitation (ISI less than 20 ms) more clearly results from corticospinal tract input onto the spinal H-reflex circuit (Wolfe et al., 1996; Cortes et al., 2011; Guzman-Lopez et al., 2012). A study by Benito Penalva et al. analyzed the effect of 40 sessions of robotic treadmill gait training on TMS-mediated soleus H-reflex facilitation in a population of subjects with incomplete SCI (Benito Penalva et al., 2010). In that study, training improved a baseline deficit in the ‘direct’ (20 ms) facilitation time window, and this correlated with clinical improvement. Other studies have utilized TMS-mediated H-reflex facilitation to measure changes in transmission to the flexor carpi radialis (Zehr et al., 2007) or tibialis anterior (Hajela et al., 2013), or during walking (Petersen et al., 1998). Interestingly, despite the emphasis on strengthening indirect supraspinal transmission, parameters of direct corticospinal transmission were most sensitive to change in this study – that is, those of short-interval H-reflex facilitation and central motor conduction velocity. This study has several limitations. One exercise session may not be enough to induce consistently detectable changes in electrophysiological outcome measures. Findings in a small number of
able-bodied volunteers are not easily generalized to those in individuals with SCI, who represent the ultimate target population for these interventions. Physical exercises, especially balance tasks requiring multiple integrated systems, cannot be expected to exclusively activate the targeted circuits. Therefore, the observed outcomes could reflect physiological changes in non-targeted circuits. Functional magnetic resonance imaging, near-infrared spectroscopy, or other techniques to assess the neural components activated in real time were not performed. Furthermore, the use of H-reflex facilitation to probe for changes in corticobulbar transmission in humans is not yet a proven method. Finally, dropout and technical artifacts prevented completion of all sessions and outcomes for each enrolled subject. It is unknown whether a longer period of repeated exercise training, in the setting of damaged rather than intact connections between the cortex and spinal cord, is likely to result in stronger neuro physiological or functional changes. Furthermore, it remains to be determined whether better synergy between cortical and brainstem signaling to the legs would be derived from combining balance exercises with concurrent skilled foot exercises (perhaps performed virtually in subjects with SCI). 5. Conclusion The acute neurophysiological effects of exercises targeted at different levels of the central nervous system were tested in ablebodied subjects. A single session of isolated balance exercise increased direct soleus H-reflex facilitation more than a single session of treadmill exercise. Single sessions of either balance or multimodal exercises increased tibialis anterior central motor conduction velocity more than a single session of treadmill exercise. Conflict of interest statement The authors declare no potential conflict of interest regarding this work. Acknowledgments This work was funded by VA Rehabilitation Research & Development Grants B0881-W and B9212-C, as well as salary and equipment support from the Department of Neurology at Icahn School of Medicine at Mount Sinai. We thank Ajax Yang, MD, DPT, for insights into different exercises related to this work. We thank William A. Bauman, MD, for review and improvement of this manuscript. References Ahmed Z. Electrophysiological characterization of spino-sciatic and cortico-sciatic associative plasticity: modulation by trans-spinal direct current and effects on recovery after spinal cord injury in mice. J Neurosci 2013;33(11):4935–46. Bareyre FM, Kerschensteiner M, Raineteau O, Mettenleiter TC, Weinmann O, Schwab ME. The injured spinal cord spontaneously forms a new intraspinal circuit in adult rats. Nat Neurosci 2004;7(3):269–77. Benito Penalva J, Opisso E, Medina J, Corrons M, Kumru H, Vidal J, et al. H reflex modulation by transcranial magnetic stimulation in spinal cord injury subjects after gait training with electromechanical systems. Spinal Cord 2010;48(5):400–6. Boutilier G, Sawatzky BJ, Grant C, Wiefelspuett S, Finlayson H. Spasticity changes in SCI following a dynamic standing program using the Segway. Spinal Cord 2012;50(8):595–8 [Nature Publishing Group]. Chen XY, Chen Y, Wang Y, Thompson A, Carp JS, Segal RL, et al. Reflex conditioning: a new strategy for improving motor function after spinal cord injury. Ann N Y Acad Sci 2010;1198(Suppl.):E12–21. Cortes M, Thickbroom GW, Valls-Sole J, Pascual-Leone A, Edwards DJ. Spinal associative stimulation: a non-invasive stimulation paradigm to modulate spinal excitability. Clin Neurophysiol 2011;122(11):2254–9 [International Federation of Clinical Neurophysiology].
N.Y. Harel et al. / Journal of Electromyography and Kinesiology 25 (2015) 438–443 Courtine G, Song B, Roy RR, Zhong H, Herrmann JE, Ao Y, et al. Recovery of supraspinal control of stepping via indirect propriospinal relay connections after spinal cord injury. Nat Med 2008;14(1):69–74. Drew T, Prentice S, Schepens B. Cortical and brainstem control of locomotion. Prog Brain Res 2004;143(03):251–61. Guzman-Lopez J, Costa J, Selvi A, Barraza G, Casanova-Molla J, Valls-Sole J. The effects of transcranial magnetic stimulation on vibratory-induced presynaptic inhibition of the soleus H reflex. Exp Brain Res 2012;220(3–4):223–30. Hajela N, Mummidisetty C, Smith A, Kinkou M. Corticospinal reorganization after locomotor training in a person with motor incomplete paraplegia. Biomed Res Int 2013 [Article ID 516427]. Harel NY, Song KH, Tang X, Strittmatter SM. Nogo receptor deletion and multimodal exercise improve distinct aspects of recovery in cervical spinal cord injury. J Neurotrauma 2010;27(11):2055–66. Harel NY, Yigitkanli K, Fu Y, Cafferty WBJ, Strittmatter SM. Multimodal exercises simultaneously stimulating cortical and brainstem pathways after unilateral corticospinal lesion. Brain Res 2013;13(1538):17–25. Hermens HJ, Freriks B, Disselhorst-Klug C, Rau G. Development of recommendations for SEMG sensors and sensor placement procedures. J Electromyogr Kinesiol 2000;10(5):361–74. Iles JF, Ali AS, Savic G. Vestibular-evoked muscle responses in patients with spinal cord injury. Brain 2004;127(Pt 7):1584–92. Isa T, Kinoshita M, Nishimura Y. Role of direct vs. indirect pathways from the motor cortex to spinal motoneurons in the control of hand dexterity. Front Neurol 2013;4:191. Jankowska E, Edgley SA. How can corticospinal tract neurons contribute to ipsilateral movements? A question with implications for recovery of motor functions. Neuroscientist 2006;12(1):67–79. Jankowska E, Hammar I, Slawinska U, Maleszak K, Edgley SA. Neuronal basis of crossed actions from the reticular formation on feline hindlimb motoneurons. J Neurosci 2003;23:1867–78. Lalonde R, Strazielle C. Brain regions and genes affecting postural control. Prog Neurobiol 2007;81(1):45–60. Lammertse D, Tuszynski MH, Steeves JD, Curt A, Fawcett JW, Rask C, et al. Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: clinical trial design. Spinal Cord 2007;45(3):232–42. Lemon RN. Descending pathways in motor control. Annu Rev Neurosci 2008;31:195–218. Nathan PW, Smith M, Deacon P. Vestibulospinal, reticulospinal and descending propriospinal nerve fibres in man. Brain 1996;119(Pt 6):1809–33. Nielsen J, Petersen N. Evidence favouring different descending pathways to soleus motoneurones activated by magnetic brain stimulation in man. J Physiol 1995;486:779–88. Petersen N, Christensen LO, Nielsen J. The effect of transcranial magnetic stimulation on the soleus H reflex during human walking. J Physiol 1998;513:599–610. Riddle CN, Edgley SA, Baker SN. Direct and indirect connections with upper limb motoneurons from the primate reticulospinal tract. J Neurosci 2009;29(15):4993–9. Robinson LR, Jantra P, MacLean IC. Central motor conduction times using transcranial stimulation and F wave latencies. Muscle Nerve 1988;11(2):174–80. Rossi S, Hallett M, Rossini PM, Pascual-Leone A. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol 2009;120(12):2008–39 [International Federation of Clinical Neurophysiology]. Rothwell JC. Overview of neurophysiology of movement control. Clin Neurol Neurosurg 2012;114(5):432–5. Sasaki S, Isa T, Pettersson LG, Alstermark B, Naito K, Yoshimura K, et al. Dexterous finger movements in primate without monosynaptic corticomotoneuronal excitation. J Neurophysiol 2004;92(5):3142–7. Seelen HA, Potten YJ, Huson A, Spaans F, Reulen JP. Impaired balance control in paraplegic subjects. J Electromyogr Kinesiol 1997;7(2):149–60. Serranova T, Valls-Sole J, Munoz E, Genis D, Jech R, Seeman P. Abnormal corticospinal tract modulation of the soleus H reflex in patients with pure spastic paraparesis. Neurosci Lett 2008;437(1):15–9. Stefan K, Wycislo M, Classen J. Modulation of associative human motor cortical plasticity by attention. J Neurophysiol 2004;92(1):66–72. Thompson AK, Pomerantz FR, Wolpaw JR. Operant conditioning of a spinal reflex can improve locomotion after spinal cord injury in humans. J Neurosci 2013;33(6):2365–75. Thompson AK, Wolpaw JR. Operant conditioning of spinal reflexes: from basic science to clinical therapy. Front Integr Neurosci 2014;8:25. Wellek S, Blettner M. On the proper use of the crossover design in clinical trials: part 18 of a series on evaluation of scientific publications. Dtsch Arztebl Int 2012;109(15):276–81. Wolfe DL, Hayes KC, Potter PJ, Delaney GA. Conditioning lower limb H-reflexes by transcranial magnetic stimulation of motor cortex reveals preserved innervation in SCI patients. J Neurotrauma 1996;13(6):281–91. Zehr EP, Klimstra M, Johnson EA, Carroll TJ. Rhythmic leg cycling modulates forearm muscle H-reflex amplitude and corticospinal tract excitability. Neurosci Lett 2007;419(1):10–4.
443
Noam Y. Harel, MD, PhD is a Staff Physician at the James J. Peters Veterans Affairs Medical Center and Assistant Professor in Neurology and Rehabilitation Medicine at the Icahn School of Medicine at Mount Sinai.
Stephanie A. Martinez, BS is a Clinical Research Coordinator at the James J. Peters Veterans Affairs Medical Center.
Steven Knezevic, BS, MS is a Health Science Technician at the James J. Peters Veterans Affairs Medical Center.
Pierre K. Asselin, BS, MS is a Health Science Specialist at the James J. Peters Veterans Affairs Medical Center.
Ann M. Spungen, EdD is a Research Scientist at the James J. Peters Veterans Affairs Medical Center, Associate Director of the Veterans Affairs Rehabilitation Research and Development National Center of Excellence for the Medical Consequences of Spinal Cord Injury, and Associate Professor of Medicine and Rehabilitation Medicine at the Icahn School of Medicine at Mount Sinai.
Contents lists available at ScienceDirect
Journal of Electromyography and Kinesiology journal homepage: www.elsevier.com/locate/jelekin
Acute changes in soleus H-reflex facilitation and central motor conduction after targeted physical exercises Noam Y. Harel a,b,c,⇑, Stephanie A. Martinez a, Steven Knezevic a, Pierre K. Asselin a, Ann M. Spungen a,c,d a
RR&D National Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peters VA Medical Center, Bronx, NY, United States Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States c Department of Rehabilitation Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States d Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States b
a r t i c l e
i n f o
Article history: Received 3 August 2014 Received in revised form 24 January 2015 Accepted 17 February 2015
Keywords: H-reflex facilitation Transcranial magnetic stimulation Corticospinal Reticulospinal Balance exercise
a b s t r a c t We tested the acute effect of exercises targeted simultaneously at cortical and brainstem circuits on neural transmission through corticobulbar connections. Corticobulbar pathways represent a potential target for rehabilitation after spinal cord injury (SCI), which tends to spare brainstem circuits to a greater degree than cortical circuits. To explore this concept, able-bodied volunteers (n = 20) underwent one session each of three exercises targeted at different nervous system components: treadmill walking (spinal locomotor circuits), isolated balance exercise (brainstem and other pathways), and multimodal balance plus skilled hand exercise (hand motor cortex and corticospinal tract). We found that short-interval soleus H-reflex facilitation increased after one session of balance and multimodal exercise by 13.2 ± 4.0% and 8.3 ± 4.7%, and slightly decreased by 1.9 ± 4.4% after treadmill exercise (p = 0.042 on ANOVA across exercise type). Increases in long-interval H-reflex facilitation were not significantly different between exercises. Both balance and multimodal exercise increased central motor conduction velocity by 4.3 ± 2.6% and 4.5 ± 2.8%, whereas velocity decreased by 4.3 ± 2.7% after treadmill exercise (p = 0.045 on ANOVA across exercise type). In conclusion, electrophysiological transmission between the motor cortex and spinal motor neurons in able-bodied subjects increased more following one session of balance exercise than treadmill exercise. Published by Elsevier Ltd.
1. Introduction After contusive spinal cord injury (SCI), spared circuits often consist predominantly of brainstem pathways (Nathan et al., 1996; Jankowska and Edgley, 2006). Descending brainstem pathways connect to many of the same spinal motor neurons to which volitional corticospinal circuits connect (Sasaki et al., 2004; Riddle et al., 2009). Therefore, in the context of SCI, strengthened connections between cortical and brainstem circuits above the injury could provide detour pathways for cortical signals to reach spinal motor neurons below the injury. Previous experiments in animals have demonstrated the potential for detour connections to mediate cortical signals after SCI (Bareyre et al., 2004; Courtine et al., 2008). Our group has applied targeted exercises designed to repetitively and simultaneously
⇑ Corresponding author at: 130 West Kingsbridge Rd, Bronx, NY 10468, United States. Tel.: +1 718 584 9000x1742; fax: +1 718 741 4675. E-mail address: [email protected] (N.Y. Harel). http://dx.doi.org/10.1016/j.jelekin.2015.02.009 1050-6411/Published by Elsevier Ltd.
stimulate cortical and brainstem circuits in animal models to maximize the potential of this mechanism (Harel et al., 2010, 2013). The current report was designed as a proof-of-principle study in able-bodied subjects prior to initiating a trial in individuals with chronic SCI. The goals were to (1) determine the preliminary sensitivity of electrophysiological parameters to detect acute change in response to single sessions of targeted physical exercises; and (2) to test how the addition of exercises stimulating cortical circuits involved in hand control would affect the response to exercises stimulating brainstem and spinal circuits involved in leg control. Volunteers underwent one session each of three different types of exercise – treadmill walking (targeted at spinal locomotor circuits); balance exercise (requiring integrated activation of multiple neural circuit types); or multimodal exercises incorporating balance and simultaneous skilled hand exercises (to activate corticospinal circuits). The main outcome measures were electrophysiological parameters of neural transmission between cortical and spinal motor centers: tibialis anterior motor evoked potentials (MEP), tibialis anterior central motor conduction time, and soleus H-reflex facilitation by subthreshold transcranial magnetic stimulation (TMS).
N.Y. Harel et al. / Journal of Electromyography and Kinesiology 25 (2015) 438–443
The latter technique, soleus H-reflex facilitation, reflects both direct and indirect cortical–spinal transmission. The spinal synapse mediating the H-reflex is subject to influence and modulation by multiple intraspinal and supraspinal inputs (Chen et al., 2010; Thompson et al., 2013; Thompson and Wolpaw, 2014). Even when a TMS pulse is subthreshold for eliciting an evoked potential directly from the target muscle, it can still alter excitability of multiple pathways that lead to modulation of the ensuing H-reflex (Wolfe et al., 1996; Cortes et al., 2011). Varying the interstimulus interval (ISI) between TMS and H-reflex pulses results in different degrees of facilitation and inhibition over different ISI (Nielsen and Petersen, 1995; Wolfe et al., 1996; Serranova et al., 2008; Benito Penalva et al., 2010). One interpretation of these phases posits that they reveal the influence of direct and indirect supraspinal pathways – modulation at short ISI between 0 and 20 ms likely reflects direct pathways, whereas modulation at longer ISI of 60 or more ms may reflect a combination of indirect pathways (Wolfe et al., 1996; Serranova et al., 2008; Benito Penalva et al., 2010). We therefore measured the acute effect of different exercises on H-reflex facilitation in both direct and indirect interval periods. 2. Methods 2.1. Participants Able-bodied volunteers between the age of 21 and 55 years were recruited. Exclusion criteria included significant neurological disease or excessive risk of TMS: history of seizures, medications that increase seizure risk, or implanted electrical or ferromagnetic devices (Rossi et al., 2009). Data were entirely excluded from four of the 24 originally enrolled participants: two did not a have reliable soleus H-reflex response, one did not have reliable tibialis anterior motor evoked potential, and one did not tolerate testing. The remaining 20 subjects had a mean age of 30.8 ± 8.8 years. 10 were female. Technical artifacts prevented complete data analysis for several other sessions as follows: for H-reflex facilitation, the numbers analyzed by exercise were 16 treadmill, 20 balance, and 14 multimodal; for MEPs, 17 treadmill, 16 balance, and 17 multimodal; and for central conduction time 16 treadmill, 17 balance, and 14 multimodal. All procedures were approved by the Institutional Review Board of the James J. Peters VA Medical Center, Bronx, NY. We certify that all applicable institutional and governmental regulations concerning the ethical use of human volunteers were followed during the course of this research. 2.2. Design Subjects underwent electrophysiological testing immediately before and after one 30-min exercise session on three separate days. Post-session testing began within 2 min after exercise termination and took approximately 15–20 min to complete. Exercises were scheduled in random order for each subject. Sessions were separated by at least three days to allow for washout of acute effects. Individual subjects had sessions at roughly the same time of day (morning or afternoon) to control for potential diurnal variation. All results are expressed as percentage change of post-session parameters compared to pre-session parameters. 2.3. Exercises (Fig. 1) Each 30-min session was broken down into 10 periods of 2min ‘on’ and 1-min ‘off’. Subjects did not receive any weight support.
439
2.3.1. Treadmill walking Subjects walked comfortably on a treadmill at 3.2 km/h (except for the initial 2-min period at 2.0 km/h). Subjects were encouraged to swing the arms while walking. 2.3.2. Balance exercise Subjects stood with feet shoulder-width apart on a Bosu™ platform (approximately 63.5 cm diameter, 23 cm height). Subjects were instructed to maintain balance without using the handrails except when needed for safety. To augment task variability, the flat and convex surfaces of the Bosu™ ball were alternated during 10 successive 2-min periods. Subjects were able to maintain balance with minimal or no use of handrails. 2.3.3. Multimodal exercise While performing balance exercises exactly as described above, subjects were asked to type a series of 9-digit numbers into a numerical keypad using one hand. Equal amounts of numbers were directed toward the subject’s left and right hand. Each subject received the same set of randomly generated numbers. To maximize motor cortex activation through fractionated finger use, subjects were instructed to use multiple fingers to type in the numbers (Lemon, 2008). To keep postural task difficulty similar to the balance-only exercise session, care was taken to avoid bearing any weight on the hand in use. 2.4. Testing All electrophysiological assessments were performed in the supine position with knees resting on a foam roll and ankles placed in passive neutral position using a footrest. Surface Ag–AgCl electrodes (Natus) were applied to the bellies of the dominant (based on side of hand used for writing) tibialis anterior and soleus muscles according to SENIAM recommendations (Hermens et al., 2000) (http://seniam.org/sensor_location.htm). Another pair of Ag–AgCl surface electrodes was placed over the tibial nerve in the popliteal fossa to be used for electrical stimulation. The positioning of the stimulating electrode was determined by response to electrical stimulation using a handheld probe (Natus). Recordings were collected with a Viking Select electromyography system (Natus) at a bandwidth of 10–1000 Hz and a sample rate of 5000 Hz. Peripheral responses – The peroneal nerve was stimulated with 0.1 ms pulses at supramaximal intensity to define the tibialis anterior maximal compound motor action potential (Mmax) as well as to elicit F-waves in the antidromic orientation. The tibial nerve was stimulated with 1.0 ms pulses at a range of intensities to determine the threshold and slope of the H-reflex recruitment curve, and the soleus Mmax. For measuring H-reflex facilitation (described below), unconditioned stimulation intensity was set to elicit an H-reflex of 10–20% of Mmax (Serranova et al., 2008). Transcranial magnetic stimulation – A MagPro R30 with MagOption system (MagVenture) was used. The first 12 subjects tested received stimulation with a 70 mm figure-of-eight coil (MC-B70), whereas the last 12 subjects received stimulation with an 80 mm winged coil (D-B80). The TMS coil was centered over the leg motor cortex hotspot for maximal tibialis anterior response. Resting motor threshold was determined as the percent of maximal stimulator output required to elicit a potential of at least 25 lV in 5 out of 10 repetitions. MEP amplitudes were measured over a range of stimulator intensities, with an average of 5 repetitions per intensity. To account for changes in electrode placement and electrode–skin impedance between testing sessions, all MEP amplitudes were normalized to each session’s peripherally evoked Mmax. Central motor conduction time (CMCT) was calculated using M- and F-wave latencies obtained from supramaximal stimulation of the peroneal nerve:
440
N.Y. Harel et al. / Journal of Electromyography and Kinesiology 25 (2015) 438–443
Fig. 1. Exercise paradigms. Treadmill walking (targeted at spinal locomotor central pattern generator (CPG)); balance exercise (targeted at brainstem and other pathways); and multimodal exercise (balance exercises plus fractionated hand exercises targeted at the corticospinal tract (CST)).
CMCT = MEP latency et al., 1988).
[(F latency + M latency
1)/2] (Robinson
2.5. Soleus H-reflex facilitation by transcranial magnetic stimulation TMS pulses (at 80% of tibialis anterior resting motor threshold) were delivered prior to tibial nerve pulses at interstimulus intervals (ISI) of 0–80 ms in pseudorandom order. A minimum of 10 s elapsed between each pulse. TMS-conditioned soleus H-reflex amplitude (average over 5 repetitions) was compared to unconditioned H-reflex amplitude to determine the percent facilitation at each ISI (Wolfe et al., 1996).
At long ISI between 60 and 80 ms, balance, multimodal, and treadmill exercise acutely increased facilitation by 14.2 ± 6.1%, 5.5 ± 6.7%, and 5.7 ± 7.2%, respectively (ns). Isolated balance exercise was the only modality to demonstrate 95% confidence interval of the percent change greater than zero for both short (95%CI 5.28– 21.05) and long (95%CI 2.16–26.30) ISI. 3.2. Tibialis anterior MEPs All exercises acutely increased tibialis anterior MEP amplitude to a similar degree. At 110% of resting motor threshold, post-session MEP amplitude increased by 71 ± 40% for treadmill, 63 ± 42% for balance, and 59 ± 41% for multimodal exercise (ns, not shown).
2.6. Statistics 3.3. Central motor conduction time (CMCT) (Fig. 3) For each exercise condition, the main variable was percent change from baseline pre-session testing. There were no significant effects of intervention order on any of the outcomes. The most rigorous method of analyzing data from crossover studies involves the use of independent-sample rather than repeated-measures tests (Wellek and Blettner, 2012). One-way analysis of variance (ANOVA) was conducted to compare the three exercise interventions on percent change from baseline. Significance was accepted at values of p = 0.05 or less. ANOVA models with statistically significant main effects were further tested by post hoc pairwise ttests. No correction was made for multiple comparisons among outcome measures. Microsoft Excel and SAS JMP 8.0 were used to perform all analyses. 3. Results 3.1. H-reflex facilitation (Fig. 2) Pre-exercise facilitation at short interstimulus intervals (ISI) was 115 ± 2%, whereas at long ISI it was 122 ± 3%. At ISI between 0 and 10 ms, one session of balance, multimodal, or treadmill exercise changed facilitation by +13.2 ± 4.0%, +8.3 ± 4.7%, or 1.9 ± 4.4%, respectively (F = 3.24, 2 df, p = 0.042; on post hoc pairwise testing, p = 0.013 for balance versus treadmill exercise, ns for other pairs). A similar trend toward significance was noted at ISI between 0 and 20 ms, with facilitation changing by +11.4 ± 3.4%, +6.2 ± 4.0%, or 1.4 ± 3.8%, respectively (F = 1.95, 2 df, p = 0.145).
Central conduction time between leg motor cortex and tibialis anterior motor neurons was 14.0 ± 0.4 ms at baseline. After one exercise session, both balance ( 4.3 ± 2.6%) and multimodal exercise ( 4.5 ± 2.8%) demonstrated a reduction in CMCT, whereas treadmill exercise increased CMCT by +4.3 ± 2.7% (F = 3.33, 2 df, p = 0.045). Post hoc pairwise testing revealed significant differences between multimodal and treadmill exercise (p = 0.032), and between balance and treadmill exercise (p = 0.029). 4. Discussion The corticospinal tract (CST) mediates volitional muscle control mostly through direct connections between the motor cortex and spinal cord. Additionally, the CST emits collateral branches as it passes through the brainstem. These corticobulbar fibers mediate indirect connections between the motor cortex and spinal motor neurons (Jankowska et al., 2003; Riddle et al., 2009; Isa et al., 2013). We are interested in using targeted exercises to exploit the potential of corticobulbar circuits to indirectly mediate cortical signals through residual nerve fibers after SCI. Short-term neurophysiological endpoints are needed to better predict clinical responses to longer courses of neurorehabilitation therapy (Lammertse et al., 2007). One goal of this study was therefore to determine whether the acute neurophysiological effects of exercises designed to increase neural transmission between the motor cortex and spinal motor neurons could be measured after
N.Y. Harel et al. / Journal of Electromyography and Kinesiology 25 (2015) 438–443
441
Fig. 2. Soleus H-reflex facilitation. (A) Tibial nerve stimulation is given at varying intervals after a subthreshold TMS pulse over the corresponding leg motor cortex. The first trace is the unconditioned H-reflex baseline. The second trace confirms that the TMS pulse is subthreshold. Other traces show varying amounts of H-reflex facilitation at different interstimulus intervals. Traces are averages of five repetitions. (B and C) Change in H-reflex facilitation after undergoing one session each of three different exercise paradigms. (B) Short-interval facilitation (0–10 ms). (C) Long-interval facilitation (60–80 ms). Balance exercise, and to a lesser degree, multimodal exercise, tend to result in greater increase in post-session facilitation than treadmill exercise. ⁄p = 0.013 for balance versus treadmill exercise on post hoc testing.
just one session of a given exercise. Using this approach, we found that in able-bodied subjects, one session of balance exercise transiently increased soleus H-reflex facilitation and central motor conduction velocity more than one session of treadmill exercise. One session of multimodal exercise combining skilled hand with balance tasks increased central motor conduction velocity but did not significantly increase H-reflex facilitation. Physical exercise represents an accessible albeit non-specific method to activate different combinations of neural circuits. Postural adaptation requires integration of proprioceptive, visual, and vestibular sensory inputs with largely axial muscle outputs (Seelen et al., 1997; Lalonde and Strazielle, 2007). Therefore, balance exercises likely activate multiple subcortical circuits, including reticulospinal and vestibulospinal pathways, spinal, basal ganglia, and cerebellar centers (Drew et al., 2004; Iles et al., 2004; Lalonde and Strazielle, 2007). The balance tasks used in this study focused on maintaining posture on an unstable platform.
This involves axial postural adjustments rather than reaching maneuvers or agility skills. We speculate that this type of balance exercise activates brainstem and spinal sensory circuits to a relatively greater degree than visual and basal ganglia centers (Boutilier et al., 2012). The multimodal exercise regimen was designed to simultaneously stimulate cortical and brainstem circuits: balance exercise was combined with a skilled typing task requiring fractionated finger movements, which are known to activate corticospinal circuits (Lemon, 2008; Rothwell, 2012). A hand motor cortex task was chosen because volitional skilled foot tasks would not be feasible in subjects with SCI, especially while performing concurrent upright balance exercises. To our knowledge, the specific combination of balance and simultaneous skilled hand exercises used in this multimodal program has not previously been used in humans (Harel et al., 2010, 2013). We hypothesized that multimodal balance plus hand exercises would strengthen polysynaptic cortico-bulbo-spinal circuits to a
442
N.Y. Harel et al. / Journal of Electromyography and Kinesiology 25 (2015) 438–443
Fig. 3. Central motor conduction time. Baseline conduction time between leg motor cortex and tibialis anterior motor neurons was 14.0 ± 0.4 ms. Conduction time decreased (velocity increased) significantly after either balance or multimodal exercise, whereas it increased (velocity decreased) after treadmill exercise (⁄, on post hoc testing, p = 0.032 for multimodal versus treadmill exercise, p = 0.029 for balance versus treadmill exercise).
greater degree than treadmill or isolated balance exercise, reflected by increased long-interval H-reflex facilitation. Contrary to our hypothesis, multimodal exercise tended to affect H-reflex facilitation to a lesser degree than isolated balance exercise. This might be explained by several non-exclusive possibilities: The numerical typing task may have excessively stimulated non-motor areas (for example, visual or language cortex) rather than motor cortical areas (Stefan et al., 2004). The use of hand exercises activates hand motor cortex, whereas the goal of the multimodal approach is to improve transmission to the legs. Therefore, simultaneous subcortical and hand motor cortex activation could interfere with corticobulbar signaling to leg circuits. However, the balance exercises used in this study had effects that were relatively robust to potential interference from hand tasks. No standardized, non-invasive method currently exists to measure the strength of indirect corticobulbar connections. The technique used in this study, soleus H-reflex facilitation by subthreshold TMS, may provide greater insight on corticobulbar transmission than commonly used electrophysiological measures such as MEPs and central motor conduction time. ‘Indirect’ H-reflex facilitation (at interstimulus intervals between 60 and 80 ms) may result from polysynaptic routes that involve both intraspinal (Guzman-Lopez et al., 2012) and supraspinal circuits (Wolfe et al., 1996; Iles et al., 2004; Ahmed, 2013). ‘Direct’ H-reflex facilitation (ISI less than 20 ms) more clearly results from corticospinal tract input onto the spinal H-reflex circuit (Wolfe et al., 1996; Cortes et al., 2011; Guzman-Lopez et al., 2012). A study by Benito Penalva et al. analyzed the effect of 40 sessions of robotic treadmill gait training on TMS-mediated soleus H-reflex facilitation in a population of subjects with incomplete SCI (Benito Penalva et al., 2010). In that study, training improved a baseline deficit in the ‘direct’ (20 ms) facilitation time window, and this correlated with clinical improvement. Other studies have utilized TMS-mediated H-reflex facilitation to measure changes in transmission to the flexor carpi radialis (Zehr et al., 2007) or tibialis anterior (Hajela et al., 2013), or during walking (Petersen et al., 1998). Interestingly, despite the emphasis on strengthening indirect supraspinal transmission, parameters of direct corticospinal transmission were most sensitive to change in this study – that is, those of short-interval H-reflex facilitation and central motor conduction velocity. This study has several limitations. One exercise session may not be enough to induce consistently detectable changes in electrophysiological outcome measures. Findings in a small number of
able-bodied volunteers are not easily generalized to those in individuals with SCI, who represent the ultimate target population for these interventions. Physical exercises, especially balance tasks requiring multiple integrated systems, cannot be expected to exclusively activate the targeted circuits. Therefore, the observed outcomes could reflect physiological changes in non-targeted circuits. Functional magnetic resonance imaging, near-infrared spectroscopy, or other techniques to assess the neural components activated in real time were not performed. Furthermore, the use of H-reflex facilitation to probe for changes in corticobulbar transmission in humans is not yet a proven method. Finally, dropout and technical artifacts prevented completion of all sessions and outcomes for each enrolled subject. It is unknown whether a longer period of repeated exercise training, in the setting of damaged rather than intact connections between the cortex and spinal cord, is likely to result in stronger neuro physiological or functional changes. Furthermore, it remains to be determined whether better synergy between cortical and brainstem signaling to the legs would be derived from combining balance exercises with concurrent skilled foot exercises (perhaps performed virtually in subjects with SCI). 5. Conclusion The acute neurophysiological effects of exercises targeted at different levels of the central nervous system were tested in ablebodied subjects. A single session of isolated balance exercise increased direct soleus H-reflex facilitation more than a single session of treadmill exercise. Single sessions of either balance or multimodal exercises increased tibialis anterior central motor conduction velocity more than a single session of treadmill exercise. Conflict of interest statement The authors declare no potential conflict of interest regarding this work. Acknowledgments This work was funded by VA Rehabilitation Research & Development Grants B0881-W and B9212-C, as well as salary and equipment support from the Department of Neurology at Icahn School of Medicine at Mount Sinai. We thank Ajax Yang, MD, DPT, for insights into different exercises related to this work. We thank William A. Bauman, MD, for review and improvement of this manuscript. References Ahmed Z. Electrophysiological characterization of spino-sciatic and cortico-sciatic associative plasticity: modulation by trans-spinal direct current and effects on recovery after spinal cord injury in mice. J Neurosci 2013;33(11):4935–46. Bareyre FM, Kerschensteiner M, Raineteau O, Mettenleiter TC, Weinmann O, Schwab ME. The injured spinal cord spontaneously forms a new intraspinal circuit in adult rats. Nat Neurosci 2004;7(3):269–77. Benito Penalva J, Opisso E, Medina J, Corrons M, Kumru H, Vidal J, et al. H reflex modulation by transcranial magnetic stimulation in spinal cord injury subjects after gait training with electromechanical systems. Spinal Cord 2010;48(5):400–6. Boutilier G, Sawatzky BJ, Grant C, Wiefelspuett S, Finlayson H. Spasticity changes in SCI following a dynamic standing program using the Segway. Spinal Cord 2012;50(8):595–8 [Nature Publishing Group]. Chen XY, Chen Y, Wang Y, Thompson A, Carp JS, Segal RL, et al. Reflex conditioning: a new strategy for improving motor function after spinal cord injury. Ann N Y Acad Sci 2010;1198(Suppl.):E12–21. Cortes M, Thickbroom GW, Valls-Sole J, Pascual-Leone A, Edwards DJ. Spinal associative stimulation: a non-invasive stimulation paradigm to modulate spinal excitability. Clin Neurophysiol 2011;122(11):2254–9 [International Federation of Clinical Neurophysiology].
N.Y. Harel et al. / Journal of Electromyography and Kinesiology 25 (2015) 438–443 Courtine G, Song B, Roy RR, Zhong H, Herrmann JE, Ao Y, et al. Recovery of supraspinal control of stepping via indirect propriospinal relay connections after spinal cord injury. Nat Med 2008;14(1):69–74. Drew T, Prentice S, Schepens B. Cortical and brainstem control of locomotion. Prog Brain Res 2004;143(03):251–61. Guzman-Lopez J, Costa J, Selvi A, Barraza G, Casanova-Molla J, Valls-Sole J. The effects of transcranial magnetic stimulation on vibratory-induced presynaptic inhibition of the soleus H reflex. Exp Brain Res 2012;220(3–4):223–30. Hajela N, Mummidisetty C, Smith A, Kinkou M. Corticospinal reorganization after locomotor training in a person with motor incomplete paraplegia. Biomed Res Int 2013 [Article ID 516427]. Harel NY, Song KH, Tang X, Strittmatter SM. Nogo receptor deletion and multimodal exercise improve distinct aspects of recovery in cervical spinal cord injury. J Neurotrauma 2010;27(11):2055–66. Harel NY, Yigitkanli K, Fu Y, Cafferty WBJ, Strittmatter SM. Multimodal exercises simultaneously stimulating cortical and brainstem pathways after unilateral corticospinal lesion. Brain Res 2013;13(1538):17–25. Hermens HJ, Freriks B, Disselhorst-Klug C, Rau G. Development of recommendations for SEMG sensors and sensor placement procedures. J Electromyogr Kinesiol 2000;10(5):361–74. Iles JF, Ali AS, Savic G. Vestibular-evoked muscle responses in patients with spinal cord injury. Brain 2004;127(Pt 7):1584–92. Isa T, Kinoshita M, Nishimura Y. Role of direct vs. indirect pathways from the motor cortex to spinal motoneurons in the control of hand dexterity. Front Neurol 2013;4:191. Jankowska E, Edgley SA. How can corticospinal tract neurons contribute to ipsilateral movements? A question with implications for recovery of motor functions. Neuroscientist 2006;12(1):67–79. Jankowska E, Hammar I, Slawinska U, Maleszak K, Edgley SA. Neuronal basis of crossed actions from the reticular formation on feline hindlimb motoneurons. J Neurosci 2003;23:1867–78. Lalonde R, Strazielle C. Brain regions and genes affecting postural control. Prog Neurobiol 2007;81(1):45–60. Lammertse D, Tuszynski MH, Steeves JD, Curt A, Fawcett JW, Rask C, et al. Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: clinical trial design. Spinal Cord 2007;45(3):232–42. Lemon RN. Descending pathways in motor control. Annu Rev Neurosci 2008;31:195–218. Nathan PW, Smith M, Deacon P. Vestibulospinal, reticulospinal and descending propriospinal nerve fibres in man. Brain 1996;119(Pt 6):1809–33. Nielsen J, Petersen N. Evidence favouring different descending pathways to soleus motoneurones activated by magnetic brain stimulation in man. J Physiol 1995;486:779–88. Petersen N, Christensen LO, Nielsen J. The effect of transcranial magnetic stimulation on the soleus H reflex during human walking. J Physiol 1998;513:599–610. Riddle CN, Edgley SA, Baker SN. Direct and indirect connections with upper limb motoneurons from the primate reticulospinal tract. J Neurosci 2009;29(15):4993–9. Robinson LR, Jantra P, MacLean IC. Central motor conduction times using transcranial stimulation and F wave latencies. Muscle Nerve 1988;11(2):174–80. Rossi S, Hallett M, Rossini PM, Pascual-Leone A. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol 2009;120(12):2008–39 [International Federation of Clinical Neurophysiology]. Rothwell JC. Overview of neurophysiology of movement control. Clin Neurol Neurosurg 2012;114(5):432–5. Sasaki S, Isa T, Pettersson LG, Alstermark B, Naito K, Yoshimura K, et al. Dexterous finger movements in primate without monosynaptic corticomotoneuronal excitation. J Neurophysiol 2004;92(5):3142–7. Seelen HA, Potten YJ, Huson A, Spaans F, Reulen JP. Impaired balance control in paraplegic subjects. J Electromyogr Kinesiol 1997;7(2):149–60. Serranova T, Valls-Sole J, Munoz E, Genis D, Jech R, Seeman P. Abnormal corticospinal tract modulation of the soleus H reflex in patients with pure spastic paraparesis. Neurosci Lett 2008;437(1):15–9. Stefan K, Wycislo M, Classen J. Modulation of associative human motor cortical plasticity by attention. J Neurophysiol 2004;92(1):66–72. Thompson AK, Pomerantz FR, Wolpaw JR. Operant conditioning of a spinal reflex can improve locomotion after spinal cord injury in humans. J Neurosci 2013;33(6):2365–75. Thompson AK, Wolpaw JR. Operant conditioning of spinal reflexes: from basic science to clinical therapy. Front Integr Neurosci 2014;8:25. Wellek S, Blettner M. On the proper use of the crossover design in clinical trials: part 18 of a series on evaluation of scientific publications. Dtsch Arztebl Int 2012;109(15):276–81. Wolfe DL, Hayes KC, Potter PJ, Delaney GA. Conditioning lower limb H-reflexes by transcranial magnetic stimulation of motor cortex reveals preserved innervation in SCI patients. J Neurotrauma 1996;13(6):281–91. Zehr EP, Klimstra M, Johnson EA, Carroll TJ. Rhythmic leg cycling modulates forearm muscle H-reflex amplitude and corticospinal tract excitability. Neurosci Lett 2007;419(1):10–4.
443
Noam Y. Harel, MD, PhD is a Staff Physician at the James J. Peters Veterans Affairs Medical Center and Assistant Professor in Neurology and Rehabilitation Medicine at the Icahn School of Medicine at Mount Sinai.
Stephanie A. Martinez, BS is a Clinical Research Coordinator at the James J. Peters Veterans Affairs Medical Center.
Steven Knezevic, BS, MS is a Health Science Technician at the James J. Peters Veterans Affairs Medical Center.
Pierre K. Asselin, BS, MS is a Health Science Specialist at the James J. Peters Veterans Affairs Medical Center.
Ann M. Spungen, EdD is a Research Scientist at the James J. Peters Veterans Affairs Medical Center, Associate Director of the Veterans Affairs Rehabilitation Research and Development National Center of Excellence for the Medical Consequences of Spinal Cord Injury, and Associate Professor of Medicine and Rehabilitation Medicine at the Icahn School of Medicine at Mount Sinai.
