preprint version: accepted by experimental brain research ....doc

Preprint version: Accepted by Experimental Brain Research (October, 2004)

Neurophysiological examination of the corticospinal system and voluntary motor control

in motor-incomplete human spinal cord injury

WB McKay, DC Lee, HK Lim, SA Holmes, AM Sherwood

Abstract

This study employed neurophysiological methods to relate corticospinal system condition with voluntary control of lower-limb muscles in persons with motor-incomplete spinal cord injury. It consisted of two phases. In a group of 10 healthy subjects, single and paired transcranial magnetic stimulation (TMS) of the motor cortex was used to study the behavior of the resulting motor evoked potentials (MEP) in lower-limb muscles. Interstimulus intervals (ISIs) of 15 to 100 ms were examined for augmentation of test MEPs by threshold or subthreshold conditioning stimuli. The second phase of this study examined 8 incomplete spinal cord injured (iSCI) subjects, American Spinal Injury Association Impairment Scale C (n=5) and D (n=3) in whom voluntary motor control was quantified using the surface EMG (sEMG) based Voluntary Response Index (VRI). Corticospinal system connections were characterized by the thresholds for MEPs, TMS % of total stimulator output (2 Tesla), in key muscles that serve as prime-movers, agonists in the voluntary movements of a rigidly administered protocol of elementary voluntary motor tasks. These tasks generated the sEMG from which the VRI similarity index (SI) and magnitude (Mag) were calculated for comparison to TMS results. Healthy-subject data showed significant increases in conditioned MEP responses with paired stimuli of 15 to 50 ms ISI. Stimulus pairs of 75 and 100 ms showed no increase in MEP peak amplitude over that of the single-pulse conditioning stimulus alone, usually no response. For the iSCI subjects, 42% of the agonists responded to single-pulse TMS and 25% required paired-pulse TMS to produce an MEP. AIS component motor scores for agonist muscles (QD, TA, and TS) were significantly lower where MEPs could not be obtained (p < 0.05). VRI values, SI and Mag, were also significantly lower for motor tasks with agonists that had no resting MEP (p < 0.01). The presence of a demonstrable connection between the motor cortex and spinal motor neurons in persons with SCI determines the quality of post-injury motor control. Also, neurophysiological laboratory measures of corticospinal system function offer objective and reliable quantification of motor control for comparison over time within the individual patient and across individuals and laboratories for multi-center population efficacy studies.

Running Title: Neurophysiological examination of corticospinal system in SCI Key words: Transcranial Magnetic Stimulation, Motor Cortex, Human, Spinal Cord Injury, voluntary motor control.

Introduction

Following injury to the spinal cord, people frequently experience loss of control over movement of their limbs that can be complete or incomplete as characterized by clinical scales such as the American Spinal Injury Association Impairment Scale (Maynard et al., 1997; Marino et al., 2003). Between ‘complete’ and ‘incomplete’ lies the neurophysiologically-defined category, ‘discomplete,’ in which weak fragments of supraspinal motor control remain (Dimitrijevic. 1988; Sherwood et al, 1992, McKay et al., 2004). The degree to which motor function is disrupted varies widely across spinal cord injured individuals and the test instruments used to evaluate this diversity are subjective self-report and expert-examination-based scales. Such measures suffer from the variance of inter-rater and test-retest inconsistencies inherent in all subjective scales (Jonsson et al., 2000; Cohen et al., 1998; Hass et al., 1996; Triolo et al., 1995; Preibe and Waring, 1991).

McKay et al. – Neurophysiological exam of Corticospinal System in SCI

Neurophysiological methods offer a stable, repeatable, and technically objective measure of motor control (Lim et al., 2004; Sherwood et al., 2000). Multi-muscle surface electromyographic (sEMG) recordings, collected during simple single and multi-joint voluntary motor tasks, and attempted in the supine position, were shown to be related to the degree of support a group of 36 incomplete spinal cord injured subjects needed to ambulate (Tang et al., 1994). Recently developed neurophysiological methods for use in characterizing voluntary motor control from sEMG recordings acquired within rigidly controlled conditions (Lee et al., 2003) are currently being validity-tested (Lim et al, submitted a; submitted b). Developed for lower-limb motor control evaluations, the voluntary response index (VRI) calculation generates a similarity index (SI) and magnitude value from multi-muscle sEMG recordings through comparison to prototypes collected from healthy subjects (ibid.).

The functional relationships between the different supraspinal systems whose axons form the long descending tracts of the spinal cord are dynamic and difficult to measure in isolation. One descending system that has become neurophysiologically testable is the corticospinal system (CS) which contains, among other connections, a monosynaptic or oligosynaptic excitatory connection between pyramidal cells of the motor cortex and spinal cord motor neurons (Ugawa et al, 1995). Transcranial magnetic stimulation (TMS) of the motor cortex elicits motor evoked potentials (MEPs) from muscles and are thought to characterize this direct or near-direct cortex-to-spinal motor neuron connections to upper (Rothwell et al., 1993) and lower-limb muscles (Booth et al., 1991). Considerable understanding about the functional connections within the human cortex has been gained using the TMS-induced MEP in healthy-subject paradigms. TMS-induced MEP paradigms have employed paired-pulses to examine intracortical inhibition for upper-limb muscle representations in the motor cortex (Hanajima et al. 2002; 1998; Ziemann et al.,1996; Ridding et al. 1995; Kujirai et al, 1993) and lower-limb muscle representations (Stokic et al., 1997). In addition, MEPs have been used to track excitability changes in the corticospinal system and the spinal motor neurocircuitry that it excites during voluntary contractions (Rothwell et al., 1987; Berardelli et al., 1985), volitional cyclic semi-automated motor tasks such as gait (Petersen et al., 2003; Bonnard et al., 2002; Schubert et al., 1999) and stationary cycling (Pyndt and Nielsen, 2003). In iSCI, lower-limb muscle MEPs have been used to examine central conduction times in the corticospinal system for conduction delays and to identify present, but impaired, connections for comparison to voluntary motor function (Calancie et al., 1999; Curt and Dietz, 1999; Dimitrijevic et al., 1988).

Unfortunately, the TMS-MEP methodology is limited by stimulus strengths that may not physiologically activate all corticospinal neurons that are capable of conducting activity through a region of spinal cord injury (Kakulas, 1988; 1984) where in addition to direct injury, many axons may become demyelinated as a result of SCI (Blight and Gruner, 1987). This is especially true for lower-limb muscle representations that originate deep within the central sulcus, further from the stimulus source than are upper-limb muscle representations. Single-pulse TMS studies have not claimed the ability to activate all of the relevant pyramidal cells in the motor cortex. To our knowledge, no supramaximal MEP has been claimed. However, the effects of repeated TMS on the threshold for activation of the motor cortex were shown to be decreased at TMS frequencies of 5 Hz, even at strengths that were below motor threshold for single pulse stimulation (Siebner et al., 2000). Further, paired-pulse TMS paradigms have indicated facilitory effects of conditioning intervals above 10 ms (Bestmann et al., 2004; Werhahn et al., 1999; Ziemann et al., 1998).

This study was designed first to determine an appropriate stimulation paradigm to increase the activation of motor cortex connections to spinal motor cells in a group of iSCI subjects. Second, this study sought to examine the relationship between the degree of remaining corticospinal connection between the brain and spinal cord and the ability to voluntarily control muscles of the lower limbs in individuals with motor-incomplete spinal cord injury.

Material and Methods

Healthy subjects – MEP augmentation using paired-pulses

Ten neurologically healthy individuals, 4 females and 6 males, ranging in age from 26 to 57 years (40.4 + 11.6) (mean + SD) were recruited for this study. Informed consent was obtained under the auspices of the local review board for human research. Subjects were asked to lie relaxed on a comfortable bed. Motor evoked potentials were recorded using recessed silver-silver chloride surface electrodes over muscles of the lower limbs. They were

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placed over the center of the muscle bellies of the right and left quadriceps (QD, hamstrings (H), tibialis anterior (TA), and triceps surae (TS) muscles on an axis parallel to the muscle fibers with a 3 cm center to center spacing. Intraelectrode impedances were reduced to 5 K Ohms. MEPs were recorded with an amplification gain of 1000, a bandwidth of 30-500 Hz, and a sample rate of 2000 samples per second in each channel. Responses were stored for computer assisted analysis.

Transcranial magnetic stimulation was provided by a pair of Magstim 200 magnetic stimulators that produce 100 microsecond pulses of up to 2 Tesla in strength triggered by a delay unit which provided the interstimulus intervals used. Stimuli were combined through a Bistim unit and delivered through a 110 deg double cone coil (9 cm diameter each) centered over the scalp vertex so that current flow inside the brain was counterclockwise in the left hemisphere and clockwise in the right hemisphere. Relaxation was monitored by continuous display of background EMG activity from the recorded muscles and delivery of stimulus sets was initiated manually. Subjects were instructed to relax and stimulation was withheld when background activity appeared.

The stimulation protocol consisted of three repetitions each for controls and pulse pairs each ISI. Initially the TA MEP threshold was established as the lowest threshold response; that strength was used throughout the healthy-subject phase of the study. Test sets for three repetitions were made up of the delivery of pulse pairs and triplets with fixed interstimulus intervals (ISIs) of 15, 20, 25, 30, 35, 40, 45, 50, 75, and 100 ms. They were delivered in a pseudorandom sequence: in groups, three trials each of 25, 100, 50, and 75 ms ISIs separated, by three trials of single pulses for threshold monitoring, from sets of 45, 15, and 30 ms followed by single pulses and completed with sets of 40, 20, and 35 ms. Trial separation was a minimum of 5 seconds.

Incomplete SCI – Motor Evoked Potentials

Eight incomplete spinal cord injured individuals (iSCI) were recruited, one female and seven males, and gave informed consent as prescribed by the local review board for human research. They were recruited as part of a project to evaluate the effects of body-weight supported treadmill ambulation training. They were selected for having preserved hip flexion against gravity on at least one side. Subjects ranged in age from 18 to 60 years (39 + 17) old with injury levels that ranged from C5 to T5 with time post-onset from 7 to 39 months (19 + 10). Motor-incomplete status was confirmed by clinical evaluation using the American Spinal Injury Association (ASIA) Impairment Scale (AIS) to be classification C (n=5) or D (n=3). The MEP recording sessions occurred at the end of a comprehensive neurophysiological assessment protocol described below. As with the healthy subjects, MEPs were recorded from the QD, HS, TA, and TS muscles of both legs and stimulation was delivered through the devices described above. The number of stimuli required to evaluate subjects in this phase of the study, were greatly reduced through the use of a threshold measurement design, beginning with single stimuli delivered at random intervals of at least 3 seconds. Thresholds were established and noted for each of the recorded muscles as that TMS intensity for which a recognizable, approximately 5 µV peak to peak, MEP appeared in at least two of the three repetitions delivered for each intensity or stimulus pair studied. Increased in increments of 10% of maximum stimulator output, intensities at which MEPs appear were noted and if any recorded muscles failed to respond with 100% single pulses, then pairs were used with a fixed ISI and increasing both stimuli together in 10% increments. Based on preliminary results of the healthy-subject phase of this study, an ISI of 25 ms was chosen for use when single pulse stimulation was ineffective in achieving an MEP in all recorded muscles. Due to a technical failure, one iSCI subject was evaluated using a 15 ms ISI. The data was included here because the differences in healthy-subject results between the two ISIs were minimal and would not alter the findings described here. Stimulation and the study sessions ended when all recorded muscles were responding or the maximum output of the two paired stimulators was reached.

Incomplete SCI – Voluntary Response Index (VRI)

The laboratory-based Brain Motor Control Assessment (BMCA) protocol used for the VRI has remained stable for decades. It records sEMG from abdominal, paraspinal, and bilateral quadriceps, adductor, hamstring, tibialis anterior, and triceps surae muscles (Sherwood et al., 1996). The sEMG data were continuously digitized for the approximately one-hour-long BMCA study with a 12 bit ADC at 1600 samples/s (CODAS, Dataq, Inc., Akron, OH). Surface EMG data were recorded with a gain of 1000 and a bandpass of 30-500 Hz. The BMCA strictly

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follows a set protocol carried out by technologists trained to instruct subjects to perform specific elementary voluntary motor tasks in a highly repeatable fashion and to deliver reflex stimuli in a consistent way. All motor tasks were attempted in the supine position and repeated three times with background activity, if any, allowed to minimize or stabilize between trials so that responses could be differentiated from any remaining background activity. The protocol sequence begins with five minutes of relaxation followed by reinforcement maneuvers, a series of bilateral and unilateral, single and multi-joint voluntary leg movements. Regardless of their ability to accomplish the requested motor task, subjects were encouraged to do their best.

Data Analysis

MEP peak to peak amplitudes were measured for the test TMS, R1 for single stimuli and R2 for the paired stimuli trials. These peak values were averaged over three repetitions on a per-muscle basis for each ISI. For the healthy-subject data, these values were averaged across individuals ANOVA was used to evaluate differences between MEPs from different ISIs with significance reached at p < 0.05. The values of interest to this study were determined to be those for the ‘prime mover’ or agonist muscle of the voluntary motor tasks recorded in the BMCA protocol. The QD was considered as the agonist for hip flexion, the TA for ankle dorsiflexion, and the TS was the agonist for ankle plantar flexion. The BMCA is performed in the supine position making hip extension a function of eccentric contraction of the quadriceps and not a contraction of the HS as would be the case in ambulation or in the prone position. Therefore, for use in comparison to VRI values, only QD, TA, and TS MEPs were analyzed. MEP response thresholds were recorded for all of the lower-limb muscles and defined as the TMS intensity which evoked an MEP of greater than 5 µV for the three repeated trials.

The voluntary segment of the BMCA protocol was quantified for the calculation of the VRI values, similarity index and magnitude. Following examination of sEMG signal quality, the envelope of sEMG activity was calculated using a root mean square (RMS) algorithm. Each motor task was identified from an event marker channel, denoting the cue tone telling the subject to move, and 5 second epochs of the RMS envelope data were extracted for each recording channel (muscle). Data from each channel were averaged over each epoch and baseline-corrected by subtracting the average activity occurring in the one-second period immediately preceding each event mark. The baseline-corrected individual maneuver responses were then averaged across the three repetitions of each motor task in the protocol. These values then served as the numerical measure of motor output for each muscle during each of the motor tasks. System noise was less than 1 µV (RMS).

Analysis of the sEMG data recorded during voluntary movement attempts was accomplished using calculated voluntary response index (VRI) values (Lee et al., 2003). Two values are generated that describe the multi-muscle activation pattern in terms of overall “magnitude” and “similarity index (SI)” relating multi-muscle patterns recorded from SCI subjects to the patterns generated by healthy subjects performing the same movements, under the same recording conditions. A minimum magnitude value of 3 µV was required before the accompanying SI value was qualified for further analysis (McKay et al., 2004). Magnitude (Mag) values reported were normalized to the healthy-subject prototypes for each voluntary motor task. The sEMG envelope values for each trial were totaled and those values for the 30 trials, spanning the 10 voluntary motor tasks in the BMCA protocol, were then averaged across the group of 10 subjects that made up the healthy-subject prototype used for this and other published studies (Lee et al., 2003, Lim et al., 2004; McKay et al., in press; Lim et al, accepted).

In iSCI subjects, the presence of MEP and VRI SI and Mag values were compared using Students t-test. MEP threshold and VRI comparisons were performed using Spearman’s rho correlations with significance set at p < 0.05.

Results

Healthy subject data

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Healthy subjects exhibited lower-limb muscle MEPs with TA thresholds of between 45% and 60% of maximum stimulator output for single stimuli (53 + 6 %). Further, responses were increased for ISIs from 15 to 50 ms with maximum facilitation seen at ISIs of 15, 20, and 25 ms (p < 0.05) (Figure 1).

Figure 1 Motor evoked potentials (MEPs) from the right side of a representative healthy subject for paired-pulsed trancranial magnetic stimulation (TMS). Three repeated trials are superimposed for each Interstimulus interval (ISI) from the quadriceps (QD), Tibialis anterior (TA), and triceps surae (TS) muscles. Amplitude scales are 300 µV, 200 µV, and 100 µV respectively. Note the threshold response to the conditioning stimulus in the TA and the facilitation seen for 15 to 50 ms is greatest for 15 through 25 ms ISIs.

Using stimulus strengths that were threshold for one or the other TA muscle, MEPs were found to be strongly augmented above control values for shorter ISIs (15, 20, 25 ms.), of lesser increase for midrange ISIs (30, 35, 40 ms.), further augmented in the longer ISIs (45, 50 ms), but absent or trace for ISIs of 75 and 100 ms (Figure 2).

The mean unconditioned MEPs were less than 20 µV (19.3 + 7.1) and the conditioned MEPs increased from 30 to 7 times that amplitude across increasing ISIs (Table 1). Hamstring MEPs behaved similarly but will not be

discussed in relation to VRI values because it does not serve as an agonist or prime-mover for leg extension in the supine position.

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Figure 2 Group mean MEP peak amplitudes averaged for QD, TA, and TS muscles (mean + SD error bars) for the range of interstimulus intervals for paired transcranial magnetic stimulation-induced MEPs. Note, the values plotted here were the average of those found in Table 1 but excluded the HS because it is not used in the second phase of this report. All four muscles showed very similar independent behavior relative to TMS ISIs but as seen in the table, the MEP amplitudes were lower in limb extensors than flexors.

iSCI subject data

MEP thresholds were measured for QD, TA, and TS muscles and recorded as the lowest intensity TMS, that elicitss a muscle response. iSCI subjects are highly dissimilar and the data analyzed displayed their individuality. All iSCI subjects had MEPs in one of the three target, agonist, muscles but thresholds were often well above those recorded for healthy subjects. Of the 48 agonist muscles studied, six per subject, 16 failed to respond to single or paired TMS, 12 required paired stimulation, and 20 responded to single-pulse TMS. For those muscles in which MEP could not be elicited with maximal paired-pulse intensity, the average ASIA impairment scale motor score value was 1.0 + 0.97, significantly lower than either those requiring paired-pulses to produce an MEP, 3.15 + 0.88 or 2.25 + 1.66 for those responding single stimuli (p < 0.05).

Interstimulus Interval

15 ms 20 ms 25 ms 30ms 35 ms 40 ms 45 ms 50 ms 75 ms 100 ms

QD 708+914 598+906 493+886

393+584

210+340 145+243

185+311

151+268

28+63 13+15

TA 1166+931

1161+933

940+929

551+942

497+690 409+588

322+472

277+423

25+58 28+63

TS 391+503 387+646 323+581

378+670

181+234 139+188

147+188

126+306

12+12 12+9

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Table 1 Peak to peak MEP amplitudes (µV)(Average + SD) for the interstimulus intervals studied here. Note that MEPs for ISIs were augmented for all ISIs of 50 ms or less.

Figure 3 illustrates the relationship between MEP presence, VRI values, and multi-muscle sEMG patterns.

Figure 3 Example Dorsiflexion sEMG patterns quantified by the SI and Mag values (see methods). Arrows denote tone cue to begin voluntary task. Note the interplay between the failure of the agonist (Iipsilateral TA) muscle contraction and the increased coactivation of other muscles. Also, note that the MEP threshold increases correspond to a decrease in SI, significant only for dorsiflexion (p < 0.05).

The average SI for those agonists responsive to single-pulse TMS was 0.78 + 0.25, those requiring paired-pulse TMS showed an SI value of 0.64 + 0.3, and those agonists that did not respond to TMS showed an SI of 0.28 + 0.37 (Figure 4).

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Figure 4 SI and Mag values for voluntary motor task in which the agonist produces No MEP, requires Paired-Pulse TMS to produce an MEP, and requires only single-pulse TMS. Note that SI and Mag are both significantly lower for those with no MEP than those in which MEPs were obtained (p < 0.01**). There was no significant difference in either SI or Mag between those requiring paired-pulse TMS and single stimulus to produce an MEP.

VRI magnitude behavior was different in that the larges value was in those agonists that required paired-pulse TMS to elicit an MEP. Although no significant differences were found in either SI or Mag when comparing the two groups that responded to TMS with each other, the non-responders were different from those responding to TMS (p < 0.01). The AIS component motor scores for the respective motor tasks studied here also showed a significant relationship to the presence of an MEP in the agonist muscle for the task (p < 0.05).

For those 20 agonists that produced MEPs with single-pulse TMS, 9 were for QD, 7 TA, and 4 from TS. The TA threshold and dorsiflexion SI correlated at -0.81 (p < 0.05), but no other correlations were found for other combinations across either single or paired-pulse MEP thresholds.

Discussion

The functional role of the direct, or near-direct, connections between the motor cortex and spinal motor neurons carried within the corticospinal system is considered to be the dexterous control of movement based on work in animal models (Heffner and Masterson, 1975). However, this relationship in humans has remained inferential, using subjective measures of complex motor functions. In this study we show that a neurophysiological measure of the quality of voluntary motor control, the voluntary response index (Lee et al., 2003), is related to the condition of the corticospinal connection between the motor cortex and spinal motor neurons as characterized by motor evoked potential presence in general and by MEP threshold in the tibialis anterior muscle specifically, where single-pulse thresholds were inversely related to the SI (-0.81). For lower-limb muscle representation in the motor cortex, close together and deep within the central sulcus where moving the stimulator location is not appropriate to “map” the cortical distribution as is has been reported for upper-limb muscles (Leipert et al., 1998). Therefore, a fixed stimulus location paradigm as used here must rely on MEP thresholds to infer relative cortical excitability across the muscles of the lower limbs.

The data presented here show that interstimulus intervals of 15 to 25 ms can facilitate MEPs in both healthy and

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iSCI subjects. The data also show that, used in this group of iSCI, conditioning TMS in a paired-pulse paradigm with interstimulus intervals of 25 ms increased the yield of identified connections remaining between the motor cortex and spinal motor neurons by more than 50%. The relationship between MEP amplitude and ISI in healthy subjects was the same in all of the prime-mover, or agonist, muscles tested suggesting that there may be a common neural mechanism involved. Although published studies examining intracortical inhibitory effects of conditioned, paired-pulse ISIs of less than 15 ms have focused on hand muscles, similar intracortical inhibition has been reported (Stokic et al., 1997). Suffice it to say that for events occurring in this short time frame, intracortical interactions are the likely mechanisms.

However, paired-pulse MEP amplitudes conditioned by ISIs of 15 ms or longer, as seen in the current data would be expected to take on some of the characteristics of the spinal neurocircuitry that processes arriving excitation into motor unit firing. When ISIs longer than the central conduction time of corticospinal tract fibers connecting motor cortex to the lumbar spinal motor cells, approximately 15 ms in healthy adults, is used as in this report, the possibility of prolonged potentiation of spinal motor neurocircuitry might be expected. Salerno and coworkers (2000) reported a similar paradigm to that used in the present study in which they use submotor (80%) of relaxed threshold TMS to condition test MEPs resulting from 150% threshold TMS in pairs with 4, 25, 55, and 85 ms ISIs. Their finding of interest here was that, for the series using sub-threshold conditioning stimuli, they found facilitation at 25 ms and a return to resting MEP amplitude at 55 ms ISIs, similar to the findings presented here (ibid). Especially as regards the responses to test stimuli following subthreshold conditioning at 15 to 25 ms ISIs, a spinal explanation is available. First, in healthy subjects, the arrival of descending corticospinal excitation in the anterior horn of the spinal cord, inadequate to bring motor unit firing will likely produce a potentiation of the neurocircutry there that may last for some time (Ugawa et al., 1995). Such a cellular potentiation mechanism may be present within the anterior horn neurocircuitry that could provide the temporal summation of descending D and I-waves after TMS (Burke et al., 1990; Di Lazzaro et al., 1998) and descending volleys during voluntary movement. In addition, using data from a single motor unit recording from volitionally activated muscles, Terao and co-workers (2000) assert that for lower-limb muscles, descending I-wave volleys predominate at low TMS intensities. And, subthreshold TMS has been shown to have a facilitatory effect on the H-reflex from the soleus muscle with cortical and peripheral nerve stimulation timed so that the peripheral volley arrives at the spinal cord after the corticospinal volley arrives at the spinal motor neural circuitry (Alexeeva et al., 1998). This study showed that the expected descending corticospinal volley from just-subthreshold TMS is adequate to modify spinal motor activity, a capability that is diminished and delayed, requiring a longer time post-TMS for accumulation of slowed D and I wave excitation to produce H-reflex augmentation after SCI.

The MEP is not a synchronous firing of all motor units recorded but rather the firing of motor units during a brief period of increased excitability determined by the duration of the descending volley of D and I waves and prolonged by characteristic spinal neurocircuitry processing. For example, we studied lower-limb MEPs in healthy subjects and found them to be complex, having durations of about 24 ms for the QD, 44 ms for the TA, and 30 ms for the TS (Dimitrijevic et al., 1992a). If we consider this duration to reflect the length of time that the spinal motor neurocircuitry is above the threshold for firing motor units, then the arrival of descending volleys during that period of time might be expected to fire motor units, increasing the number of units fired and MEP peak amplitude for the test response. Therefore, taken together, for roughly 30 ms following arrival of the conditioning volleys at the spinal cord, there may an increased responsiveness to a second test volley to the spinal motor neurocircuitry of lower-limb muscles as is reported in this manuscript. This conditioned excitability would be expected to decrease with time as was seen in the healthy-subject data presented here.

The corticospinal system is made up of axons from pyramidal cells in the supplementary motor area that end near spinal motor neurons and in the dorsal horn of the spinal cord respectively (Dum and Strick, 2002) where they excite inhibitory spinal neurocircuitry (ibid). It is the motor cortex connection to the spinal motor cell, and excitatory neurocircuitry, that is responsible for the MEP data collected here. However, it is the combination of excitation of the agonist and inhibition of antagonistic muscles that produces accurate, efficient movement. We compare here the patency of the excitatory corticospinal connections, using MEP presence and threshold, with the ability of the iSCI subject to isolate that activation to the agonist muscles of elementary voluntary movements. These motor tasks were loaded only by gravity and performed in the supine position without cognitive spatial or strength targets to provide a quantified objective view of the inhibitory component added by the posterior

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connections. The VRI is a measure in which SI values decrease with the failure of these two systems to control the muscles of the lower limbs. The loss of isolated contraction in a motor task, the spread of activity to antagonistic or irrelevant muscles has been demonstrated in fatigue paradigms (Dimitrijevic et al., 1992b). Further, the pattern of spreading from a set of fatiguing isometric exercise paradigms showed that there were rules to the coactivation, suggesting plurisegmental organization is uncovered as fatigue is perceived and effort increases (ibid).

Based on the premise that the presence of a demonstrable connection between the motor cortex and spinal motor neurons can determine the quality of voluntary motor control, an objective laboratory measure of corticospinal system function should be quite useful to clinicians in neurorehabilitation settings dealing with disorders of motor control. A standard protocol of neurophysiological measurement of corticospinal system excitatory function as presented here would provide objective quantification comparable over time within the individual patient and across laboratories for multicenter population studies. Further, the methods used here do not require the cooperation of the person being assessed other than that they lie relaxed on a comfortable examination table and tolerate the sensations that accompany TMS. Therefore, a standard paired-pulse TMS method might be a useful monitor of corticospinal system function in unconscious or anesthetized persons (Neuloh et al., 2004). Moreover, the isolation of the corticospinal system through the methods used here might make it possible to objectively measure the effects of treatments that have been shown to have specific impact on the corticospinal system in animal models. For example, treatments that would seek to selectively manipulate neurotransmitter physiology (Werhahn et al., 1999; Ziemann, 2003), genetically manipulate structure formation (Blesch et al., 1999; Grill et al., 1997), and/or neuro-remodeling through functional-use therapies (Leipert et al., 1998, Protas et al., 2001) in human models. Regardless of which methodologies are employed, the restoration of functional movement in the lower-limbs, specifically ambulation, will require such physiological manipulation and physical training in careful application (Fouad and Pearson, 2004).

Numerous characteristic neurophysiological behaviors attributable to corticospinal system function remain to be processed from the recordings reported here. For example, qualities of control that include the temporal characteristics, sEMG RMS envelope shape for the agonist muscle during the voluntary motor task holds information about initiation, maintenance, and maybe most importantly, cessation of the contraction. This will require that a standard measure of corticospinal system activation of spinal inhibitory neurocircuitry, connections to posterior spinal cord structures be developed, a topic for future work.

Conclusion

As presented here, it is possible to objectively quantify the quality of elementary voluntary motor control in the lower limbs and to objectively relate that quality of control to the relative presence of corticospinal system connection to spinal motor neurocircuitry in a human spinal cord injured model. In treating disorders of motor control, the ability to selectively assess central nervous system subsystem function, the corticospinal system here, and to document specific changes in that function should improve the clinicians’ abilities to tailor treatment strategies, targeting specific weaknesses and making use of documented strengths within the individual patient through specific supportive and augmenting strategies.

Acknowledgements:

The authors would like to acknowledge the excellent technical support provided for this study by Lillian Scott Wielder, R.EEG.T., Dora Garcia, R.EEG.T., and Teresa Joe, B.S. We would also like to thank Mary Green, BSN, Huma Quershey, LPT, MS., and Amanda Williams, LPT, MS for their efforts in subject recruitment and clinical scale data collection. This project was supported by the Department of Veterans Affairs Rehabilitation Research and Development Service.

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