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. Author manuscript; available in PMC: 2022 Oct 1.
Published in final edited form as: J Physiol. 2021 Sep 16;599(19):4441–4454. doi: 10.1113/JP281862

Distinct Patterns of Spasticity and Corticospinal Connectivity Following Complete Spinal Cord Injury

Sina Sangari 1,2, Steven Kirshblum 3, James D Guest 4, Martin Oudega 1,5,6, Monica A Perez 1,2,5,6
PMCID: PMC9053045  NIHMSID: NIHMS1714104  PMID: 34107068

Abstract

The loss of corticospinal axons has implications for the development of spasticity following spinal cord injury (SCI). However, the extent to which residual corticospinal connections and spasticity are present across muscles below the injury remains unknown. To address this question, we tested spasticity using the Modified Ashworth Scale and transmission in the corticospinal pathway by examining motor evoked potentials elicited by transcranial magnetic stimulation over the leg motor cortex (cortical MEPs) and by direct activation of corticospinal axons by electrical stimulation over the thoracic spine (thoracic MEPs), in the quadriceps femoris and soleus muscles, in 30 individuals with motor complete thoracic SCI. Cortical MEPs were also conditioned by thoracic electrical stimulation at intervals allowing their summation or collision. We found three distinct sub-groups of participants: 47% showed spasticity in the quadriceps femoris and soleus muscle, 30% showed spasticity in the quadriceps femoris muscle only, and 23% showed no spasticity in either muscle. While cortical MEPs were present only in the quadriceps in participants with spasticity, thoracic MEPs were present in both muscles when spasticity was present. Thoracic electrical stimulation facilitated and suppressed cortical MEPs, showing that both forms of stimulation activated similar corticospinal axons. Cortical and thoracic MEPs correlated with the degree of spasticity in both muscles. These results provide the first evidence that related patterns of residual corticospinal connectivity and spasticity exist in muscles below the injury after motor complete thoracic SCI and highlight that a clinical exam of spasticity can predict residual corticospinal connectivity after severe paralysis.

Introduction

Following spinal cord injury (SCI), the excitability of neuronal networks below the injury increases to compensate for the loss of corticospinal neurons, leading to the development of spasticity (Dietz, 2000; D’Amico et al., 2014). For example, lesions of the corticospinal tract at the pyramids (Tan et al., 2012) or the spinal cord (Murray & Goldberger, 1974) in animals causes sprouting of afferents in the spinal cord linked to symptoms of hyperreflexia. In humans, electrophysiological data showed that imbalanced contributions from the corticospinal pathway and other descending motor tracts is present in individuals with spasticity (Sangari & Perez, 2019) but not when spasticity is absent (Sangari & Perez, 2020). In addition, therapies aiming to improve corticospinal drive influence symptoms of spasticity (Wirz et al., 2005; Kumru et al., 2010; Benito et al., 2012). Although extensive evidence link the corticospinal pathway and spasticity, the extent to which residual corticospinal connections and spasticity are present across muscles below the injury level remains unknown.

Most common mechanisms of SCI in humans involve contusions and compressions (Tator, 1995; Layer et al., 2017). These injuries can leave some variable parenchymal continuity across the lesion (Kakulas, 1988; Bunge et al., 1993) resulting in different patterns of descending connectivity to muscles below the injury (Vallotton et al., 2019). This is consistent with electrophysiological studies in people with clinically motor complete SCI showing that reinforcement maneuvers generated electromyographic (EMG) signals in some but not all lower limb muscles tested below the injury, implying preservation of spared descending connections to isolated populations of motor units (Dimitrijevic et al., 1984). This also agrees with results showing that the probability of evoking motor evoked potentials (MEPs) by transcranial magnetic stimulation (TMS) over the primary motor cortex differs across different limb muscles below the injury in humans with motor complete SCI (Calancie et al., 1999; Squair et al., 2016; Santamaria et al., 2021). Corticospinal responses and lesser spinal cord atrophy in areas corresponding to the location of the corticospinal tract have been found in people who have no voluntary control of muscles below the injury or motor complete SCI with spasticity compared with individuals without spasticity (Sangari et al., 2019). Thus, if an association exists between corticospinal responses and spasticity, patterns of spared descending connections might accompany patterns of spasticity. We hypothesized that individuals with motor complete SCI would show residual connectivity in muscles that have spasticity and that different patterns of connectivity and spasticity exist in muscles below the injury.

To test our hypothesis, we examined spasticity in quadriceps femoris and soleus muscles bilaterally using the Modified Ashworth Scale (MAS) in 30 individuals with a diagnosis of motor complete SCI. We examined transmission in the corticospinal pathway by testing MEPs elicited by TMS over the leg representation of the primary motor cortex (referred as ‘cortical MEPs’) and by direct activation of corticospinal axons by electrical stimulation over the thoracic spine above the injury (referred as ‘thoracic MEPs’) in the quadriceps femoris and soleus muscles. Cortical MEPs were also conditioned by thoracic electrical stimulation at inter-stimulus intervals (ISIs) allowing summation or collision of volleys.

Materials & Methods

Subjects.

Thirty individuals with SCI (mean age=39.1±12.8 years, 3 females; Table 1) participated in the study. All participants gave informed consent to the experimental procedures, which were approved by the local ethics committee at Northwestern University and performed in accordance with the Declaration of Helsinki (IRB protocol #00209714). Participants with SCI had a chronic injury (≥1 year) and were classified using the International Standards for Neurological Classification of Spinal Cord Injury examination as having a T4-T11 level SCI and by the American Spinal Injury Association Impairment Scale (AIS) as AIS A (n=26) or AIS B (n=4). Nineteen SCI individuals were prescribed antispasticity medication (baclofen and/or gabapentin and/or tizanidine and/or diazepam; see Table 1). All subjects were asked to perform voluntary knee extension and ankle plantar flexion with both sides, but none of them was able to exert voluntary EMG activity in the quadriceps femoris and soleus muscles, respectively.

Table 1. SCI participants.

Individuals showing cortical MEPs and thoracic MEPs in the quadriceps femoris and soleus muscle are identified with an x. AIS=American Spinal Injury Association Impairment Scale; BAC=baclofen; DIAZ=diazepam; F=female; GBP=gabapentin; Quad=quadriceps femoris; M=male; NT=non-traumatic; Sol=soleus; T=traumatic; TIZ=tizanidine.

TSS TMS
Left Right Left Right
Participant Age (yr) Gender AIS Level Etiology Time after injury (yr) Medication(s) Quad Sol Quad Sol Quad Sol Quad Sol
1 22 M A T5 T 1 BAC, GBP x x x x x x
2 46 M A T5 T 25 BAC x x x x x
3 37 M A T10 T 4 BAC x x x x x x
4 35 F A T9 T 9 GBP, TIZ x x x x x x
5 65 M A T6 T 1 BAC, GBP x x x x
6 21 M A T5 T 2 BAC, GBP x x x x x
7 42 M A T10 T 5 none x x x x x
8 54 M A T11 T 35 none x x x x x x
9 28 M B T9 T 7 none x x x x x
10 30 M A T4 T 3 BAC x x x x x
11 51 M B T4 NT 10 GBP x x x x x x
12 23 M A T10 T 2 none x x x x x
13 39 F A T9 T 9 GBP x x x x x x
14 35 M A T7 T 5 BAC x x x x x
15 23 M A T6 T 4 none x x x
16 59 M A T11 T 17 none x x x x
17 52 M A T6 T 28 none x x x
18 58 M B T7 T 36 BAC, TIZ x x x
19 24 M A T6 T 4 none x x x x
20 31 M B T5 T 13 GBP x x x
21 24 M A T10 T 3 none x x x x
22 55 M A T8 T 5 BAC, GBP x x x
23 32 F A T10 T 2 BAC, GAB, TIZ x x x x
24 49 M A T4 T 8 BAC, GBP, DIAZ
25 31 M A T4 T 13 none
26 38 M A T5 T 8 GBP
27 39 M A T7 T 6 GAB
28 34 M A T7 T 2 GBP, DIAZ
29 38 M A T8 T 13 GAB
30 58 M A T10 T 39 none
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Spasticity.

The degree of spasticity was examined in knee extensors and the ankle plantar flexors muscles bilaterally in all SCI participants. The MAS (Bohannon & Smith, 1987) is a clinical scale that measures resistance encountered during manual passive muscle stretching using a six point ordinal scale (0: No increase in muscle tone; 1: Slight increase in muscle tone, manifested by a catch and release or by minimal resistance at the end of the range of motion (ROM) when the affected part(s) is moved in flexion or extension; 1+: Slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout the reminder (less than half) of the ROM; 2: More marked increased in muscle tone through most of the ROM, but affected part(s) easily moved; 3: Considerable increase in muscle tone, passive movement difficult; and 4: Affected part(s) rigid in flexion or extension). During the MAS assessment, subjects were lying in a semi-supine position with the trunk at an angle of 30° of flexion in a relaxed position. The same rater performed all MAS assessments. MAS scores were similar across sides in the quadriceps femoris (Cohen’s κ and 95% CI=0.7; 0.5, 0.9) and soleus (0.9; 0.8, 1.0) muscles.

EMG recordings.

Participants were comfortably seated in an armchair with the hip, knee and ankle positioned with angles of ~90°. EMG was recorded bilaterally from the quadriceps femoris and soleus muscles through bipolar surface electrodes (Ag-AgCl, 10 mm diameter, 1 cm apart) secured on the skin. The signals were amplified, filtered (30–2,000 Hz) and sampled at 2 kHz for offline analysis (CED 1401 with Signal software; Cambridge Electronic Design, Cambridge, UK).

Cortical MEPs.

TMS was delivered over the leg representation of the primary motor cortex using a DuoMAG-MP Dual (DEYMED Diagnostic s.r.o, Hronov, CZ) through a double-cone coil with a monophasic current waveform. The coil was positioned over the vertex and moved around this point to determine the optimal position for eliciting MEPs (referred as ‘cortical MEPs’; Figure 1) in both leg muscles. In individuals in whom MEPs were not observed when using a single TMS pulse, pairs of TMS pulses with ISIs of 0 and 20 milliseconds were used. Pairs of TMS pulses at ISI 0 ms delivered a stronger stimuli than the maximal output delivered with a single TMS pulse. Pairs of TMS pulses at ISI 20 ms increase the size of MEPs through a rise in cortical excitability induced by a conditioning stimulus (Valls-Solé et al., 1992). Evidence showed that a Jendrassik maneuver also increases MEP size in lower limb muscles (Kawakita et al., 1991; Péréon et al., 1995; Santamaria et al., 2021). Therefore, responses were acquired with and without performing a Jendrassik maneuver to ensure maximum drive to spinal motoneurons, where they needed to clench their teeth and flex their fingers or arms bilaterally into a hooklike form, with rest periods as needed. Note that the same results were found in both cases. TMS stimuli were delivered with at least 4 s intervals (0.25 Hz) at an intensity of 100% of the maximum stimulator output (MSO, single and paired pulses). Thirty magnetic stimuli (10 single pulse, 10 pairs of pulse at ISI=0 ms and 10 pairs of pulse at ISI=20ms) were delivered. We measured the MEPs peak-to-peak amplitude of the non-rectified responses. MEPs onset latencies were defined when the rectified EMG reached 2xSD calculated over a 100ms period of the pre stimulus baseline activity. Muscles with detectable cortical MEP in at least five out of ten stimulus was defined as “present” (Squair et al., 2016). When cortical MEPs were not present, the peak-to-peak EMG activity was measured 10 ms after the stimulus artifact over a 40 ms period and was referred to absent cortical MEPs. Note that cortical MEPs were never present in the soleus muscle. Cortical MEPs amplitude (left=0.9±0.8% of the M-max, right=1.4±1.2% of the M-max; p=0.9) and latency (left=20.2±2.7 ms, right=20.4±2.2 ms; p=0.8) when present were similar across sides in the quadriceps femoris.

Figure 1. Experimental setup.

Figure 1.

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A, Transcranial magnetic stimulation was applied over the leg representation of the primary motor cortex to activate corticospinal neurons projecting onto lower limb muscles to elicit motor evoked potentials (cortical MEPs). Electrical stimulation was applied over the thoracic spine to activate corticospinal axons directly to elicit thoracic MEPs. Note the shortening of latency of the thoracic MEP compares with the cortical MEP in quadriceps femoris. B, The Modified Ashworth Scale (MAS) showed that in the quadriceps femoris muscle spasticity was present in 77% of individuals while 23% did not show spasticity. In the soleus muscle, spasticity was present in 47% of individuals while 53% did not show spasticity.

Thoracic MEPs.

Thoracic electrical stimulation was applied using a previously described paradigm to elicit thoracic MEPs (Ugawa et al., 1995; Martin et al., 2008). High-voltage electrical current (1 millisecond rectangular electrical stimulus, 1000 mA) was delivered from a Digitimer DS7R through an cathode (7.5×13 cm) placed between the spine of T3 and T4 and an anode 5–10 cm above it (Figure 1). During stimulation, responses were acquired with and without performing a Jendrassik maneuver. The same results were found in both cases. Ten stimuli were delivered manually with at least 4 s intervals (0.25 Hz). Thoracic MEPs were measured as peak-to-peak amplitude of the non-rectified responses and onset latencies were defined when the rectified EMG reached 2xSD calculated over 100 ms period of the pre stimulus baseline activity. Muscles with detectable thoracic MEP in at least five out of ten stimulus was defined as “present”. When thoracic MEPs were not present, the peak-to-peak EMG activity was measured 8 ms after the stimulus artifact over a 40 ms period and was referred to absent thoracic MEPs. Thoracic MEPs amplitude (quadriceps femoris: left=6.4±7.2% of the M-max, right=6.8±7.6% of the M-max; p=0.4; soleus: left=7.0±7.7% of the M-max, right=7.7±8.8% of the M-max; p=0.9) and latency (quadriceps femoris: left=9.5±1.1 ms, right=9.2±1.4; p=0.4; soleus: left=25.2±5.5 ms, right=25.1±5.0 ms, p=0.9) when present were similar across sides in both muscles.

Cortical MEPs conditioned by thoracic electrical stimulation.

Cortical MEPs were conditioned by thoracic electrical stimulation at different ISIs using a previously described paradigm (Martin et al., 2008). Here, the TMS intensity was set up to 100% of the MSO and the thoracic stimulation intensity was adjusted to evoke a thoracic MEP of around a half of the size of the cortical MEP in the quadriceps femoris (cortical MEP size=1.9±1.1% of the M-max, thoracic MEP size=1.3±1.4% of the M-max). The ISIs were calculated prior to each experiment by comparing the onset latencies of cortical and thoracic MEPs and the difference was used to estimate the time required for the first volley evoked by the TMS to arrive at the segmental level where activation will occur. Thus, the ISIs included intervals when thoracic electrical stimulation was delivered before (ISI +3 ms or referred as ‘conditioned MEPs+3 ms’) or after (ISI −3 ms or referred as ‘conditioned MEPs-3 ms’) the expected arrival of the cortical volley at this segmental level. In control participants, a positive ISI suppress the MEPs through collision of cortical and thoracic volleys, while negative ISI facilitates the MEPs thought summation of both volleys (Martin et al., 2008). Forty stimuli (10 cortical MEPs, 10 thoracic MEPs, 10 conditioned MEPs+3 ms, and 10 conditioned MEPs-3 ms) were delivered at 0.16 Hz in a randomized order. We measured the MEP peak-to-peak amplitude of the non-rectified responses by positioning a cursor at the onset and offset of the MEP in each condition. The conditioned MEPs were normalized to the cortical MEP and the ratio was used to estimate the effect of thoracic electrical stimulation on cortical MEPs. This test was performed in participants in whom responses were present 10/10 times in order to examine facilitation and suppression when conditioned by thoracic electrical stimulation (n=3).

Maximal motor response (M-max).

Percutaneous electrical stimulation of the femoral nerve (FN) and posterior tibial nerve (PTN) was delivered from a Digitimer DS7R (1 ms rectangular electrical stimulus) by increasing the stimulus intensities up to reach the M-max at rest (0.2 Hz) in the quadriceps femoris and soleus muscles, respectively. The stimulus intensity was increased until no further increases in the peak-to-peak amplitude of the non-rectified response was observed. FN stimulation was delivered through a cathode (10-mm-diameter Ag-AgCl electrode) placed in the femoral triangle and an anode (Ag-AgCl plaque) placed over the posterior aspect of the thigh. PTN stimulation was delivered through a cathode (10-mm-diameter Ag-AgCl electrode) placed in the popliteal fossa and an anode (Ag-AgCl plaque) placed over the patella. The peak-to-peak amplitude of the M-max was used to normalize cortical and thoracic MEPs amplitudes in each participant. M-max values were similar across sides in the quadriceps femoris (left=4.3±1.9 mV, right=4.3±1.6 mV; p=0.9) and soleus (left=4.0±2.0 mV, right=4.0±1.9 mV; p=0.9) muscle.

Data analysis.

Cohen’s kappa for agreement was estimated to compare MAS scores between SIDE (left, right) within MUSCLE (quadriceps femoris, soleus). McNemar’s test of paired proportions was used to compare any evidence of spasticity between MUSCLE. The Mann-Whitney U test was performed to compare M-max, cortical and thoracic MEPs, and latencies between sides. A generalized linear model with a cumulative logit link was used to determine the association of GROUP (Group I, Group II, Group III) and MAS scores while accounting for the repeated measurements within individuals. A mixed model ANOVA was used to determine the effect of MUSCLE and GROUP on M-max, cortical and thoracic MEPs. Kruskas-Wallis one-way ANOVA was used to examine the effect of CONDITION (cortical MEPs, conditioned MEPs+3 ms, conditioned MEPs-3 ms) on the mean amplitude of corticospinal responses elicited by TMS. Holm-Sidak post hoc analysis was used to test for significant comparisons. Wilcoxon Signed Rank tests was used to assess if an association exist between cortical and thoracic MEPs, and MAS scores. Spearman correlation coefficient analysis was used as needed. The statistical analysis was conducted using SigmaPlot (Systat Software, Inc, San Jose, CA, USA) and SASv9.4 (cary, NC) and the significance was set at p<0.05. Group data is presented as means±SDs in the text. MAS scores are presented as median [range] in the text.

Results

Spasticity

MAS scores showed that spasticity was present in the quadriceps femoris in 77% (n=23) of individuals while 23% (n=7) did not show spasticity. In the soleus muscle, spasticity was present in 47% (n=14) of individuals and 53% (n=16) did not show spasticity (Figure 1B). Overall, spasticity was more prominently detected in the quadriceps femoris (23/30 participants) compared with the soleus muscle (14/30 participants, McNemar’s p=0.003).

Figure 2 shows the distribution of MAS scores in the quadriceps femoris (top panel) and the soleus (bottom panel) on the left (white bars) and right (black bars) side in all participants. Note that we found three distinct groups of participants: 47% showed spasticity in both the quadriceps femoris and soleus muscle (referred as ‘Group I’, n=14), 30% showed spasticity only in quadriceps femoris (referred as ‘Group II’, n=9) and 23% had no detectable spasticity in either muscle (referred as ‘Group III’, n=7). None of our participants presented spasticity in the soleus but not in the quadriceps muscle. A generalized linear model showed differences of GROUP (χ2(2)=19.8, p<0.001) by MAS score: group I: 4 [range 1-4]; group II: 1 [range 0-4]; group III: 0 [range 0-0].

Figure 2. Spasticity.

Figure 2.

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Individual distribution of the MAS score in the quadriceps femoris (top panel) and soleus (bottom panel) muscle in the left (white) and right (black) side. The abscissa shows the participants identified by their number as listed in Table 1. The ordinate shows the MAS scores. Individuals with MAS scores of 1+ are identified by a “+” within the bars. Note that 47% of participants presented spasticity in quadriceps femoris and soleus (purple, Group I), 30% of participants presented spasticity only in quadriceps femoris (orange, Group II), and 23% of participants showed no spasticity in both muscles (green, Group III). Spasticity was never observed in soleus alone.

Cortical MEPs

Figure 3A shows raw data from participant #21. Note that in this participant cortical MEPs were present in the quadriceps femoris but not in the soleus muscle. Figure 3B shows cortical MEPs in the quadriceps femoris (top panel) and soleus (bottom panel) muscle on the left (white triangle) and right (black circle) side in all participants. In Group I, 13/14 participants showed cortical MEPs in the quadriceps femoris. In Group II, 9/9 participants showed cortical MEPs in quadriceps femoris muscle. Notably, cortical MEPs were never observed in the soleus muscle in Groups I, II and III.

Figure 3. Cortical MEPs.

Figure 3.

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A, Representative cortical MEPs elicited in quadriceps femoris in participant #21. Five traces are shown for each muscle. Note that cortical MEPs were elicited in quadriceps femoris but not in the soleus in Group I and Group II. B, Individual cortical MEPs are shown in the quadriceps femoris (top panel) and the soleus (bottom panel) on the left (white triangle) and right (black circle) side. The abscissa shows participants identified by their number as listed in Table 1. The ordinate shows cortical MEPs normalized to the M-max. Note that cortical MEPs were never observed in the soleus muscle in any of the groups. C, Box plot charts show the merged cortical MEPs from the left and right side for the quadriceps femoris (top panel) and soleus (bottom panel) muscle. The abscissa shows the groups tested and the ordinate shows the size of cortical MEPs normalized to the M-max. Top and bottom lines of the box indicate the 75th percentile (top quartile) and 25th percentile (bottom quartile), respectively. Line in the box indicates the 50th percentile (median). The two bars extend from the maximum and minimum value. The dot within the box indicates the arithmetical mean.

A mixed model ANOVA showed no effect of MUSCLE (F(2,19)=2.2, p=0.1), GROUP (F(1,19)=0.2, p=0.6), nor in their interaction (F(2,19)=2.2, p=0.1) on the M-max (quadriceps femoris: Group I=4.8±1.4 mV, Group II=4.2±1.3 mV and Group III=2.6±1.7 mV; soleus: Group I=4.5±1.6 mV, Group II=2.8±2.2 mV and Group III=3.8±2.4 mV). In addition, a mixed model ANOVA showed an effect of GROUP (F(2, 19)=8.0, p=0.002), MUSCLE (F(1, 19)=35.0, p<0.001), and in their interaction (F(2, 19)=7.2, p=0.005) on cortical MEPs (Figure 3C). Post-hoc tests showed that cortical MEPs in the quadriceps femoris were not different between groups I (0.7±0.6% of the M-max) and II (1.2±1.1% of the M-max; p=0.09) and absent in Group III. Cortical MEPs in soleus were absent in all groups.

Thoracic MEPs

Figure 4A shows raw data from participant #7. In this participant, thoracic MEPs were present in the quadriceps femoris and soleus muscle. Note that in this participant, cortical MEPs were present only in the quadriceps muscle. Figure 4B shows thoracic MEPs in the quadriceps femoris (top panel) and soleus (bottom panel) muscle on the left (white triangle) and right (black circle) side in all participants. In Groups I (14/14) and II (9/9), participants showed thoracic MEPs in the quadriceps femoris on both sides. In the soleus muscle, thoracic MEPs were observed in Group I (14/14) but not in Groups II (0/9) and III (0/7).

Figure 4. Thoracic MEPs.

Figure 4.

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A, Representative thoracic MEPs elicited in quadriceps femoris and soleus in participant #7. Five traces are shown for each muscle. Note that thoracic MEPs, in contrast to cortical MEPs, were elicited in both muscles. B, Individual thoracic MEPs in the quadriceps femoris (top panel) and soleus (bottom panel) muscle on the left (white triangle) and right (black circle) side. The abscissa shows participants identified by their number as listed in Table 1. The ordinate shows thoracic MEPs normalized to the M-max. Note that thoracic MEPs were elicited on both sides in the quadriceps femoris and soleus in Group I and Group II when spasticity was present but never in Group III. C, Box plot charts show merged thoracic MEPs from the left and right side in the quadriceps femoris (top panel) and soleus (bottom panel) muscle. The abscissa shows the groups tested and the ordinate shows the thoracic MEPs normalized to the M-max. Top and bottom lines of the box indicate the 75th percentile (top quartile) and 25th percentile (bottom quartile), respectively. Line in the box indicates the 50th percentile (median). The two bars extend from the maximum and minimum value. The dot within the box indicates the arithmetical mean. *p<0.05

A mixed model ANOVA showed an effect of GROUP (F(2, 19)=70.2, p<0.001), MUSCLE (F(1, 19)=28.0, p<0.001), and in their interaction (F(2, 19)=17.1, p<0.001) on thoracic MEPs (Figure 4C). Post-hoc tests showed that thoracic MEPs in the quadriceps femoris were larger in Group I (9.1±8.1% of the M-max) compared with Group II (2.7±1.2% of the M-max; p=0.04) and absent in Group III. Thoracic MEPs in the soleus muscle were present in Group I (7.3±7.8% of the M-max) and absent in Groups II and III. No difference was found between groups II and III (p=0.4). Within Group I, no difference was found between the size of thoracic MEPs in the quadriceps femoris and soleus muscle (p=0.1).

Cortical and thoracic MEPs response probability

Figure 5 shows the percentage of presence and absence of cortical MEPs (left panel) and thoracic MEPs (right panel) in the quadriceps femoris (Figure 5A) and soleus (Figure 5B) muscle. The abscissa shows the side tested and the ordinate shows the percentage of participants with present (black) and absent (white) responses to each stimulation. Note that in the quadriceps femoris, cortical MEPs were present in 63% (left side) and 43% (right side) of participants whereas thoracic MEPs were present in 77% of participants on both sides. In the soleus muscle, cortical MEPs were never present while thoracic MEPs were present in 47% of participants on both sides. Overall, these results indicate that regardless of the technique used to elicit responses, corticospinal connectivity was more frequently observed in a more proximal compared with a more distal leg muscle.

Figure 5. Cortical and thoracic MEPs response probability.

Figure 5.

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Percentage of cortical MEPs (left panel) and thoracic MEPs (right panel) present or absent in the quadriceps femoris (A) and soleus (B) muscle. The abscissa shows the side tested and the ordinate shows the percentage of participant with present (black) and absent (white) responses to each stimulation. Note that in the quadriceps femoris, cortical MEPs were present in 63% (left side) and 43% (right side) of the participants while thoracic MEPs were present in 77% of participants on both sides. In soleus, cortical MEPs were never present while thoracic MEPs were present in 47% of participants on both sides.

MEPs conditioned by thoracic electrical stimulation

Figure 6 shows raw data from participants #3 (left panel), #4 (middle panel), and #21 (right panel). Cortical MEPs (first row), thoracic MEPs (second row), conditioned MEPs-3 ms (third row), and conditioned MEPs+3 ms (fourth row) are shown for each participant. At a negative ISI, cortical MEPs were facilitated (purple arrow) by thoracic electrical stimulation. Whereas, at a positive ISI, cortical MEPs were suppressed (green arrow) by thoracic electrical stimulation. Across conditions, the horizontal blue lines show the size of the cortical MEP in the absence of an effect of a thoracic volley elicited by electrical stimulation. We found similar results in all subjects. In participant #3, conditioned MEPs at ISI of −3 ms were facilitated by 119.4±9.0% and conditioned MEPs at ISI +3 ms were suppressed by 69.0±7.3% compared with cortical MEPs. In participant #4, conditioned MEPs at ISI −3 ms were facilitated by 112.4±10.5% and conditioned MEPs at ISI +3 ms were suppressed by 77.4±6.2% compared with cortical MEPs. In participant #21, conditioned MEPs at ISI −3 ms were facilitated by 110.2±5.1% and conditioned MEPs at ISI +3 ms were suppressed by 57.0±6.8% compared with cortical MEPs. Kruskas-Wallis one-way ANOVA showed an effect of CONDITION (H(3)=7.4, p=0.004) on the conditioned MEPs. Post-hoc tests showed that conditioned MEPs-3 ms were facilitated (114.0±4.8% of the cortical MEPs, p=0.04) and conditioned MEPs+3 ms were suppressed (67.8±10.3% of the cortical MEPs, p=0.002) compared with cortical MEPs.

Figure 6. Cortical MEPs conditioned by thoracic electrical stimulation.

Figure 6.

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Representative responses recorded from the quadriceps femoris from participants #3 (left panel), #4 (middle panel) and #21 (right panel). Cortical MEPs (first row, peak-to-peak amplitude noted by horizontal blue lines), thoracic MEPs (second row), conditioned cortical MEPs by a stimuli given at interstimulus intervals (ISIs) of −3 ms (third row) and +3 ms (fourth row) around the expected arrival of the cortical volley at this segmental level, were randomly tested. Note that at the negative ISI cortical MEPs were facilitated (purple arrow) by thoracic volleys compared with cortical MEP elicited alone (referenced by the horizontal blue lines). At the positive ISI, cortical MEPs were suppressed (green arrow) by thoracic volleys compared with the cortical MEP elicited alone (referenced by the horizontal blue lines). Bar graphs show that cortical MEPs were facilitated at ISI −3 ms (purple) and suppressed at ISI +3 ms (green) in all subjects. The horizontal blue line represents the size of the cortical MEP elicited alone in the absence of effect of thoracic volley.

Correlations

An association was found between MAS scores and cortical MEPs and thoracic MEPs in the quadriceps femoris muscle and also between MAS scores and thoracic MEPs in the soleus muscle (see Table 2). No correlation was found between physiological outcomes and the level of injury (quadriceps: cortical MEPs, r=0.4, p=0.09, thoracic MEPs, r=0.4, p=0.06; soleus: thoracic MEPs, r=0.02, p=0.9), the time post-injury (quadriceps: cortical MEPs, r=−0.05, p=0.8, thoracic MEPs, r=−0.05, p=0.8; soleus: thoracic MEPs, r=−0.3, p=0.07) and medication intake (quadriceps: cortical MEPs, r=−0.2, p=0.3, thoracic MEPs, r=−0.2, p=0.3; soleus: thoracic MEPs, r=0.2, p=0.3).

Table 2.

Association between MAS scores, cortical MEPs and thoracic MEPs in the quadriceps femoris and the soleus muscles. [N] median (25th, 75th).
Left Right
N Cortical MEPs Thoracic MEPs N Cortical MEPs Thoracic MEPs
Quadriceps femoris
  MAS 0 7 0 (0, 0) 0 (0, 0) 7 0 (0, 0) 0 (0, 0)
  MAS 1 2 (0, 0.5) (2.2, 19.7) 2 (0, 0.4) (6.4, 20.3)
  MAS 1+ 2 (0.3, 0.6) (1.1, 3.2) 1 0.4 3.4
  MAS 2 4 1.2 (0.5, 2.4) 2.4 (1.9, 3.1) 8 0 (0, 1.1) 2.3 (1.6, 3.0)
  MAS 3 8 0.6 (0.5, 0.8) 3.2 (2.2, 7.9) 7 0.4 (0, 2.7) 3.5 (2.7, 3.8)
  MAS 4 7 0.3 (0, 1.1) 1.7 (1.1, 16.3) 5 0.4 (0.4, 0.7) 9.1 (4.0, 23.9)
p-value 0.009 0.005 0.1 0.001
Soleus
  MAS 0 16 -- 0 (0, 0) 16 -- 0 (0, 0)
  MAS 1 1 -- 1.7 1 -- 1.0
  MAS 1+ 0 -- -- 0 -- --
  MAS 2 3 -- 19.6 (0.6, 20.6) 2 -- (6.7, 21.4)
  MAS 3 0 -- -- 1 -- 0.6
  MAS 4 10 -- 2.7 (1.2, 11.6) 10 -- 3.3 (1.1, 12.6)
p-value <0.001 <0.001
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Discussion

A new view of the association between the corticospinal pathway and spasticity emerges from our findings. We found concomitant patterns of residual corticospinal responses and spasticity in muscles below the injury in humans with motor complete SCI. Three distinct sub-groups of people with SCI were identified: participants with spasticity and corticospinal responses in the quadriceps femoris and soleus muscle, participants with spasticity and corticospinal responses in the quadriceps femoris muscle only, and participants with no spasticity or corticospinal responses in either muscle. While cortical MEPs were present only in the quadriceps in participants with spasticity, thoracic MEPs were present in quadriceps and soleus when spasticity was present, suggesting that direct activation of corticospinal axons represents a more sensitive outcome to assess residual corticospinal connectivity. Thoracic electrical stimulation facilitated and suppressed cortical MEPs, which is consistent with the view that both forms of stimulation activate similar corticospinal axons. Cortical and thoracic MEP amplitudes correlated with the degree of spasticity. Based on our findings, we propose that a clinical exam of spasticity can be a valuable predictor of residual corticospinal connectivity after severe paralysis due to SCI.

Spasticity and corticospinal connectivity after SCI

In humans with SCI, after resolution of spinal shock, the intrinsic excitability of neuronal networks below the injury increases to compensate for the loss of descending motor output (Dietz, 2000; Hiersemenzel et al., 2000). This increase in excitability in motor neurons is reflected by larger reflexes (Leis et al., 1996; Little et al., 1999), re-emerging persistent inward currents (Gorassini et al., 2004), and prolonged excitatory postsynaptic potentials (Norton et al., 2008), which all may contribute to the development of spasticity. In our study, 77% of the participants showed spasticity in at least one of the muscles tested. This is consistent with previous evidence showing that spasticity manifests in ~70% of people with SCI (Little et al., 1989; Sköld et al., 1999; Holtz et al., 2017; Sangari et al., 2019). We measured spasticity using the MAS, which is an exam widely used in clinical settings and recommended by the National Institute of Neurological Disorders and Stroke as a supplemental common data element for clinical SCI research (Biering-Sørensen et al., 2015). Although limitations (Haas et al., 1996; Sherwood et al., 2000) and strengths (Sköld et al., 1998; Akpinar et al., 2017) have been discussed about the use of MAS scores for quantifying spasticity, studies have shown that MAS scores are sensitive to reflect overall changes that are comparable with other more quantitative measures of spasticity (Bohannon et al., 2009; Tancredo et al., 2013; Sangari et al., 2019). Importantly, among our study participants, we found that 47% had spasticity in the quadriceps femoris and soleus muscle, 30% had spasticity in the quadriceps femoris muscle only, and 23% had no spasticity in either muscle. This is consistent with evidence showing that the distribution of spasticity varies across muscles below the injury (Sköld et al., 1999). Interestingly, spasticity was always present in the quadriceps with or without spasticity in the soleus muscle but never only in the soleus, suggesting a proximal to distal gradient of symptoms of hyperreflexia. This is supported by our analysis showing a larger prevalence of spasticity in the quadriceps femoris compared with the soleus muscle. Evidence showed that motor neuron excitability increases distally to the injury site (Thomas et al., 2017), which due to the location of motor neurons would suggest that spasticity would be more apparent in the soleus than in the quadriceps muscle. However, evidence also showed a greater loss among motor neurons closer to the injury site with a recovery that began about 3 segments below the injury (Grumbles & Thomas, 2017). Based on the level of injury, we estimated that quadriceps and soleus motor neurons were located more than 3 segments below the injury and M-max responses were similar in quadriceps and soleus on both sides. This suggests that it is less likely that differences in the surviving motor neuron pool contributed to the observed spasticity in quadriceps but not in the soleus. This also agrees with previous evidence showing that H-reflexes are similar in amplitude in people with and without spasticity (Sangari et al., 2019; Chen et al., 2020).

We favor the hypothesis that differences in spasticity across muscles was related, at least to some extent, to residual corticospinal innervation. The mechanisms contributing to spasticity remain incompletely understood; however, several studies agreed that the loss of corticospinal axons is implicated in the development of spasticity. Earlier evidence suggested that damage to axons derived from neurons located in the primary motor cortex precedes spasticity (Hines, 1929). In animals, lesions of the corticospinal tract at the pyramids (Tan et al., 2012) or the spinal cord (Murray & Goldberger, 1974) causes sprouting of afferents in the spinal cord, leading to symptoms of hyperreflexia. In humans with motor complete SCI, magnetic resonance imaging showed that the amount of spared tissue in the lateral regions of the spinal cord, where the corticospinal tract is located, correlated positively with the severity of spasticity (Sangari et al., 2019). In the present study, we found that cortical MEPs were present in the quadriceps femoris muscle only in participants who had spasticity whereas thoracic MEPs were present in quadriceps and soleus when spasticity was present, which is consistent with the concept that residual corticospinal connectivity contributes to spasticity. This is also supported by our results showing that thoracic electrical stimulation facilitated and suppressed cortical MEPs, indicating that both responses where mediated by similar corticospinal axons. Antidromic volleys produced by electrical stimulation over the thoracic spinal cord can occlude the response produced by cortical stimulation using TMS, which suggests that the cortical and thoracic stimuli activated some of the same corticospinal axons (Martin et al., 2008). However, it is important to consider that factors such as the size and timing of descending volleys evoked by the cortical stimulus and interactions at the motor neuron level can influence the magnitude of the occlusion between the cortical and thoracic stimuli. It is also possible that other descending axons might be stimulated by the cortical and thoracic stimuli. TMS over the motor cortex can stimulate projections to other cortical (Siebner et al., 2001) and subcortical (Strafella et al., 2001; Fisher et al., 2012) regions. Electric or magnetic stimulation of the spinal cord can result in activation of different descending motor pathways including the corticospinal tract (Ugawa et al., 1991; Maertens de Noordhout et al., 1992; Martin et al., 2008; Fisher et al., 2012).

An important consideration is to determine why it is possible to evoke cortical MEPs in the quadriceps but not in the soleus muscle? The synchronization of corticospinal volleys elicited by TMS decreases in people with SCI compared with control subjects (Cirillo et al., 2016). A possibility is that the larger desynchronization of corticospinal volleys could contribute to the inability to observe cortical MEPs in the soleus muscle. This is consistent with our results showing that direct stimulation of corticospinal axons, having a lesser temporal dispersion of volleys, produced thoracic MEPs in all participants with spasticity in the soleus, highlighting that thoracic MEPs might be a more sensitive outcome to assess corticospinal connectivity by stimulating above the injury in humans with severe paralysis. Interestingly, in Group II, thoracic MEPs were present in the quadriceps femoris but not in the soleus muscle. Corticospinal facilitation seems similar across quadriceps femoris and soleus motor units in monkeys (Hudson et al., 2015) and humans (Brouwer & Ashby, 1992). Thus, it is unlike that our results are related to differences in the strength of corticospinal inputs across muscles. Most common mechanisms of SCI in humans involve contusions and compressions (Tator, 1995; Layer et al., 2017), which typically leave some parenchymal continuity across the lesion epicenter at multiple spinal cord segments (Kakulas, 1988; Bunge et al., 1993). The variable presence of residual parenchyma might result in different patterns of descending connectivity to muscles below the injury, which might contribute to explain our results. This is consistent with electrophysiological studies showing that in people with motor complete SCI, reinforcement maneuvers generated EMG responses in some, but not all, lower limb muscles tested below the injury, implying preservation of spared descending connectivity to discrete populations of motor units (Dimitrijevic et al., 1984). This also agrees with results showing that the probability for evoking MEPs by TMS over the primary motor cortex varies across different limb muscles below the level of the injury in humans with motor complete SCI (Calancie et al., 1999; Squair et al., 2016; Santamaria et al., 2021). Another possibility is that the TMS intensity was insufficient to generate cortical MEPs in the soleus muscle. Previous studies and unpublished data from our laboratory suggest that in control participants relatively similar TMS intensities are needed to elicit motor threshold responses in the soleus (Lauber et al., 2018) and quadriceps (Stevens-Lapsley et al., 2013; Kittelson et al., 2014) muscles. The frequency of MEP occurrence in the quadriceps and soleus muscles also seems to be similar at 100% MSO (Dimitrijević et al., 1992), which is the TMS intensity used in our study. However, little information exists about the extent of overlap of TMS hotspot locations of different lower limb muscles in humans (Kesar et al., 2018) and to our knowledge there are no previous studies comparing motor threshold responses in the quadriceps and soleus muscle in a single study, therefore, this possibility cannot be completely excluded.

Functional considerations

Two main implications arise from our findings. First, our results suggest that a link exists between corticospinal connectivity and spasticity, with distinct patterns of spared descending connections accompanying patterns of spasticity. This is supported by the strong positive correlation that we found between the degree of spasticity and the amplitude of cortical and thoracic MEPs in both muscles. This is also consistent with evidence showing that therapies aiming to increase corticospinal excitability (i.e., repetitive TMS and exercise training) influence symptoms of spasticity (Wirz et al., 2005; Kumru et al., 2010; Benito et al., 2012). It is interesting to note that in these studies, increases in corticospinal excitability resulted in decreases in spasticity. Thus, approaches aiming to decrease spasticity might benefit from increasing corticospinal drive. This is consistent by evidence showing that spastic muscles in humans with chronic incomplete SCI have corticospinal responses, but reduced in size, compared with non-spastic muscles (Sangari & Perez, 2019). Second, our results showed that a clinical exam of spasticity might provide reliable information about residual corticospinal connectivity after severe paralysis. This is consistent with results in participants with chronic SCI showing that the presence of spasticity is associated with better functional recovery (Peña Pino et al., 2020). Plasticity in the corticospinal pathway has been associated with functional recovery following SCI (Oudega & Perez, 2012; Bunday & Perez, 2012; Jo & Perez, 2020). This might open avenues to determine which participants with severe paralysis might have a better possibility for recovery – the expectation will be that people with motor complete paralysis in acute rehabilitation settings with spasticity might have a better possibility for recovery compared with people without spasticity. However, further studies are needed to directly assess this possibility. In the present study, we only tested individuals with thoracic SCI to ensure that thoracic MEPs were elicited by electrical stimulation over the spine above the injury level. Animal studies have shown that regeneration and pathologies may differ between cervical and thoracic SCI (Ulndreaj et al., 2017). Our previous observations showing residual descending connectivity in spastic muscles in individuals with a motor complete cervical and thoracic SCI (Sangari et al., 2019) suggest that these results might extrapolate to a variety of injuries.

Supplementary Material

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Key points:

  • Damage to corticospinal axons have implications for the development of spasticity following spinal cord injury (SCI). Here, we examined to which extent residual corticospinal connections and spasticity are present in muscles below the injury (quadriceps femoris and soleus) in humans with motor complete thoracic SCI.

  • We found three distinct sub-groups of people: participants with spasticity and corticospinal responses in the quadriceps femoris and soleus, participants with spasticity and corticospinal responses in the quadriceps femoris only, and participants with no spasticity or corticospinal responses in either muscle. Spasticity and corticospinal responses were present in the quadriceps but never only in the soleus muscle, suggesting a proximal to distal gradient of symptoms of hyperreflexia.

  • These results suggest that concomitant patterns of residual corticospinal connectivity and spasticity exist in humans with motor complete SCI and that a clinical exam of spasticity might be a good predictor of residual corticospinal connectivity.

Funding:

M.A.P. was supported by the National Institute of Neurological Disorders and Stroke and the Department of Veterans Affairs. S.S. was supported by the Craig H. Neilsen Foundation.

Biography

Sina Sangari is a postdoctoral associate at Shirley Ryan AbilityLab, Chicago, IL. He received his PhD in Neuroscience from University Pierre and Marie Curie (Paris, France) where he studied sensory-motor alterations in patients with amyotrophic lateral sclerosis. To study the contribution of descending motor pathways in spasticity and recovery in individuals with spinal cord injury, he joined the lab of Dr Monica Perez. His research is focused on understanding the mechanisms underlying spasticity and functional recovery and their relations in humans after spinal cord injury.

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Footnotes

Competing interests: None

Data availability:

The data that support the findings of this study are available from the corresponding author, upon reasonable request.

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Supplementary Materials

sm2
NIHMS1714104-supplement-sm2.xlsx (58.2KB, xlsx)
sm1
NIHMS1714104-supplement-sm1.pdf (52.4KB, pdf)

Data Availability Statement

The data that support the findings of this study are available from the corresponding author, upon reasonable request.

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