Abstract
When the foot dorsum contacts an obstacle during locomotion, cutaneous afferents signal central circuits to coordinate muscle activity in the four limbs. Spinal cord injury disrupts these interactions, impairing balance and interlimb coordination. We evoked cutaneous reflexes by electrically stimulating left and right superficial peroneal nerves before and after two thoracic lateral hemisections placed on opposite sides of the cord at 9–13 weeks interval in seven adult cats (4 males and 3 females). We recorded reflex responses in ten hindlimb and five forelimb muscles bilaterally. After the first (right T5-T6) and second (left T10-T11) hemisections, coordination of the fore- and hindlimbs was altered and/or became less consistent. After the second hemisection, cats required balance assistance to perform quadrupedal locomotion. Short-latency reflex responses in homonymous and crossed hindlimb muscles largely remained unaffected after staggered hemisections. However, mid- and long-latency homonymous and crossed responses in both hindlimbs occurred less frequently after staggered hemisections. In forelimb muscles, homolateral and diagonal mid- and long-latency response occurrence significantly decreased after the first and second hemisections. In all four limbs, however, when present, short-, mid- and long-latency responses maintained their phase-dependent modulation. We also observed reduced durations of short-latency inhibitory homonymous responses in left hindlimb extensors early after the first hemisection and delayed short-latency responses in the right ipsilesional hindlimb after the first hemisection. Therefore, changes in cutaneous reflex responses correlated with impaired balance/stability and interlimb coordination during locomotion after spinal cord injury. Restoring reflex transmission could be used as a biomarker to facilitate locomotor recovery.
Keywords: cutaneous reflexes, interlimb coordination, locomotion, spinal cord injury
Graphical Astract
Contacting an obstacle during locomotion activates cutaneous afferents to maintain balance and coordinate all four limbs. Spinal cord injuries disrupt neural communications between spinal networks controlling the fore- and hindlimbs, impairing balance and limb coordination. Cutaneous reflex pathways can be used to develop therapeutic approaches for restoring ascending and descending transmission to facilitate locomotor recovery.
INTRODUCTION
The control of locomotion involves dynamic interactions between supraspinal structures, spinal circuits and somatosensory feedback to coordinate limb movements and maintain balance/stability [for reviews, see (Rossignol et al., 2006; Frigon, 2017; Frigon et al., 2021)]. Spinal cord injury (SCI) disrupts these interactions, leading to severe sensorimotor deficits, including impaired balance and limb coordination (Barbeau et al., 2002; Edgerton et al., 2004; Van Hedel & Dietz, 2010; Rossignol & Frigon, 2011). Although complete SCI abolishes all communication between the brain and spinal sensorimotor circuits located below the lesion, most SCIs are incomplete, and some communication between spinal circuits controlling the arms/forelimbs and legs/hindlimbs remains possible. Somatosensory feedback, proprioceptive and tactile, plays an important role in the recovery of hindlimb locomotion after thoracic SCI (Goldberger, 1977; Muir & Steeves, 1995; Bouyer & Rossignol, 2003a, 2003b; Smith et al., 2006; Takeoka et al., 2014). However, its role in limb coordination after incomplete SCI is not clear.
One way to address this issue is to evoke reflexes by stimulating peripheral nerves and recording responses in all four limbs before and after SCI. Studies in cats have shown changes in reflex responses in the hindlimbs following incomplete or complete thoracic SCI (Frigon & Rossignol, 2008; Frigon et al., 2009; Gossard et al., 2015). However, only a few studies have investigated changes in reflex pathways that send signals between circuits located at cervical and lumbosacral levels that are thought to coordinate the arms/forelimbs and legs/hindlimbs, respectively, after SCI. One study reported an increased ascending transmission two weeks after a unilateral cervical SCI in rats by electrically stimulating the sciatic nerve and recording responses in a forelimb extensor muscle bilaterally at rest (Côté et al., 2012). In humans, interlimb reflexes evoked in arm muscles with electrical stimulation of the tibial nerves at rest, were strengthened following cervical SCI (Calancie et al., 2002). We know that interlimb reflexes evoked by stimulating cutaneous nerves of the fore- and hindlimbs are modulated during locomotion in cats and humans (Haridas & Zehr, 2003; Hurteau et al., 2018; Merlet et al., 2022; Mari et al., 2023), likely contributing to limb coordination, but we do not know how they change following SCI and if their loss could explain impairments in limb coordination during locomotion.
In the present study, we electrically stimulated the superficial peroneal nerve (SP) that innervates the foot dorsum, responsible for the stumbling corrective reaction in cats and humans (Forssberg et al., 1977; Prochazka et al., 1978; Forssberg, 1979; Duysens & Loeb, 1980; Wand et al., 1980; Schillings et al., 1996; Van Wezel et al., 1997; Zehr et al., 1997; Quevedo et al., 2005b, 2005a), during treadmill locomotion. In cats, stimulating the SP nerve elicits short- (7–19 ms), mid- (19–34 ms) and long-latency (35–60 ms) responses in all four limbs (Hurteau et al., 2018; Merlet et al., 2022; Mari et al., 2023). Mid- and long-latency responses are thought to involve supraspinal contributions (Fuwa et al., 1991; LaBella et al., 1992; Frigon & Rossignol, 2008; Hurteau & Frigon, 2018). We stimulated the SP nerve before, after a mid-thoracic lateral hemisection on the right side and then after a second lateral hemisection on the left side a few spinal segments caudal to the first hemisection 9–13 weeks later. This staggered hemisections paradigm disrupts direct ascending and descending spinal pathways that communicate between the brain/cervical cord and lumbosacral circuits, severely impairing fore-hind coordination (Jane et al., 1964; Kato et al., 1984, 1985; Stelzner & Cullen, 1991; Courtine et al., 2008; Van Den Brand et al., 2012; Cowley et al., 2015; Audet et al., 2023). Here, we used this paradigm to probe changes in neural pathways projecting to the four limbs and to determine their potential role in forelimb-hindlimb coordination. We asked three main questions. First, how are cutaneous reflexes in muscles of the four limbs evoked by stimulating SP nerve afferents from the right (ipsilesional to the first lesion) and left (contralateral to the first lesion) hindlimbs altered after sectioning descending and ascending pathways on the right side of the cord with a lateral hemisection? Two, how are these cutaneous reflexes further affected by a second lateral hemisection placed on the opposite (left) side of the cord a few segments below, which disrupts direct descending and ascending spinal pathways bilaterally? Third, do these changes in reflexes reflect impaired/altered coordination of the fore- and hindlimbs during locomotion? Our results show that the occurrence of mid- and long-latency reflex responses in all four limbs was considerably reduced after the first and second spinal lesions, including those in the forelimbs. These changes in cutaneous reflexes correlated with altered coordination between the fore- and hindlimbs during locomotion as well as with a loss in balance.
MATERIAL AND METHODS
Ethical approval
All procedures were approved by the Animal Care Committee of the Université de Sherbrooke (Protocol 442–18) in accordance with policies and directives of the Canadian Council on Animal Care. We obtained the current data set from seven adult purpose-bred cats (> 1 year of age at the time of experimentation), 3 females and 4 males, weighing between 3.4 kg and 6.5 kg, purchased from Marshall BioResources. Before and after experiments, cats were housed and fed (weight-dependent metabolic diet and water ad libitum) in a dedicated room within the animal care facility of the Faculty of Medicine and Health Sciences at the Université de Sherbrooke. We followed the ARRIVE guidelines 2.0 for animal studies (Grundy, 2015; Percie Du Sert et al., 2020). The investigators understand the ethical principles under which the journal operates and our work complies with this animal ethics checklist. In order to maximize the scientific output of each animal, they were used in other studies to investigate different scientific questions, some of which have been published (Lecomte et al., 2022, 2023; Merlet et al., 2022; Audet et al., 2023; Mari et al., 2023).
General surgical procedures
All surgeries (implantation and spinal lesions) were performed under aseptic conditions with sterilized equipment in an operating room. Prior to surgery, cats were sedated with an intramuscular (i.m.) injection of butorphanol (0.4 mg/kg), acepromazine (0.1 mg/kg), and glycopyrrolate (0.01 mg/kg). We then injected a mixture (0.05 mg/kg, i.m.) of diazepam (0.25 mg/kg) and ketamine (2.0 mg/kg) in a 1:1 ratio five minutes later for induction. We shaved the animal’s fur (back, stomach, fore- and hindlimbs) and cleaned the skin with chlorhexidine soap. Cats were anesthetized with isoflurane (1.5–3%) and O2 delivered with a mask and then with a flexible endotracheal tube. The depth of anesthesia was confirmed by applying pressure to a paw (to detect limb withdrawal) and by assessing the size and reactivity of pupils. Isoflurane concentration was adjusted throughout the surgery by monitoring cardiac and respiratory rates. Body temperature was maintained constant (37 ± 0.5°C) using a water-filled heating pad placed under the animal, an infrared lamp placed ~50 cm over it and a continuous infusion of lactated Ringers solution (3 ml/kg/h) through a catheter placed in a cephalic vein. At the end of surgery, we injected subcutaneously an antibiotic (cefovecin, 8 mg/kg) and a fast-acting analgesic (buprenorphine, 0.01 mg/kg). We also taped a fentanyl (25 μg/h) patch to the back of the animal 2–3 cm rostral to the base of the tail for prolonged analgesia, which we removed 4–5 days later. After surgery, cats were placed in an incubator and closely monitored until they regained consciousness. We administered another dose of buprenorphine ~7 hours after surgery. At the end of experiments, cats were anaesthetized with isoflurane (1.5–3.0%) and O2 before receiving a lethal dose of pentobarbital (120 mg/kg) through the left or right cephalic vein. Cardiac arrest was confirmed using a stethoscope to determine the death of the animal. Spinal cords were then harvested for histological analysis (Audet et al., 2023; Lecomte et al., 2023).
Staggered hemisections
After collecting data in the intact state, we performed a lateral hemisection between the 5th and 6th thoracic vertebrae (T5-T6) on the right side of the spinal cord. Before surgery, we sedated the cat with an intramuscular injection of a cocktail containing butorphanol (0.4 mg/kg), acepromazine (0.1 mg/kg) and glycopyrrolate (0.01 mg/kg) and inducted with another intramuscular injection (0.05 ml/kg) of ketamine (2.0 mg/kg) and diazepam (0.25 mg/kg) in a 1:1 ratio. We shaved the fur overlying the back and the skin was cleaned with chlorhexidine soap. The cat was then anesthetized with isoflurane (1.5–3%) and O2 using a mask for a minimum of 5 minutes and then intubated with a flexible endotracheal tube. Isoflurane concentration was confirmed and adjusted throughout the surgery by monitoring cardiac and respiratory rates, by applying pressure to the paw to detect limb withdrawal and by assessing muscle tone. Once the animal was deeply anesthetized, an incision of the skin over T5-T6 was made and after carefully setting aside muscle and connective tissue, a small laminectomy of the corresponding dorsal bone was performed. Lidocaine (xylocaine, 2%) was applied topically followed by 2–3 intraspinal injections on the right side of the cord. We then sectioned the spinal cord laterally from the midline to the right using surgical scissors. We placed hemostatic material (Spongostan) within the gap before sewing back muscles and skin in anatomical layers. In the days following hemisection, voluntary bodily functions were carefully monitored. The bladder and large intestine were manually expressed if needed. Once data were collected following the first hemisection (9–13 weeks), we performed a second lateral hemisection between the 10th and 11th thoracic vertebrae (T10-T11) on the left side of the spinal cord using the same surgical procedures and post-operative care described above.
Electromyography and nerve stimulation
To record the electrical activity of muscles (EMG, electromyography), we directed pairs of Teflon-insulated multistrain fine wires (AS633; Cooner Wire) subcutaneously from two head-mounted 34-pin connectors (Omnetics Connector). Two wires, stripped of 1–2 mm of insulation, were sewn into the belly of selected forelimb/hindlimb muscles for bipolar recordings. The head-mounted connectors were fixed to the skull using dental acrylic and four to six screws. We verified electrode placement during surgery by stimulating each muscle through the appropriate head connector channel to assess the biomechanically desired muscle contraction. During experiments, EMG signals were pre-amplified (×10, custom-made system), bandpass filtered (30–1,000 Hz) and amplified (100–5,000×) using a 16-channel amplifier (model 3500; AM Systems). EMG data were digitized (5,000 Hz) with a National Instruments card (NI 6032E), acquired with custom-made acquisition software and stored on computer. Five forelimb muscles were implanted bilaterally: biceps brachii (BB, elbow and shoulder flexor), the long head of the triceps brachii (TRI, elbow and shoulder extensor), latissimus dorsi (LD, shoulder retractor), extensor carpi ulnaris (ECU, wrist dorsiflexor) and flexor carpi ulnaris (FCU, wrist plantarflexor). Ten hindlimb muscles were implanted bilaterally: anterior sartorius (SRT, hip flexor and knee extensor), semitendinosus (ST, knee flexor and hip extensor), vastus lateralis (VL, knee extensor), iliopsoas (IP, hip flexor), biceps femoris posterior (BFP, hip extensor and knee flexor), biceps femoris anterior (BFA, hip extensor), lateral gastrocnemius (LG, ankle plantarflexor and knee flexor), soleus (SOL, ankle plantarflexor), medial gastrocnemius (MG, ankle plantarflexor and knee flexor), and tibialis anterior (TA, ankle dorsiflexor).
For bipolar nerve stimulation, pairs of Teflon-insulated multistrain fine wires (AS633; Cooner Wire) were passed through a silicon tubing. A horizontal slit was made in the tubing and wires within the tubing were stripped of their insulation. The ends protruding through the cuff were knotted to hold the wires in place and glued. The ends of the wires away from the cuff were inserted into four-pin connectors (Hirose or Samtec) and fixed to the skull using dental acrylic. Cuff electrodes were directed subcutaneously from head-mounted connectors to the left and right SP nerves at the ankle which are purely cutaneous at these levels (Bernard et al., 2007).
Experimental design
We collected EMG and kinematic data before and at different time points after staggered hemisections during quadrupedal locomotion at the cat’s preferred treadmill speed (0.3–0.5 m/s). Cats KA and KI stepped at 0.3 and 0.5 m/s, respectively, while the other five cats stepped at 0.4 m/s. The treadmill consisted of two independently controlled belts 130 cm long and 30 cm wide (Bertec) with a Plexiglas separator (130 cm long, 7 cm high, and 1.3 cm wide) placed between the two belts to prevent limbs impeding each other. In the intact, preoperative state, cats were trained for 2–3 weeks in a progressive manner, first for a few steps and then for several consecutive minutes, using food and affection as rewards. Once cats could perform 3–4 consecutive minutes, we started the experiments. During experiments, we delivered trains of electrical stimuli consisting of three 0.2 ms pulses at 300 Hz using a Grass S88 stimulator. At the start of the experiment, we determined the motor threshold, defined as the minimal intensity that elicited a small motor response in an ipsilateral flexor muscle (e.g., ST or TA) during the swing phase. We then set stimulation intensity at 1.2 times the motor threshold. A locomotor trial lasted 4–5 min and consisted of ~60 stimuli delivered pseudo-randomly every 2–4 cycles. Stimuli were delivered at specific points of the stimulated limb (left or right hindlimb) movement: mid-stance, the transition from stance-to-swing, mid-swing and the transition from swing-to-stance. At the start of the experiment, stimulation delays were determined using real-time EMG to detect the onset of an extensor burst in relation to stance and swing phases. We then set delays in relation to this extensor EMG so that stimuli were delivered at the four desired time points. The timing of the stimuli was assessed during off-line analysis and stimuli that did not fall in the desired phases were excluded. We characterized responses in muscles of the stimulated limb (homonymous), the opposite limb of the same girdle (crossed), the limb on the same side (homolateral) and the diagonal limb (diagonal). Figure 1A describes the timeline of data collection in all seven cats at two time points after the first hemisection (H1T1 and H1T2) and/or at 1–2 time points after the second hemisection (H2T1 in 2 cats and H2T2 in 6 cats). Some cats only have one time point after the second hemisection because they took longer to recover quadrupedal locomotion. No data were collected for cat KI after the second hemisection due to technical issues with the implants.
Figure 1. Experimental timeline and staggered hemisections paradigm.
(A) Chronology showing the first (T1) and second (T2) experimental time points after the first (H1) and second (H2) hemisections in all cats. (B) Schematic representation of the staggered hemisections, with the first and second hemisections at right (T5–T6) and left (T10–T11) thoracic levels, respectively. Spinal lesions (cat TO) are highlighted with Cresyl violet staining.
Histology
After confirming euthanasia (i.e., no cardiac and respiratory functions), we harvested an approximately 2 cm long section of the spinal cord centered on the lesions. Segments of the dissected spinal cord were then placed in a 25 ml 4% paraformaldehyde solution (PFA; 0.1 M PBS, 4°C). After 5 days, we placed the spinal cord in a new PBS (0.2 M) solution containing 30% sucrose for 72 h at 4°C, then froze it in isopentane at −50°C for cryoprotection. The spinal cord was then sliced in 50 μm coronal sections using a cryostat (Leica CM1860) and mounted on gelatinized-coated slides. The slides were dried overnight and then stained with a 1% cresyl violet acetate solution for 12 min. We washed the slides for 3 min in distilled water before being dehydrated in successive baths of ethanol (50%, 70% and 100%, 5 min each) and transferring them in xylene for 5 min. Dibutylphthalate polystyrene xylene was next used to mount and dry the spinal cord slides before being scanned by a Nanozoomer. We then performed qualitative and quantitative analyses to estimate lesion extent using ImageJ by selecting the slide with the greatest identifiable damaged area. Using the scarring tissue stained with cresyl violet acetate, we estimated lesion extent by dividing the lesion area by the total area of the selected slice and expressed it as percentage. Figure 1B shows a schematic of the staggered hemisections with histological cross-section images for the first and second lesion in a representative cat.
Reflex analysis
We describe the reflex analysis in several of our publications (Hurteau et al., 2017, 2018; Hurteau & Frigon, 2018; Merlet et al., 2020, 2021; Mari et al., 2023). The step-by-step procedure for quantifying reflex responses is illustrated for the left soleus with stimulation of the left SP nerve (Fig. 2). For all locomotor sessions, EMG signals were low-pass filtered (250 Hz) to facilitate the visualization of the EMG activity envelope. We first defined locomotor cycles from successive burst onsets of the left sartorius and separated them as stimulated (i.e., cycles with stimulation) or control (i.e., cycles without stimulation) cycles. Sections where the cat stepped irregularly were removed from analysis based on EMG and video data. Stimulated cycles were then sorted and divided into 4 subphases based on stance onset of the stimulated limb: swing-to-stance, mid-stance, stance-to-swing and mid-swing. Control () cycles were averaged and rectified to provide a baseline locomotor EMG, an indication of the excitability level of the motor pool at stimulation. We averaged the stimulated () cycles and time normalized to cycle durations and superimposed them. To determine response onsets and offsets, defined as prominent positive or negative deflections away from , we set windows using previous studies as guidelines (Duysens & Stein, 1978; Duysens & Loeb, 1980; Pratt et al., 1991; Loeb, 1993; Hurteau et al., 2017, 2018; Hurteau & Frigon, 2018; Mari et al., 2023) with 97.5% confidence intervals. We measured the latencies of responses from stimulation onset to response onset. We also measured response durations as the time interval between response onset and offset. We termed short-latency (7–18 ms; SLR) excitatory and inhibitory responses as P1 and N1 responses, respectively, based on the terminology introduced by (Duysens & Loeb, 1980). Responses in the crossed, homolateral, and diagonal limbs that had an onset ≤18 ms were classified as P1 or N1, as the minimal latency for spino-bulbo-spinal reflexes in the cat is 18 ms (Shimamura & Livingston, 1962). Mid-latency (19–34 ms; MLR) excitatory and inhibitory responses were termed P2 and N2, respectively. Long-latency (35–60 ms; LLR) excitatory and inhibitory responses were termed P3 and N3, respectively. The EMG of reflex responses was then integrated and subtracted from the integrated in the same time window to provide a net reflex value. This net reflex value was then divided by the integrated value to evaluate reflex responses. This division helps identify if changes in reflex responses across the cycle are independent of changes in activity (Matthews, 1986; Frigon & Rossignol, 2007, 2008, 2009; Hurteau et al., 2017, 2018; Hurteau & Frigon, 2018; Mari et al., 2023).
Figure 2. Reflex methodology.
Electromyographic (EMG) bursts in a single intact cat (AR) are shown for the left soleus during locomotion with stimulation of the left superficial peroneal nerve at mid-stance. From the raw EMG waveforms, we tagged cycles as stimulated (S) when a stimulus fell within the cycle or control (C) if it was not preceded by a stimulated cycle. Rectified EMG. We averaged and rectified control cycles (dark gray trace; ) aligned to ipsilateral sartorius onset. Each stimulated cycle (black trace) is rectified then time-normalized to match duration from . Mean rectified EMG. Stimulated cycles (black trace; ) were then averaged and superimposed on the baseline provided from (dark gray trace). This allowed us to determine positive (in red) and negative (in blue) responses. Onsets and offsets of responses, defined as a prominent positive or negative deflection away from the baseline , were determined visually using confidence intervals at 97.5% (gray dashed traces). The baseline occurring in the same time window as the response was subtracted from the response in the stimulated cycles to provide a net reflex value. This value was then divided by the baseline occurring in the same time window giving N1 and P3 normalized amplitudes for the left soleus.
Statistical analysis
We performed statistical tests with IBM SPSS Statistics V26 (IBM Corp., Armonk, NY, USA). We quantified reflex responses in five forelimb muscles (BB, ECU, FCU, LD, and TRI) and in ten hindlimb muscles (BFA, BFP, IP, LG, MG, SRT, SOL, ST, TA, and VL) when stimulation was delivered to the left or right SP. To evaluate whether homonymous, crossed, homolateral and diagonal responses were modulated by phase, we performed a one factor (phase) ANOVA on all responses (P1, P2, P3, N1, N2 and N3) in each cat and state/time point. Because we have several responses within a given phase, we considered all responses during a locomotor session as a population. In our statistical analysis, we used mixed models to deal with incomplete data sets. For instance, reflex responses are sometimes absent after spinal lesions. Response occurrence probabilities, defined as the fraction of evoked responses obtained out of all cats for pooled SLR, MLR and LLR from the different states/time points were compared using a generalized linear mixed model (GLMM) with a binomial distribution and a logit link (mixed logistic regression) in all four limbs. Dependent variables, such as response latencies and durations of homonymous SLR, MLR and LLR, were analyzed using linear mixed model (LMM). The GLMM and LMM analyses were performed using state/time point as a fixed factor. We incorporated random intercepts at two distinct levels to consider the hierarchical relationships present in our dataset. A random intercept on individual cats at the upper level to capture variability across cats. A random intercept on muscle nested within cat at a lower level, acknowledging that the same muscle response data were repeatedly measured within each cat to help us account for any correlation or non-independence of observations within the same cat-muscle pair. Statistical significance for all tests was set at p < 0.05.
RESULTS
Recovery of quadrupedal locomotion after staggered hemisections and extent of spinal lesions
We recently described changes in the quadrupedal locomotor pattern after staggered thoracic lateral hemisections, including six cats of the present study (Audet et al., 2023). Briefly, cats spontaneously recover quadrupedal locomotion following staggered hemisections but require balance assistance after the second one. The coordination between the forelimbs and hindlimbs displays 2:1 patterns (two cycles of one forelimb within one hindlimb cycle) and becomes weaker and more variable after the first and second hemisections.
Histological analysis shows lesion extent estimations for individual cats after the first and second spinal lesions (Fig. 3). They ranged from 40.7% to 66.4% (49.2 ± 8.9%) and 33.5% to 53.7% (46.0 ± 7.6%) for the first and second hemisections, respectively. After the first hemisection, all seven cats regained quadrupedal locomotion on the treadmill within one to two weeks. They were able to perform reflex sessions for several consecutive minutes at the first (H1T1) and second (H1T2) time points. After the second hemisection, of the six cats tested, all recovered quadrupedal locomotion within two to five weeks. However, they required mediolateral balance assistance during reflex sessions, provided by an experimenter that held the tail of the animal but without supporting its weight. As stated in the Methods, some cats only have one time point after the second hemisection because they took longer to recover quadrupedal locomotion. Only two cats, KA and JA, participated in reflex sessions at the first time point (H2T1), i.e., approximately two weeks after the second hemisection. All six cats performed reflex sessions eight weeks later at the second time point (H2T2).
Figure 3. Estimation of the extent of the first and second lesions for individual cats.
The black area represents the estimation as a percentage of total cross-sectional area. Note that we only performed one lesion in cat KI.
Cutaneous reflexes after staggered hemisections in hindlimb muscles.
To determine how cutaneous reflex pathways and transmission were affected by spinal lesions, we stimulated the left and right SP before and after the first (right T5-T6) and second (left T10-T11) hemisections in the same cats during quadrupedal treadmill locomotion and evaluated reflex responses in muscles of the four limbs and their potential role in locomotor recovery. Due to the large number of sampled muscles and because reflexes varied from one cat to another (Loeb, 1993; Frigon, 2011), out of 10 hindlimb muscles, we illustrate homonymous and crossed reflex responses in four muscles (SOL, VL, SRT and ST) bilaterally in representative cats. The SOL and VL muscles are mostly active during stance while SRT and ST are active during swing and/or at the stance-to-swing transition.
Homonymous responses.
We stimulated the left and right SP nerves and recorded homonymous responses in muscles of the left and right hindlimbs, respectively, before and after staggered hemisections (Fig. 4 and Table 1). Figure 4 shows bilateral homonymous reflex responses in four phases in representative cats. For each state/time point, filled areas highlight evoked responses and are optimized for display according to the strongest response obtained in one of the four locomotor phases. The scale is optimized per state/time point and differs across state/time points. This is to show the pattern of evoked responses and its phase-dependent modulation at a given state/time point.
Figure 4. Phase-dependent modulation of cutaneous reflexes evoked in homonymous hindlimb muscles during locomotion before and following staggered hemisections.
Each panel shows, from left to right, stance phases of the stimulated hindlimb (empty horizontal bars) with its averaged rectified muscle activity normalized to cycle duration in the different states/time points and homonymous reflex responses in representative cats for the left and right (A) soleus (SOL, cat AR), (B) vastus lateralis (VL, cat AR), (C) anterior sartorius (SRT, cat JA), and (D) semitendinosus (ST, cat GR). Reflex responses are shown with a post-stimulation window of 80 ms in four phases in the intact state, and after the first (H1) and second (H2) hemisections at time points 1 (T1) and/or 2 (T2). At each state/time point, evoked responses are scaled according to the largest response obtained in one of the four phases. The scale, however, differs between states/time points.
Table 1. Homonymous reflex responses before and after staggered hemisections.
The table shows homonymous responses (P1, P2, P3, N1, N2 and N3) evoked in individual cats in left and right hindlimb muscles in the intact state, and after the first (H1) and second (H2) hemisections at 1–2 time points (T1 or T2). Asterisks indicate a significant phase modulation (one factor ANOVA, p < 0.05). x, No response. -, Non-implanted or non-analyzable (lost or excessive noise) muscle. BFA, biceps femoris anterior; BFP, biceps femoris posterior; IP, iliopsoas; LG, lateral gastrocnemius; MG, medial gastrocnemius; SOL, soleus; SRT, anterior sartorius; ST, semitendinosus; TA, tibialis anterior; VL, vastus lateralis.
| Homonymous responses in left hindlimb (left SP nerve stimulation) | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Cat | State | BFA | BFP | IP | LG | MG | SOL | SRT | ST | TA | VL |
| AR | Intact | N1/P1* P2* P3* | P1* P2* | P1* P2* | N1/P1* P2* P3* | N1/P1* P2* P3 | N1/P1* P2* P3* | N1/P1* P2* | P1* P2* | P1* P2* | N1* P2* P3* |
| H1T1 | P1* | P1* P2* | P2* | N1/P1* P3* | N1/P1* P3* | N1* P3* | N1 P2 | P1* | P1* P2 | N1 P2* | |
| H1T2 | N1/P1* | P1* | P1* P2* | N1/P1* P2* | N1/P1* P3* | N1/P1* P3* | N1* P2* | P1* P2* | P1* P2* | N1/P1* P3* | |
| H2T2 | P1* | - | P1* P2 | P1* | P1* P2* | P1* | N1* P2 | - | P1 P2* | P1* | |
| GR | Intact | N1* | P1 | - | N1/P1 P3* | - | N1* | P2 | P1* P2* | - | N1* |
| H1T1 | N1/P1* P3* | P1* P2* | - | P1* | - | N1/P1* P2* P3* | N1/P1 P2 | P1* P2 | P1* P2* | - | |
| H1T2 | N1/P1* | P1* | - | P1* | - | N1/P1* | N1 P2* | P1* P2* | P1* P2* | N1/P1* | |
| H2T2 | N1/P1* | P1 | - | P1 | - | N1/P1* P2* P3 | P1* | P1 | x | - | |
| HO | Intact | N1/P1* P3* | P1* P2* | P1* | N1/P1* P2* P3* | N1* P3* | N1/P1* P2* P3* | N1/P1* P2* | P1* P2* | - | N1* P3* |
| H1T1 | N1* P3 | - | P1 | N1/P1* P2* | N1/P1* | N1* P3* | N1* | P1* | P1* P2* | N1* | |
| H1T2 | P3* | P1* P2* | P1* | P1* | N1/P1* | N1* P3 | P2* | - | P1* P2* | N1 P3* | |
| H2T2 | x | - | P1* P2* | N1/P1* N2* | N1/P1* P2* | N1/P1* P3 | P2 | - | P1* P2* | N1* | |
| JA | Intact | N1/P1* P3* | - | P1* P2* | N1/P1* P3* | P1* | N1/P1* P3* | N1* P3 | P1* P2* | P1* P2* | N1* P3* |
| H1T1 | - | P1* | x | N1/P1* P3* | P1* | N1* | N1* P2 | P1* | P1 | x | |
| H1T2 | N1/P1* | x | N1* P2* | N1/P1* P3* | P1* P2* | N1/P1* P2* P3* | N1* P2* | - | P1* P2* | - | |
| H2T1 | P1* | - | P2* | N1/P1* P2* | P1* P2* | N1/P1* P2* P3* | N1* P2* | - | P1* P2* | P2* | |
| H2T2 | - | - | N1* P2* | P1* | P1* P2* | N1/P1* | N1 P2* | - | N1/P1* P2* | - | |
| KA | Intact | P2* | P1* P2* | - | P2* | P2* | P2* | N1* P2* | P2* | P2* | x |
| H1T1 | N1/P1* P2* P3* | P1* P2* | - | P1* P2* | N1/P1* P2* | N1/P1* P2* | N1/P1* P2* | P1* P2* | P1* P2* | N1/P1* | |
| H1T2 | N1/P1* P2* P3* | P1* P2* | - | P1* P2* | N1/P1* P2* P3* | N1/P1* P2* | P1* P2* | P1* P2* | P1* P2* | N1/P1* | |
| H2T1 | - | - | - | P1* | - | - | P1* | P1* P2* | P1* P2* | - | |
| H2T2 | - | - | - | P1* | - | - | N1 P2 | P1* P2* | P1* P2* | - | |
| KI | Intact | N1* P3* | P1* P2* | - | P1* P2* | P1* P2* | N1/P1* P2* | P1* P2* | P1 P2* | P1* P2* | N1/P1* P2* P3* |
| H1T1 | x | P2* | - | N1/P1* P2* | x | N1/P1* P2* P3* | P1* | P1 P2* | P1* P2* | P1 | |
| H1T2 | - | - | - | - | - | - | - | - | - | - | |
| TO | Intact | N1* | P1* P2* | N1/P1* P3* | N1/P1* P2* P3* | N1* P2* P3* | N1* | P2* | P1* P2* | N1* P2* | N1 P2* P3 |
| H1T1 | N1* | P1* | N1* P2* | P1* N2* | N1/P1* | N1/P1* | N1* P3* | P1* | P1* P2* | x | |
| H1T2 | N1/P1* | P1* P2* | N1/P1* P2* | P1* N2/P2* | N1/P1* | N1/P1* | N1* P2* P3 | P1* | P1 P2 | N1/P1* | |
| H2T2 | N1/P1* P3 | - | N1/P1* P2* | N1/P1* P2* | N1/P1* P2* | N1/P1* P2* P3* | P1* | - | N1/P1* P2* | N1/P1* P2* | |
| Homonymous responses in right hindlimb (right SP nerve stimulation) | |||||||||||
| Cat | State | BFA | BFA | IP | LG | MG | SOL | SRT | ST | TA | VL |
| AR | Intact | N1/P1* P2* P3* | N1/P1* P2* P3* | P1* P2* | P1* N2/P2* | N1/P1* P3 | N1/P1* P3* | N1* P2* | P1* P2* | P1* P2 | N1* P3 |
| H1T1 | N1/P1* | N1/P1* | N1/P1* P2* | P1* | N1/P1* | N1* P3 | N1/P1* | P1* | P1* P2* | - | |
| H1T2 | N1/P1* | N1/P1* | N1/P1* P2* | P1* | N1/P1* | N1/P1* | N1* P2 | P1* | P1* | x | |
| H2T2 | N1/P1* P2* | N1/P1* P2* | P1* P2* | P1* P3* | N1/P1* P3* | N1/P1* | N1 P2* | P1* | P1* P2* | x | |
| GR | Intact | N1* P3* | N1* P3* | - | P1* | - | N1/P1* | N1 P2* | P1 P2* | P2* | N1* P3* |
| H1T1 | N1/P1* | N1/P1* | - | P1* | - | P1* | P1* | P1* | P1* | N1/P1* | |
| H1T2 | N1/P1* | N1/P1* | - | P1* | - | P1* | P1* | P1* | P1* | N1/P1* P3* | |
| H2T2 | - | - | - | - | - | - | N1 P2 | P1* | P1* | - | |
| HO | Intact | N1/P1* P3 | N1/P1* P3 | P1* P2* | P1* N2* P3* | N1/P1 P2 P3* | N1* P3* | P1* | P1* P2* | P1* P2* | N1* P3* |
| H1T1 | - | - | P1 P2* | P1* | N1/P1* P2* | N1* | N1* P2* | P1* | P1* P2* | N1/P1* P2 | |
| H1T2 | - | - | P1* | P1* | N1/P1* | N1/P1* | N1* P2 | P1* P2* | P1* P2 | N1* P2* | |
| H2T2 | - | - | P2* | P1* | N1/P1* P2* | N1/P1* P3 | N1* P2* | P1* P2* | P1* | N1* P2 | |
| JA | Intact | N1/P1* P2* P3 | N1/P1* P2* P3 | P1* | P1* P3* | N1/P1* P2* P3 | N1* P3* | N1* P3* | P1* P2 | P1* P2* | - |
| H1T1 | N1/P1* P2* | N1/P1* P2* | - | P1* | N1/P1* | N1* P3* | N1 P2 | P1* P2* | P1* P2* | N1 P3* | |
| H1T2 | N1/P1* P2* | N1/P1* P2* | - | P1* | P1* P2* | N1* P3* | N1* P2* | P1* | P1* P2* | N1* P3* | |
| H2T1 | P1* | P1* | - | P1 | P1* P2* | N1* | N1* P2* | P1* | P1* P2* | N1/P1* | |
| H2T2 | - | - | - | P1* | P1* P2* | N1/P1* | N1 P2* | P1* | - | N1/P1* | |
| KA | Intact | N1/P1* P3* | N1/P1* P3* | - | P1* P2 | N1* P2* | N1* P3* | P1* P2* | P1* | P1* P2 | P1* |
| H1T1 | N1/P1* P3* | N1/P1* P3* | - | P1* P2* | N1/P1* | N1/P1* P2* | P1* | P1* | P1* P2* | P1* | |
| H1T2 | N1/P1* P3 | N1/P1* P3 | - | P1* N2* | N1/P1* P2* | N1/P1* P2* | P1* | P1* | P1* P2* | P1* | |
| H2T1 | - | - | - | P1* P2* | - | - | P1* | P1* | P1* P2* | - | |
| H2T2 | - | - | - | P1* P2* | - | - | x | P1* | P1* P2* | - | |
| KI | Intact | N1/P1* P2* P3* | N1/P1* P2* P3* | - | P1* P2* | N1/P1* P3* | N1* P3* | N1* P2* | - | P1* P2* | N1* P3* |
| H1T1 | P1* P2* | P1* P2* | - | P1* N2/P2* P3* | N1/P1* P2* P3* | N1* P3* | N1/P1* P2* | - | P1* P2* | N1/P1* P2* P3* | |
| H1T2 | P1* P2* | P1* P2* | - | P1* N2/P2* | N1/P1* P2* P3* | N1/P1* | N1/P1* N2/P2* | - | P1* P2* | N1/P1* P2* P3* | |
| TO | Intact | N1* | N1* | P1* P2* | P1* | N1* P2* | N1* | P1* P2* | P1* P2* | P1 P2* | N1* P3* |
| H1T1 | N1* | N1* | P1* N2 | P1* | - | N1/P1* P2* | P1* P2* | P1* | x | N1/P1* | |
| H1T2 | N1/P1* | N1/P1* | P1* N2* | P1* | N1/P1* P2* | N1/P1* | N1/P1* N2* | P1* P2* | P1* P2* | N1* | |
| H2T2 | N1/P1* | N1/P1* | P1* | P1* | N1/P1* P2* | N1/P1* P3 | P1* | P1* P2* | P1* | N1/P1* P3* | |
In the left and right SOL (Fig. 4A), stimulating the SP nerve evoked homonymous N1 responses followed by P3 responses when the muscle was active (swing-to-stance and mid-stance) while weak P1 or N1 responses were observed at stance-to-swing and mid-swing in the intact state. After the first hemisection, N1 and P3 responses remained bilaterally at swing-to-stance and mid-stance at H1T1 but at H1T2 only N1 responses were observed in the right SOL. In the right SOL, homonymous P1 responses became prominent during mid-swing. After the second hemisection, at H2T2, reflex responses disappeared in the left SOL, despite a normal burst, while a prominent N1 was observed in the right SOL at swing-to-stance and mid-stance. We observed homonymous P1 responses at mid-swing bilaterally.
In the left and right VL (Fig. 4B), stimulating the SP nerve evoked homonymous N1 responses and/or P3 responses in all four phases in the intact state. After the first hemisection, at H1T1, we observed weaker and shorter duration N1 responses in some phases bilaterally while P3 responses disappeared bilaterally and P2 responses appeared, but in the right VL only. At H1T2, N1 responses were weak bilaterally, P2/P3 responses were present in the left VL at swing-to-stance and mid-stance and in all phases in the right VL. After the second hemisection, at H2T2, we observed N1 responses in left VL in all phases and no excitatory responses while in the right VL, we observed responses at the stance-to-swing transition only, with N1 followed by P2 responses.
In the left and right SRT (Fig. 4C), stimulating the SP nerve evoked homonymous N1 responses and/or P3 responses in all four phases in the intact state. The strongest responses, N1 followed by P3 responses, were found at-mid swing when the muscle had peak activity. After the first hemisection, at H1T1 and H1T2, responses in the right SRT disappeared at mid-swing while an N1 response remained in the left SRT and a P2 response appeared at H1T2. In the other phases, we observed weak N1 and P2 responses. After the second hemisection, at H2T1 and H2T2, we observed prominent P2 responses during mid-swing, with weak N1 and/or P2 responses in the other phases or no responses.
In the left and right ST (Fig. 4D), stimulating the SP nerve evoked homonymous P1 responses in most phases that could be followed by P2 responses, particularly at stance-to-swing and at mid-swing in the intact state. After the first and second hemisections, at H1T1, H1T2 and H2T2, P1 responses remained but P2 responses were lost or greatly reduced bilaterally. The P1 responses remained largest at mid-swing.
Table 1 presents homonymous reflex response patterns observed in all 10 hindlimb muscles bilaterally for the 7 cats before and after staggered hemisections. Responses in bold with an asterisk indicate that they were significantly phase modulated. Some response patterns could change after the first or second hemisections, depending on the individual cat, but in general the phase-dependent modulation remained. Some notable changes include the loss of P2 and/or P3 responses in the right hindlimb, especially in LG, MG, BFA, BFP and ST. Thus, overall, short-latency excitatory and inhibitory responses remained after staggered hemisections while mid- and long-latency responses were reduced or lost in homonymous hindlimb muscles bilaterally.
Crossed responses.
We stimulated the left and right SP nerves and recorded crossed responses in muscles of the right and left hindlimbs, respectively, before and after staggered hemisections in the four phases (Fig. 5 and Table 2). Although the four phases are defined according to the stimulated limb, it is important to consider the phase of the contralateral limb where the muscles are recorded.
Figure 5. Phase-dependent modulation of cutaneous reflexes evoked in crossed hindlimb muscles during locomotion before and following staggered hemisections.
Each panel shows, from left to right, stance phases of the stimulated hindlimb (empty horizontal bars) and crossed hindlimb (filled horizontal bars) with its averaged rectified muscle activity normalized to cycle duration in the different states/time points and crossed reflex responses in representative cats for the left and right (A) soleus (SOL, cat HO), (B) vastus lateralis (VL, cat TO), (C) anterior sartorius (SRT, cat HO), and (D) semitendinosus (LST, cat GR; RST, cat AR). Reflex responses are shown with a post-stimulation window of 80 ms in four phases in the intact state, and after the first (H1) and second (H2) hemisections at time points 1 (T1) and/or 2 (T2). At each state/time point, evoked responses are scaled according to the largest response obtained in one of the four phases. The scale, however, differs between states/time points.
Table 2. Crossed reflex responses before and after staggered hemisections.
The table shows crossed responses (P1, P2, P3, N1, N2 and N3) evoked in individual cats in left and right hindlimb muscles in the intact state, and after the first (H1) and second (H2) hemisections at 1–2 time points (T1 or T2). Asterisks indicate a significant phase modulation (one factor ANOVA, p < 0.05). x, No response. -, Non-implanted or non-analyzable (lost or excessive noise) muscle. BFA, biceps femoris anterior; BFP, biceps femoris posterior; IP, iliopsoas; LG, lateral gastrocnemius; MG, medial gastrocnemius; SOL, soleus; SRT, anterior sartorius; ST, semitendinosus; TA, tibialis anterior; VL, vastus lateralis.
| Crossed responses in left hindlimb (right SP nerve stimulation) | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Cat | State | BFA | BFP | IP | LG | MG | SOL | SRT | ST | TA | VL |
| AR | Intact | P2* | - | N1* P2* | P2* | N1* P2 | P2* | N1 P2* | P2 | P1* P2* | P2* |
| H1T1 | x | N1* | P1 N2* | P1* N2* | x | P1* N2* | P2* | - | P2* | x | |
| H1T2 | P2 | x | N1* | P1* N2* | P1* P2* | N1/P1* | N1* | - | x | N1/P1* | |
| H2T2 | P2* | - | N1* P2* | x | P2* | x | P2* | - | P2* | P2* | |
| GR | Intact | P2 | P2 | - | P2 N3* | - | P2 N3* | P2* | P3* | - | P2 |
| H1T1 | x | P2* | - | x | - | P2 | P2* | x | P1* | - | |
| H1T2 | P2 | P2* | - | P1* | - | P2 | P1* | P1* | P1* | P2 | |
| H2T2 | P2* | P2* | - | x | - | x | P1* | x | P1* | - | |
| HO | Intact | N1* P2 | N1* | P2* | x | P2 N3 | P2 N3* | P2* | - | - | P2 N3* |
| H1T1 | P2* | N1* | N1* P2* | x | P2 | P2* | P2 | x | P2* | P2* | |
| H1T2 | P1* | P1* | P2* | x | P1* | P2 N3* | P2* | - | P1* | P2* N3* | |
| H2T2 | P2* | - | P2 | x | P2* | P2* | P2* | - | P2* | P2* | |
| JA | Intact | x | N1 P2 | N1 | P2 | x | P1 N3* | N1 P2* P3 | x | x | P2* |
| H1T1 | - | x | x | x | x | P2 | x | x | x | x | |
| H1T2 | - | x | N1* P2* | x | x | P2* | N1* P2 P3 | - | x | x | |
| H2T1 | x | - | P2* | N2 P3* | x | N2* P3* | P2* | - | P2* | x | |
| H2T2 | - | - | N1 P2* | x | x | P1* N2* P3* | P2* | - | P2* | - | |
| KA | Intact | P2 | x | - | x | P2* | P2* | P2* | x | x | P2* |
| H1T1 | P2* | P1* | - | P2* | P2* | P2 | P2* | x | x | P2* | |
| H1T2 | P2 | x | - | P2* | P2 | P2 | N2* | P2* | P2* | P2* | |
| H2T1 | - | - | - | x | - | - | P1* | x | x | - | |
| H2T2 | - | - | - | x | - | - | P1* | x | x | - | |
| KI | Intact | x | P2* N3* | - | x | P2* N3* | P2* N3* | P2* | x | P2* | P2* N3* |
| H1T1 | x | x | - | P1* | P1* | P1* | N1* P2* | N1* | x | P2* | |
| H1T2 | P2* P3* | N1* P2* | - | P1* | P1* P2* | P1* P2* | P2* | x | P1* | P2* | |
| TO | Intact | P2* | P2* | P2* | P2 N3* | P2* | P2 N3* | N1* | x | P2* | P2* |
| H1T1 | N1* P2* | x | x | P2* | P2* | P2* | P2* | x | x | P2* | |
| H1T2 | P2* | x | P1* P2* | P2* | P2* | P2* | x | x | P2* | P2* | |
| H2T2 | P2* | - | P1* P2 | P2* | P2* | P2* | P1* P2* | - | P1* P2* | P2* | |
| Crossed responses in right hindlimb (left SP nerve stimulation) | |||||||||||
| Cat | State | BFA | BFP | IP | LG | MG | SOL | SRT | ST | TA | VL |
| AR | Intact | P2* | N1* | N1* P2* | x | N1* P2* | N2* | N1 P3* | P2* | x | P2* |
| H1T1 | x | x | N1* P2* | N1* | x | x | x | N1* | x | x | |
| H1T2 | P2* | N1* | x | N1* | P2* | x | N1* | N1* | x | x | |
| H2T2 | x | x | N1 P2 | P1* | P2* | P1* N2* P3 | P2* | x | x | P1* | |
| GR | Intact | x | x | - | - | - | x | x | x | x | x |
| H1T1 | x | x | - | x | - | x | x | x | x | x | |
| H1T2 | x | x | - | x | - | x | N1* P2 | x | x | x | |
| H2T2 | x | x | - | x | - | x | x | x | x | x | |
| HO | Intact | N1 P2* | N1* P3 | P2* | x | N1* P2 | P2* N3 | N1 P2* | P2* | P1* P2* | P2 |
| H1T1 | x | N2* | N1* P2* | x | P2* | P2 | P2 | x | x | P2* | |
| H1T2 | P2* | N1* | P1 | x | P2* | P2 | P2* | x | P2* | P2 | |
| H2T2 | x | x | P2* | P2* | P2* | P2* | P2 | P2* | P2* | P1 | |
| JA | Intact | P2 | x | N1* P2* | P1* P2* | P2* | P2* N3* | N1* P2* P3* | x | P2* | - |
| H1T1 | x | x | - | N2* | x | x | N1 P2* | x | x | P2* | |
| H1T2 | x | P1* N2* | - | N2* | x | P2* | P2* P3* | - | x | - | |
| H2T1 | x | N1* | - | N2* | N1* | N1* P2 P3* | N1* P2* N3* | x | x | x | |
| H2T2 | - | x | - | x | P2* | P2 | P1* | x | - | x | |
| KA | Intact | x | x | - | P2 | P2* | x | P2* | P3* | P2* | - |
| H1T1 | P2* | x | - | P2* | P2* | P2* | P2* | - | P2 | P2* | |
| H1T2 | N1* P2* | x | - | P2* | P2 | P2* | x | x | P2* | x | |
| H2T1 | - | - | - | P1 P2* | - | - | P1* | x | P1* | - | |
| H2T2 | - | - | - | P1* | - | - | P1* | x | P1* | - | |
| KI | Intact | P2* | P2* | - | P1* P2* P3* | P2* | x | N1* P3* | - | P1 P2* | P2* |
| H1T1 | P1* | x | - | N2 P3* | N2/P2* | x | N1* P2 | - | x | P2* | |
| H1T2 | - | - | - | - | - | - | - | - | - | ||
| TO | Intact | P2* | P2* | x | P2* | N1* P2* | P2* | P2* | P2* | x | P2* |
| H1T1 | P2* | x | P1 | x | P2* | P2* | P2 | x | x | P2* | |
| H1T2 | P2* | x | x | P2* | P2 | P2* | x | x | P1* | P2* | |
| H2T2 | x | x | P2* | P2* | P2* | P2* | x | x | P1* P2* | P2* | |
In the left and right SOL (Fig. 5A), stimulating the SP nerve in the intact state evoked crossed P2 responses followed by N3 responses in all four phases that were most prominent when the muscle was active, at stance-to-swing and mid-swing of the stimulated limb. After the first hemisection, at H1T1 and H1T2, P2 responses remained in all four phases, with the largest responses observed when the muscle was active (stance-to-swing and mid-swing of the stimulated limb). We observed that N3 responses disappeared at H1T1 before reappearing at H1T2, but only in the left SOL during stance to swing of the stimulated limb. After the second hemisection, at H2T2, P2 responses were present bilaterally in all phases, except at mid-stance of the stimulated limb when the muscle was inactive.
In the left and right VL (Fig. 5B), stimulating the SP nerve in the intact state evoked crossed P2 responses particularly during the muscles’ activity (mid-swing and swing-to-stance of the stimulated limb). After the first and second hemisections, at H1T1, H1T2 and H2T2, P2 responses remained prominent bilaterally when VL was active and during its inactivity (mid-stance of the stimulated limb) for the left VL, except at H1T2.
In the left and right SRT (Fig. 5C), stimulating the SP nerve in the intact state evoked crossed P2 responses in all four phases that were most prominent when the muscle was inactive (mid-swing of the stimulated limb). In the right VL, P2 responses were also preceded by N1 responses during its activity (mid-stance of the stimulated limb). After the first and second hemisections, at H1T1, H1T2 and H2T2, we observed large P2 responses bilaterally during mid-swing of the stimulated limb, with weaker responses in most other phases.
In the left and right ST (Fig. 5D), stimulating the SP nerve in the intact state evoked crossed P2/P3 responses in all four phases. After the first hemisection, at H1T1, P2 responses disappeared bilaterally while strong N1 responses appeared in the right ST during mid-stance of the stimulated limb. At H1T2, P1 responses appeared in the left ST during stance-to-swing and mid-swing of the stimulated limb, while N1 responses remained in the right ST. After the second hemisection, at H2T2, no crossed responses were evoked bilaterally.
Table 2 shows crossed reflex response patterns observed in all 10 hindlimb muscles bilaterally for the 7 cats before and after staggered hemisections. Although some response patterns changed after the first or second hemisections, the phase-dependent modulation generally remained. Some notable changes in crossed reflex response patterns include a greater number of P2 responses disappearing in the right hindlimb (BFP, BFA) compared to the left, and a loss of long-latency P3/N3 responses bilaterally (SOL and SRT).
Cutaneous reflexes before and after staggered hemisections in forelimb muscles.
We recorded from 5 forelimb muscles and we illustrate homolateral and diagonal reflex responses evoked by stimulating the SP nerves in 3 muscles (ECU, TRI and BB) bilaterally in representative cats. The ECU and TRI muscles are mostly active during stance while BB is active during swing and/or at the stance-to-swing transition. As with homonymous and crossed responses in hindlimb muscles, the four phases are defined according to the stimulated limb. It is thus important to consider the phase of the forelimb where the muscles are recorded.
Homolateral responses.
We stimulated the left and right SP nerves and recorded homolateral responses in muscles of the left and right forelimbs, respectively, before and after staggered hemisections (Fig. 6 and Table 3).
Figure 6. Phase-dependent modulation of cutaneous reflexes evoked in homolateral forelimb muscles during locomotion before and following staggered hemisections.
Each panel shows, from left to right, stance phases of the stimulated hindlimb (empty horizontal bars) and homolateral forelimb (filled horizontal bars) with its averaged rectified muscle activity normalized to cycle duration in the different states/time points and homolateral reflex responses in representative cats for the left and right (A) extensor carpi ulnaris (ECU, cat HO), (B) triceps brachii (TRI, cat TO), and (C) biceps brachii (BB, cat HO). Reflex responses are shown with a post-stimulation window of 80 ms in four phases in the intact state, and after the first (H1) and second (H2) hemisections at time points 1 (T1) and/or 2 (T2). At each state/time point, evoked responses are scaled according to the largest response obtained in one of the four phases. The scale, however, differs between states/time points.
Table 3. Homolateral and diagonal reflex responses before and after staggered hemisections.
The table shows homolateral and diagonal responses (P1, P2, P3, N1, N2 and N3) evoked in individual cats in left and right forelimb muscles in the intact state, and after the first (H1) and second (H2) hemisections at 1–2 time points (T1 or T2). Asterisks indicate a significant phase modulation (one factor ANOVA, p < 0.05). x, No response. -, Non-implanted or non-analyzable (lost or excessive noise) muscle. BB, biceps brachii; ECU, extensor carpi ulnaris; FCU, flexor carpi ulnaris; LD, latissimus dorsi; TRI, triceps brachii.
| Left SP stimulation | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Homolateral responses in left forelimb | Diagonal responses in right forelimb | ||||||||||
| Cat | State | BB | ECU | FCU | LD | TRI | BB | ECU | FCU | LD | TRI |
| AR | Intact | - | P1 N2* | - | N1* | P2 | P2* | P2 | x | P1* | P2 |
| H1T1 | - | - | - | x | x | x | x | x | x | x | |
| H1T2 | x | x | x | x | - | - | P2* | - | x | x | |
| H2T2 | x | x | - | x | x | x | P2* | x | x | x | |
| GR | Intact | x | P2 | P2* | x | P2 | x | x | x | P2 | x |
| H1T1 | x | x | x | - | x | x | x | x | x | x | |
| H1T2 | x | x | P1* | - | x | x | x | x | x | x | |
| H2T2 | N1 | x | x | - | x | x | x | x | x | x | |
| HO | Intact | P2* | N2* | N2* | x | N2* P3* | P2 N3* | P1* | x | P2* | P2* |
| H1T1 | x | x | x | x | x | x | x | x | x | x | |
| H1T2 | P2* | N2* | x | x | x | x | x | x | P2* | x | |
| H2T2 | x | x | x | N1* P2* | x | x | x | x | P2 N3* | x | |
| JA | Intact | N2* | x | x | N2* | P2* | P3* | x | x | N1* P2* | x |
| H1T1 | x | x | x | x | x | x | x | x | x | x | |
| H1T2 | x | x | x | x | x | x | N2* | x | x | x | |
| H2T1 | x | x | x | x | x | x | x | x | x | x | |
| H2T2 | x | x | x | x | x | x | x | x | x | x | |
| KA | Intact | x | P1 N2* | N2* | P2* | P2* | P2 N3 | N1 P3 | P3* | x | P3* |
| H1T1 | x | P1* N2* | P1* N2* | P2* | x | P2* | N1* | P2* | x | x | |
| H1T2 | x | P1* N2* | P1* N2* | P1* P2* | x | - | N1* | x | x | P3* | |
| H2T1 | x | N3* | N3* | - | x | x | x | x | - | x | |
| H2T2 | x | x | - | x | x | x | x | - | x | ||
| KI | Intact | x | N2 | N2* | x | P1* N2* | x | x | N2* P3* | P2* | x |
| H1T1 | N2* | N2/P2* | N2/P2* | P1* | P2* | x | x | x | P2* | x | |
| H1T2 | - | - | - | - | - | - | - | - | - | - | |
| TO | Intact | x | x | x | x | P2* | x | P2* | x | x | P2* |
| H1T1 | x | x | x | x | x | x | x | x | x | x | |
| H1T2 | x | x | x | x | x | x | x | x | x | x | |
| H2T2 | x | x | x | x | x | - | x | x | x | x | |
| Right SP stimulation | |||||||||||
| Homolateral responses in right forelimb | Diagonal responses in left forelimb | ||||||||||
| Cat | State | BB | ECU | FCU | LD | TRI | BB | ECU | FCU | LD | TRI |
| AR | Intact | P1 N2* | P1* N2* | P1 N2* | P1* N2* | P1 | N2* | P2* | x | N1* | x |
| H1T1 | x | x | x | x | x | x | x | x | x | x | |
| H1T2 | - | - | - | x | x | P1 | P3* | - | x | - | |
| H2T2 | x | x | x | P1* | x | x | P3* | x | P2 | P1* | |
| GR | Intact | x | P2* | P2* | N1* P2* | P2 | x | x | x | x | x |
| H1T1 | x | P1* | P1* | x | x | P1* | x | x | x | x | |
| H1T2 | x | P1 | P1* | P1* | x | P1* | x | x | - | x | |
| H2T2 | x | x | x | x | x | P1* | x | x | - | x | |
| HO | Intact | P2 N3* | N2* | x | x | P3* | P2 N3* | P2* | N1* | x | x |
| H1T1 | x | x | x | x | x | x | x | x | x | x | |
| H1T2 | P2* | x | x | x | x | x | x | x | P2* | x | |
| H2T2 | x | x | x | x | x | x | N1* | x | x | x | |
| JA | Intact | x | x | x | x | x | x | x | x | N1* | x |
| H1T1 | x | x | x | x | x | x | x | x | P2* | x | |
| H1T2 | x | x | x | P1* | x | x | x | x | P2 | x | |
| H2T1 | x | x | x | P1* | x | x | x | x | x | x | |
| H2T2 | x | x | x | P1* | x | x | x | x | x | x | |
| KA | Intact | x | N2* | x | x | x | x | P2* | x | x | P3* |
| H1T1 | x | N2* | N2* | x | x | x | P1* | P1* | P1* | x | |
| H1T2 | P1* | N1* | x | x | x | x | P1* | P1* | P1 N2* | P3* | |
| H2T1 | x | x | x | - | x | x | x | x | - | x | |
| H2T2 | x | x | x | - | x | x | x | x | - | x | |
| KI | Intact | P2* | N2* | N2* | N1* P2* | N2 | x | x | x | P2* | N2* |
| H1T1 | P1* | x | x | P1* N2* | P2* | P2* | P1* | N2* | x | N2* | |
| H1T2 | P1* P2* | x | x | P1* | P1* N2* | P2* | P1* | x | P2* | N2* | |
| TO | Intact | x | P2* | x | x | P2 | x | x | x | N1 P2 | N1 P2 |
| H1T1 | x | x | x | x | x | x | x | x | x | x | |
| H1T2 | - | x | x | x | x | - | x | x | P1* | x | |
| H2T2 | x | x | x | x | x | x | x | x | P1* | x | |
In the left and right ECU (Fig. 6A), stimulating the SP nerve in the intact state evoked homolateral N2 responses mostly when the muscle was active or at the end of its activity (mid-stance and stance-to-swing of the stimulated hindlimb). After the first hemisection, at H1T1, no responses were observed bilaterally while N2 responses reappeared on the left side at H1T2. After the second hemisection, at H2T2, stimulation of the left or right SP did not evoke responses.
In the left and right TRI (Fig. 6B), stimulating the SP nerve in the intact state evoked homolateral P2 responses in all four phases that were most prominent at the muscle’s peak activity (mid-stance of the stimulated hindlimb). After the first and second hemisections, at H1T1, H1T2 and H2T2, P2 responses completely disappeared bilaterally, and we observed no other responses.
In the left and right BB (Fig. 6C), stimulating the SP nerve in the intact state evoked homolateral P2 responses bilaterally followed by N3 responses but only for the right side in this cat. The most prominent P2 and N3 responses were observed when the muscle was active (swing-to-stance of stimulated hindlimb). After the first hemisection, at H1T1, no responses were observed bilaterally but P2 responses reappeared at H1T2 when the muscle was active (mid-swing of stimulated hindlimb). After the second hemisection, at H2T2, stimulation of the left or right SP did not evoke responses.
Diagonal responses.
We stimulated the left and right SP nerves and recorded diagonal responses in muscles of the right and left forelimbs, respectively, before and after staggered hemisections (Fig. 7 and Table 3).
Figure 7. Phase-dependent modulation of cutaneous reflexes evoked in diagonal forelimb muscles during locomotion before and following staggered hemisections.
Each panel shows, from left to right, stance phases of the stimulated hindlimb (empty horizontal bars) and diagonal forelimb (filled horizontal bars) with its averaged rectified muscle activity normalized to cycle duration in the different states/time points and diagonal reflex responses in representative cats for the left and right (A) extensor carpi ulnaris (ECU, cat AR), (B) triceps brachii (TRI, cat KA), and (C) biceps brachii (BB, cat HO). Reflex responses are shown with a post-stimulation window of 80 ms in four phases in the intact state, and after the first (H1) and second (H2) hemisections at time points 1 (T1) and/or 2 (T2). At each state/time point, evoked responses are scaled according to the largest response obtained in one of the four phases. The scale, however, differs between states/time points.
In the left and right ECU (Fig. 7A), stimulating the SP nerve in the intact state evoked diagonal P2 responses in all four phases that were most prominent when the muscle was active (mid-swing and swing-to-stance of the stimulated hindlimb). After the first hemisection, at H1T1, P2 responses disappeared bilaterally. At H1T2, P2 or P3 responses appeared bilaterally and were generally present in all four phases. The strongest responses were found at swing-to-stance or mid-swing of the stimulated hindlimb in the left and right ECU, respectively. After the second hemisection, at H2T2, P2 and P3 diagonal responses remained in the right and left ECU, respectively.
In the left and right TRI (Fig. 7B), stimulating the SP nerve in the intact state evoked diagonal P3 responses mostly when the muscle was active (mid-stance of the stimulated hindlimb). After the first hemisection, at H1T1, P3 responses disappeared bilaterally then reappeared at H1T2 at mid-stance and stance-to-swing of the stimulated hindlimb. After the second hemisection, at H2T2 and H2T2, no diagonal responses were evoked bilaterally.
In the left and right BB (Fig. 7C), stimulating the SP nerve in the intact state evoked diagonal P2 responses bilaterally followed by N3 responses. We observed the most prominent P2 and N3 responses during the muscles’ inactivity, when the stimulated hindlimb was in mid-stance and at the stance-to-swing transition. After the first and second hemisections, at H1T1, H1T2 and H2T2, P2 and N3 diagonal responses disappeared bilaterally and no other responses were evoked.
Table 3 shows homolateral and diagonal reflex response patterns observed in all 5 forelimb muscles bilaterally for the 7 cats before and after staggered hemisections. Although the phase-dependent modulation of responses generally remained after staggered hemisections, when responses were present, we observed a loss in response occurrence in most muscles after the first and/or second hemisections.
Staggered hemisections reduce the occurrence of evoking mid- and long-latency responses.
After complete or incomplete spinal lesions in cats, mid- and long-latency responses in hindlimb muscles are generally reduced or abolished (Fuwa et al., 1991; LaBella et al., 1992; Frigon & Rossignol, 2008; Frigon et al., 2009; Hurteau et al., 2017). Here, we investigated the probability of evoking reflex responses in all four limbs before and after staggered hemisections by evaluating the distribution of SLRs (N1/P1), MLRs (N2/P2) and LLRs (N3/P3). We did this by calculating the fraction of the total number of SLRs or MLRs/LLRs separately, on recorded muscles for each limb across cats. We excluded the H2T1 time point as only two cats were recorded.
We found no significant difference in response occurrence probability for left (p = .444, GLMM) and right (p = .954, GLMM) homonymous SLRs across states/time points (Fig. 8A). However, we found a significant main effect of state/time point for left (p = .008, GLMM) and right (p = 4.50 × 10−5, GLMM) homonymous MLRs/LLRs. Left homonymous MLRs/LLRs in the intact state were 4.6 (p = .001), 3.1 (p = .019) and 4.0 (p = .006) times more likely to be evoked compared to H1T1, H1T2 and H2T2, respectively. For right homonymous MLRs/LLRs, they were 6.9 (p = 2.50 × 10−5), 7.4 (p = 1.20 × 10−5) and 4.8 (p = .001) times more likely to be evoked compared to H1T1, H1T2 and H2T2, respectively. The probability of evoking crossed SLRs in left (p = .101, GLMM) or right (p = .335, GLMM) hindlimb muscles as well as crossed MLR/LLRs in the left hindlimb (p = .051, GLMM) did not differ across states/time points (Fig. 8B). However, the probability of evoking crossed MLRs/LLRs in right hindlimb muscles was significantly affected by state/time point (p = .003, GLMM), with 4.1 (p = .001), 3.8 (p = .004) and 4.2 (p = .002) more chance of being evoked in the intact state compared to H1T1, H1T2 and H2T2, respectively.
Figure 8. Reflex response occurrence in all four limbs before and after staggered hemisections.
Response occurrence probabilities are shown for short- (SLR) and mid-/long-latency (MLRs/LLRs) responses with stimulation of the left or right superficial peroneal nerve before (intact) and after the first (H1) and second (H2) hemisections at time points 1 (T1) and/or 2 (T2). Tables 1,2 and 3 provide details on the number of pooled data for SLRs, MLRs and LLRs. Each filled circle represents the mean probability ± confidence interval (95%) in 10 hindlimb or 5 forelimb muscles pooled across cats for homonymous/crossed (A and B) and homolateral/diagonal (C and D) responses, respectively. If a significant main effect of state/timepoint was found (generalized linear mixed model), we compared states/time points. Asterisks indicate significant differences at p < 0.05*, p < 0.01** and p < 0.001***. When one state/time point was significantly different from two states/time points, the comparison starts with a longer horizontal line.
For homolateral (Fig. 8C) and diagonal (Fig. 8D) responses in the left and right forelimbs, we only evaluated MLRs/LLRs because of weaker occurrence and fewer sampled muscles. We found a significant main effect of state/time point on homolateral (p = 4.30 × 10−4, GLMM) and diagonal (p = 2.29 × 10−4, GLMM) MLRs/LLRs occurrence probability with left SP nerve stimulation and in homolateral (p = 1.87 × 10−4, GLMM) MLRs/LLRs with right SP nerve stimulation. Responses were always more likely to be evoked in the intact state compared to after the first and second hemisections. Note that no diagonal responses were evoked in the left forelimb with right SP nerve stimulation. Homolateral responses in the left forelimb were 7.8 (p = .002), 7.6 (p = .004) and 45.5 (p = .001) times more likely to be evoked in the intact state compared to H1T1, H1T2 and H2T2, respectively. Diagonal responses in the right forelimb were 13.7 (p = .001), 6.5 (p = .008) and 17.5 (p = .001) times more likely to be evoked in the intact state compared to H1T1, H1T2 and H2T2, respectively. Homolateral responses in the right forelimb were 13.5 (p = 2.60 × 10−4) and 25.0 (p = 1.70 × 10−4) times more likely to be evoked in the intact state compared to H1T1 and H1T2, respectively. We observed no difference between states/time points in diagonal MLR/LLR of the left forelimb (p = .138, GLMM) likely because occurrence probability was low in the intact state.
Therefore, overall, after the first or second hemisection, the probability of evoking MLRs/LLRs in all four limbs with both left and right SP nerve stimulation is generally always lower in all four limbs compared to the intact state. The only exceptions were for crossed and diagonal MLRs/LLRs in the left hindlimb (p = .051, GLMM) and left forelimb (p = .136, GLMM), respectively.
Temporal characteristics of hindlimb cutaneous reflexes change after staggered hemisections.
To determine whether temporal characteristics of homonymous responses were affected after the first and second hemisections, we measured latencies for SLRs and MLRs/LLRs, as well as durations of short-latency inhibitory responses. We excluded the H2T1 state/time point as only two cats were recorded.
Latencies.
The latency of reflex responses provides an estimate of the number of synaptic relays in the pathway. We measured the latencies of homonymous SLRs by pooling N1 and P1 responses for the left and right hindlimbs (Fig. 9A). We found no significant differences in left SLR latencies in the left hindlimb (p = .128, LMM). In the right hindlimb, we found a main effect of state/time point (p = .043, LMM) with significantly longer SLRs at H1T1 compared to the intact state (p = .046) and H1T2 (p = .012). For homonymous MLRs/LLRs in the left (p = .060, LMM) and right (p = .213, LMM) hindlimbs (Fig. 9B), we found no effect of state/time point on their latencies.
Figure 9. Latencies of homonymous reflex responses before and after staggered hemisections.
Each panel shows changes in homonymous response latencies in different muscles compared to the intact state for (A) short-latency (SLRs) and (B) mid-/long-latency (MLRs/LLRs) responses in left and right hindlimb muscles after the first (H1) and second (H2) hemisections at time points 1 (T1) and/or 2 (T2). Large circles represent the mean ± SD while small circles show individual data points. When a significant main effect of state/time point was found (linear mixed model), we compared states/time points. Asterisks in parentheses indicate a significant difference from the intact state while other asterisks indicate significant differences between states/time points at *p < 0.05. BFA, biceps femoris anterior; BFP, biceps femoris posterior; IP, iliopsoas; LG, lateral gastrocnemius; MG, medial gastrocnemius; SOL, soleus; SRT, anterior sartorius; ST, semitendinosus; TA, tibialis anterior; VL, vastus lateralis.
Durations.
We measured the duration of homonymous N1 responses by pooling responses in extensors (BFA, LG, MG, SOL, and VL) of the left and right hindlimbs (Table 4). To compare states/time points, we pooled durations of the different hindlimb extensors obtained across cats. We found a significant main effect of state/time point (p = .001, LMM) in left hindlimb extensors. N1 durations were significantly reduced at H1T1 (p = .022) and H2T2 (p = 2.23 × 10−4) compared to the intact state, and at H1T1 (p = .033) and H2T2 (p = 3.93 × 10−4) compared to H1T2. We observed no significant difference for right hindlimb extensors (p = .084, LMM).
Table 4. Short-latency inhibitory response durations in homonymous extensors before and after staggered hemisections.
The table shows the mean (± SD) durations of N1 responses in left (L) and right (R) hindlimb extensors, for the first hemisection (H1) at two time points (T1/T2) and at the second time point (T2) after the second hemisection (H2). The number in brackets indicates the number of cats. BFA, biceps femoris anterior; LG, lateral gastrocnemius; MG, medial gastrocnemius; SOL, soleus; VL, vastus lateralis.
| Intact | H1T1 | H1T2 | H2T2 | ||
|---|---|---|---|---|---|
| Left SP stimulation | LBFA | 33.5 ± 3.9 ms (6) | 27.4 ± 7.5 ms (4) | 32.0 ± 6.1 ms (5) | 27.7 ± 6.1 ms (2) |
| LLG | 26.3 ± 3.1 ms (4) | 23.8 ± 8.4 ms (4) | 24.6 ± 4.5 ms (3) | 23.6 ± 1.9 ms (2) | |
| LMG | 27.0 ± 9.7 ms (3) | 25.4 ± 3.6 ms (3) | 29.1 ± 6.7 ms (3) | 18.9 ± 1.2 ms (2) | |
| LSOL | 39.5 ± 3.8 ms (6) | 31.1 ± 7.7 ms (7) | 38.3 ± 6.4 ms (6) | 26.5 ± 4.1 ms (4) | |
| LVL | 28.2 ± 6.4 ms (6) | 28.2 ± 4.7 ms (4) | 29.6 ± 8.4 ms (5) | 20.3 ± 12.1 ms (2) | |
| Total mean | 30.9 ms | 27.2 ms | 30.7 ms | 23.4 ms | |
| Right SP stimulation | RBFA | 30.9 ± 5.3 ms (7) | 33.5 ± 7.7 ms (5) | 33.5 ± 6.4 ms (5) | 31.8 ± 10.8 ms (2) |
| RMG | 27.3 ± 9.7 ms (4) | 26.9 ± 9.9 ms (3) | 35.3 ± 16.5 ms (3) | 22.6 ± 9.6 ms (3) | |
| RSOL | 36.9 ± 9.5 ms (7) | 36.5 ± 8.5 ms (6) | 40.3 ± 10.3 ms (6) | 37.9 ± 8.1 ms (4) | |
| RVL | 31.9 ± 3.2 ms (5) | 25.2 ± 9.2 ms (5) | 28.1 ± 7.5 ms (5) | 23.0 ± 5.9 ms (3) | |
| Total mean | 31.8 ms | 30.5 ms | 34.3 ms | 28.8 ms |
DISCUSSION
In the present study, we showed changes in reflex responses in muscles of the four limbs evoked by electrically stimulating cutaneous afferents of the left and right SP nerves during locomotion after staggered lateral hemisections (right lateral hemisection at T5-T6 followed 9–13 weeks later by left lateral hemisection at T10-T11). Changes in reflex responses included a loss/reduction of mid and long-latency responses in all four limbs after the first and second hemisections. The durations of short-latency inhibitory responses in left ipsilateral extensors were also significantly shorter early after the first hemisection, before returning towards intact values and reduced again after the second hemisection. These many changes in reflex responses correlated with altered fore-hind coordination and impaired balance during quadrupedal locomotion reported in our recent study (Audet et al., 2023). The main changes in reflex responses are summarized in Table 5. We discuss how these findings provide insight on neural pathways and locomotor control/recovery after SCI.
Table 5.
Summary of main reflex changes.
| Left muscles | Right muscles | ||||
|---|---|---|---|---|---|
| Response occurrence probability | Homonymous | MLR/LLR | Intact > H1T1, H1T2 and H2T2 | MLR/LLR | Intact > H1T1, H1T2 and H2T2 |
| Crossed | MLR/LLR | Intact > H1T1, H1T2 and H2T2 | |||
| Homolateral | MLR/LLR | Intact > H1T1, H1T2 and H2T2 | MLR/LLR | Intact > H1T1 and H1T2 | |
| Diagonal | MLR/LLR | Intact > H1T1, H1T2 and H2T2 | |||
| Latency | Delayed latency at H1T1 compared to intact and H1T2 for homonymous SLRs in right hindlimb muscles | ||||
| Duration | Shorter durations at H1T1 and H2T2 compared to intact and H1T2 for homonymous N1 responses in extensors of the left hindlimb | ||||
Altered coordination of the fore- and hindlimbs and impaired dynamic balance after staggered hemisections.
All cats, except one (KI), performed cycles with 2:1 fore-hind patterns after spontaneously recovering quadrupedal locomotion after the first and second hemisections, as shown previously after a single lateral hemisection (Barrière et al., 2010; Thibaudier et al., 2017) or with staggered hemisections (Kato et al., 1984, 1985; Audet et al., 2023). In our recent study (Audet et al., 2023), we showed more variable and weaker fore-hind coordination on a step-by-step basis, consistent with previous studies in rats and cats following staggered hemisections (Kato et al., 1984; Stelzner & Cullen, 1991; Murray et al., 2010; Cowley et al., 2015). Following various types of incomplete SCIs, studies reporting 2:1 fore-hind patterns proposed that it was due to lesion extent rather than the loss of a particular spinal pathway (English, 1980, 1985; Kloos et al., 2005; Górska et al., 2013). For instance, lesioning the dorsal columns at thoracic levels disrupts fore-hind coordination without producing a 2:1 pattern (English, 1980). Another possible explanation for 2:1 patterns may result from reduced inhibition from the hindlimb central pattern generators (CPGs) to the forelimb CPGs (Budakova & Shik, 1974; Górska et al., 2013; Thibaudier et al., 2017), thereby increasing forelimb CPG excitability and/or rhythmicity. Given different biomechanical constraints imposed on the forelimbs compared to the hindlimbs, the adoption of 2:1 patterns may be a compensatory strategy to improve fore-hind coordination and possibly stability/balance. Intact cats also perform 2:1 patterns on a transverse split-belt treadmill when the forelimbs step faster than the hindlimbs (Frigon et al., 2014; Thibaudier & Frigon, 2014; Thibaudier et al., 2017). Functionally, performing more and shorter forelimb steps could maximize stability by shifting the center of gravity rostrally and having it more centered within the support polygon (Cartmill et al., 2002), as well as preventing interference between homolateral limbs (Lecomte et al., 2022; Audet et al., 2023).
An important caveat is that balance assistance was required after the second hemisection to conduct reflex testing during locomotion, with an experimenter holding the tail for medio-lateral stability, but without providing weight support. Without this balance assistance, cats stumbled and fell every few steps. Thus, consistent quadrupedal locomotion after the second hemisection was only possible with balance assistance. Balance assistance undoubtedly affected reflex responses and their phase-dependent modulation but without it, we could not have conducted reflex testing and compared it to the other states (i.e. intact and following the first hemisection). Other studies that reported impaired fore-hind coordination after staggered hemisections did not provide balance assistance (Kato et al., 1984; Murray et al., 2010; Cowley et al., 2015). Indeed, a main challenge during walking after SCI in cats and humans is controlling posture/balance (Fouad & Pearson, 2004; Van Hedel & Dietz, 2010; Rossignol & Frigon, 2011). Spinal-transected cats can support their weight during quiet standing but cannot maintain balance when moving or when perturbed (Pratt et al., 1994; Fung & Macpherson, 1999; Macpherson & Fung, 1999). Supraspinal structures are required for dynamic balance (reviewed in Deliagina et al., 2014).
Changes in reflex responses after staggered lateral hemisections and potential neural pathways involved.
Staggered lateral hemisections disrupted descending and ascending spinal pathways first unilaterally (right side) and then bilaterally, with the magnitude of this disruption depending on lesion extent (Fig. 3). These lesions and the occurrence of reflex responses (Tables 1–3 and Figure 8) allow us to suggest putative neural pathways/mechanisms involved in short-, mid-, and long-latency responses. For instance, short-latency N1 and P1 responses in muscles of the ipsilateral (homonymous) and contralateral (crossed) hindlimb remained after the first and second hemisections with both left and right SP nerve stimulations. They also maintained their phase-dependent modulation. This indicates that these pathways are mainly mediated and modulated within lumbosacral circuits, although we cannot exclude some supraspinal/cervical contributions. Studies have shown that phase-dependent short-latency reflex responses remain following thoracic spinal transection, although some response patterns are altered (Forssberg et al., 1977; LaBella et al., 1992; Frigon & Rossignol, 2008; Hurteau et al., 2017; Hurteau & Frigon, 2018). Although N1 responses in homonymous extensor muscles still occurred after the first and second hemisections, their duration was considerably shortened early after the first hemisection (i.e., at H1T1) in the left hindlimb before returning towards intact values later on (i.e. at H1T2), and then shortened once again after the second hemisection (Table 4). Thus, the loss of descending pathways reduces the capacity to sustain short-latency inhibition. This could be due to increased excitatory and/or reduced inhibitory transmission within reflex pathways (Robinson & Goldberger, 1985, 1986; De Leon et al., 1999; Tillakaratne et al., 2000, 2002; Ichiyama et al., 2011). However, studies in cats have found increased GABA synthesis in lumbar interneurons following complete thoracic SCI, consistent with increased inhibition (Tillakaratne et al., 2000, 2002). A recent study showed that the increased inhibitory phenotype at synaptic terminals of spinal interneurons, particularly in the dorsal and intermediate laminae, occurred through switching from excitatory to inhibitory after complete thoracic SCI in adult mice (Bertels et al., 2022). How these molecular synaptic changes influence reflex transmission is not known.
When considered as a whole, mid- and long-latency responses occurred less frequently after staggered hemisections in all four limbs (Fig. 8). Mid-/long-latency homonymous responses were significantly reduced after staggered hemisections in both hindlimbs, as well as mid-/long-latency crossed responses in right hindlimb muscles but not left hindlimb muscles. When present, responses maintained their phase-dependent modulation. This suggests that pathways responsible for mid- and long-latency homonymous and crossed responses likely require supraspinal contributions/loops (Shimamura & Livingston, 1962; Shimamura & Aoki, 1969; Shimamura, 1973; Shimamura & Kogure, 1979; Shimamura et al., 1990). Several supraspinal pathways modulate cutaneous reflexes and the stumbling corrective reaction during locomotion (Batson & Amassian, 1986; Fleshman et al., 1988; Amassian & Batson, 1988; Drew et al., 1996; Bretzner & Drew, 2005), including, medullary reticulospinal (Shimamura 1990, Drew 1996), rubrospinal (Rho et al., 1999), and vestibulospinal (Matsuyama & Drew, 2000) pathways. In addition, cells in the reticular formation, motor cortex and red nucleusshow changes in their activity in response to limb perturbations (Shimamura & Aoki, 1969; Hongo et al., 1972; Shimamura et al., 1982; Shimamura & Kogure, 1983; Palmer et al., 1985; Drew et al., 1996; Marple-Horvat & Armstrong, 1999). We also cannot exclude the involvement of a transcortical loop, as suggested by the facilitation of cutaneous reflexes observed in healthy cats and humans through microstimulation (Bretzner & Drew, 2005) or transcranial magnetic stimulation (Christensen et al., 1999) of the motor cortex. Spinal lesions also disrupt brainstem pathways that release monoamines throughout the spinal cord and increase neuronal excitability (Noga et al., 2009, 2011). Serotonin is known to facilitate cutaneous reflexes in spinal-transected cats (Barbeau & Rossignol, 1990), and their loss likely contributed to reduced reflex responses.
However, not all mid- and long-latency responses in homonymous and crossed muscles disappeared after the first and second hemisections. This suggests that these responses are also mediated in part by polysynaptic spinal reflex pathways. This is supported by the inconsistent or incomplete elimination of these responses in spinal-transected cats (Frigon & Rossignol, 2008). Moreover, performing perfect lateral hemisections is not feasible and spared ascending and descending tracts (see Fig. 3) likely contributed to the maintenance and/or recovery of mid- and long-latency responses, as well as their phase-dependent modulation. The precise contribution of individual structures and pathways in cutaneous reflex responses remains to be determined. Furthermore, spinal reorganization and plasticity could have contributed to their persistence and/or recovery. Differences in crossed responses between left and right hindlimb muscles could reflect asymmetrical compensatory mechanisms within spinal sensorimotor circuits (Hultborn & Malmsten, 1983; Helgren & Goldberger, 1993; Frigon et al., 2009; Martinez et al., 2011; Audet et al., 2023). Homolateral and diagonal responses in forelimb muscles occurred less frequently in the intact state compared to homonymous and crossed responses and were strongly reduced after the first and second hemisections. Thus, mid- and long-latency responses in muscles of the four limbs are highly dependent on the integrity of spinal pathways and putative new connections are insufficient to support and restore them. The observation that phase-dependent modulation of reflex responses in fore- and hindlimb muscles was largely unaffected after staggered hemisections suggests that reflexes were modulated by spinal mechanisms, such as by CPGs and/or interactions with primary afferent inputs (Prochazka et al., 2002; Frigon & Rossignol, 2006; Frigon et al., 2021; Lalonde & Bui, 2021), although we cannot exclude a supraspinal contribution (Fleshman et al., 1988; Bretzner & Drew, 2005), particularly in forelimb muscles.
Lumbosacral circuits also undergo substantial reorganization following an incomplete thoracic SCI, such as after a lateral hemisection (Barriere et al., 2008; Frigon et al., 2009; Barrière et al., 2010; Martinez et al., 2011, 2012), or staggered lateral hemisections (Jane et al., 1964; Kato et al., 1984, 1985; Stelzner & Cullen, 1991; Courtine et al., 2008; Van Den Brand et al., 2012; Cowley et al., 2015; Audet et al., 2023) making them less dependent on supraspinal signals. At the circuit level, this can include collateral sprouting of primary afferent projections (Krenz & Weaver, 1998), which can affect reflex transmission and sensorimotor interactions between primary afferent inputs and CPGs. The mid- and long-latency reflex responses still observable in hindlimb muscles might reflect the reinforcement of remaining descending pathways, the activation of latent connections, and/or the establishment of new connections (Edgerton et al., 2004; Cai et al., 2006; Maier & Schwab, 2006; Basaldella et al., 2015; Higgin et al., 2020; Zavvarian et al., 2020).
Neural plasticity in lumbosacral circuits likely contributed to maintaining phase-dependent modulation of reflex responses in hindlimb muscles. The supraspinal contribution is more difficult to assess. Studies using staggered lateral hemisections have shown that transmission from the brainstem to lumbar levels remains possible (Cowley et al., 2008, 2010). Supraspinal pathways can synapse on propriospinal neurons undergoing reorganization above and/or below the lesion (Bareyre et al., 2004; Zaporozhets et al., 2006; Courtine et al., 2008; Cowley et al., 2008). New, short-distance propriospinal relays can allow bidirectional communication between cervical and lumbar levels (Courtine et al., 2008; Cowley et al., 2010; Zaporozhets et al., 2011; Laliberte et al., 2019). However, whether this transmission from supraspinal structures or from ascending somatosensory pathways through new propriospinal circuits can influence locomotion and reflex pathways in a meaningful way is not known. Figure 10 schematically presents a scenario explaining changes in reflex responses to the four limbs after staggered hemisections with left and right SP nerve stimulation.
Figure 10. Schematic illustration of putative pathways and mechanisms contributing to cutaneous reflexes and their modulation before and after staggered hemisections.
In the intact state, afferents from the left (A) and right (B) superficial peroneal (SP) nerve contact spinal interneurons that project on motoneurons within the hemisegment (homonymous responses) at lumbar levels and commissural interneurons projecting contralaterally (crossed responses). SP nerve afferents also make contacts with propriospinal neurons that project to cervical levels, terminating ipsilaterally (homolateral responses) or contralaterally via collateral projections at different segments (diagonal responses). The pathways responsible for short-latency responses (SLRs) are mainly confined to spinal circuits, including SLRs in forelimb muscles. The pathways contributing to mid- and long-latency responses (MLRs/LLRs) transmit sensory information to supraspinal structures via long ascending projection neurons (propriospinal and/or dorsal lemniscal pathways) that project back to spinal circuits controlling the fore- and hindlimbs. After the first hemisection (on the right side), SLRs in hindlimb muscles remain present although their response pattern can change due to functional changes in lumbosacral circuits. The occurrence of MLRs/LLRs decreases (dashed lines) due to disruptions in ascending and descending pathways to and from supraspinal structures. Spared supraspinal axons are potentially strengthened or sprout to form new connections to transmit descending signals. After the second hemisection (on the left side), direct ascending and descending pathways are both disrupted, and reorganization of short propriospinal neurons is required to relay information through lesions, although their ability to do so is limited, leading to a considerable loss in MLRs and LLRs in all four limbs.
Functional considerations.
Stimulating the SP nerve elicits stumbling corrective and preventive reactions during the swing and stance phases of locomotion, respectively, as observed in both cats and humans (Forssberg et al., 1977; Prochazka et al., 1978; Forssberg, 1979; Duysens & Loeb, 1980; Wand et al., 1980; Schillings et al., 1996; Van Wezel et al., 1997; Zehr et al., 1997; Quevedo et al., 2005b, 2005a). Short-latency responses can rapidly modify limb trajectory and the locomotor pattern. During the swing phase, homonymous P1 responses in flexor muscles allow the stimulated limb to move the foot away and over a simulated obstacle. In contrast, during the stance phase, homonymous N1 responses reduce the activity of extensor muscles, briefly pausing forward progression and potentially lowering the center of gravity. In humans, a brief suppression in the activity of the ipsilateral medial gastrocnemius is observed after tripping at short latency (Potocanac et al., 2016). This suppression is thought to generate a brief pause in the walking pattern, enabling the nervous system to mobilize additional resources for subsequent functional adjustments. However, these short-latency responses, present at birth in humans (Rowlandson & Stephens, 1985), become relatively rare with age, smaller in amplitude, and with less-pronounced phase-modulation (Baken et al., 2005), in contrast to cats where they remain prominent. Cats thus seem to rely more heavily on spinal control mechanisms in response to a perturbation, whereas in humans, supraspinal influences become more dominant as neural circuits mature. This likely reflects greater supraspinal control for postural corrections in humans that walk bipedally in an upright posture. After SCI, the ability to maintain balance and interlimb coordination during dynamic forward progression is altered or impaired, making adequate responses to perturbations even more essential (Ryu & Kuo, 2021). However, the ability to quickly respond to a perturbation is impaired after SCI. The latencies of short-latency responses in the ipsilesional right hindlimb slightly increased early after the first hemisection before returning toward intact values after eight weeks (Fig. 9). After an incomplete lateral SCI, cats shift their weight support to the contralesional hindlimb, which spends more time on the ground (Martinez et al., 2011, 2012; Audet et al., 2023). We observed shorter N1 response durations in extensors of the left contralesional hindlimb after the first hemisection (Table 4). This could be a compensatory mechanism to reinforce weight support. In a similar vein, Frigon and Rossignol (2008) showed the appearance of homonymous P1 responses in extensor muscles after spinal transection, instead of N1 responses.
While short-latency reflex responses can rapidly alter limb trajectory of the stimulated hindlimb, mid- and long-latency responses can be integrated into descending motor commands from the brain (Pruszynski & Scott, 2012), to assist in postural control for example. In the present study, the loss of mid- and longer-latency responses after staggered hemisections correlated with altered and/or impaired coordination of the fore- and hindlimbs and in dynamic balance. Studies in humans showed that cutaneous reflexes were modulated as a function of a real or perceived threat to stability (Llewellyn et al., 1990; Haridas et al., 2005, 2006, 2008; Lamont & Zehr, 2006, 2007). Thus, the loss of balance/stability can lead to reflex changes. We recently proposed in intact and spinal-transected cats that a signal related to an increase in left-right asymmetry, which affects walking stability (Dambreville et al., 2015; Huijben et al., 2018), reduced cutaneous reflex amplitudes during split-belt locomotion (Hurteau & Frigon, 2018; Mari et al., 2023). Single or staggered lateral hemisections induce temporal and spatial asymmetries in the locomotor pattern in cats (Kato et al., 1985; Martinez et al., 2011, 2013; Audet et al., 2023). Consequently, somatosensory signals related to these asymmetries in the locomotor pattern could have contributed to the loss/reduction of reflex responses after staggered hemisections.
Limitations and concluding remarks.
In conclusion, we showed that cutaneous reflex pathways from the foot dorsum projecting to the four limbs undergo considerable changes after staggered hemisections. These changes, especially a reduction/loss in their occurrence, correlated with impaired balance and fore-hind coordination. We are not proposing that changes in cutaneous reflexes led to these impairments but the changes in reflex pathways reflect the loss of communication between lumbosacral levels and circuits located at cervical and supraspinal levels. Many factors likely contributed to reflex changes, as discussed, but some are difficult to control experimentally. For example, cats have varying levels of physical activity after spinal lesions, with some more active than others. Before and after staggered hemisections, cats performed a variety of treadmill and walkway tasks to answer other scientific questions (Lecomte et al., 2022, 2023; Merlet et al., 2022; Audet et al., 2023; Mari et al., 2023). We believe that these tasks standardized the level of physical activity across animals, providing a minimal baseline. Lesion extent and the amount of secondary damage is also difficult to control, which undoubtedly affects locomotor recovery and changes in spinal pathways/circuits that contribute to reflexes and their modulation. We are currently investigating reflexes in the four limbs using the same dual lesion paradigm with stimulation of forelimb cutaneous afferents. Quantifying cutaneous reflex responses in the four limbs could be used as biomarkers to evaluate the efficacy of various therapeutic approaches (e.g., epidural stimulation of the spinal cord) in restoring transmission in ascending and descending spinal pathways and in sensorimotor control mechanisms.
Key points:
Cutaneous afferent inputs coordinate muscle activity in the four limbs during locomotion when the foot dorsum contacts an obstacle.
Thoracic spinal cord injury disrupts communication between spinal locomotor centers located at cervical and lumbar levels, impairing balance and limb coordination.
We investigated cutaneous reflexes during quadrupedal locomotion by electrically stimulating the superficial peroneal nerve bilaterally, before and after staggered lateral thoracic hemisections of the spinal cord in cats.
We showed a loss/reduction of mid- and long-latency responses in all four limbs after staggered hemisections, which correlated with altered coordination of the fore- and hindlimbs and impaired balance.
Targeting cutaneous reflex pathways projecting to the four limbs could help develop therapeutic approaches aimed at restoring transmission in ascending and descending spinal pathways.
Acknowledgments:
We thank Philippe Drapeau for providing data acquisition and analysis software, developed in the Rossignol and Drew laboratories at the Université de Montréal. We thank the Biostatistics department of the Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke for statistical assistance.
Support or grant information:
This work was supported by a grant from the National Institutes of Health: R01 NS110550 to AF, IAR and BIP. AF is a Fonds de Recherche-Santé Quebec (FRQS) Senior Research Scholar. JA and JH were supported by FRQS doctoral scholarships and ANM by a FRQS postdoctoral scholarship.
Biography
Footnotes
Ethics statement: The animal study was reviewed and approved by the Animal Care Committee of the Université de Sherbrooke.
Competing statement: The authors declare no competing financial interests.
Data availability statement:
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
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