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Published in final edited form as:
Exp Neurol. 2007 July ; 206(1): 146–158.

Parallel facilitatory reflex pathways from the foot and hip to flexors
and extensors in the injured human spinal cord
Maria Knikoua,b,d,*, Elizabeth Kaya, and Brian D. Schmita,b,c
a Sensory Motor Performance Program, Rehabilitation Institute of Chicago, Chicago, IL 60611, USAb Department of Physical Medicine and Rehabilitation, Feinberg Medical School, Northwestern University,
Chicago, IL 60611, USAc Department of Biomedical Engineering, Marquette University, Milwaukee, WI 53201, USAd Department of Physical Therapy and Neuroscience, The Graduate Center, City University of New York,Staten Island, NY 10314, USA

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Abstract

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Spinal integration of sensory signals associated with hip position, muscle loading, and cutaneous
sensation of the foot contributes to movement regulation. The exact interactive effects of thesesensory signals under controlled dynamic conditions are unknown. The purpose of the present study
was to establish the effects of combined plantar cutaneous afferent excitation and hip movement on
the Hoffmann (H) and flexion reflexes in people with a spinal cord injury (SCI). The flexion and Hreflexes were elicited through stimulation of the right sural (at non-nociceptive levels) and posterior
tibial nerves respectively. Reflex responses were recorded from the ipsilateral tibialis anterior (TA)(flexion reflex) and soleus (H-reflex) muscles. The plantar cutaneous afferents were stimulated atthree times the perceptual threshold (200 Hz, 24-ms pulse train) at conditioning–test intervals that
ranged from 3 to 90 ms. Sinusoidal movements were imposed to the right hip joint at 0.2 Hz withsubjects supine. Control and conditioned reflexes were recorded as the hip moved in flexion andextension. Leg muscle activity and sagittal-plane joint torques were recorded. We found that
excitation of plantar cutaneous afferents facilitated the soleus H-reflex and the long latency flexion
reflex during hip extension. In contrast, the short latency flexion reflex was depressed by plantar
cutaneous stimulation during hip flexion. Oscillatory joint forces were present during the transition
phase of the hip movement from flexion to extension when stimuli were delivered during hip flexion.
Hip-mediated input interacts with feedback from the foot sole to facilitate extensor and flexor reflex
activity during the extension phase of movement. The interactive effects of these sensory signals
may be a feature of impaired gait, but when they are appropriately excited, they may contribute to
locomotion recovery in these patients.

Keywords
H-reflex; Flexion reflex; Locomotion; Reflex circuits; Rehabilitation; Sensorimotor integration

Introduction
Spinal integration of sensory signals is necessary for movement regulation and is especially
important for the recovery of walking in people with a spinal cord lesion. Although locomotion* Corresponding author. City University of New York, The Graduate Center, Department of Neuroscience and Physical Therapy, 2800
Victory Boulevard, 5N-207, Staten Island, NY 10314, USA. Fax: +1 718 982 2984. E-mail addresses: knikou@mail.csi.cuny.edu, mknikou@northwestern.edu (M. Knikou).

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can be induced without any sensory input from the periphery (Grillner and Zangger, 1979),
extensive studies in lower vertebrates and humans have demonstrated that sensory signals
associated with afferents that register hip position, muscle loading, and cutaneous sensationfrom the foot sole have specific regulatory effects on locomotion (Whelan, 1996;Rossignol etal., 2006). An improved understanding of the physiologic processing of these sensory signals
in human spinal cord injury (SCI) is important to the design and implementation of therapeuticinterventions for locomotor rehabilitation. In particular, the sensory feedback from plantar
cutaneous afferents is expected to have a powerful effect on locomotor reflex function. To thisend, the purpose of this study was to identify the combined neuromodulatory effects of plantar
cutaneous and hip sensory feedback on spinal reflexes in people with clinically incomplete
SCI.

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In this context, electrical stimulation of cutaneomuscular afferents from the plantar or puresensory nerves has demonstrated the existence of complex synaptic actions on active ankle
muscles (Aniss et al., 1992;Zehr et al., 1997). For example, a short latency inhibitory pathway
from plantar cutaneous afferents to ankle extensors following low-threshold stimulation to theposterior tibial nerve is enabled in spinal intact subjects when the foot sole contacts a surface(Abbruzzese et al., 1996). Excitation of cutaneous afferents arising from the sural nerve or footsole induces long-lasting facilitation of the ipsilateral extensor motoneurons in the cat(Schieppati and Crenna, 1984) and human (Fallon et al., 2005) and induces crossed inhibitory
postsynaptic potentials in the knee and ankle extensors (Edgley and Aggelopoulos, 2006).
These effects may be related to the postulated action of plantar cutaneous afferents on thepresynaptic inhibition acting on Ia afferent terminals (Iles, 1996), to their interaction with themachinery of reciprocal innervation (Rossi and Mazzocchio, 1988), and to their actions on Ib
inhibitory pathways during which soleus exerts facilitation (instead of inhibition) to quadriceps
when the triceps surae muscle is contracting (Pierrot-Deseilligny et al., 1981,1982). Following
SCI, the reflex excitability of many pathways is altered (Hultborn, 2003), resulting in changes
in reflex function that impact motor control and movement.

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The spinal reflex effects from cutaneous afferents of the foot sole have also been implicatedin the reflex regulation of locomotion, particularly with low-threshold afferents from the footto reinforce stance (Aniss et al., 1992). The contribution of low-threshold plantar afferents towalking is clearly seen in cases where cutaneous input from the hind paws of spinalized cats
is absent, resulting in an inability of the cats to be trained to step or walk. Preservation ofminimal cutaneous input, however, is sufficient to allow re-education of the spinal cord to step.
This loss in training ability is correlated to a reorganization of the plantar flexors activation
patterns that is also attributed to the removal of plantar cutaneous input (Bouyer and Rossignol,
2003a,b). Similar effects have been reported for people with a sensory polyneuropathy of thefeet, where a large variability in the step cycle duration and associated gait impairment areassociated with a loss of reflex action of low-threshold cutaneous afferents (Van Wezel et al.,1997). In this respect, when foot sole stimulation is used as a conditioning stimulus it candepress soleus H-reflex excitability during assisted walking of people with a chronic SCI,
resulting in a more normalized soleus H-reflex modulation pattern during walking (Fung andBarbeau, 1994).
A second sensory signal that is critical to locomotor reflex function is the hip position, which
substantially affects the locomotor rhythm in both animals and humans. Evidence from studies
conducted in lower vertebrates (Andersson and Grillner, 1983;Kriellaars et al., 1994;Hiebert
et al., 1996;Lam and Pearson, 2001) suggest that this input accesses circuits responsible forwalking contributing to phase transition and swing initiation. Blocking of the knee joint during
human walking fails to alter the soleus H-reflex modulation pattern (Schneider et al., 2000),
while pronounced hip extension enhances the swing phase during assisted walking in human
SCI (Dietz et al., 1998,2002). Further, sensory signals mediating static hip angle and sensation

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NIH-PA Author Manuscriptfrom the foot sole interact and induce a hip-dependent graded facilitation of the soleus H-reflex
and tibialis anterior (TA) non-nociceptive flexion reflex in people with intact or injured spinal
cord at rest (Knikou and Rymer, 2002;Knikou, 2005;Knikou et al., 2006b).
Accordingly, the current experiments were conducted to establish the combined effects ofplantar cutaneous and hip-mediated sensory feedback on the soleus H- and TA flexion reflexes
under well-controlled dynamic conditions in people with chronic incomplete SCI. Specifically,reflex conditioning effects were investigated during imposed sinusoidal hip movements.
Muscle responses and forces exerted at the leg joints associated with the imposed sinusoidal
hip movements were concurrently established. We hypothesized that hip movement would
alter the conditioning effects of foot cutaneous afferents on H- and TA flexion reflex pathways,
consistent with the reflex regulation of locomotion.

Materials and methods
Subjects

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Experiments were conducted after a full institutional review board (IRB) approval of theexperimental protocol (Northwestern University, IRB No. 1236-001) and according to the 1964
Declaration of Helsinki and Belmont Report. Written informed consent from each subject was
obtained before testing. Eight subjects with lesions ranging from cervical (C) C5–8 to thoracic(T) T3–11 spinal segments participated in the study. Subject characteristics are summarizedin Table 1.
All subjects participated in two tests that were conducted on different days. In the first test, weinvestigated the effects of plantar cutaneous afferent excitation on the soleus H-reflex, whilein the second test we established the effects on the TA flexion reflex. Both tests were conductedduring imposed hip movements. The hip range of movement (ROM) during both experimental
trials is indicated in Table 1. Different hip ROMs were used for each subject, based largely on
day-to-day as well as subject-to-subject differences in passive ROM, muscle tone, and spasms.
In particular, the hip flexion range was limited in some subjects by an increased hip adductor
tone.
Experimental apparatus and imposed sinusoidal hip movements

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With subjects’ supine, the right leg was secured in a leg brace with single-axis torquetransducers (Himmelstein Inc., Hoffman Estates, IL, USA) aligned with the axes of rotationof the knee and ankle joints. The leg brace was affixed to the motor head of a Biodex system(Biodex Medical Systems Inc., Shirley, NY) that also measured the hip torque. The brace’s
footplate had a clamp to hold the fore-foot and a strap to secure the heel. The hip–knee andknee–ankle links of the brace were adjustable to accommodate each subject’s leg length. The
pelvis was secured to the seat with a strap.
After the leg brace was secured, the hip’s center of rotation was aligned with the center of the
Biodex motor head unit and sinusoidal movements at the hip in the sagittal plane were imposed.
Hip movements were controlled by the Biodex system using the Researcher’s Toolkit pattern
files. The hip was moved through 10 full cycles of flexion and extension at 0.2 Hz (i.e., each
hip movement cycle lasted 5 s). Although the movement was relatively slow, it allowed testingunder dynamic hip conditions and resulted in similar hip positions during all conditioning
paradigms. The ankle and knee joints were set at 20° of plantar flexion and 30° of flexion,
respectively.
In all tests, surface electromyograms (EMGs) were recorded from the right TA, soleus (SOL),
medialis gastrocnemius (MG), medial hamstrings (MH), vastus medialis (VM), and rectus
femoris (RF) muscles in all subjects using differential bipolar electrodes (DE-2.1; DelSys, MA,
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NIH-PA Author ManuscriptUSA). All electrodes were placed following standard procedures. EMG signals were band passfiltered (20–250 Hz) before being sampled at 2 kHz using a data acquisition card (National
Instruments, Austin, TX) and customized acquisition programs (LabVIEW software, National
Instruments), and saved for further analysis.
Stimulation and recording protocols of the spinal reflexes
The TA flexion reflex was elicited and recorded according to procedures identical to thosepreviously employed in the same SCI subjects (Knikou, 2007b;Knikou et al., 2006b). Briefly,
the flexion reflex was evoked following sural nerve stimulation by a 30-ms train of 1-ms pulses
delivered at 300 Hz using a constant current stimulator (DS7A, Digitimer, UK), and recorded
from the TA muscle. For each subject, the stimulus delivered to the sural nerve was increased
progressively, and the response was monitored to observe its sensitivity to the stimulus intensity
strength. The stimulus intensity required to induce the initial EMG activity in the TA was
identified as the reflex threshold (RT). Reflex responses were categorized as short reflex loop
(SRL) responses when their latency was less than 100 ms or long reflex loop (LRL) responses
when their latency was beyond 120 ms (Spaich et al., 2004;Knikou and Conway, 2005). During
testing, the sural nerve was stimulated at 1.5 times the RT and ranged from 12 to 45 mA (32±13.7) across subjects. At these intensities, limb movement or pain were not evoked.

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The soleus H-reflex was elicited and recorded according to procedures identical to thosepreviously employed in the same SCI subjects (Knikou, 2005;Knikou et al., 2006a). Briefly,
the H-reflexes were elicited on the ascending part of the recruitment curve by stimulation of
the posterior tibial nerve using a single pulse of 1 ms that were 15–30% of the maximal Mwave (Mmax), and the corresponding M-waves were monitored online for each stimulus. Hreflexes were recorded from the right soleus muscle via a single differential electrode (Delsys
Inc., Boston, USA) having established the correct site of stimulation by using a stainless steel
monopolar electrode as a probe (see more details in Knikou et al., 2006a).
Plantar cutaneous afferent conditioning stimulation

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Plantar skin stimulation was identical to that previously employed in the same SCI subjects(Knikou et al., 2006b;Knikou, 2007a). Cutaneous afferents were excited with a pulse train of
24 ms at 200 Hz delivered through two Ag-AgCl surface electrodes placed transversely acrossthe 1st and 3rd metatarsals. The conditioning stimulation was delivered at 3 times the perceptual
threshold (PT) in all subjects. Although the cutaneous excitation threshold may be decreasedin people with SCI, on the basis that tactile units remain intact after chronic SCI (Thomas andWestling, 1995) transmission of plantar cutaneous sensation was not regarded as problematicin the current study and the excitation threshold was used as a tool to normalize the level ofthe conditioning stimulation across subjects. This stimulation intensity did not elicit any
movement of the intrinsic foot muscles and no pain was reported, verifying that theconditioning afferent volley excited mostly large cutaneous afferents of the foot sole.
The conditioning pulse train preceded the soleus H-reflex and TA flexion reflex at different
conditioning–test (C–T) intervals, measured as the time between the end of the pulse train
delivered to the foot sole and the beginning of the pulse train or single pulse delivered to thesural or posterior tibial nerves, respectively. The different C–T intervals were delivered in
random order and ranged from 3 to 90 ms (3, 6, 9, 15, 30, 60, and 90 ms) in order to observe
short and long latency effects on both spinal reflexes.
Experimental protocol
In each subject, two control reflexes (10 repeated responses without plantar cutaneous
excitation during hip flexion or extension; Hohomonymous) were recorded randomly with theconditioned reflexes (H-reflex preceded by foot sole stimulation at short and long C–T intervals
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while the hip was moving in flexion or in extension). The control and conditioned reflexes
were elicited only once in every movement cycle of the leg. Stimuli were sent at each of the
10 cycles either at mid-flexion (2.5 s) or mid-extension (0 s) depending on the test condition.
The M-wave size was continually monitored to ensure stability in the stimulation procedures
and especially to maintain a constant Ia afferent volley. M-wave amplitude constituted theintra-subject criterion for accepting the conditioned H-reflexes during hip movement. Whenthe M-wave of the conditioned H-reflex was different from the M-wave of the control reflex(both reflexes recorded during hip movement), the stimulus intensity was adjusted so that thesizes of the M-waves of both reflexes were similar. Experimental data were rejected when asignificant difference between the M-wave of the conditioned and Hohomonymous reflexes wasestablished. The same procedure was employed for the TA flexion reflex recordings during
hip movement, and the control flexion reflex during hip movement was identified as
SRLhomonymous or LRLhomonymous, respectively.
In each experimental session, surface EMG and joint torques were also collected during
imposed hip movements (10 cycles) without stimulation of the sural or posterior tibial nerves.
The data collected during the hip movement cycle with quiescent muscles were used as ameasure of the combined effects of inertia, gravity, and the passive resistance of the limb andinstrumented leg brace.

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Data analysis

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The soleus H-reflex and TA flexion reflex were full wave rectified and their sizes were
measured as the area under the corresponding waveforms. The rectified area of the flexion
reflexes was measured from the onset latency and the point in time during which the response
fell below 1.5 standard deviations of the baseline EMG activity. The reflexes recorded at each
C–T interval as the hip moved in flexion or extension were expressed as a percent of the mean
size of the control reflex collected with the hip in the same movement direction (e.g., flexion
or extension, Hohomonymous or SRLhomonymous; LRLhomonymous). A one-way analysis ofvariance (ANOVA) along with post hoc Bonferroni tests were applied to the experimental data
for each subject and reflex (flexion or H-reflex) separately to determine whether theconditioned reflexes were statistically significant different from the control reflex, and whether
the conditioned reflexes varied across C–T intervals. Having established statisticallysignificant differences between the control and conditioned reflexes, the average size of eachsubject’s conditioned flexion or H-reflex was then grouped based on the C–T interval and the
hip movement direction and a one-way ANOVA with repeated measures was applied to thedata to determine changes in the size of the conditioned reflexes across the C–T intervals
investigated for the subject group. This analysis was performed separately for tests conductedduring hip flexion and extension. A two-way ANOVA and/or a paired t-test was also conductedon the pool data so to establish statistically significant differences between the conditioned
reflexes recorded during hip extension and hip flexion.
For each subject, the M-waves of the control and conditioned H-reflexes were expressed as apercentage of the maximal M-wave. A one-way ANOVA with post hoc Bonferroni tests wasused to test for differences between the M-waves of the reflexes recorded under control
conditions and during limb movement. When significant differences were encountered the trial
was rejected.
For each subject, the TA and SOL activities were measured from the rectified EMG recordings
100 ms before sural or posterior tibial nerve stimulation, and 200–250 ms after nerve
stimulation in order to identify different underlying muscle activation levels across the test
conditions. For both cases, the mean rectified EMG was computed for a period of 50 ms. This
calculation was conducted separately for conditioned reflexes elicited during mid-flexion andmid-extension of the hip. Then, the pre- and post-stimulus TA and SOL EMG activities during
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hip flexion were compared to the EMG activity during hip extension using a paired t-test. The
average pre- and post-stimulus TA and SOL EMG activities from each subject were groupedbased on the phase of the movement when the stimulus was delivered (flexion or extension)and a three-way ANOVA with repeated measures was applied to that data.
The pattern of muscle responses produced by the sinusoidal oscillation at the hip wascharacterized for each subject to establish the effects of peripheral nerve and/or plantar
afferents stimulation on the reflex response produced by the hip movement. The timing andduration of the muscle responses were measured when nerve or cutaneous afferents were either
stimulated or not. For each subject and trial, the EMG data from each muscle were band passfiltered (20–500 Hz, Butterworth 2nd order filters with no phase lag), full-wave rectified,smoothed and averaged over the 10 consecutive hip movement cycles. Then, the average EMG
signal for each muscle was normalized using the average integrated area under its rectified
curve and the resultant normalized EMG was plotted as a function of time.

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The joint torque data produced by the imposed sinusoidal hip oscillations were used todetermine the net reflexive effects at the hip, knee, and ankle. A movement cycle without any
EMG activity was used to estimate the effects of passive movement, inertia, and gravity on the
joint torques of the leg and brace. In order to obtain the reflex torques, the respective joint
torques from the “no-EMG” trial were aligned with individual torques from the active trials,
based on the hip position data, and the difference was calculated. This difference was the torqueresponse attributed to the reflexive movement and was filtered with a 2nd-order, 2-Hz low pass
Butterworth filter. The average of the filtered data from all trials from each subject andparticular test condition are reported as the torque response for the particular joint and subject.
In all statistical tests, significant differences were established at 95% of confidence level.
Results are presented as mean values along with the standard error of the mean (SEM).

Results
Combined effects of foot sole stimulation and hip movement on the TA flexion reflex
The effects of low-threshold plantar cutaneous afferent excitation on the TA flexion reflex
depended on the direction of the imposed hip movement. Representative examples of theseeffects are illustrated for two subjects (S7 and S10) in Fig. 1. The LRL TA responses were
substantially facilitated at the C–T interval of 90 ms in both subjects during hip extension (toptraces of Fig. 1). In contrast, plantar conditioning during hip flexion depressed the SRL TA
response in subject 7, while the LRL was not affected (bottom traces of Fig. 1).

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One-way ANOVA showed that plantar cutaneous afferent excitation during imposed hip
extension resulted in a significant facilitation of the LRL flexion reflex in all subjects (datafrom each subject are not illustrated). For each C–T interval, the average size (all subjects
tested) of the TA LRL responses during hip extension or flexion is illustrated in Fig. 2A. During
hip extension, the conditioned TA LRL response reached overall amplitude of 140±21% and
143±24.7% (P<0.05) of the LRLhomonymous at C–T intervals of 9 and 90 ms, respectively. A
one-way ANOVA along with post hoc Bonferroni tests revealed that the facilitation of theconditioned TA LRL responses during hip extension did not change significantly (F6, 47 =0.061, P=0.99) across C–T intervals. In contrast, excitation of low-threshold plantar cutaneousafferents did not induce significant effects on the TA LRL responses during hip flexion at anyof the C–T interval tested (P>0.05) (Fig. 2A). A two-way ANOVA conducted between theconditioned LRL flexion reflexes from all subjects recorded during hip extension and hip
flexion at all C–T intervals revealed that the conditioned LRL flexion reflexes during hip
flexion were significantly different from the conditioned reflexes recorded during hip extension(F1,5 = 6.99, P=0.03).

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The SRL TA response was observed in 5 of the 8 subjects during hip extension, and for all
subjects, the reflex was not significantly modulated by stimulation of the foot sole at either
short or long C–T intervals (single subject one-way ANOVA, P>0.05). The average size (allsubjects tested) of the SRL TA flexion reflex during hip extension is shown in Fig. 2B. In
contrast, the SRL TA responses were observed in 7 out of 8 subjects during hip flexion andwere depressed with foot sole stimulation at the longer C–T intervals tested (e.g., 30, 60, and90 ms) (Fig. 2B). A two-way ANOVA along with post hoc Bonferroni tests revealed that there
were significant effects due to limb movement only during hip flexion and for the C–T intervalsof 30 to 90 ms (P<0.05). Overall, during hip extension, the conditioned LRL TA responses
were facilitated while the associated conditioned SRL TA responses were similar to control
reflex values. The opposite effect was observed during hip flexion (compare Figs. 2A and B).
The hip-phase-dependent modulation of the flexion reflex following excitation of plantar
cutaneous afferents coincided with no changes in TA background activity. A three-way
ANOVA revealed that there were no significant main effects due to limb movement (flexion/
extension, P =0.39), C–T interval (9 to 90 ms, P=0.37), and timing of stimulus (pre- and poststimulus, P =0.2) on the TA activity during sinusoidal leg movement (see Fig. 2C).

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In general, the underlying leg muscle activity measured during the imposed hip movement withconditioning–test stimuli was similar to trials with only the flexion reflex stimuli. A constantbehavior of muscle responses was observed across C–T intervals, which coincided mostly withthe stimulus timing. One exception to the association of the EMG with the stimuli was anactivation of the MH during flexion of the hip in trials when stimuli were delivered during hip
extension (Fig. 3), consistent with stretch reflex activation of the MH. Similar to the EMGs,
the underlying torque responses during the conditioning–test recordings were similar to thosefor sural nerve stimulation alone. The torque data are summarized for conditioned TA flexion
reflex recordings during hip extension and flexion in Fig. 4A for the longest C–T interval tested(i.e., 90 ms). When the leg moved from mid- to peak extension, the torques at the hip were
mostly flexor for stimuli sent at mid-extension (Fig. 4Ai), and extensor for stimuli sent at midflexion (Fig. 4Aii). Further, an oscillatory spasmodic activity at the hip was present during thetransition phase of the hip from flexion to extension and was only observed when stimuli weredelivered during hip flexion. This spasmodic response appeared to be associated with the timingof the sural stimulation and not with the conditioning stimulus from the plantar cutaneousafferents since the effect was also observed with no conditioning stimulus (Fig. 4B). The flexorand extensor torques at the hip coincided with a similar behavior of the torque responses at theankle joint, while in this trial, the torques at the knee joint were rejected. For comparison, thetorque data for unconditioned flexion reflexes are indicated in Fig. 4B. It is apparent that thetorque responses across the lower limb joints with sural stimulation alone were generally
similar to those observed during the reflex conditioning trials.

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Combined effects of foot sole stimulation and hip movement on the soleus H-reflex
Plantar cutaneous afferent excitation produced significant changes in the soleus H-reflex thatwere hip-phase-dependent. Fig. 5A shows the waveform averages of the soleus H-reflexes
following excitation of plantar cutaneous afferents at 9 and 90 ms C–T intervals for one subject(S4) superimposed on the control H-reflex (Hohomonymous), both recorded during hip extension.
It is clear that excitation of plantar skin facilitated the soleus H-reflex.
One-way ANOVA (single subject) between the control and the conditioned H-reflexes revealed
that excitation of plantar cutaneous afferents had significant effects during hip extension but
not during hip flexion. A summary of changes (all subjects tested) in the conditioned H-reflex
following excitation of low-threshold plantar sole stimulation for all C–T intervals during hip
flexion and extension is illustrated in Fig. 5B. One-way ANOVA showed that the overall
conditioned soleus H-reflex (all subjects tested) varied significantly with changes in the C–T

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NIH-PA Author Manuscriptinterval during hip extension. Excitation of plantar cutaneous afferents with the hip in midextension resulted in a significant facilitation of the soleus H-reflex at the C–T interval of 6
ms. At 6 ms, the conditioned H-reflex reached an amplitude of 130± 15% of Hohomonymous.
Similarly, the H-reflex was significantly facilitated at C–T intervals of 9 and 15 ms, but reduced
to control reflex values at 30 and 60 ms. Reflex facilitation re-emerged during the longest C–
T interval (i.e., 90 ms). Thus, it is apparent that plantar cutaneous input induced an early
followed by a late soleus H-reflex facilitation during hip extension. In contrast, excitation ofplantar cutaneous afferents induced no significant effects on the amplitude of the soleus Hreflex at either short or long C–T intervals (one-way ANOVA, F6, 35 = 0.534, P=0.78) during
hip flexion. A paired t-test showed that the overall conditioned reflexes during hip extension
were statistically significant different compared to those observed during hip flexion (Tst=−
3.9, df=31, P<0.05).

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The modulation of the soleus H-reflex following excitation of plantar skin afferents during hip
movement occurred with no significant changes on the SOL pre- and post-stimulus EMG
activity. A summary of the SOL EMG activity (all subjects tested) before and after posterior
tibial nerve stimulation during hip flexion and extension for all C–T intervals is indicated inFig. 5C. A three-way ANOVA for repeated measures showed no significant differences
between pre- and post-stimulus SOL EMG activity during hip flexion and extension across C–
T intervals (flexion/extension, P =0.813; pre- and post-stimulus, P=0.167; C–T interval,
P=0.074), suggesting that the hip-phase-dependent reflex modulation during cutaneous plantar
stimulation was not due to simple changes in the underlying soleus motoneuronal excitability.
The H-reflex and plantar cutaneous stimuli did not appear to affect the underlying reflex
response to imposed hip movements. The hip, knee, and ankle reflexive torques when the soleus
H-reflex was conditioned with plantar cutaneous afferent excitation at 90 ms during hip
extension and flexion are illustrated in Fig. 6A. At the hip joint, flexor torques were observed
when the leg moved from mid- to peak extension, while during the transition phase of the leg
from peak flexion to mid-extension a spasmodic oscillatory behavior of this joint was apparent
when the hip was flexed. The hip flexor torques coincided mostly with extensor torques at theknee and ankle. For comparison we also illustrate the joint torques observed following soleus
H-reflex elicitation without the conditioning stimulation (Hohomonymous) (Fig. 6B). It isapparent that the torque responses across the lower limb joints were similar to those observed
during the reflex conditioning trials. Similarly, most EMG responses coincided with the timingof the stimulus, with stimulus-independent activity observed only in the MH and the VM, abehavior that was observed across C–T intervals (data not shown graphically).

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Comparing the joint torque responses following stimulation of a mixed peripheral nerve(posterior tibial) (Fig. 4) or a pure cutaneous nerve (sural) (Fig. 6) during imposed sinusoidal
hip movements, it is apparent that the ankle joint torques were manifested in a similar patternregardless the combination of stimuli. However, this was not the case for the hip joint torques,
which were in extension upon sural nerve stimulation and flexion upon posterior tibial nerve
stimulation when the hip moved from mid-extension to mid-flexion, suggesting that flexion
reflex stimulus affected the response to hip movement.

Discussion
The main finding of this study was that in SCI subjects, plantar cutaneous stimulation induced
a long-lasting facilitation of the soleus H- and TA flexion reflexes during hip extension that
occurred with stable ongoing background activity of the involved muscles. The reflex
modulation pattern was largely dependent on the phase of the hip movement such that during
hip flexion no significant effects on the monosynaptic H-reflex were observed, while the early
component of the flexion reflex (SRL) was depressed. These observations are consistent with

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the modulation of reflex pathways by afferent systems that have been implicated in the reflex
regulation of locomotion. Consequently, these results have implications in the reflex controlof gait in people with SCI and emphasize the importance of sensory feedback in locomotor
rehabilitation.
Contribution of feedback from the foot sole and hip to spinal reflex circuits and locomotorrelated neuronal pathways
Plantar cutaneous conditioning stimulation facilitated the LRL TA flexion reflex responses
and the soleus H-reflex during imposed hip extension, indicating a mixed effect on flexor andextensor reflex pathways. Specifically, the TA LRL flexion response was facilitated during
hip extension when the foot sole was stimulated, but no effects on the LRL were observed
during hip flexion (Fig. 2A). Further, the SRL TA response was depressed during hip flexion
at C–T intervals that varied from 30 to 90 ms (Fig. 2B), supporting further the involvement ofdifferent interneuronal circuits in the expression of the flexion reflex components (Knikou andConway, 2005). Similarly, the soleus H-reflex displayed an early followed by a lateconditioning effect during hip extension (Fig. 5B) but was not affected by foot sole stimulation
at either short or long C–T intervals during hip flexion. Thus, the conditioning effect of
cutaneous afferents from the foot sole on both spinal reflexes during hip extension was
facilitatory.

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The sensitivity of spinal reflexes to convergent feedback from hip proprioceptors and plantar
cutaneous afferents suggests that locomotor reflexes may be involved, since these same afferent
sources have modulatory effects on locomotor activity (Rossignol et al., 2006). If we thenassume that locomotor-related pathways were involved in the modulation of the spinal reflexes
in this study, one might anticipate that facilitation of extensor reflex pathways by cutaneousafferents during hip extension would have been accompanied by an inhibition of the flexor
reflex pathways. In this respect, it has been postulated that skin afferent input is capable ofblocking the onset of swing phase and inducing extensor muscle activity (Schomburg et al.,
1998;Duysens and Pearson, 1976). Thus, the lack of observing a differential effect on flexorand extensor reflex pathways by plantar conditioning stimulation during hip extension might
be attributed to the loss of spinal inhibitory mechanisms as a result of the SCI (Knikou,
2005,2007a;Hultborn, 2003).

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The facilitatory effects of the plantar cutaneous afferents on the TA flexion reflex during hip
extension is inconsistent with the general increase in the response during swing and suppression
during the transition phase from swing to stance observed in spinal-intact subjects (Yang andStein, 1990). Similarly, a phase-dependent modulation and reversal of cutaneous reflexes isobserved in spinal cats during fictive locomotion (Duysens et al., 1990;Schmidt et al.,
1989;Moschovakis et al., 1991;Degtyarenko et al., 1996). Cutaneous afferents innervating theankle and the foot-pad skin enhance and prolong stance and can increase the extensor burst by
as much as 100% (Duysens and Pearson, 1976). However, the conditioning effects of theplantar cutaneous afferents on the TA flexion reflex were facilitatory during the hip extension
phase of the cyclic movement in the current study, contradicting the decrease in flexion reflexes
typically observed during stance. The difference may be related to a lower level of activity inthe spinal locomotor generator in the supine subjects in the current study.
The joint torque oscillations observed during the transition phase from flexion to extension
when either conditioning or test stimuli were delivered during hip flexion (Fig. 6) could be
potentially interpreted to indicate that spinal locomotor pathways were activated by thestimulation. We have previously observed a similar behavior when group Ia afferents (but not
Ib afferents) from the common peroneal nerve or flexion reflex afferents were excited during
imposed hip movements in the same SCI subjects (Knikou et al., 2006a;Knikou, 2007b). In
those cases, oscillatory activity was observed during hip extension and flexion, but its
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amplitude was half of that observed here (compare Fig. 4 with Fig. 6 in Knikou et al., 2006a).
This oscillatory rhythmic activity resembles the one seen during fast paw shake following
stimulation of specific skin sites described in animals (Pearson and Rossignol, 1991) and also
resembles clonus of the leg in humans (Beres-Jones et al., 2003), with the latter proposed tobe mediated by a spinal stepping generator.
Sensory feedback associated with hip position and cutaneous sensation from the foot sole is
known to contribute to gait regulation. The long latency TA flexion reflex is strongly modulated
by hip position in the acute spinal cat (Grillner and Rossignol, 1978), while imposed flexion
at the hip during fictive locomotion in L-DOPA-treated spinal cats shortens the flexor burst
duration when applied near the end of the flexor bursts (Andersson and Grillner, 1983;Lam
and Pearson, 2001). Analogously, afferents originating from the foot sole delay the initiationof swing and inhibit long latency flexion reflexes promoting stance (Duysens and Pearson,
1976;Conway et al., 1995). Although specific afferents or neuronal pathways have not been
identified in humans, hip-mediated sensory signals affect the walking pattern of spinal injured
people by enhancing the swing phase (Dietz et al., 1998,2002), while input from the foot soleacting either in isolation or in combination with input from the hip affect reflexly mediatedmotor behavior (Knikou and Conway, 2001;Knikou, 2007a;Knikou et al., 2006b).

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It is likely that during our experiments, spinal locomotor-related circuits participated in themodulation of the spinal reflexes, but in the absence of limb loading and upright posture of the
SCI subjects, the effects of sensorimotor reflex conditioning resulted in an exaggerated or
fragmented expression of the locomotor-related muscle activation. To conclude, it is suggested
that sensory feedback from the hip and plantar cutaneous afferents contribute to locomotorreflexes and likely contribute to the locomotor recovery of people with SCI following treadmill
walking training. However, demonstration of these same reflex pathways remains to be tested
during treadmill walking or step training.
Possible neuronal mechanisms
The imposed sinusoidal hip motion was delivered without a stop in either flexion or extension,
providing an ongoing signal reflecting hip proprioception. Thus, proprioceptive hip muscle
afferents sensitive to stretch and to dynamic changes of muscle length (i.e., primary andsecondary muscle spindle afferents) interacted with low-threshold plantar cutaneous afferents
to mediate the observed reflex modulation. Given that both spinal reflexes and conditioning
stimulation were delivered at non-nociceptive levels, low-threshold sensory afferents were
implicated in the reflex responses. Significant evidence suggests that hip proprioceptors
interact with segmental Ia and Ib inhibitory interneurons (Knikou, 2005;Knikou et al.,2006b), thereby affecting motor output of the injured human spinal cord.

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Ipsilateral and contralateral sural nerve stimulation has been reported to decrease presynaptic
inhibition of soleus Ia afferent terminals in spinal intact subjects (Delwaide et al., 1981;Iles,
1996), a phenomenon that has been described in people with clinically complete SCI (RobyBrami and Bussel, 1992). In this respect, cutaneous stimuli can reduce the level of presynaptic
inhibition of group I afferents during fictive stepping in the cat (Menard et al., 2002;EnriquezDenton et al., 2002) without changing the pattern of phase-dependent modulation (Menard etal., 2002). Similarly, input from the foot sole influences alpha motoneuronal excitability
through segmental inhibitory inter-neuronal circuits (Pierrot-Deseilligny et al., 1982;Rossi and
Mazzocchio, 1988;Iles, 1996). Further, the presynaptic inhibition acting on soleus Ia afferent
is abolished following static hip angle changes in spinal-intact and spinal-injured subjects(Knikou, 2005,2006), while the stepping generator itself does not presynaptically inhibit thesoleus H-reflex during the extension phase of locomotor activity (Misiaszek et al., 2000),
suggesting a pre-motoneuronal reflex regulation by hip muscle and plantar cutaneous afferents.
Nonetheless, current findings might be related to the recruitment of excitatory interneurons or
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dis-facilitation of inhibitory interneurons projecting to excitatory interneurons in group I andflexion reflex afferents. However, given the indirect nature of the current experiments, a
specific neuronal mechanism cannot be assigned.
Functional implications
The present study provides evidence that actions of plantar cutaneous afferents on the soleus
H-reflex and TA flexion reflex are modulated by hip movement in a phase-dependent manner.
Both reflexes were facilitated during hip extension. Hip-mediated sensory feedback is known
to shape the walking pattern of the injured human spinal cord and to account for phasetransitions and swing phase initiation in spinal cats during fictive locomotion. It is suggested
that hip proprioceptors might contribute to the recovery of walking in people with a SCI byadjusting extensor and flexor spinal reflexes through cutaneous afferent pathways. This ispartially supported by findings in spinal cats during locomotion training, where skin input thatsignals ground contact is modified by step training (Côte and Gossard, 2004). Further researchis thus needed to establish the interactive effects of hip proprioceptors and plantar cutaneousafferents on spinal reflexes before and after locomotor training in human SCI so that
sensorimotor reflex conditioning systems may be developed to enhance locomotor training andthus promote recovery of walking in people with a sensorimotor incomplete SCI.
Acknowledgements

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Authors are in debt to the subjects for participating in many experiments during this project. This work was supportedby the National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH),
under the Grant No. R03HD043951 (MK).

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Fig 1.

For two subjects (S7 and S10) the average (n=10) control TA flexion reflexes (black lines)
recorded during hip extension (upper traces) and during hip flexion (lower traces) are illustrated
superimposed on the TA flexion reflexes conditioned by plantar cutaneous afferents at aconditioning–test interval of 90 ms (grey lines). It is clear that in both subjects, excitation ofplantar cutaneous afferents during hip extension facilitated the long reflex loop (LRL) TA
flexion reflex. In contrast, during hip flexion the LRL TA flexion reflex was not affected by
the conditioning stimulus, while the short reflex loop (SRL) response was depressed in subject
7. In subject 10, no significant changes in the amplitude of the SRL TA response were noted
following reflex conditioning during hip flexion.

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Fig 2.

NIH-PA Author Manuscript(A) Effects of plantar sole conditioning stimulation on the TA long reflex loop (LRL) response
during hip extension and hip flexion. Data represent the overall mean size (all subjects tested)of the conditioned TA flexion reflex expressed as a percentage of the associated control reflex(LRLhomonymous) and grouped according to the conditioning–test (C–T) interval and hip
movement. (B) Average size (all subjects tested) of the TA short reflex loop (SRL) response
as a percentage of the associated control flexion reflex (SLRhomonymous) during hip extension
and flexion. (C) Overall amplitude (all subjects tested) of the pre-and post-stimulus TA
background activity during hip flexion and extension is illustrated for all C–T intervals. See
text for more details on the statistical analysis. Error bars in all graphs designate the standard
error of the mean and asterisks the cases of statistically significant differences between theconditioned and the control reflexes across the C–T intervals at 95% of confidence level.

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Fig 3.

Normalized average muscle responses when the TA flexion reflex was conditioned by lowthreshold plantar cutaneous afferent stimulation at the conditioning–test interval of 90 ms (A)and when the conditioning stimulus was not present (B) during hip extension and flexion.
Bottom traces indicate the sinusoidal motion at the hip joint, as recorded by the Biodex system.
The dotted lines indicate the position of the hip (0 s for mid-extension and 2.5 s for mid-flexion)
during which stimuli (sural nerve and/or combined sural nerve and foot sole) were delivered.

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Fig 4.

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The reflexive joint torques (Nm) at the hip and ankle are indicated for cases when the TA
flexion reflex was conditioned by plantar sole stimulation at 90 ms during hip extension andflexion (A), and when the conditioning stimulus was not present (B). Each waveform represents
the average of 10 consecutive hip movement cycles (each cycle lasted 5 s). Arrows at the bottomof the figure indicate the position of the hip during a hip sinusoidal movement cycle (midextension at 0 s, peak extension at 1.25 s, mid-flexion at 2.5 s, and peak flexion at 3.75 s). For
extension trials stimuli were delivered at 0 s and for flexion trials at 2.5 s. Torques above zerodesignate extension and those below zero designate flexion. Oscillatory torques at the hip andankle were mostly observed during the transition phase of the hip from flexion to extension,and only when stimuli were delivered during hip flexion.

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Fig 5.

(A) The average H-reflex (n=10) recorded under control conditions (Hohomonymous; dashedlines) and during conditioning of the soleus H-reflex with stimulation of low-thresholdcutaneous afferents of the foot sole at the conditioning–test (C–T) intervals of 9 and 90 ms(solid lines) during hip extension are presented. It is clear that during hip extension plantar solestimulation resulted in a significant soleus H-reflex facilitation. Note that the increment in Hreflex amplitude occurs without significant changes in the M-wave. (B) Effects of variation of
the C–T interval on the soleus H-reflex during hip extension and hip flexion. Data represent
the overall mean (all subjects tested) of the conditioned soleus H-reflex expressed as apercentage of the associated control reflex (Hohomonymous) and grouped according to the C–T
interval and hip movement direction. Asterisks indicate cases of statistically significant
differences between the control and the conditioned reflex. (C) Overall mean amplitude of the

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Page 19pre- and post-stimulus SOL background EMG activity for conditioned H-reflexes elicitedduring hip extension and flexion is indicated for each C–T interval.

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Fig 6.

Hip, knee, and ankle reflexive torques (Nm) when the soleus H-reflex was conditioned byplantar sole stimulation at 90 ms during hip extension and flexion (A), and when theconditioning stimulus was not present (B). Each waveform represents the average of 10
consecutive hip movement cycles. Arrows at the bottom of the figure indicate the position of
the hip during a hip sinusoidal movement cycle (mid-extension at 0 s, peak extension at 1.25
s, mid-flexion at 2.5 s, and peak flexion at 3.75 s). For extension trials, stimuli were delivered
at 0 s and for flexion trials at 2.5 s. Torques above zero designate extension and those below
zero designate flexion. Oscillatory joint responses were mostly observed during the transition

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Page 21phase of the hip from peak flexion to extension but only when stimuli were delivered during
hip flexion.

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36

52

25
29
47
22
61
52

Age (years)

39

189

99
39
81
48
53
213

Postinjury (months)

2

3

1
0
2
2
0
1

Ashworth score

B

C

C
C
C
C
C
C

ASIA

T8

C5

C5
C5
C6
T11
T9
C5

Lesion level

IntactIntactIntactIntactIntactNosensation ofcold/warmNosensation ofcold/warm
IntactSensation

Baclofen pump–––
Baclofen 60 mg––
Baclofen 30 mg

Medication per day

60°

50°

40°
50°
55°
60°
60°
48°

HreflexHip ROM

58°

60°

43°
45°
55°
65°
57°
55°

Flexion reflex

Spasticity at the ankle was scaled according to the Ashworth (1964) score. Lesion completeness was classified according to the American Spinal Injury Association (ASIA) impairment scale(Maynard et al., 1997) with ASIA C representing a sensory and motor incomplete lesion where more than half of the muscles below the injury level have a strength of less than 3 (out of 5), and ASIA
B representing sensory incomplete but motor complete spinal cord lesion. S#: subject number; F: female; M: male; ROM: range of sinusoidal hip movement.

M

S12

a

M

M
M
M
M
F
M

S1
S3
S4
S5
S7
S10

S11

GenderS#

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Table 1

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Summarized characteristics of SCI subjectsa
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