ic
isco
Spasticity
uton
aut
e th
sp
up
e leg and bladder percussion. Flexor reflexes were quantified using torque
amine
duced
I). Both
Experimental Neurology 219 (2009) 507–515
Contents lists available at ScienceDirect
Experimental
.e lresulting from uncontrolled sympathetic reflexes, and flexor spasms,
consisting of paroxysmal muscle contractions, can both contribute to
disability in this patient population. Consequently, an improved
understanding of the mechanisms underlying these problems and
their possible interrelationship could potentially lead to improved
clinical management of both AD and spasticity.
Autonomic dysreflexia is a common condition post SCI that has
been clinically linked to increasedmuscle spasms, yet themechanisms
remain undetermined. AD can be triggered in 45–90% of individuals
from the increase in the severity and frequency of flexor spasms
during bouts of AD induced by bladder distention, suggesting a link
between autonomic and flexor reflex pathways.
Following these early observations of flexor spasms during
episodes of increased sympathetic activity, several investigators
have examined the role of bladder distention and prolonged
cutaneous stimulation on lower extremity flexor reflexes. Bladder
distention in acute spinal cats results in the facilitation of an induced
flexor reflex (Evans and McPherson, 1959). Similarly, spontaneouswith quadriplegia or high paraplegia (Tease
1994) by a variety of stimuli from afferent s
level including the bowel and bladder, c
⁎ Corresponding author. Fax: +1 414 288 7938.
E-mail address: brian.schmit@marquette.edu (B.D. S
1 Current address: University of Central Arkansas, De
Conway, Arkansas 72035, USA.
0014-4886/$ – see front matter © 2009 Elsevier Inc. Al
doi:10.1016/j.expneurol.2009.07.004autonomic and somatic
plications in SCI. Auto-
ute hypertensive events
relationship between spinal autonomic and motor systems was first
documented by Riddoch who coined the term “mass reflex” to
describe AD (Head and Riddoch, 1917; Riddoch, 1917). This term arosereflex pathways have important clinical im
nomic dysreflexia (AD), characterized by acIntroduction
The purpose of this study was to ex
reflex windup during episodes of in
chronic human spinal cord injury (SCfoot. Both bladder percussion and skin conditioning stimuli produced a reduction (43–67%) in the ankle and
hip flexor torques (pb0.05) of the flexor reflex. This reduction was accompanied by a simultaneous reduction
in vascular conductance, measured using venous plethysmography, with a time course that matched the
flexor reflex depression. While there was an overall attenuation of the flexor reflex, windup of the flexor
reflex to repeated stimuli was maintained during periods of increased sympathetic activity. This paradoxical
depression of flexor reflexes and minimal effect on windup is consistent with inhibition of afferent feedback
within the superficial dorsal horn. The results of this study bring attention to the possible interaction of
motor and sympathetic reflexes in SCI above and below the T5 spinal level, and have implications for
clinicians in spasticity management and for researchers investigating motor reflexes post SCI.
© 2009 Elsevier Inc. All rights reserved.
the modulation of flexor
sympathetic activity in
receptors (Corbett et al., 1975; Corbett et al., 1971a,b). Importantly,
an increase in muscle spasms is commonly associated with induced
sympathetic responses (Kewalramani, 1980; Riddoch, 1917) and is
anecdotally reported by SCI individuals during bladder infections. AAutonomic dysreflexia
Windupmeasurements of the response to a noxious electrical stimulus applied to the skin of the medial arch of the
Keywords: stimulation to the oppositFlexor reflex decreases during sympathet
cord injury
M. Kevin Garrison 1, Brian D. Schmit ⁎
Marquette University, Department of Biomedical Engineering, P.O. Box 1881, Milwaukee, W
a b s t r a c ta r t i c l e i n f o
Article history:
Received 3 April 2009
Revised 29 June 2009
Accepted 6 July 2009
Available online 15 July 2009
A better understanding of a
the clinical management of
of this study was to examin
activity in chronic human
conductance and the wind
j ourna l homepage: wwwll et al., 2000; Yarkony,
ources below the injury
utaneous, and muscle
chmit).
partment of Physical Therapy,
l rights reserved.stimulation in chronic human spinal
nsin 53233, USA
omic influence on motor reflex pathways in spinal cord injury is important to
onomic dysreflexia and spasticity in spinal cord injured patients. The purpose
e modulation of flexor reflex windup during episodes of induced sympathetic
inal cord injury (SCI). We simultaneously measured peripheral vascular
of the flexor reflex in response to conditioning stimuli of electrocutaneous
Neurology
sev ie r.com/ locate /yexnrflexor spasms are known to coincide with detrusor contractions in
chronic human spinal injuries (Pedersen et al., 1986). In contrast, a
study of noxious stimulation induced flexor reflexes during bladder
distention in humans with neurological conditions, including chronic
SCI, reported either facilitation or inhibition of the flexor EMG (Mai
and Pedersen, 1976). Noxious cutaneous stimulation has been shown
to produce AD (Corbett et al., 1971) and lower extremity vasoconstric-
tion in high and low level injuries (Garrison et al., 2008), yet there are

no studies of its concurrent influence on flexor reflexes. While the
sympathetic response was not monitored, several studies of electrical
stimulation of peripheral nerves have shown inhibition of flexor
reflexes in human SCI (Gregoric, 1998; Roby-Brami and Bussel, 1992).
These contradictory findings of facilitation and inhibition may stem
from differences in completeness and chronicity of the spinal cord
lesion as well as the array of afferent pathways thought to be involved
in flexor spasms.
In SCI, flexor spasms consisting of hip and ankle flexion are often
observed in response to exteroceptive stimuli and may be associated
with an increase in the baseline excitability of the flexion withdrawal
reflex (Young and Shahani, 1986). Hyperexcitability of the flexion
withdrawal reflex is evidenced by decreased thresholds to electro-
cutaneous stimuli and increased EMG responses in human SCI
(Dimitrijevic and Nathan, 1968; Shahani and Young, 1971). Besides
508 M.K. Garrison, B.D. Schmit / Experimental Neurology 219 (2009) 507–515cutaneous Aδ and C fiber afferents, there is evidence for muscle
afferent input (groups III–IV and possibly non-spindle group II fibers)
based on flexor reflexes imposed by movements of the ankle (Schmit
et al., 2002) and intramuscular stimulation (Hornby et al., 2003).
Regardless of the afferent source, Jankowska has proposed that the
increase in excitability of flexor reflex pathways following SCI is due, at
least in part, to the loss of descending inhibition from monoaminergic
pathways (Jankowska and Hammar, 2002). This change in neuromo-
dulation could contribute to windup of flexor reflexes, consisting of a
buildup of the flexor reflex response to successive noxious skin
stimuli, which has been observed in chronic human SCI (Dimitrijevic
and Nathan, 1970; Hornby et al., 2003). One benefit of studying the
windup phenomenon is that it provides indirect insight into the flexor
reflex spinal circuitry based on the reduced preparation evidence for
windup in motoneurons (Bennett et al., 2004) or deep dorsal horn
interneurons (reviewed in Hornby et al. (2003).
In the current study, we examined the windup of flexor reflex
torque and EMG responses to repeated noxious skin stimuli applied to
the arch of the foot.Modulation of theflexor reflex during contralateral
noxious skin stimuli and bladder percussionwasmeasured, alongwith
the vascular conductance of the contralateral leg as a measure of the
sympathetic response. This provided a controlled test of flexor reflex
modulation by two dissimilar stimuli that both produced sympathe-
tically mediated lower extremity vasoconstriction.
Materials and methods
Subjects
Eight volunteers with SCI were recruited for participation in this
study. All subjects were at least 2-year post injury and lacked
sensation and volitional motor control of the lower extremities,
(American Spinal Injury Association (ASIA) classification A). Addi-
tional subject characteristics including injury level, gender, and
medications are listed in Table 1. Subjects were used as their own
Table 1
Subject characteristics.
Subject
number
Injury
level
Age Time post
injury (years)
Gender Medications
1a,b T6 24 3 M None
2a,b T6 24 4 M Oxybutynin, imipramine
3a,b T6 39 13 M Baclofen, oxybutynin
4a T8 43 24 M Oxybutynin
5a C6–7 48 22 M None
6a C7-T1 20 2 F Baclofen
7a,b T3–5 32 4 M Baclofen, tolterodine, imipramine
8a,b T6 47 6 M Baclofen/morphine pump,
neurontin
a Denotes participation in skin stimulation experiment.
b Denotes participation in bladder percussion experiment.controls to eliminate the need to alter medication dosage or schedule,
prior to the experiments. None of the subjects was smokers and
consumption of caffeine and alcohol was avoided prior to each
experiment. Exclusion criteria included unhealed pressure sores,
bladder or other infection, and hypertension. Informed consent was
obtained from all subjects prior to participation in the study. The
experimental protocol was approved by the Marquette University IRB
and adhered to the principles of the Helsinki Declaration of 1975.
Experimental procedures
Subjects were seated in a semi-reclined position with both legs
elevated to heart level and the extremities were supported and
stabilized to prevent movement. Static joint angles ranged from 70 to
90° of hip flexion, 130 to 140° of knee flexion, and 0 to 15° of ankle
plantarflexion, depending on the available range of motion. For
quantification of flexor reflex torques, the right foot was secured to
an instrumented footplate. Right leg joint angle and body segment
length measurements were recorded for each subject and used for
joint torque calculations. A six-axis load cell (JR3, Woodland, CA)
providedmeasurements of the two forces andmoment that were used
to calculate the static, sagittal plane, joint torques of the ankle, knee
and hip.
Surface electromyogram (EMG) measurements of the right leg
muscles were made for the purpose of confirmation of torque
measurements and for validating estimates of individual muscle
activity. Surface EMGs were recorded from the tibialis anterior, soleus
and medial gastrocnemius. After preparing the skin, active preampli-
fier electrodes were applied over the respective muscle bellies, and
shielded leads were attached to an AMT-8 Octopus EMG amplifier
(Bortec, Calgary, Alberta, Canada) with amplification of 1000 and
bandpass filtering (10 Hz–1.5 kHz).
In order to measure sympathetic reflexes produced by bladder
percussion and noxious skin conditioning stimuli, arterial flows of
the left leg were recorded with a venous plethysmography system
(EC6, D.E. Hokanson Inc, Bellevue, WA). The system consisted of a
mercury-in-silastic strain gauge placed around the largest circum-
ference of the calf. A venous occlusion cuff was placed around the
thigh and connected to a rapid inflator set at 55 mmHg. The
inflation duty cycle was controlled by a digital pulse from the
computer, producing 8 s of inflation followed by 12 s of rest to allow
for flow measures every 20 s. A second cuff was placed just
proximal to the ankle and was manually inflated to suprasystolic
pressure for the duration of the experiment. These flow measures
were alternated with a flexion reflex stimulus in order to minimize
movement artifact. Although arterial flow was measured during
both bladder percussion and noxious skin conditioning stimulation
of the left leg, muscle contractions associated with the noxious skin
conditioning stimulus sometimes produced artifacts that precluded
meaningful results. Previous studies with contralateral stimulation
indicate that noxious cutaneous conditioning stimulation consis-
tently produces an immediate and robust sympathetic reflex in the
contralateral lower extremity (Garrison et al., 2008).
Measures of the flexion reflex response were made in the 12 s
interval between venous plethysmography measurements. Flexion
reflexes were elicited using a stimulus applied to the medial arch of
the right foot. A pair of Ag–AgCl, 2.5 cm square pregelled electrodes
(Vermed, Bellows Falls, VT) was placed on the medial arch of the foot,
spaced approximately 3 cm apart. The stimulus was delivered using a
Digitimer constant current stimulator (Model DS7A, Digitimer Ltd.,
Hertfordshire, England), triggered from the experiment control
computer. Test stimuli consisted of a 200 Hz pulsetrain of 1 ms
duration pulses applied for 50 ms (i.e. 10 pulses). The stimulus
amplitude was set to 50 mA, a stimulus that typically generated a
vigorous response (ankle torque N5 Nm). A total of 3 stimuli were
applied at a 1 s interval to obtain a measure of windup of the flexor