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Department of Neurosurgery, SUNY Upstate Medical University, 750 E. Adams St, IHP #1213, Syracuse, NY 13210, USA
spasticity (Brown, 1994; Priebe et al., 2002). This involves little as a few days post-injury (Stauffer, 1975), to a period
Clinical Neurophysiology1388-2457/$30.00 q 2004 International Federation of Clinical Neurophysib
The Miami Project to Cure Paralysis, University of Miami School of Medicine, Miami, FL 33136, USA
Accepted 9 July 2004
Available online 21 August 2004
Abstract
Objective: Previous reports from our laboratory have described short-latency contractions in muscles of the distal upper limb following
stimulation of lower limb nerves or skin in persons with injury to the cervical spinal cord. It takes 6 or more months for interlimb reflexes
(ILR) to appear following acute spinal cord injury (SCI), suggesting they might be due to new synaptic interconnections between lower limb
sensory afferents and motoneurons in the cervical enlargement. In this study, we asked if once formed, the strength of these synaptic
connections increased over time, a finding that would be consistent with the above hypothesis.
Methods: We studied persons with sub-acute and/or chronic cervical SCI. ILR were elicited by brief trains of electrical pulses applied to
the skin overlying the tibial nerve at the back of the knee. Responses were quantified based on their presence or absence in different upper
limb muscles. We also generated peri-stimulus time histograms for single motor unit response latency, probability, and peak duration.
Comparisons of these parameters were made in subjects at sub-acute versus chronic stages post-injury.
Results: In persons with sub-acute SCI, the probability of seeing ILR in a given muscle of the forearm or hand was low at first, but
increased substantially over the next 1–2 years. Motor unit responses at this sub-acute stage had a prolonged and variable latency, with a
lower absolute response probability, compared to findings from subjects with chronic (i.e. stable) SCI.
Conclusions: Our findings demonstrate that interlimb reflex activity, once established after SCI, shows signs of strengthening synaptic
contacts between afferent and efferent components, consistent with ongoing synaptic plasticity.
Significance: Neurons within the adult human spinal cord caudal to a lesion site are not static, but appear to be capable of developing
novel—yet highly efficacious—synaptic contacts following trauma-induced partial denervation. In this case, such contacts between
ascending afferents and cervical motoneurons do not appear to provide any functional benefit to the subject. In fact their presence may limit
the regenerative effort of supraspinal pathways which originally innervated these motoneurons, should effort in animal models to promote
regeneration across the lesion epicenter be successfully translated to humans with chronic SCI.
q 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
Keywords: Spinal cord injury; Plasticity; Regenerative sprouting; Human; Interlimb reflex
1. Introduction
One defining consequence of severe spinal cord injury
(SCI) in humans is the development of different forms
of involuntary movements—collectively referred to as
an enhancement of cutaneous and stretch-induced reflexes,
often leading to recruitment of distant muscles in the limb or
contralateral limb (Kirshblum, 1999; Little et al., 1999).
Various properties contributing to the spastic state have
been reported to develop over a wide range of time, from asInterlimb reflex activity after spin
response patterns are consisten
Blair Calancie
a,
*
, Natalia Alexeevacord injury in man: strengthening
ith ongoing synaptic plasticity
mes G. Broton
b
, Maria R. Molano
b
116 (2005) 75–86
www.elsevier.com/locate/clinphThis discrepancy likely stems from the seldom-reported
observation that hyper-reflexia, as a subset of spasticity
tends to become evident much earlier, and be more
ology. Published by Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.clinph.2004.07.018
* Corresponding author. Tel.: C1-315-464-9935; fax: C1-315-464-
9848.
E-mail address: calancib@upstate.edu (B. Calancie).of weeks or months (Curt and Dietz, 1999; Ko et al., 1999).

hand (Calancie et al., 2002); and (3) is highly reproducible
in terms of the effective stimulus, and the resultant motor
europunit recruitment pattern. We proposed that ILR activity
reflected plasticity in cord segments caudal to the injury, in
which damage to axons at the injury site resulted in a
combination of: (a) degeneration of corticospinal tract
axons lying caudal to the injury and partial denervation of
motoneurons in the distal cervical enlargement; and (b)
axotomy of lower limb afferent fibers. The close proximity
between this population of partially denervated motoneur-
ons and afferent fibers without targets leads to (c) local
sprouting of these afferents onto the nearby motoneuron
somata and their dendrites.
As a follow-up to our earlier report showing a delay of 6
or more months between SCI and ILR emergence (Calancie
et al., 2002), the present study sought evidence of whether
or not once established, interlimb reflex activity remained
constant, or instead showed a progressive expansion and/or
strengthening of synaptic contacts. To answer this question,
we conducted repeated measures of ILR activity in persons
with sub-acute SCI, comparing findings at different times
within this group. We also compared ILR properties at their
emergence (i.e. at the sub-acute stage) in this population to
those in a separate group of subjects with chronic—and
presumably stable—cervical SCI.
2. Methods
Subjects. Two groups of subjects were studied. Subjects
with acute, traumatic cervical SCI made up the ‘Acute’
group. Repeated examinations in these subjects beginning
within days of their injury showed that ILR activity became
evident no sooner than 6 months post-injury (Calancie et al.,
2002). A subset of these acute subjects was tested at least
one more time after first observing ILR activity. Almost all
subjects in the acute group were recruited during a 3-year
period from 1997 to 2000. Persons in the second group
(‘Chronic’) were first examined not fewer than 2 years after
injury, and were determined at that time to have ILR activity
present, using the same criteria as described below.pronounced, in persons with neurologically incomplete SCI
(Calancie et al., 2004; Hiersemenzel et al., 2000; Maynard
et al., 1990).
One form of involuntary movement in persons with
cervical SCI that has not been implicated in the develop-
ment of hyper-reflexia and spasticity are what we have
previously described as ‘interlimb reflexes’ (ILR): short-
latency recruitment of motoneurons innervating muscles
of the distal upper limbs in response to stimulation
of cutaneous or muscle afferents from the lower limb
(Calancie, 1991; Calancie et al., 1996). Relative to
traditional spastic-like behaviors, ILR activity: (1) takes
longer to develop post-injury (Calancie et al., 2002); (2) is
seen almost exclusively in distal muscles of the forearm and
B. Calancie et al. / Clinical N76However, the time following injury at which ILR activityfirst emerged was not established in these subjects. One
subject in the chronic group was examined on more than one
occasion. Subjects in the chronic group were all recruited
and studied between 1989 and 1995, with two of the authors
(BC and JGB) directly involved with data collection and
analysis for all subjects in both groups. This study was
approved by the Institutional Review Board of the
University of Miami, and all subjects gave their informed
consent (and assent, for children) to participate.
Stimulation. ILR were elicited with electrical stimulation
to the tibial nerve at the popliteal fossa. Stimulation was via
self-adhesive surface electrodes, with the cathode at the
popliteal fossa and the anode approximately 7 cm distal. A
brief pulse train of very high frequency was used (3 pulses at
500 Hz), as this pattern was previously shown to be highly
effective in eliciting ILR activity at minimal response
latencies (Calancie, 1991; Calancie et al., 1996). Pulse
trains were delivered at a rate not exceeding 1 Hz, as faster
deliver rates can cause prolonged, intense motor unit
discharge, known as ‘wind-up’ (Calancie et al., 1996). In
all cases, we tested left- and right-side nerves indepen-
dently. Square-wave, constant-voltage stimuli were used at
all times. Subjects in the chronic group were tested with a
Grass S88 stimulator using a 1 ms pulse duration. Subjects
in the acute group were tested with a Digitimer D185
stimulator using a 50 ms pulse duration (pulse duration is
non-adjustable on the D185 stimulator). Given the different
pulse durations of these two stimulators, absolute stimulus
intensities for testing were not directly comparable. Instead,
all testing was done at a similar point of the soleus H-reflex
curve (based on single-pulse inputs), for which the H-reflex
was on the declining phase while the soleus M-wave was
increasing rapidly in magnitude (M-wave amplitude
typically exceeded 2 mV peak-to-peak). With this stimulus
intensity, each train delivery resulted in a forceful contrac-
tion of the triceps surae group, and brisk plantar-going
twitches of the ankle. We are confident that this input
resulted in stimulation of a large percentage of myelinated
fibers at the tibial nerve, regardless of the stimulator used.
Recording. Subjects were seated either in their wheel-
chair or in a dental chair. Muscle electromyogram (EMG)
was recorded with pairs of electrodes. These were usually
self-adhesive surface electrodes, but we used non-insulated
EEG-type needle electrodes in 5 subjects of the chronic
group; both types of electrodes give comparable results
(Hugon, 1973; Nuwer et al., 1993). Electrodes were placed
3–5 cm apart over the following left-side muscles or muscle
groups: biceps brachii, triceps brachii, wrist extensors
(including extensor carpi radialis (ECR)), wrist flexors
(including flexor carpi radialis (FCR)), thenar group
(including abductor pollicis brevis (APB)), and hypothenar
group (including abductor digiti minimi (ADM)). EMG was
also recorded from the soleus muscle. For all muscles, EMG
was pre-amplified close to the source (Intronix 2315),
filtered (100 Hz–2.5 kHz), amplified (1 or 10 k gain) and
hysiology 116 (2005) 75–86tape-recorded (Vetter 4000AS or MicroData Instruments