Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT02136823 |
| Other study ID # |
STU00012823 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
N/A
|
| First received |
May 9, 2014 |
| Last updated |
May 9, 2014 |
| Start date |
June 2009 |
Study information
| Verified date |
May 2014 |
| Source |
Rehabilitation Institute of Chicago |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
United States: Institutional Review Board |
| Study type |
Interventional
|
Clinical Trial Summary
This study is being done to measure the differences between the electrical activity of
muscles and /single muscle fibers in individuals with long-term spinal cord injury and
neurologically intact individuals without spinal cord injury. This study is also being done
to find out if muscle and /single muscle fiber electrical activity, voluntary strength,
reflex measurements, and/or spasms are changed after a single, oral dose of three commonly
prescribed drugs, Rilutek®, isradipine, and Namenda®. These medications are approved by the
FDA for treatment of disorders other than the control of spasms and strength. In this study,
they are being used in an experimental manner. Finally, this study is also being done to
find out whether or not a brief stretching exercise influences reflex measurements.
The main hypothesis of this study is that aberrant current activity in spinal motoneurons
contributes to spastic hyper-reflexia following chronic spinal cord injury.
Description:
Background/Rationale/Literature Review
Hyper-reflexia, spasms and loss of motor coordination are common impairments in individuals
with SCI. Though not thoroughly understood, recent studies suggest that persistent inward
currents (PICs) in motoneurons play an important role in generating hyper-reflexia and
involuntary spasms (Gorassini et al. 2004; Nickolls et al. 2004; Norton et al. 2008; Thomas
et al. 2002). Animal models of chronic spinal cord injury point further to the differential
involvement of increased sodium and calcium PICs in prolonged reflexes associated with
spasticity (Harvey et al. 2006; Li and Bennett 2003; Li et al. 2004a; Li et al. 2004c). In
addition, oral administration of the drug Rilutek®, a selective, progressive persistent
sodium current inhibitor, has been shown to decrease flexion withdrawal responses in
individuals with chronic SCI (Theiss et al. 2008), presumably because of the reduction of
persistent sodium currents in participating neurons.
In addition to the loss of descending cortical drive, monoaminergic input to the spinal cord
is also often disrupted in SCI. As hypothesized by Jacobs and Fornal (Jacobs and Fornal
1993; Jacobs et al. 2002), serotonin acts to facilitate motor output and inhibit sensory
input. Removal of monoaminergic input in humans may therefore lead to motor weakness and
hyperexcitable reflexes resulting in impaired motor function.
In addition to changes in facilitative or inhibitory modulation of spinal circuits, loss of
descending monoaminergic input may also change the intrinsic excitability of the spinal
neurons themselves. Following complete spinal transection, studies of electrical properties
of spinal neurons below the lesion reveal that initially, interneurons, especially in the
dorsal horn, become hyperexcitable, whereas motoneuron excitability plummets. In the
motoneuron, a key factor in this drastic decrease is a loss of persistent inward currents
(PICs). Persistent currents are conductances that, once activated, do not turn off, or at
least inactivate at an extremely slow rate. PICs have a profound effect on the excitability
of spinal neurons, both amplifying and prolonging their input (Prescott and De Koninck 2005)
and allowing them to produce long lasting outputs, plateau potentials and bistable behavior
(Heckman et al. 2005; Hounsgaard et al. 1984; Lee and Heckman 1998). The loss of PICs has
such a strong impact that motoneurons produce only brief and weak outputs to the
hyperexcitable interneuron inputs (Baldissera et al. 1981; Heckman 1994; Kehne et al. 1985;
Nygren and Olson 1976).
In animal models of chronic injury, however, motoneuronal PICs return (Li and Bennett 2003;
Li et al. 2004a), restoring the ability of motoneurons to produce sustained output in
response to synaptic input. The return of motoneuronal PICs, which allows motoneurons to
fully recover their ability to produce sustained output in response to synaptic input,
coincides with the appearance of spasticity (Li et al. 2004b). In addition, blocking these
PICs and long-lasting plateau potentials inhibits spastic behavior (Bennett et al. 2001a; Li
et al. 2004a). To summarize, in the animal model of the chronic SCI condition, motoneurons
demonstrate remarkable recovery of PICs, which likely play a major role in transmitting
synaptic reflex inputs that generate spasticity.
Previous studies in animal models have shown that NaP is essential for the production of
rhythmic firing to sustained or slowly rising inputs, such as the action potential
afterhyperpolarization (AHP) (Kuo et al. 2006; Lee and Heckman 2001). Blocking NaP with
riluzole decreases repetitive-firing capabilities (Harvey et al. 2006; Kuo et al. 2006; Kuo
et al. 2005; Ptak et al. 2005; Theiss et al. 2007; Urbani and Belluzzi 2000) and reduces
gain accompanied by a rightward bias shift in the input-output relation (Kuo et al. 2006;
Theiss et al. 2007), which is indicative of an increase in input needed to initiate output.
In addition, NaP amplifies and prolongs depolarization responses to brief stimuli (Prescott
and De Koninck 2005). CaP, such as the L-type calcium current, are responsible for plateau
potentials, which are a sustained depolarization following cessation of current input
(Hounsgaard and Kiehn 1989; Morisset and Nagy 1999; Russo and Hounsgaard 1996; Voisin and
Nagy 2001). In addition, CaP contributes to prolongation of depolarizing responses to brief
stimuli (Prescott and De Koninck 2005).
In human studies, firing patterns in single motor units from chronic SCI subjects have shown
differences in rate modulation (Thomas and Ross 1997), force-speed relations (Thomas et al.
1997), increases in discharge variability (Thomas et al. 2002), and prolonged duration of
post-synaptic potentials in response to transient inputs using the PSF technique (Norton et
al. 2008). These phenomena, especially those reflecting prolonged involuntary muscle
activity in response to short duration stimuli, have been attributed to the presence of PICs
in motoneurons. Recent results from Theiss (project co-investigator) et al. (2008) have also
shown that administration of pharmacological agents that reduce PICs, e.g. riluzole, (which
reduces NaP), decreases the flexion-withdrawal response in such a way that mimics the
effects of riluzole seen in animal models. These are a right-ward bias shift and gain
decrease in the input-output relation of animal spinal neurons (Kuo et al. 2006; Theiss et
al. 2007). Interestingly, riluzole administration also enhanced agonist specificity in
voluntary torque production by decreasing co-contraction and increasing total torque area
during a maximum voluntary contraction (Theiss et al. 2008).
Several pharmacological agents that artificially reduce PICs in animal spinal neurons are
available for human use. Riluzole, a specific, progressive NaP current inhibitor (Ptak et
al. 2005; Urbani and Belluzzi 2000) has been proposed as a promising neuroprotective
treatment for acute SCI (Baptiste and Fehlings 2006; Fehlings and Baptiste 2005; Hawryluk et
al. 2008; Schwartz and Fehlings 2002). CaP current blockers, such as nimodipine, (Harvey et
al. 2006; Li and Bennett 2003), have also been tested as a potential treatment in acute SCI
to reduce neuronal excitability (Fehlings and Baptiste 2005; Pointillart et al. 2000;
Winkler et al. 2003). Isradipine, a channel-specific CaP current blocker (Fitton and
Benfield 1990), has been proposed as a preventative and acute treatment for Parkinson's
disease (Surmeier 2007).
Interestingly, with the exception of investigations by Theiss (project co-investigator) and
colleagues on the effects of riluzole and isradipine on flexion-withdrawal response and
changes in volitional strength (Theiss et al. 2008, Theiss et al, 2011), the effects of
either agent on motor function, spasms, spasticity and motor unit firing behaviors in
chronic SCI have not been systematically studied. As studies by Theiss et al. (2008, 2011)
have shown, they provide a safe mechanism to examine contributions of intrinsic neuronal
currents to motor impairments.
Studies in animal models have also shown that NMDA-mediated currents have a role in the
production of spastic reflexes in chronic SCI (Bennett et al, 2001b). These currents have
been discussed as another possible contributor to prolonged spasms in human chronic SCI as
well (Norton et al, 2008). Taking these additional studies into account, an additional aim
is to expand our study to include preliminary investigation of a possible contribution of
post-synaptic NMDA-mediated currents to spinal neuron excitability and hyperexcitable
reflexes in chronic SCI.
Finally, muscle stretching is a commonly used, therapist-recommended clinical intervention
for reducing the negative impact of spasticity on motor function (Smania et al 2010, Harvey
& Herbert 2002). As much as seven hours per week of therapy time is spent on stretching
(Taylor-Schroeder et al 2011) and 27-41% of persons with SCI who undergo inpatient
rehabilitation (Zanca et al 2011) report that they stretch as part of their rehabilitation
program. However, there is no conclusive evidence at present that shows that stretching
influences reflex excitability in persons with spinal cord injury (Bovend'Eerdt et al 2008).
Hypothesis/Key Questions, Research Objectives
The objectives of this study are to investigate the contribution of sodium and calcium
persistent inward currents (PICs) towards mediating the hyper-reflexia and motor control
impairments seen in chronic spinal cord injury (SCI) using targeted pharmacological agents.
This study will test the hypothesis that aberrant current activity in spinal motoneurons
contributes to spastic hyper-reflexia following chronic spinal cord injury. Three specific
aims are proposed to evaluate this hypothesis:
1. to investigate the key features that distinguish spastic muscle in chronic spinal cord
injured individuals from that of spinally intact controls by assessing differences in
single motor unit firing patterns and time course of responses to transient and
sustained reflex inputs, as well as during voluntary control, and
2. to dissect the relative impact of persistent sodium and persistent calcium conductances
underlying the differences between spastic and non-spastic muscles by assessing changes
in single motor unit firing patterns and time course following oral administration of
Rilutek®, a persistent sodium current inhibitor, and isradipine, a persistent calcium
current blocker.
3. to investigate the impact of NMDA-mediated post-synaptic currents on the differences
between spastic and non-spastic muscles by assessing changes in single motor unit
firing patterns and reflex excitability following oral administration of memantine
(Namenda®), a drug that decreases NMDA currents.
An additional objective of this study is to investigate the effects of a brief intermittent
muscle elongation procedure on reflex excitability by testing reflex responses before and
after a stretching intervention.
Research Purpose All procedures in this study are for research purposes.
This study will advance the understanding of the cellular mechanisms underlying hyperactive
reflexes and loss of motor control in chronic SCI. Though not proposed as treatment agents
at this stage, the pharmacological PIC antagonists and NMDA antagonist used in this study
are intended as tools to understand the mechanisms of hyperexcitability. Therapeutically,
the ability to manipulate neuronal excitability (e.g. to increase specificity in volitional
strength or decrease hyper-reflexia) may lead to more effective treatments. Riluzole and
isradipine provide artificial, yet specific, control of PICs. Memantine also provides a
degree of control of synaptic NMDA-mediated post-synaptic currents. Understanding the
cellular mechanisms of SCI impairments and their modulation may identify novel approaches to
control spinal neuron excitability and provide appropriate tailoring of pharmacological
treatments specific to the attributes of an individual's spasticity and impairments.
This study will also add to existing knowledge about the physiological effects of a commonly
used yet with limited evidence base therapeutic intervention for reducing the negative
impacts of reflex hyperexcitability on motor function in SCI.
