Stroke survivors don't need lazy 'assessments' of MEP(Motor Evoked Potentials). Neither get you recovered! We need protocols. WHEN THE HELL WILL YOU GET THERE?
Paired Associative Stimulation as a Tool to Assess Plasticity Enhancers in Chronic Stroke
Joshua Silverstein1, 
Mar Cortes2, 
Katherine Zoe Tsagaris1, Alejandra Climent3, Linda M. Gerber4, Clara Oromendia4, 
Pasquale Fonzetti5,6, 
Rajiv R. Ratan5,7,8, 
Tomoko Kitago1,5*, 
Marco Iacoboni9,10, Allan Wu10,11, 
Bruce Dobkin12 and 
Dylan J. Edwards13,14- 1Human Motor Recovery Laboratory, Burke Neurological Institute, White Plains, NY, United States
- 2Department of Rehabilitation and Human Performance, Icahn School of Medicine at Mount Sinai, New York, NY, United States
- 3Sant Joan de Deu Hospital, Department of Neurology, University of Barcelona, Barcelona, Spain
- 4Department of Healthcare Policy and Research, Weill Cornell Medical College, New York, NY, United States
- 5Department of Neurology, Weill Cornell Medical College, New York, NY, United States
- 6Memory Evaluation and Treatment Service, Burke Rehabilitation Hospital, White Plains, NY, United States
- 7Burke Neurological Institute, White Plains, NY, United States
- 8Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, United States
- 9Department of Psychiatry and Biobehavioral Sciences, UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, United States
- 10Ahmanson-Lovelace Brain Mapping Center, University of California, Los Angeles, Los Angeles, CA, United States
- 11Department of Neurology, University of California, Los Angeles, Los Angeles, CA, United States
- 12Department of Neurology, Geffen School of Medicine, Reed Neurologic Research Center, University of California, Los Angeles, Los Angeles, CA, United States
- 13Moss Rehabilitation Research Institute, Elkins Park, PA, United States
- 14School of Medical and Health Sciences, Edith Cowan University, Perth, WA, Australia
Background and Purpose: The potential for
adaptive plasticity in the post-stroke brain is difficult to estimate,
as is the demonstration of central nervous system (CNS) target
engagement of drugs that show promise in facilitating stroke recovery.
We set out to determine if paired associative stimulation (PAS) can be
used (a) as an assay of CNS plasticity in patients with chronic stroke,
and (b) to demonstrate CNS engagement by memantine, a drug which has
potential plasticity-modulating effects for use in motor recovery
following stroke.
Methods: We examined the effect of PAS in
fourteen participants with chronic hemiparetic stroke at five
time-points in a within-subjects repeated measures design study:
baseline off-drug, and following a week of orally administered memantine
at doses of 5, 10, 15, and 20 mg, comprising a total of seventy
sessions. Each week, MEP amplitude pre and post-PAS was assessed in the
contralesional hemisphere as a marker of enhanced or diminished
plasticity. Strength and dexterity were recorded each week to monitor
motor-specific clinical status across the study period.
Results: We found that MEP amplitude was
significantly larger after PAS in baseline sessions off-drug, and
responsiveness to PAS in these sessions was associated with increased
clinical severity. There was no observed increase in MEP amplitude after
PAS with memantine at any dose. Motor threshold (MT), strength, and
dexterity remained unchanged during the study.
Conclusion: Paired associative stimulation
successfully induced corticospinal excitability enhancement in chronic
stroke subjects at the group level. However, this response did not occur
in all participants, and was associated with increased clinical
severity. This could be an important way to stratify patients for future
PAS-drug studies. PAS was suppressed by memantine at all doses,
regardless of responsiveness to PAS off-drug, indicating CNS engagement.
Introduction
The capacity of the brain to make structural,
physiological, and genetic adaptations following stroke, otherwise known
as plasticity, is likely to be critical for improving sensorimotor
impairments and functional activities. Promotion of adaptive plasticity
in the central nervous system (CNS) leading to sustained functional
improvement is of paramount importance, given the personal suffering and
cost associated with post-stroke disability (Ma et al., 2014).
In addition to rehabilitation therapies to retrain degraded motor
skills, animal and human studies have tried to augment recovery with
neuropharmacologic interventions. Unfortunately, few if any have had a
notable effect in patients or have come into routine use (Martinsson et al., 2007; Chollet et al., 2011; Cramer, 2015; Simpson et al., 2015).
Methods to screen drugs based on their presumed mechanism of action on
plasticity in human motor systems could speed translation to patients.
However, there is currently no accepted method in stroke patients for
evaluating the potential effectiveness or individual responsiveness to
putative “plasticity enhancing” drugs in an efficient, low-cost,
cross-sectional manner, in order to establish target engagement in
humans and to avoid the extensive time and cost of protracted clinical
trials.
Paired associative stimulation (PAS) is a safe,
painless, and non-invasive technique known to result in short-term
modulation of corticospinal excitability in the adult human motor
system, lasting ∼90 min (Stefan et al., 2000; Wolters et al., 2003).
Post-PAS excitability enhancement has been considered an LTP-like
response thought to relate to transient changes in synaptic efficacy in
the glutamatergic system at the N-methyl-D-aspartate (NMDA) receptor, since both human NMDA receptor deficiency (Volz et al., 2016) and pharmacological manipulation with dextromethorphan (Stefan et al., 2002)
can block the effect. While PAS has been explored as a potential
therapeutic intervention in patients with residual motor deficits after
stroke (Jayaram and Stinear, 2008; Castel-Lacanal et al., 2009),
it has not previously been investigated for its potential use as an
assay of motor system plasticity in this context. Prior studies have
suggested that motor practice and PAS share the same neuronal
substrates, modulating LTP and LTD-like plasticity in the human motor
system (Ziemann et al., 2004; Jung and Ziemann, 2009); therefore, as an established non-invasive human neuromodulation method (Suppa et al., 2017),
we reasoned that PAS would be a suitable assay in the present study to
examine the effect of a drug on motor system plasticity.
Here, we examine the effect of memantine, a drug used
for treatment of Alzheimer’s disease, on the PAS response in patients
with chronic stroke. Memantine is described pharmacologically as a low
affinity, voltage dependent, non-competitive, NMDA antagonist (Rogawski and Wenk, 2003).
At high concentrations, like other NMDA-R antagonists, it can inhibit
synaptic plasticity. At lower, clinically relevant concentrations,
memantine can, under some circumstances, promote synaptic plasticity by
selectively inhibiting extra-synaptic glutamate receptor activity while
sparing normal synaptic transmission, and hence may have clinical
utility for rehabilitation (Xia et al., 2010).
Interest in specifically using the drug for its interaction with stroke
pathophysiology stems from animal models of both prevention (Trotman et al., 2015),
in which pre-conditioning reduced infarct size, as well as for
functional recovery, in which chronic oral administration starting >2
h post-stroke resulted in improved function through a
non-neuroprotective mechanism (López-Valdés et al., 2014).
In humans, memantine taken over multiple days has been used to
demonstrate that the NMDA receptor is implicated in specific
transcranial magnetic paired-pulse measures (Schwenkreis et al., 1999), and short-term training-induced motor map reorganization (Schwenkreis et al., 2005). In studies of neuromodulation, memantine blocked the facilitatory effect of intermittent theta-burst stimulation (iTBS) (Huang et al., 2007).
Similarly, LTP-like plasticity induced by associative pairing of
painful laser stimuli and TMS over primary motor cortex (M1) can also be
blocked by memantine (Suppa et al., 2013).
The effects of memantine on the PAS response have not yet been
demonstrated, including examination of potential dose-response effects,
which would be important for the potential clinical application of
memantine for stroke recovery.
In our study, we set out to determine whether PAS might
be a useful tool to probe the potential for plasticity after stroke in
persons with chronic hemiparesis and apply PAS as an assay to look at
drug effects on motor system plasticity using memantine. We hypothesized
that (a) PAS would enhance corticospinal excitability in the
contralesional hemisphere of stroke patients, and that (b) since
PAS-induced plasticity is thought to involve a short-term change in
glutamatergic synaptic efficacy, memantine would have a dose-dependent
effect on PAS response. We predicted that at low doses, memantine would
enhance PAS-induced plasticity through selective blockade of
extrasynaptic NMDA receptors, whereas higher doses would inhibit
PAS-induced plasticity.
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