Good descriptions but useless since no protocols came out of this.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5377239/?
Abstract
Spasticity
and weakness (spastic paresis) are the primary motor impairments after
stroke and impose significant challenges for treatment and patient care.
Spasticity emerges and disappears in the course of complete motor
recovery. Spasticity and motor recovery are both related to neural
plasticity after stroke. However, the relation between the two remains
poorly understood among clinicians and researchers. Recovery of strength
and motor function is mainly attributed to cortical plastic
reorganization in the early recovery phase, while reticulospinal (RS)
hyperexcitability as a result of maladaptive plasticity, is the most
plausible mechanism for poststroke spasticity. It is important to
differentiate and understand that motor recovery and spasticity have
different underlying mechanisms. Facilitation and modulation of neural
plasticity through rehabilitative strategies, such as early
interventions with repetitive goal-oriented intensive therapy,
appropriate non-invasive brain stimulation, and pharmacological agents,
are the keys to promote motor recovery. Individualized rehabilitation
protocols could be developed to utilize or avoid the maladaptive
plasticity, such as RS hyperexcitability, in the course of motor
recovery. Aggressive and appropriate spasticity management with
botulinum toxin therapy is an example of how to create a transient
plastic state of the neuromotor system that allows motor re-learning and
recovery in chronic stages.
Keywords: spasticity, motor recovery, stroke, neuroplasticity, rehabilitation
Introduction
According
to the CDC, approximately 800,000 people have a stroke every year in
the United States. The continued care of seven million stroke survivors
costs the nation approximately $38.6 billion annually. Spasticity and
weakness (i.e., spastic paresis) are the primary motor impairments and
impose significant challenges for patient care. Weakness is the primary
contributor to impairment in chronic stroke (
1). Spasticity is present in about 20–40% stroke survivors (
2).
Spasticity not only has downstream effects on the patient’s quality of
life but also lays substantial burdens on the caregivers and society (
2).
Clinically,
poststroke spasticity is easily recognized as a phenomenon of
velocity-dependent increase in tonic stretch reflexes (“muscle tone”)
with exaggerated tendon jerks, resulting from hyperexcitability of the
stretch reflex (
3).
Though underlying mechanisms of spasticity remain poorly understood, it
is well accepted that there is hyperexcitability of the stretch reflex
in spasticity (
4–
7). Accumulated evidence from animal (
8) and human studies (
9–
18)
supports supraspinal origins of stretch reflex hyperexcitability. In
particular, reticulospinal (RS) hyperexcitability resulted from loss of
balanced inhibitory, and excitatory descending RS projections after
stroke is the most plausible mechanism for poststroke spasticity (
19). On the other hand, animal studies have strongly supported the possible role of RS pathways in motor recovery (
20–
36), while recent studies with stroke survivors have demonstrated that RS pathways may not always be beneficial (
37,
38).
The relation between spasticity and motor recovery and the role of
plastic changes after stroke in this relation, particularly RS
hyperexcitability, remain poorly understood among clinicians and
researchers. Thus, management of spasticity and facilitation of motor
recovery remain clinical challenges. This review is organized into the
following sessions to understand this relation and its implication in
clinical management.
Poststroke spasticity and motor recovery are mediated by different mechanisms
Motor recovery are mediated by cortical plastic reorganizations (spontaneous or via intervention)
Reticulospinal hyperexcitability as a result of maladaptive plastic changes is the most plausible mechanism for spasticity
Possible roles of RS hyperexcitability in motor recovery
An example of spasticity reduction for facilitation of motor recovery
Poststroke Spasticity and Motor Recovery are Mediated by Different Mechanisms
In
the course of complete motor recovery, motor recovery follows a
relatively predictable pattern regardless of stoke types (hemorrhagic or
ischemic, cortical or subcortical) (
39). Brunnstrom (
40,
41)
empirically described the stereotypical stages of motor recovery: (1)
flaccidity; (2) appearance of spasticity; (3) increased spasticity with
synergistic voluntary movement; (4) movement patterns out of synergy and
spasticity begins to decrease; (5) more complex movements and
spasticity continues to decrease; (6) spasticity disappears; and (7)
full recovery of normal function with coordinated voluntary movements.
Broadly speaking, there are three recovery stages: flaccid, spastic
(emerging, worsening, and decreasing, stages 2–5), and recovered
(voluntary control without spasticity, stages 6–7). During the course of
motor recovery, stroke survivors could progress from one recovery stage
to the next at variable rates, but always in an orderly fashion and
without omitting any stage. However, recovery may be arrested at any one
of these stages (
39,
41).
The classification of motor recovery stages is well accepted and used
in clinical practice. The pattern of motor recovery and spasticity is
confirmed in a recent longitudinal study in 2011 (
42).
It
is commonly observed that hyperreflexia and spasticity are gradually
developed after stroke. There is no sudden change to hyperreflexia (
43). The emergence of spasticity, though highly variable (
44), is usually seen between 1 and 6 weeks after the initial injury (
45).
This implies that the development of poststroke spasticity is related
to neuronal plastic changes within the central nervous system after the
initial injury [see reviews (
4–
7,
45–
47)]. Intensive therapy improves motor function, but has no effect on spasticity (
48).
A single dose of selective serotonin reuptake inhibitors (10 mg
escitalopram) significantly increased spasticity (measured by reflex
torque) without affecting muscle strength of spastic leg muscles after
stroke (
49). In contrast, another study (
50) showed that cyproheptadine, an anti-serotonergic agent, helped reduction of muscle relaxation time possibly
via
reduction of RS excitability and spasticity reduction in the finger
flexors, but without affecting muscle strength in spastic hand muscles
after stroke. These findings indicate that (1) spasticity and motor
recovery are mediated by different mechanisms; (2) the development of
spasticity is a milestone in the course of recovery, but reflects a
phenomenon of abnormal plasticity; and (3) In chronic stroke, motor
recovery is arrested or plateaued. Different stages of motor recovery in
chronic stroke could reflect different underlying pathophysiology in
the course of motor recovery and spasticity.
Motor Recovery are Mediated by Cortical Plastic Reorganizations (Spontaneous or via Intervention)
Plastic
reorganization occurs immediately after stroke. Following focal damage
to the motor cortex and its descending pathways, the surviving portions
of the brain usually undergo substantial structural and functional
reorganization that occurs in the peri-lesional areas, as well as in the
ipsilesional and contralesional cortices in an animal study (
51), and human neuroimaging studies (
52–
66).
These plastic changes reflect the capability of the brain, particularly
the cerebral cortex, to alter the structure and function of neurons and
their networks in response to damage caused by stroke. As such, neural
plasticity provides a foundation for recovery of motor function after
stroke (
67,
68).
Motor rehabilitation relies on a combination of recovery and
compensation through spontaneous recovery and motor learning during
rehabilitation. True motor recovery means that undamaged brain regions
generate commands to the same muscles to produce the same motor
patterns, while motor compensation refers to new motor patterns
(different muscles) that are controlled by alternative brain areas to
accomplish the task goal (
69,
70).
Longitudinal studies have shown that motor recovery from hemiparesis
proceeds through a series of fairly predictable stages over the first
6 months after stroke, regardless of the type of therapeutic
intervention (
71).
During this period, there is a process of spontaneous recovery which
peaks approximately in the first 4 weeks and then tapers off over
6 months. However, this does not impose physiological limits in
recovery. Through novel rehabilitation protocols and mass practice,
considerable motor improvement could be realized in the chronic stages
(>1 year) (
72).
Such motor rehabilitation programs should include repetitive and
task-specific practice at high intensity in a multidisciplinary
environment to promote neural plasticity for motor recovery (
73,
74).
These motor training protocols could be realized by a number of novel
neurorehabilitation methods, such as constraint-induced movement therapy
(CIMT) (
75,
76), robotic training (
77–
79), and body weight-supported treadmill training (
80,
81).
Accumulated evidence has supported the idea that the recovery-related
cortical plastic reorganization and activation changes after the above
training methods are used in chronic stroke (
57,
82–
85).
Pharmacological agent, e.g., early prescription of fluoxetine, with
physical therapy in the FLAME trial has shown to enhance motor recovery
after stroke
via modulation of spontaneous neural plasticity (
86).
Both
ipsilesional and contralesional motor cortices undergo plastic
reorganization following a stroke, as mentioned above. Activation of
bilateral sensorimotor cortices during voluntary movement of the paretic
hand in stroke patients was reported (
87). Activation of the contralesional hemisphere is greater in patients with poor motor function (
88,
89), but decreases over time with motor recovery (
57).
Such changes result in abnormal interhemispheric interaction.
Specifically, there is an abnormally high inhibitory drive from the
contralesional hemisphere to the ipsilesional hemisphere (
90).
This abnormal interhemispheric inhibition correlates negatively with
motor function in stroke patients. It is viewed as maladaptive
plasticity (
91).
Based on the interhemispheric competition model, two main strategies of
modulation of motor cortex excitability using non-invasive brain
stimulation have been used to restore the balance of interhemispheric
inhibition between lesioned and contralesional hemispheres, i.e.,
upregulation of excitability of the motor cortex of the lesioned
hemisphere and downregulation of excitability of the motor cortex in the
contralesional hemisphere (
92). Restoration of interhemispheric inhibition
via tDCS (
58,
93) or rTMS (
59,
94,
95) has shown to facilitate recovery of motor function in stroke patients (
96).
RS Hyperexcitability as a Result of Maladaptive Plastic Changes is the Most Plausible Mechanism for Spasticity
Spasticity is resulted from hyperexcitability of the stretch reflex, which is gradually developed after stroke (
4–
7).
It is attributed to disinhibition of stretch reflexes as a result of
altered descending inputs to spinal stretch reflex circuits after stroke
(
97). Disruption of descending supraspinal inputs after stroke could lead to plastic rearrangement at segmental levels (
4,
5,
7,
98). In a recent animal study, Sist et al. (
98)
have demonstrated that there is a time-limited period of heightened
poststroke structural plasticity in both brain and spinal cord after a
sensorimotor stroke. The spinal plastic change correlates with the
severity of cortical injury.
Excitability of the stretch reflex
circuit (afferent fibers, spinal motor neurons, and efferent fibers) is
predominantly regulated by excitatory and inhibitory descending signals
of supraspinal origins (
4,
6,
7,
99,
100).
In a neurologically intact person, the descending reticulospinal tract
(RST) and vestibulospinal tract (VST) provide a balanced excitatory and
inhibitory descending regulation. Other descending pathways are either
not related to the spinal stretch reflex (corticospinal and tectospinal)
(
6,
8,
100) or absent in humans (rubrospinal tract) (
101).
Dorsal RST descends in parallel with CST in the dorsolateral funiculus
and provides a dominant inhibitory effect on the spinal stretch reflex,
while medial RST and VST descend in the ventromedial cord, providing
excitatory inputs. It is important to note that dorsal RST receives
facilitation from the motor cortex
via corticoreticular
projections, which run in close proximity with the corticospinal tract.
In stroke with cortical and internal capsular lesions, damages often
happen to both CST and corticoreticular tracts due to their anatomical
proximity, resulting in loss of cortical facilitatory input to the
medullary inhibitory center, thus less inhibition from dorsal RST. This
leaves the facilitatory medial RST and VST unopposed, since they are
independent of cortical control, thus the stretch reflex
hyperexcitability [see Figure 2 in Ref. (
19)].
This mechanism could also explain why a stereotyped pattern of
spasticity is observed regardless of affected areas (cortical or
subcortical stroke).
There is experimental evidence from animal
and human studies to support the important role of RST in spasticity
[reviewed in Ref. (
6,
8,
100)]. For example, surgical section of unilateral or bilateral VST in the anterior cord has little effect (
102) or a transient effect (
103) on spasticity. With more extensive cordotomies that damaged the medial RST, spasticity was drastically reduced (
103). Given unilateral nature of vestibulospinal projections (
104), the role of VST in spasticity was recently tested in chronic stroke (
105).
Vestibular-evoked myogenic potentials in the sternocleidomastoid muscle
in response to high-level acoustic stimuli (130 dB) to the ears of
stroke survivors were greater on the impaired side than the non-impaired
side. There existed a strong positive relationship between the degree
of asymmetry and the overall severity of spasticity from upper and lower
limbs in spastic-paretic stroke survivors. The findings thus suggest a
possible role of hyperexcitability of VST in poststroke spasticity (
105). Yet, this level of acoustic stimuli is also likely to activate RS pathways
via acoustic startle reflex (ASR) (
106,
107).
Acoustic startle reflex has been used to examine RS excitability non-invasively in stroke survivors (
17,
18,
108–
111).
In stroke survivors with cerebral infarcts normal, ASR responses could
be elicited in flaccid muscles in the acute phase, although no muscle
response to magnetic cortical stimulation of the primary motor cortex
was elicited in these subjects (
108).
This suggests that the circuit of ASR remained intact in these
patients. In chronic stroke, exaggerated ASR responses were observed in
spastic muscles (
109), indicating increased RS excitability. In a recent study (
17,
18),
ASR responses were examined in chronic stroke at different stages of
motor recovery (flaccid, spastic, and recovered). Exaggerated ASR
responses were observed only in spastic biceps muscles. Since motor
recovery has been arrested in chronic stage, such findings support the
important role of RS hyperexcitability in mediating poststroke
spasticity. Given its role in maintaining joint position and posture
against gravity (
112),
RS hyperexcitability and its anti-gravity effect is expected to lead to
a new neuromuscular balance, reflecting a shift in reference
configuration after stroke (
113,
114).
This new balance could be reflected by a change in the resting angle of
a joint. Bhadane et al. recently found that there were strong
correlations between the resting angle of the elbow joint and severity
of spasticity as reflected by clinical (MAS and Tardieu R1 angle) and
biomechanical (reflex torque) measurements (
115). Pharmacological agents acting on serotonin, the primary neurotransmitter for RS pathways, could either increase (
49) or decrease (
50) spasticity. Collectively, emerging evidence supports the important role of RS hyperexcitability in poststroke spasticity.
Possible Roles of RS Hyperexcitability in Motor Recovery
Contributions
to motor recovery from ipsilesional and contralesional cortical
reorganization through spontaneous recovery and facilitation and
modulation of cortical plasticity are well recognized, as stated above.
In contrast, RS hyperexcitability has been viewed consistently to play a
major role in spasticity from both animal and human studies. The role
of neural plasticity at the subcortical and bulbospinal pathways in
motor recovery has been suggested from animal studies but remains
controversial in human studies. In general, recovery of motor function
after stroke depends on structural integrity, including both CST and RST
(
66,
116–
118).
Findings
from recent animal studies suggest the potential role of existing
descending bulbospinal pathways, particularly RS projections to spinal
interneurons and motoneurons (
23,
26–
29,
36). Riddle and Baker (
29)
reported that RS (descending from medial brainstem) and corticospinal
pathways descended in parallel and had largely overlapping effects on
spinal interneurons and motoneurons; importantly, responses from spinal
motoneurons to stimulation of either pathway at supraspinal levels were
of similar amplitudes during a reach and grasp task. The findings
suggest the important role of RST in the distal limb muscles, in
addition to its known contribution to proximal limb muscles (
30). Buford and colleagues also reported significant RS contributions to motor output (
35) and motor recovery (
36). The rubrospinal tract descending from the lateral brainstem is almost absent in humans (
101).
In the context of damage to M1 and/or corticospinal pathways,
strengthening the existing intact RS projections is thus plausible to
compensate for the damage as demonstrated in these animal models (
29,
32,
33,
35,
36).
The
possible role of RS pathways in motor recovery after the corticospinal
(CST) damage as result of a stroke in humans has been controversial (
37,
38).
Recently, Byblow and colleagues recommended that the importance of the
cortico-reticulo-spinal pathway needs to be considered before using
non-invasive brain stimulation to suppress contralesional motor cortex
excitability because it may contribute to motor recovery, particularly
in patients with severe paresis (
37). However, they agreed with previous reports (
58,
59,
62,
63)
that suppression of contralesional cortical excitability is beneficial
for those with less motor impairment. This view is further supported by
findings of another recent study (
38).
Auditory stimulation improves motor performance of wrist extension in
chronic stroke patients with spasticity and severe paresis (spastic
paresis), but not in patients with more spasticity and relatively less
paresis (spastic co-contraction) or with minimal paresis. The main
mechanism is thought to be stimulation of RS pathway
via auditory stimulation (
38,
119,
120).
Taken together, these studies in stroke survivors suggest that RS
hyperexcitability and spasticity are phenomena of maladaptive changes in
the course of motor recovery (
19), and the role of RS hyperexcitability depends on the severity of motor impairments.
The findings (
38)
further suggest that RS pathway plays different roles at different
stages of motor recovery, likely because of its potential role in
spasticity after stroke. Individualized rehabilitation protocols
utilizing RS pathways could be developed to facilitate motor recovery in
some patients. In patients with severe motor impairment and spasticity,
RS pathway activation
via auditory stimulation training (
38) may contribute to gross motor strength
via synergistic activation (
121),
thus improving motor performance. However, such synergistic activation
is not likely to improve performance of isolated wrist extension in
patients with spastic co-contraction in both wrist flexors and extensors
or in patients without spasticity (
38).
Furthermore, motor recovery after stroke follows a predictable pattern,
from flaccid to spastic and to recovered stages. Auditory stimulation
training
via activation of the RS pathway (rhythmic cueing, music therapy, etc.) (
38,
122–
125)
may be recommended for use in patients with severe motor impairment and
in acute and subacute phases; as such, this intervention could
potentially facilitate the progress of motor recovery after stroke,
i.e., moving through the recovery stages faster in some patients.
An Example of Spasticity Reduction for Facilitation of Motor Recovery
Spasticity
is an important milestone in the course of motor recovery. It emerges
and disappears as the recovery progresses. In chronic stroke when motor
recovery is plateaued or arrested, e.g., spastic stages (Brunnstrom
stages 2–5), spasticity usually leads to synergistic patterns of
abnormal movement and impaired motor control (
39,
41,
126).
A stroke survivor actually flexes the fingers in an attempt of
voluntary finger extension, due to abnormal co-activation of spastic
finger flexors overriding weak finger extensor muscles (
127).
In a study examining arm pointing movements to different targets on a
horizontal surface, Levin reported that stroke subjects with severe
spasticity were able to plan and move the arm to all parts of available
workspace, but their actual movement was deviated from smooth straight
lines with increased dispersion and segmentation (
128).
The results demonstrate deficits in inter-joint coordination of
activation of spastic muscles in spastic stroke survivors. Hemiplegic
stroke survivors could accurately perceive and reproduce a force within a
limb either by the spastic-paretic limb or contralateral limb (
129). Force produced by one limb could not be accurately perceived by the contralateral limb in hemiplegic stroke survivors (
130). Interactions between two limbs are altered (
17,
18,
131).
Impaired motor control in spastic stroke survivors is related to
spontaneous firing of motor units and involuntary control of activation
of spastic muscles (
13,
14,
16), possibly caused by RS hyperexcitability (
19).
On the other hand, it is also important to point out that spasticity
could be beneficial in the lower extremity. For example, spasticity in
quadriceps may help stabilize the knee joint during the stance phase and
thus help transfers.
Understanding of these two separate
mechanisms underlying motor recovery and spasticity and of the role of
spasticity in impaired motor control is critical for its successful
management. Aggressive management of spasticity with botulinum toxin
(BoNT) in carefully selected muscles can purposefully reduce involuntary
activation of spastic muscles, thus to improve voluntary control of
movement and motor function. BoNT blocks the release of acetylcholine
presynaptically at the neuromuscular junction and transiently weakens
the muscle (
132).
BoNT injection induces synapse plasticity of muscular afferents and
generates synaptic plastic reorganization at spinal motor neurons and
interneuron system and beyond. As such, the central effect of BoNT
therapy converts the neuromotor system into a transient labile state (
133).
This allows regrowth or strengthening of appropriate synapses and
suppression of inappropriate ones, i.e., neural plasticity and motor
re-learning, if coupled with sustained activity-based, goal-oriented
training programs (
134).
This is particularly important for motor recovery in chronic stroke
when motor recovery is usually plateaued or arrested. For example,
injection of BoNT to spastic finger flexors weakens grip strength as
expected, however, the patient is able to release her grip better with
decreased co-activation from finger flexors and, therefore, to engage
the spastic-paretic hand more in bimanual tasks (
135).
Similarly, suppression of involuntary activation of periscapular
muscles improves arm function and thus activities of daily living (
136). This concept of “therapeutic weakness” is further supported by a recent study (
137).
After BoNT injection to elbow, wrist, and finger flexors, spastic
hemiparetic stroke survivors are able to perform reaching (elbow and
wrist extension) tasks better. The authors have attributed this
functional improvement to better voluntary control of antagonists
(extensors), despite of weakness of injected flexors.
Concluding Remarks
Neural
plasticity is an important process mediating substantial recovery of
motor function after stroke. However, some changes may be maladaptive.
The RS hyperexcitability is the most plausible mechanism for spasticity,
while recovery of strength and motor function is mainly related to
cortical reorganization. It is important to differentiate and understand
that motor recovery and spasticity have different mechanisms.
Facilitation and modulation of neural plasticity through rehabilitative
strategies, such as early interventions with repetitive goal-oriented
intensive therapy, appropriate non-invasive brain stimulation, and
pharmacological agents are the keys to promote motor recovery after
stroke. Individualized rehabilitation protocols could be developed to
utilize or avoid the maladaptive plasticity, such as RS
hyperexcitability in the course of motor recovery. Aggressive and
appropriate spasticity management with BoNT therapy is an example of how
to create a transient plastic state of the neuromotor system that
allows motor re-learning and recovery in chronic stages.
