# The Role of Noninvasive Techniques in Stroke Therapy

Authors: Daniel Maxwell Bernad; Julien Doyon
Journal: International Journal of Biomedical Imaging
 (2008)

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## Abstract

Noninvasive techniques such as functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) have provided insight into understanding how neural connections are altered in consequence to cerebrovascular injury. The first part of this review will briefly survey some of the methodological issues and limitations related to noninvasive poststroke motor recovery studies. The second section will investigate some of the different neural mechanisms that underlie neurorehabilitation in stroke patients. The third part will explore our current understanding of motor memory processing, describe the neural structures that subserve motor memory consolidation, and discuss the current literature related to memory reconsolidation in healthy adults. Lastly, this paper will suggest the potential therapeutic applications of integrating noninvasive tools with memory consolidation and reconsolidation theories to enhance motor recovery. The overall objective of this work is to demonstrate how noninvasive technologies have been utilized in the multidisciplinary field of clinical behavioral neuroscience and to highlight their potential to be employed as clinical tools to promote individualized motor recovery in stroke patients.


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## Body

## 1. Introduction and Outline

Stroke is a debilitating disorder that
has the potential to cause substantial sensory, motor, and cognitive impairment.
Roughly half of all stroke victims will
have some degree of residual motor impairment [1], becoming partially dependent
for performing activities of daily living [2].
Acute stroke onset, usually defined as the first six to twelve hours
following the interruption of blood supply to neurons, results in a core of
dead neurons surrounded by a penumbra where neural tissue remains dysfunctional.
If blood flow is not reinstated, the neurons within the penumbra will die and
clinical deficits will tend to stabilize. Research efforts have focused on
understanding the mechanisms that subserve plasticity or functional
modifications in consequence to neuronal damage. Modifications in neural
connections and networks are believed to result from cellular or synaptic
changes in neuronal functioning following injury. To this extent, a framework describing
neurorehabilitation can be conceptualized from a cellular, systems, and
behavioral perspective [3]. For example, changes that occur at a cellular level
can initiate different molecular mechanisms such as engaging remyelination. Adaptation
that arises at a systems level can involve the recruitment of new neural
regions, which can activate the same final output pathway. In addition, behavioral
level changes can result from enhanced motivation or altered cognitive
strategies to regain function by completing a particular motor task [3]. Diagnostic
tools that can detect early stroke onset is crucial for neuronal survival and
provides clinicians and rehabilitation specialists with a wider range of treatment
options, which ultimately is more effective in helping patients recover motor
function.Recent advances in noninvasive
imaging techniques have enabled physicians to diagnose stroke at an earlier
point in time and have provided greater comprehension of the changes in neural
activity that transpire after stroke [3]. In particular, the application of functional
magnetic imaging (fMRI) and transcranial magnetic stimulation (TMS) has
provided a better understanding of the neural substrates that subserve
recovery. The first part of this review article will briefly survey some of the
methodological issues and limitations related to noninvasive poststroke motor
recovery studies. The second section will investigate some of the different
mechanisms that underlie neurorehabilitation in recovering stroke patients. The
third part will explore our current understanding of procedural memory
processing and explore some of the neural regions that subserve motor memory
consolidation and recent studies on reconsolidation in human subjects. Lastly,
this article will explore some of the potential applications of integrating noninvasive
tools with memory consolidation and reconsolidation theories to promote motor
recovery. The overall objective of this work is to
provide a better understanding of the compensatory mechanisms that are involved
in poststroke motor recovery and neural regions engaged in motor memory
formation in healthy adults, to demonstrate how noninvasive technologies have been
utilized in the multidisciplinary field of clinical behavioral
neuroscience, and to highlight their potential to be employed as clinical tools
to promote individualized motor recovery in stroke patients.


## 2. Patient-Related Limitations Associated with Imaging Techniques

There are many important patient-related
limitations to consider when using MRI. For example, in addition to general MRI
contraindications (e. g., pacemaker, metallic implants, etc.), acute stroke (i.e.,
stroke onset within 24 hours) patients are more easily agitated, are medically
unstable in consequence to underlying haemodynamic issues,
are more likely to have a diminished level of consciousness associated with
vomiting (i.e., increased risk of aspiration), and usually have other
coexisting medical problems [4, 5]. In consequence to these issues and in order
to investigate the neural mechanisms that drive recovery over and above the
spontaneous time-dependent process, most fMRI studies are performed on the
chronic (i.e., at least three months after stroke onset) stroke patient
population and thus generalization may be limited to this cohort.Another important patient-related
methodological issue to consider is that fMRI studies may be confounded because
when patients with vascular lesions are compared with normal controls, the
blood oxygenation-level-dependent (BOLD) signal may reflect the underlying
diseased hemodynamics and not differences in cortical activation. For example,
the BOLD signal captured in recovering stroke patients is typically delayed and
lower in amplitude, which could reflect disruptions in neurovascular coupling
due to diffuse vascular disease [6].


## 3. fMRI Methodological Issues

Despite such limitations related to
the patient population, fMRI offers excellent spatial (i.e., few millimeters) and
temporal (i.e., few seconds) resolution [7–9]. In addition, early poststroke
motor recovery fMRI studies have been designed as cross-sectional experiments
that compared neural changes in fully recovered stroke patients and normal
controls at a single point in time [7–9].
Such experiments have been limited because they do not show changes in
neural activity throughout the duration of the recovery process. Recently, longitudinal
studies have been designed to investigate neural activity in patients recovering
from stroke over an extended period of time [7–9]. Such studies have allowed investigators to
correlate changes in neural activation with specific motor gains during the
recovery process.Most studies have used a block
design, whereby data is acquired in correlation to a distinct cognitive state (i.e.,
during a behavioral task) and then compared to a control period [7]. However, recent experiments have employed event-related
design, whereby data is acquired during the repetition of discrete stimuli or
responses (i.e., finger tapping task). In comparison to block design, the event-related
paradigm has a longer acquisition time, but has certain advantages such as
providing the option of using either periodic or randomized stimuli. Both block-
and event-related designs enable continuous data collection usually with a repeat
time of 2–5 seconds [7]. Such parameters
must be taken into consideration in order to optimize data acquisition and
derive meaningful results.


## 4. TMS Methodological Issues

TMS uses a strong but transient magnetic
field that induces an electric current in the underlying cortical tissue
[10, 12, 13]. Repetitive TMS involves repeated stimuli at
intervals of 1–50 Hz for periods that range from 1–30 minutes [10, 12, 13].
Regular stimulation at low frequencies (up to 1 Hz) can inhibit cortical
activation, whereas higher frequencies can stimulate cortical activity. TMS has
been used to map functional cortical regions and inhibit or stimulate neural
activity [10, 12, 13].
TMS is an excellent noninvasive instrument because it is of
low cost, multifunctional, and relatively safe to the patient [10, 12, 13].


## 5. Neural Substrates That Underlie Compensatory Mechanisms

Through the implementation of noninvasive techniques such as
fMRI, investigators have been able to explore the neural regions that subserve
compensatory mechanisms in recovering stroke patients. One important
observation is that the integrity of the corticospinal tract, the main pathway
from the cortical motor regions through the spinal cord to the muscles,
correlates with functional motor recovery [14].
For example, Heald et al. [15] conducted a longitudinal study to
evaluate the neurophysiological measurements of central motor conduction time (CMCT)
immediately after stroke onset. They showed that normal or delayed CMCT
correlated with a higher probability of survival and motor recovery. In
addition, they found that patients
with the poorest functional recovery at twelve months and greatest probability
of stroke-related death responded least to intial cortical stimulation. In
corroboration, Fujii and Nakada [16] demonstrated that the integrity of the ipsilesional
sensorimotor cortex and corticospinal tract play an important role in motor
recovery. They conducted an fMRI study in which they demonstrated that the rate
of motor recovery, but not the absolute level of motor function, correlated
with patterns of activation that were observed after subcortical stroke. Patients that recovered quickly, defined as within
one month poststroke, showed similar patterns of activation in comparison to
controls. However, patients that recovered more slowly, defined as within the
end of the third month poststroke, showed greater activation in contralesional
sensorimotor and supplementary motor areas. These studies suggest that patients
with sufficient ipsilesional sensorimotor cortex and corticospinal tract
integrity regain motor function more rapidly in comparison to patients with
signifcant lesions.There is also evidence that secondary
cortical motor networks may play an important role in motor recovery. It has been suggested that motor function may
be facilitated by projections from secondary motor regions and neural fibers
originating in the primary motor region (M1), premotor cortex (PM), and
supplementary motor area (SMA), which constitute parallel-independent motor networks with separate
projections to spinal cord motor neurons and cortical regions [8, 17]. This
implies that parallel motor networks could compensate for one another in
consequence to neural damage [8]. In addition,
Johansen-Berg et al. [20] illustrated through constraint-induced movement therapy
(CIMT) that improvement in hand function correlated with increased fMRI
activity in the ipsilesional premotor and somatosensory cortex; and Miyai et al.
[21] reported increased ipsilesional premotor cortical (PM) activity in
correlation with therapy-induced improvement in gait function.Although such work does not
directly prove that secondary motor regions subserve motor recovery, the
application of TMS has been used to address this hypothesis more directly. Fridman
et al. [22] applied TMS to four chronic stroke patients with focal subcortical
lesions and showed that inhibition of the ipsilesional dorsal PM resulted in delays
in a simple reaction time task, whereas TMS targeted to the contralesional dorsal
PM of patients or in normal controls did not. In addition, Johansen-Berg et al.
[23] showed that transient interference of the dorsal PM with TMS was more
disruptive in patients with greater injury. In corroboration of both studies,
Ward et al. [24] demonstrated that impaired functional integrity of the
corticospinal system is associated with recruitment of bilateral secondary
motor networks. Together, such work suggests that both secondary motor regions may
also represent a compensatory pathway in motor recovery.It is well established that the ipsilesional
primary motor cortex plays an important role in motor recovery. The evidence
surrounding the role of contralesional motor cortex remains controversial;
however Chen et al. [25] demonstrated that temporarily inhibiting the
contralesional M1 results in errors in both complex and simple motor tasks,
suggesting that this region may play a role in planning and organizing motor
movements [20]. In contrast, Johansen-Berg et al. [20] showed that disruption
of the contralesional M1 using TMS does not impair performance in simple motor task,
hence raising questions whether it subserves recovery after stroke. They also found
that patients with moderate or poor outcome activate unaffected contralesional
cortical motor regions more than those who recovered better. Furthermore, Murase et al. [26] has proposed that
contralesional M1 may impair recovering motor function in patients with small
subcortical stroke through interhemispheric inhibitory projections on
ipsilesional M1 during attempted voluntary movement of the affected hand. More
work is still needed, however, to better understand the role of the contralesional
M1 in motor recovery.Longitudinal studies have been
designed to investigate the dynamic changes in neural regions in correlation to
motor recovery. Calautti et al. [27] found that patients had greater bilateral
activation in the sensorimotor region during paretic hand movement early after
stroke onset in comparison to normal controls, but this pattern normalized in
association with regained motor function (~ 8 months poststroke). In addition, Feydy
et al. [28] demonstrated patterns of activation correlated with location of
stroke-induced lesions. They showed that after initial recruitment of bilateral
areas, activation gradually shifted towards the ipsilesional sensorimotor
cortex. Ward et al. [29] showed that patterns of activation increased in the
sensorimotor area in stroke patients during paretic hand movement early after
stroke onset, but this trend decreased toward a normal pattern in correlation
with motor recovery. In addition, Zemke et al. [30] used fMRI to study
recovering subcortical stroke patients while they performed a hand-grip task over
six months. They found an initial overactivation within the primary and secondary
motor regions, and characterized a focusing of task-related brain activation
towards a more “normal” lateralized pattern. Taken together, these studies
suggest that normalization of activation in the sensorimotor network, following
early increased activation, also correlates with better motor recovery after
stroke.Other quantitative indices have demonstrated
changes in neural activity in correlation to motor recovery. For example,
Cramer et al. [31] showed that recovered stroke patients had a significantly
lower laterality index (LI) = (C−I)/ (C+I), where C = contralesional and I = ipsilesional
regions, in comparison to controls. The LI can range from +1, which is
exclusively ipsilesional, to −1, which is exclusively contralesional. Other studies
have also shown that normalization in the LI shifts towards the ipsilesional sensorimotor
networks in correlation with motor recovery after stroke [6, 32]. In addition, Marshall
et al. [33] demonstrated the laterality of activation in primary sensorimotor
cortex during paretic hand movement shifted towards the contralesional
hemisphere within the first week of stroke onset but returned back to the
ispsilesional hemisphere in correlation to good motor recovery (~ three to six
months after stroke onset). Jang et al. [34] showed that motor recovery (5–15
months poststroke) is
correlated with a shift in laterality of primary sensorimotor cortex activation
during paretic hand movement from nearly bilateral to strongly ipsilesional. These
studies suggest that normalization of sensorimotor cortex laterality is again linked
to good recovery of motor function after stroke.


## 6. Neural Substrates of Motor Memory Formation

Neural regions that are re-engaged after
injury afford an evolutionarily adaptive process to provide a pathway for continued
motor output. Similar functional plasticity is also observed in the procedural
memory system. For example, after learning a sequence of finger movements (i.e.,
finger-to-thumb opposition task), the motor trace is believed to be processed
offline, characterized by at least two distinct stages; an initial (i.e.,
within a single training session) fast learning stage measured by significant
improvements in task performance, followed by a slower stage where further
gains transpires over several sessions [35–38]. Within 6–8 hours an initially
labile motor trace becomes resistant to interference from various amnesic
agents (i.e., learning another motor sequence task) and eventually persists despite
periods without practice. The process by which newly learned motor information is
transformed from a labile state into a robust memory trace is referred to as
consolidation and is subserved by specific neural structures and networks
[35–38].Noninvasive
imaging techniques have been used to investigate the neural regions that
participate in motor memory processing and consolidation. For example, Karni et
al. used fMRI to study the changes in BOLD signals underlying motor skill learning
[38]. They showed that after weeks of practicing finger-to-thumb sequences
within a brief period of time, there was a noticeable enhancement of activation
of the M1 region, which persisted for several months, and further suggests that
motor sequence learning is subserved by a slowly evolving long-term experience
dependent reorganization of the primary motor cortex. In addition, Shadmehr and
Holcomb used fMRI to study the underlying neuroanatomical correlates of
short-term motor skill learning [39]. They showed that during the earlier
stages of motor learning there is a shift from prefrontal cortical regions to
the premotor cortex, posterior parietal, and cerebellar structures. Both
studies highlight that motor memory processing is subserved by functional
reorganization of neural regions.It has also been proposed that procedural memories can undergo a higher level
memory formation process, referred to as system consolidation, whereby over
longer periods of time, which can range from days to years pending on memory
system, newly learned information is transferred from one neural processing
region to another location for long-term storage [40]. For example, Doyon and
Ungerleider [41] proposed that during the fast-learning stage, defined as a
noticeable improvement in performance within a single training session, the
corticocerebellar (CC) and corticostriatal (CS) systems are engaged pending on
the motor skill learning task. However,
when a motor sequence or adaptation task is well learned, the neural
representations are thought to be distributed in one of two circuits, whereby
the CS pathway supports the new motor sequence trace and the CC subserves motor
adaptation [41, 42]. This theory was recently revised to incorporate findings
that suggest that cerebral functional plasticity exists within the striatum and
cerebellum in the later stages of motor sequence learning and motor adaptation,
respectively [35]. For example, a 3T fMRI study that tracked motor sequence
learning within the basal ganglia circuitry and motor-related structures showed
improvements in task performance correlated with a change in signal from the
associative to sensori-motor regions within the putamen, which suggests that
this switch or transfer of information is functionally important for a motor
memory trace to persist with time [43]. Understanding the neural regions that
are engaged in motor memory formation may provide further insight into ways to
enhance motor recovery in stroke patients.Although noninvasive imaging techniques have provided much insight into the neural
regions that underlie memory consolidation, our overall assumption that this
process is permanent has been challenged [44–46, 49]. Misanin
et al. used electroconvulsive shock treatments (ECST) to show that memory could
be disrupted when in transition from a stored to an active state [45]. The
process by which consolidated memories become labile and require stabilization
after reactivation is now referred to as reconsolidation [44]. More
recently, Nader et al. showed that the reactivation of a consolidated fear
memory requires de novo protein
synthesis in order for such information to persist with time [46]. Debiec et
al. further expanded on these findings by demonstrating that hippocampal-dependent
memories undergo both reconsolidation within the hippocampus, referred to as
cellular reconsolidation, and at a second level of processing termed systems
reconsolidation [47].Whereas most work characterizing the reconsolidation of reactivated, once well
consolidated, memories have been performed mostly on animals, there are ample
publications showing the reconsolidation effect in human subjects. For example,
Rubin reported that all twenty-eight psychiatric patients that received
ECST after recall or recurrence of their psychiatric symptoms dramatically
improved, some being symptom free when interviewed ten years after treatment
[48]. In addition, Walker et al. utilized a motor skill finger tapping paradigm
to show that overnight improvements in accuracy were significantly lost when a
second interference trace (i.e., from a competing sequence task) was learned
immediately after reactivating the first motor trace [49]. They showed that reactivating
that trace one day after learning brought the trace back into a labile state
that became sensitive to disruption from the interference trace. Although they
failed to show the effect on their main dependent variable (i.e., the speed at
which sequences are executed in a 30-second period), this study provides the
first evidence that the reactivation of a stable and well-consolidated motor
memory brings certain components back again into a labile state. More recently,
Hupbach et al. showed in a group of college students that providing subjects
with a reminder enhanced recall twenty-four hours after the reactivation of a
consolidated list of items [50]. The latter finding suggests that
reconsolidation may have a constructive effect on episodic memory processing. Although
more work is necessary to further characterize and identify the boundary
conditions associated with reconsolidation, it may be feasible to apply reconsolidation
theory to enhance neurorehabilitation in stroke patients undergoing physical
therapy.


## 7. Future Implications for Novel Therapy

How can our understanding of the
neural substrates that subserve post-stroke compensatory mechanisms and
procedural memory formation in healthy adults assist in clinical therapy? To a
certain extent, most neurorehabilitation therapies consist of training patients
how to perform previously learned tasks in a different way [3]. For example, arm
ability training was developed for patients with mild hemiparesis and maximizes
the retention and generalization of what is learned during the rehabilitation
session through varying the difficulty of repetitive motor tasks [51, 52]. In
addition, another behavioural therapy mentioned previously is CIMT, which has
two components that are administered over two weeks. For example, the patient
overcomes learned nonuse of the less functional extremity by practicing motor
tasks for six hours per day while simultaneously restraining the use of the
more functional extremity for 90% of the patient’s waking hours [52].In both of these training protocols, success
relies on learning novel ways to regain lost motor functions, which requires
learning new procedural movements that are mediated by similar neural regions
that drive procedural memory formation. Therefore, it is plausible that manipulation
of these regions may enhance neurorehabilitation. For example, it has been
proposed that the application of TMS to the nonaffected hemisphere could be
employed to disrupt the interhemispheric inhibition that has previously been
described [52–56]. In addition, TMS could also be used to target the
affected hemisphere in order to stimulate regions that are damaged or enhance the
neural substrates that underlie motor memory formation [52]. Although speculative,
it is conceivable that inhibiting the reconsolidation of a nonfunctional motor
memory trace via TMS may help a patient learn how to use a corresponding
unaffected limb. Moreover, this may be facilitated through simultaneously
enhancing the underlying neural substrates that promote forming functional
motor memory traces via TMS. These procedures could be used in concert with other
neurorehabilitation therapies in order to reprogram novel motor movements.Numerous variables such as the
neuroanatomical regions affected, the period of time since injury, and the patients’
previous experiences will all influence the neural substrates that are engaged
after stroke [3, 8]. Thus, another potential application of fMRI could be used as a clinical tool
to identify a patient’s specific type of neurocompensatory mechanism. This could enable physicians and rehabilitation
specialists to tailor their treatment strategy to more accurately address their
patient’s individual needs and requirements.


## 8. Conclusion

This review surveyed some of the literature which has examined the application of fMRI and TMS to study the neural
substrates that underlie compensatory mechanisms in both stroke recovery and the
neural regions that drive procedural memory formation in healthy adults.
Although more work is necessary to further understand the mechanisms that subserve
neural plasticity, the current literature suggests that specific
neuroanatomical regions can be identified with fMRI and be stimulated or
inhibited with TMS to cause functional changes in motor output. Such noninvasive
tools may one day be more routinely applied to promote neurorehabilitation to
benefit patients recovering from poststroke motor impairments.



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