Neural Plasticity
Volume 2020 (2020), Article ID 9484298, 12 pages
https://doi.org/10.1155/2020/9484298

Review Article

Neurobiology of Recovery of Motor Function after Stroke: The Central Nervous System Biomarker Effects of Constraint-Induced Movement Therapy

Auwal Abdullahi,1,2 Steven Truijen,² and Wim Saeys²

¹Neurological Rehabilitation Unit, Department of Physiotherapy, Bayero University Kano, Nigeria
²Department of Rehabilitation Sciences and Physiotherapy, University of Antwerp, Movant, Wilrijk, Belgium

Correspondence should be addressed to Auwal Abdullahi; aabdullahi.pth@buk.edu.ng

Received 1 January 2019; Revised 25 February 2019; Accepted 31 October 2019; Published 15 June 2020

Academic Editor: Eckart Altenmüller

Copyright © 2020 Auwal Abdullahi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Recovery of motor function after stroke involves many biomarkers. This review attempts to identify the biomarker effects responsible for recovery of motor function following the use of Constraint-Induced Movement Therapy (CIMT) and discuss their implications for research and practice. From the studies reviewed, the biomarker effects identified include improved perfusion of motor areas and brain glucose metabolism; increased expression of proteins, namely, Brain-Derived Neurotrophic Factor (BDNF), Vascular Endothelial Growth Factor (VEGF), and Growth-Associated Protein 43 (GAP-43); and decreased level of Gamma-Aminobutyric Acid (GABA). Others include increased cortical activation, increased motor map size, and decreased interhemispheric inhibition of the ipsilesional hemisphere by the contralesional hemisphere. Interestingly, the biomarker effects correlated well with improved motor function. However, some of the biomarker effects have not yet been investigated in humans, and they require that CIMT starts early on poststroke. In addition, one study seems to suggest the combined use of CIMT with other rehabilitation techniques such as Transcortical Direct Stimulation (tDCs) in patients with chronic stroke to achieve the biomarker effects. Unfortunately, there are few studies in humans that implemented CIMT during early poststroke. Thus, it is important that more studies in humans are carried out to determine the biomarker effects of CIMT especially early on poststroke, when there is a greater opportunity for recovery. Furthermore, it should be noted that these effects are mainly in ischaemic stroke.

1. Introduction

Stroke is a leading cause of long-term disability. It is a neurological deficit due to impaired blood supply to the brain areas caused by ischaemia or haemorrhage or occasionally both [1, 2]. Impaired blood supply to the brain results in a cascade of pathological processes that disrupt neurophysiological mechanisms and expression of Central Nervous System (CNS) biomarkers that eventually cause neuronal cell injury or death. When neuronal cells are injured, they discharge cytotoxic molecules that further injure or damage other apparently healthy neuronal cells [2–4]. This in turn creates a vicious cycle of cell injury and/or death that cause impairments in brain functions such as motor, sensory, and cognitive functions. Therefore, preventing or reducing the disruption of neurophysiological mechanisms and expression of CNS biomarkers by these pathological processes should be the target of treatment and rehabilitation following stroke. This may help prevent neuronal cell damage, improve neuronal cell homeostasis, and restore functions of the CNS.

One of the most promising rehabilitation techniques used for recovery of motor function after stroke is Constraint-Induced Movement Therapy (CIMT). The CIMT is a technique that comprises of massed task practice with the affected limb, constraint of the unaffected limb, and transfer package [5–7]. It has been reported to improve the use of limbs in daily activities and improve the quality, quantity, and precision of movement [8, 9]. However, these findings relate to the system or functional level of the nervous system. According to Cohen, to effectively understand the functions of the nervous system, it needs to be studied at the molecular and functional levels, and possibly also at other sublevels between them [10]. Consequently, current evidence has shown that repetitive functional activity or modulation of afferent inputs can induce growth, modification, degradation, and death of neuronal cells which can help the CNS to recover from injury [11, 12].

In practice, however, understanding the precise biomarkers of the process of recovery after stroke may be difficult due to differences in patients’ presentations and the recovery processes [13]. The aim of this article is to review some of the CNS biomarkers CIMT targets after stroke and their correlations with motor function outcomes in both humans and animals (since animal studies serve as basic foundations for studies in humans). This will help us further understand the biomarkers of motor recovery following stroke, and possibly help researchers and clinicians identify the type of patients CIMT is more suitable for. A biomarker can be a gene, a naturally occurring molecule, or a particular characteristic by which a physiological or pathological process or disease can be identified [14]. It includes imaging biomarkers that are identified using computed tomography, positron emission tomography, transmagnetic stimulation, and magnetic resonance imaging; and molecular biomarkers such as a particular protein or gene expression [15–17]. The search engine PubMed was used using the search term Constraint-Induced Movement Therapy. The biomarkers extracted from the CIMT studies obtained from PubMed were further searched on Google Scholar in order to obtain more information. The characteristics of some of the reviewed studies in humans are presented in Table 1.

Table 1: Characteristics of some of the reviewed studies.

Study
Design
Stage of stroke

Duration of therapy
Constraint
Additional therapy
Outcome measures

Wang et al. (2012)
Self-control experiment
Subacute
5
CIMT for 4 hours, 20 minutes, 5 times a week for 4 weeks
Nil
4 hours of lower limb loading exercise (Bobath) divided into 2 sessions per day for 6 weeks
MWS, BBS, fMRI

Blicher et al. (2014)
Clinical controlled trial
Subacute and chronic
41
CIMT for 2 weeks in the experimental group
Mitt for 90% of waking hours
Nil
WMFT, MRI, mRS

Könönen et al. (2005)
Pretest
Posttest
Chronic
12
CIMT for 6 hours per day for 10 days
Lightweight sling worn during the exercise and for 10 hours per day
Nil
WMFT, MRI, SPECT

Di Lazzaro et al. (2014)
RCT
Acute
14
40 mins and 30 s tDCs for experimental and control groups, respectively, for 5 days
Resting sling for 90% of waking hours
Standard physical therapy protocol
9HPT, MAL, NIHSS (motor), hand grip, mRS

Rijntjes et al. (2011)

Chronic
12
6 hours of CIMT/day for 2 weeks
Splint for 90% of the waking hours
Nil
Same as above plus TMS

Boake et al. (2007)
RCT
Acute
23
3 hours of CIMT and traditional therapy for CIMT and control groups, respectively
Constraint for 90% of the waking hours

FM, TMS, GPT, MAL

Chouinard et al. (2006)
Pretest
Posttest
Chronic

4 hours of CIMT for 2 weeks
Wearing of mitt at home
Nil
TMS/PET

Ro et al.(2006)
RCT
Acute
8
3 hours of CIMT and traditional therapy, respectively, 6 days a weeks for 2 weeks
Constraint for 90% of the waking hours
Nil
TMS, MAL

Key: MWS=Mean walking speed; BBS=Berg balance scale; fMRI=Functional magnetic resonance imaging; SPECT=Single-photon emission computerized tomography; fMRI=functional magnetic resonance imaging; FM=Fugl Meyer; ARAT=action research arm test; WMFT=Wolf motor function test; MAL=motor activity log; MRI=magnetic resonance imaging; mRS=modified Rankin scale; 9HPT=nine-peg hole test; NIHSS=National Institute of Health Stroke Scale; TMS=transmagnetic stimulation; PET=positron emission tomography; GPT=groove peg test.

2. The Biomarker Effects of CIMT

2.1. Increased Perfusion (Cerebral Blood Flow) of Motor Areas

Cerebral blood flow (CBF) is important to help maintain an adequate supply of oxygen and glucose to the brain [18, 19]. Glucose and oxygen are essential for the growth, maturation, and functions of neurons [19]. An adequate supply of glucose is an important factor for cerebral metabolism which is also a major determinant of CBF [18, 20, 21]. CBF decreases shortly after stroke, and this disrupts the relationship between CBF and cerebral blood volume [18, 22, 23]. Additionally, decreased CBF results in hypoperfusion and inadequate supply of oxygen and glucose to the brain, following which neurons begin to get damaged or die [18]. CIMT can, however, help increase perfusion in the motor areas of the brain. According to Könönen et al., CIMT results in increased perfusion of motor areas in both the affected and nonaffected hemispheres [24]. In the affected hemisphere, the areas with increased perfusion were the precentral gyrus, superior frontal gyrus, premotor cortex, and frontal cortex; whereas in the unaffected hemisphere, the areas were the cingulate gyrus and frontal gyrus. The areas in which there was increased perfusion receive and integrate information from sensory systems and plan movement execution [24, 25].

Similarly, increased cortical activation bilaterally following CIMT may serve as an indication of increased cerebral perfusion [26]. In addition, increased perfusion and cortical activation bilaterally may also serve as signs of an increased cortical map. When the cortical map increased in size by recruitment of nonaffected brain areas, motor function was observed to be significantly improved [27, 28]. Interestingly, increased perfusion following the use of CIMT was associated with gain in motor function [29]. However, this was a case report on children with hemiplegic cerebral palsy, and therefore, there is still a need to determine this association in patients with stroke. Furthermore, CIMT should start very early after stroke to help improve CBF since persistence of ischaemia up to 24 hours will lead to lesion expansion and subsequent neuronal cell damage [30, 31]. In humans, there is little evidence on the safety of the use of CIMT very early after stroke [32].

2.2. Improved Brain Glucose Metabolism

The brain exclusively uses glucose for energy metabolism which is supplied under normal circumstance by CBF [18, 19]. Metabolism on the other hand determines the direction of blood flow [15, 16]. In the brain, local blood flow regulation is significantly related to intracellular partitioning of glucose transport and metabolism [19]. The glucose supplied by CBF is also required to provide the precursors for neurotransmitter synthesis and the ATP to stimulate their actions [33]. These indicate that the whole process is a sort of positive feed forward mechanism in which improved glucose metabolism affects local CBF, and increased CBF provides the brain cells with oxygen and glucose necessary for their growth and function.

When there is increased CBF in motor areas, movement planning and execution improves [24]. In addition, the cerebral metabolic rate of glucose (CMRglu) is significantly correlated with functional recovery [34]. However, brain glucose metabolism is impaired after stroke [35]; and as this affects local CBF, brain cells will be deprived of essential nutrients such as glucose and oxygen. The deprivation of these vital nutrients can also be confounded by lack of glucose and oxygen stores in the brain [19, 36]. Therefore, the reduced delivery of glucose and oxygen during brain ischemia will cause ATP depletion, which will in turn trigger processes leading to cell death [37].

To improve glucose metabolism following stroke, CIMT has been used. According to Li et al., after two weeks of CIMT in animals, the CIMT group showed improved glucose utilization indicated by lower standardized uptake values (SUVs) in the ipsilesional cingulate, motor, and somatosensory cortices and in the anterodorsal hippocampus compared to the control group [38]. It was also noted that in the AcbCore shell and cortex insular of the contralateral hemisphere responsible for rewarding behaviour and motor control, there were higher SUVs in the CIMT group than in the control. Increase in glucose utilization improves brain functions, and in a brain with normal oxygen concentration, aerobic glucose oxidation is solely responsible for over 95% of ATP production [35]. Improved glucose metabolism can also determine the direction of CBF [19, 20], and following the use of CIMT, improved perfusion was noted in motor areas responsible for movement control [24]. However, studies are still needed in humans to determine whether CIMT improves brain glucose metabolism. Additionally, since metabolic changes including decreased glucose metabolism occurs within the first 24 hours after stroke [39], it is important that CIMT is started as early as possible after stroke to prevent further neuronal cell damage. However, this should be done with caution, as hyperglycaemia during acute brain ischaemia in animals has been shown to exacerbate brain injury [40, 41].

2.3. Increased Brain-Derived Neurotrophic Factor (BDNF) Expression

Following stroke in animals, production of neuroblasts, which are undifferentiated precursors of neurons, significantly increases especially in the subventricular zone (a structure in the lateral walls of the lateral ventricles) [42]. Differentiation and survival of these neuroblasts are promoted by the Brain-Derived Neurotrophic Factor (BDNF) [43, 44]. The BDNF is a secretory growth factor that supports the survival of existing neurons and promotes synaptogenesis and differentiation of new neurons [45–47]. When new neurons survive and differentiate, synaptic integration occurs [48, 49]. Unfortunately, during the acute phase of stroke (first day after stroke), the concentration of BDNF decreases and this is associated with low functional neurological status [50]. However, BDNF can be secreted in response to an activity [46, 51, 52]. For instance, in humans, a combination of two weeks CIMT and repetitive transmagnetic stimulation (rTMS) increased the concentration of BDNF and its precursor, matrix metalloproteinase-9 (MMP-9) in participants who were more than one month poststroke [53]. Similarly, in animals, CIMT alone increased the expression of BDNF [54]. In the animal study, CIMT started on the first day after stroke; whereas in the human study, it started more than a month after stroke. These findings seem to suggest that CIMT alone may be sufficient to increase the concentration of BDNF when it is administered very early poststroke. In the chronic stage, CIMT may need to be combined with neurostimulation techniques such as rTMS to increase the concentration of BDNF.

In addition, BDNF genotype has been shown to interact with rehabilitation intervention and functional status in patients with stroke [55]. This seems to suggest that BDNF may be an important biomarker for CIMT and that a particular group of patients who possess this allele may benefit more from CIMT due to their genetic predisposition. Thus, researchers need to characterize their patients in planning rehabilitation intervention using CIMT in order to know who will benefit the most. Researchers also need to possibly combine CIMT with other rehabilitation strategies/techniques for those groups of patients who are less likely to benefit from the sole use of CIMT due to their genetic predisposition. However, more studies in humans are needed to verify the potential effect of CIMT on BDNF concentration in people with stroke.

2.4. Decreased Level of γ-Aminobutyric Acid (GABA)

γ-Aminobutyric acid (GABA) is the dominant neurotransmitter in the human brain that has an inhibitory effect and is involved in the process of neuroplasticity [56, 57]. Following stroke, the delicate balance between it and the excitatory neurotransmitters, such as glutamate and aspartate, becomes disrupted [58, 59]. Glutamate and aspartate levels become raised in the first six hours, while GABA and glycine levels are at their peak after the first day following ischaemic injury [59]. From then on, GABA level may remain high or at its peak, suggesting that treatment or rehabilitation to reduce the level of GABA should begin very early after stroke.

Decreased GABA level is a precursor to long-term potentiation, an important cellular biomarker for nervous system activity and motor learning [60, 61]. Therefore, decreasing GABA level should be an important goal of rehabilitation. Accordingly, Blicher et al. reported a decreased level of GABA in relation to creatine after two weeks of CIMT in subacute and chronic stroke patients [56]. They also showed that the decrease had good correlation with improvement in motor function. The correlation between motor function and a decreased level of GABA could also be a result of improved brain glucose metabolism; CIMT has been shown to improve brain glucose metabolism [38]. Effective brain glucose metabolism is required to provide the precursors for synthesis of neurotransmitters [19]. Therefore, it is possible that CIMT results in increased synthesis of excitatory neurotransmitters such as glutamate which may counteract the dominant inhibitory effect of GABA in the brain. Reducing GABA-mediated inhibition resulted in improved forelimb function in mice [62]. However, this claim needs to be further determined or investigated. Additionally, the effect of CIMT on GABA after stroke requires further studies in humans.

2.5. Increased Expression of Growth-Associated Protein 43 (GAP-43)

Growth-Associated Protein 43 (GAP-43) is involved in the regulation of axonal outgrowth, synaptic plasticity, and learning and memory functions [63]. After an injury to the CNS such as stroke, there is upregulation of GAP-43 which occurs between seven days and three weeks after the ischaemic injury [64, 65]. The upregulation is positively related to long-term potentiation (LTP), which is a precursor for neural plasticity [66]. In an animal model, CIMT that was initiated on the first day poststroke resulted in increased expression of GAP-43 [54]. In contrast, CIMT performed seven days after stroke produced different results [54, 67]. In the study by Ishida et al., CIMT did not yield increased expression of GAP-43 [54]; but in the study by Zhao et al., it yielded increased expression of GAP-43 [67].

Possibly, the difference in the results of the two studies could be because of the types of stroke. Whereas in the study by Ishida et al. the stroke was due to subcortical haemorrhage induced by injection of collagenase, in the study by Zhao et al., the stroke was due to focal cerebral ischaemia induced by intracerebral injection of endothelin-1. Ischaemic stroke usually has a better outcome than the haemorrhagic type [68]. Therefore, since GAP-43 is normally upregulated seven days following ischaemic injury [65], early CIMT (starting on the first day after the ischaemic injury) may help raise GAP-43 level early on to help in the process of neural plasticity through induction of long-term potentiation. This is important since at approximately six days after ischaemic injury, lymphocytes and macrophages accumulate in the perivascular vicinity [69]. Accumulation of these cells may further damage neuronal cells. However, there seems to be no study as yet in humans reporting on the role GAP-43 has on the recovery of motor function in stroke following CIMT.

2.6. Increased Expression of Hypoxia-Inducible Factor-1α (HIF-1α) and Vascular Endothelial Growth Factor (VEGF)

In rats, CIMT performed for two weeks resulted in a significant increased total length of microvessels and number of bromodeoxyuridine+ (BrdU+)/NeuN+ double-labeled cells [70]. These changes correlated well with increases in Hypoxia-Inducible Factor-1α (HIF-1α) and Vascular Endothelial Growth Factor (VEGF) expressions and a decrease in Factor Inhibiting HIF-1α (FIH-1α) expression. Hypoxia-Inducible Factor-1α (HIF-1α) is a key regulator in hypoxia, and due to the functions of its downstream genes, it has been suggested to be an important player in neurological outcomes following ischemic stroke [71]. The downstream genes include those that promote glucose metabolism, angiogenesis, erythropoiesis, and cell survival [72, 73]. Additionally, HIF-1α is a key regulator of VEGF [74]. Furthermore, HIF-1α, VGEF, CBF, and glucose metabolism are part of the system that restores the oxygen supply to tissues when blood circulation is inadequate such as in hypoxic conditions like stroke [24, 38, 75]. This synergy may perhaps be the one that helps prevent cell death in stroke and improve CNS functions following the use of CIMT. However, it is not yet known whether these findings can be related to humans, as the effect of CIMT on HIF-1α and VGEF has not yet been determined in the human species.

2.7. Downregulation of Phosphorylated Extracellular Regulated Protein Kinase Expression

The Extracellular Regulated Protein Kinase (ERK) pathway, which is a subfamily of mitogen-activated protein kinases, is a key player in cerebral ischaemia [76, 77]. It plays roles in the mediation of a number of physiological and pathological processes in cells, such as proliferation and differentiation [77, 78]. Additionally, p-ERK plays roles in the activation of inflammation response and oxidative stress during early poststroke [77]. During this period, specifically up to 24 hours, infarct volume increases as the ischaemia persists [29, 30]. Secondary changes such as early phase vasogenic oedema and a later phase with inflammatory infiltration develop after 24 hours [79–81]. This is the period when p-ERK plays its role.

Inhibition of ERK phosphorylation (p-ERK) results in reduced infarct volume and protection of neural cells [82]. This is achieved when its expression is downregulated. Consequently, use of CIMT in rats significantly lowered the expression of p-ERK in the bilateral cortex and hippocampi similar to the sham group levels than that in the model group [82, 83]. The authors argued that these data suggest that functional recovery after CIMT may be related to decreased expression of phosphorylated extracellular regulated protein kinase in the bilateral cortex and hippocampi. Furthermore, since the pathophysiological changes such as the lesion expansion and the inflammatory responses to ischaemia occur with the first few days after stroke, CIMT needs to start very early poststroke to help downregulate p-ERK. However, these findings need further investigation in human stroke.

2.8. Upregulation of Stromal Cell-Derived Factor 1 (SDF-1)

Stromal Cell-Derived Factor 1 (SDF-1) is upregulated following stroke and is especially localized to the ischaemic penumbra [84]. Following the use of CIMT in rats, motor function significantly improved with a corresponding increase in SDF-1 protein levels in the cortex and dentate gyrus [85]. An increased level of SDF-1 is positively correlated with an increased concentration of endothelial progenitor cells (EPC), which are important for vascularization of brain tissues [86]. Vascularization helps provide the brain tissue with oxygen and glucose which are important for the healthy growth and function of brain cells [18, 19]. Additionally, upregulation of SDF-1 is inversely correlated with the volume of the lesion (as SDF-1 level increases, the volume of the lesion decreases) [86]. This is because SDF-1 is noted to be localized around the ischaemic penumbra, and its role is to prevent the lesion from expanding by improving vascularization of the area. Since the infarct volume expands up to 24 hours when ischaemia persists [30, 31], CIMT needs to be started very early after stroke in order to help increase the level of SDF-1 and possibly enhance vascularization and the attendant neurogenesis. Accordingly, in the study by Zhao et al., CIMT was initiated early on poststroke (at 7 days after stroke) [85]. However, as yet, there seems to be no study that reported on the effect of CIMT on SDF-1 in humans.

2.9. Increased Numbers of ΔFosB-Positive Cells

The ΔFosB-positive cells are transcription factors responsible for mediating long-term neural and behavioural plasticity [87]. They encode proteins necessary for cell proliferation, differentiation, and transformation [88]. Therefore, they serve as biomarkers for use-dependent neuronal activity [89] and can be activated by repetitive stimulation [90]. Previously, enriched environment training was shown to increase expression of ΔFosB-positive cells in the perilesional cortex [91].

Similarly, in rats, early CIMT (initiated on the first day after stroke) was associated with greater numbers of ΔFosB-positive cells in the ipsilesional sensorimotor cortex layers II-III and V [54]. Therefore, starting CIMT within the first 24 hours after stroke may help raise the number of ΔFosB-positive cells and prevent further pathological processes that will lead to cell death. However, this effect has not yet been reported in humans, and therefore, future CIMT studies should look at the possible role of CIMT in modulating ΔFosB-positive cells. Additionally, the effect seen even in animals was only in haemorrhagic stroke. Thus, even though the pathophysiology of haemorrhagic stroke may eventually take the form of ischaemic stroke, studies in the latter are equally needed. This is especially important because the latter type of stroke is more common and tends to have better prognosis than the former [1, 68].

2.10. Improved Cortical Activation

Cortical activation refers to the stimulation of the brain structures responsible for its function. Following CIMT, a significant increase in primary motor cortex (PMC) and somatosensory cortex (SMC) activation in both ipsilesional and contralesional hemispheres has been reported [92–97]. In each one of the following studies, increased activation occurred during the acute stage [93] and subacute stage [94]. In four studies, increased activation occurred during the chronic stage [92, 95–97]. These findings seem to suggest that increasing cortical activation following CIMT is possible at any stage of stroke. However, during the chronic stage, CIMT was combined with either tDCs or bilateral arm training [97, 98], probably suggesting that during this period, a combination of CIMT with another rehabilitation therapy may be required to increase cortical activation.

Similarly, it was also suggested that in chronic stroke patients, CIMT should be combined with electrical stimulation since a close relationship was found between increased hand function with peak changes in activation within the ipsilesional SMC following the combination of these two therapy techniques [95]. In contrast, in acute stroke patients, CIMT alone may be used. According to El-Helow et al., there were improved resting motor threshold (RMT), central motor conduction time (CMCT), and amplitude of motor-evoked potentials (MEPs) which are evidences of increased cortical activation when CIMT alone was used in acute stroke patients [99]. However, evaluating cortical activation depends on the type of probe used. In four studies, transmagnetic stimulation (TMS) was used [92, 93, 98, 99]. The TMS measures motor-evoked potentials (MEPs), neuroelectrical signals produced by the spinal cord and peripheral muscles when the brain is stimulated. In three studies, functional magnetic resonance imaging (fMRI) was used [94–96]. The fMRI records blood oxygen-level-dependent (BOLD) signal activity changes [100]. According to Liew et al., when evaluating cortical activation, it is better to combine the use of more than one probe technique [13]. Interestingly, one of the cited studies combined the use of TMS and fMRI and reported a significant positive correlation between the two probe techniques [96].

In addition, the severity of the patient’s motor impairment before intervention is a factor to note in determining an increase in cortical activation. According to Könönen et al., increased cortical activation is higher in those patients with poor motor ability before intervention with CIMT or in those whose motor ability improved remarkably after the intervention [96]. Similarly, when the pyramidal tract (PT) is intact, improvement in motor function initially correlates with a decrease in activation in SMC and then an increase after 6 months [101]. When PT is affected, improvement consistently correlates with an increase in a lateral extension of SMC. Improvement in cortical activation has been shown to correlate well with motor functions [26, 27, 93, 96]. These may be because those with mild and/or moderate impairment in motor function have activation patterns similar to apparently healthy individuals. However, different regions of the brain may be activated differently following CIMT as different patients show different patterns of activation [26, 97, 101]. Patients with chronic stroke usually show a bilateral pattern of activation [13]; this is probably because of the recruitment of areas distant to or interconnected with the areas of the lesion. Those with greater motor impairment display increased fMRI activity in the contralesional hemisphere [102, 103], but those with better motor function show normal activation patterns in the ipsilesional hemisphere [104, 105].

Another variable which needs to be considered when attempting cortical activation is the use of constraint. This is because it has been reported that restriction of the contralesional limb led to decreased cortical activation in people with right hemispheric stroke especially in the cortical and basal ganglia motor areas [106]. In those with left hemispheric stroke, a decreased activation pattern was noted even in the absence of limb restriction, which can induce an additional cortical silencing (which is an indicator of cortical disinhibition). Since use or no use of constraint did not show any difference in improvement in motor function following CIMT [107], these findings seem to suggest that the use of a constraint may not be necessary, though it has been argued that it may help to increase the number of task repetitions which is essential for motor recovery [108]. One of the clinical significance of these findings is that they further affirm that what matters the most is the frequency of repetition of the functional tasks during CIMT.

2.11. Downregulation and Upregulation of Intracortical Inhibition

Output from the cortex is dependent upon the balance between different inhibitory and facilitatory circuits in the brain [109, 110]. Stroke results in intracortical inhibition in the affected hemisphere [111]. This intracortical inhibition was shown to be significantly downregulated or upregulated in the ipsilesional hemisphere compared to the contralesional hemisphere after a few weeks of CIMT [111, 112]. The amount of disinhibition was related to the degree of spasticity [112]. Additionally, evaluation of inhibition depends on the type of probe used. In the study by Liepert et al., TMS and fMRI were used to evaluate intracortical inhibition [111], while in the study by Liepert, TMS was used to evaluate intracortical inhibition [112]. Thus, combining TMS and fMRI in evaluating cortical activity should be encouraged in studies since they measure motor-evoked potentials (MEPs) and record blood oxygen-level-dependent (BOLD) signal activity changes, respectively. These will provide better outcomes for studying brain activity. However, further studies are still needed to determine which of the upregulation or downregulation of intracortical inhibition is significantly related to improvement in motor function.

2.12. Modulation of Interhemispheric Imbalance

Under normal circumstances, interhemispheric inhibition plays an important role during performance of a unimanual task such as brushing one’s teeth or writing. Following stroke, cortical excitability of the ipsilesional hemisphere tends to be lower than that of the contralesional hemisphere [98, 113]. Thus, the contralesional hemisphere may tend to inhibit the ipsilesional hemisphere. However, rehabilitation therapy can help either counteract or reduce this inhibition. A combination of tDCs with CIMT reduced interhemispheric imbalance between the affected and unaffected hemispheres when motor evoked potential values were compared between baseline and after intervention [98, 114, 115]. In one study, what exactly happened was that the ability of the ipsilesional hemisphere to counter inhibition by the contralesional hemisphere improved even though the inhibition by the contralesional hemisphere did not change significantly [115].

In addition, on modulation of interhemispheric imbalance, two factors need consideration: the stage of stroke and the type of probe used. In one study, the participants were within acute stage of stroke and the probe used was fMRI-guided TMS [114]. In contrast, in three studies, the participants were within chronic stage of stroke and the probe used was only TMS [98, 114, 115]. In all these studies, CIMT was combined with brain stimulation, which seems to suggest that a combination of CIMT with brain stimulation is required to reduce interhemispheric inhibition following stroke. However, since CIMT was administered in these studies for a period not longer than five weeks, it is possible that when CIMT alone is administered for a longer period, interhemispheric inhibition could also be modulated. This is needed since even in healthy individuals, a combination of tDCs with motor training showed a decrease in cortical excitability in the dominant hemisphere and a decrease in transcallosal inhibition from the dominant to nondominant hemisphere [116]. Additionally, studies that combine different probe methods are needed to help elucidate neural activities in both hemispheres.

2.13. Increased Cortical Map Size

Motor map size is the extent to which control of movement of a part of the body is represented in the brain. It is in essence a measure of the size of the area that represents or controls movement of a part of the body. Motor map size shrinks after stroke, but it can be enlarged with the use of rehabilitation therapy. Accordingly, following the use of CIMT for 10 days, motor map size increased significantly in the experimental group compared with that of the control and the increase correlated well with motor function [27, 28]. Specifically, the correlation was higher and more significant between baseline and four months postintervention [28]. Additionally, the cortical silent period which is a measure of disinhibition increased significantly in the experimental group, though it was not significantly correlated with motor function. This seems to suggest that an increase in motor map size is more important in motor recovery than decreased disinhibition in the ipsilesional cortex. This is probably because the extra map could carry the brunt of control of the areas represented by the cortex.

On increase of motor map size, three issues are worthy of note. One, a study reported that there was no significant difference in motor map size and motor function between early and delayed CIMT at four months follow-up [28]. This is because, at the time of the follow-up, the participants in both the experimental and the control groups would have been in chronic stage. Secondly, no significant difference in the silent period was found between the CIMT group and the control group recently [117]. Thirdly, a posterior shift in the center of gravity (COG) was observed in the late group from baseline to four months, and that the shift was more in the late group compared to the early group; in the same way, a considerable shift in mean COG was reported earlier in chronic stroke patients [92]. Thus, it seems that in stroke patients, it is highly likely that CIMT improves the recovery of motor function by recruiting adjacent brain structures than by improving cortical activation especially in chronic stroke patients. According to Sawaki et al., the late CIMT group showed decreased excitability in the ipsilesional hemisphere [118]. Similarly, in monkeys, delayed training resulted in a decrease in spared hand representation [119], probably affirming my previous claim. However, these studies reporting on increased cortical map size used only TMS which is a measure of evoked potentials. Therefore, future studies should use a combination of different probe techniques to enable the provision of more cogent evidence on increased cortical map size.

2.14. Changes in the Effective Connectivity of Primary Motor Cortex

The primary motor cortex is a part of the motor cortex involved in the control and execution of voluntary movement [25]. Under normal circumstance, it is effectively connected to other parts of the motor cortex such as the premotor, posterior parietal, and primary somatosensory cortices and to other parts of the brain such as the cerebellum and thalamus that play roles during movement control and execution. However, the effective connectivity of the primary motor cortex may get altered after stroke [120].

When the effective connectivity of the primary motor cortex is altered, it can be effectively reconnected with rehabilitation therapy. In a group of patients with chronic stroke, two weeks of CIMT showed changes in the local response of TMS in the ipsilesional and contralesional primary motor cortex (M1); changes in the strength of interhemispheric connectivity between M1s; and changes in the effective connectivity of the ipsilesional and contralesional M1s with the nonprimary motor areas, the basal ganglia, and the motor nuclei of the thalamus [121]. Thus, improving effective connectivity of the primary motor cortex of the ipsilesional and contralesional hemispheres, between the ipsilesional primary motor cortex, and different areas of the brain is an important mechanism through which CIMT aids in the recovery of motor function after stroke. This is because motor function is controlled by the motor system that comprises of a series of cortical and subcortical areas interacting via anatomical connections [122].

2.15. Structural Changes

Anatomical changes are important biomarkers for recovery after stroke. In animals, abundant dendritic arborization of pyramidal neurons in the sensorimotor area was noted following the use of CIMT [50]. Abundant dendritic arborization of pyramidal neurons helps in the formation of new synapses which results in improved neuronal communication and function. Similarly, three hours of CIMT for 10 consecutive days resulted in increased gray matter in sensory, motor, and hippocampi areas in both ipsilesional and contralesional hemispheres in humans [123]. Gray matter consists of neuronal cell bodies and synapses which are important for functions of the CNS. However, it is important to note that the process of cerebral reorganization is a slow one and may take months to complete [124].

3. Conclusion

CIMT facilitates and enhances neuronal cell homeostasis. In animals, this is achieved through improved perfusion of motor areas and brain glucose metabolism; increased expression of BDNF, SDF-1, HIF-1α, VEGF, and GAP-43; increased number of ΔFosB-positive cells; and decreased levels of GABA and p-ERK among others. In humans, there are so far a few studies reporting on improved perfusion, decreased level of GABA, and a potential interaction between increased level of BDNF and motor function; but a number of studies reported on increased cortical activation and motor map size, increased and decreased intracortical inhibition, and decreased transcallosal or interhemispheric inhibition of the ipsilesional hemisphere. Additionally, most of the findings on the biomarkers such as increased cortical activation and map size, SDF-1 expression, and greater numbers of ΔFosB-positive cells, indicate that it is important that CIMT is initiated early poststroke. However, implementation of CIMT has been very difficult during early poststroke in humans and as such there are still just a few studies related to this area. Furthermore, there is limited evidence that CIMT is more effective when it is combined with other therapies such as tDCs in chronic cases of stroke. It should also be noted that these effects are mostly in ischaemic stroke. Thus, studies in humans are needed to further elucidate the biomarkers for recovery of motor function following CIMT.

3.1. Implications for Research and Practice

The fact that there is good positive correlation between increased cortical map size and motor function improvement and between increased cortical activation and motor function improvement shows that CIMT has a strong theoretical basis. However, further research is needed to characterize those who have genetic affinity for improvement considering the BDNF gene and possibly other genetic constituents. Secondly, more rigorous studies with adequate sample sizes are needed to verify the discussed evidence especially on the molecular biomarkers in humans. Clinicians also need to create algorithms to be able know how much CIMT is required to produce effects on these biomarkers based on the patient’s presentations and the likely duration of treatment and prognosis.

Conflicts of Interest

The authors declare no conflict of interest.

Acknowledgments

The authors would like to thank Roberta Said, a Maltese Speech Therapist who spared her time to review the initial draft of the manuscript and give them valuable feedback.

References

K. Balci, U. Utku, T. Asil, and E. Unlu, “Simultaneous onset of hemorrhagic and ischemic strokes,” The Neurologist, vol. 13, no. 3, pp. 148-149, 2007.

R. L. Sacco, S. E. Kasner, J. P. Broderick et al., “An updated definition of stroke for the 21st century: a statement for healthcare professionals from the American Heart Association/American Stroke Association,” Stroke, vol. 44, no. 7, pp. 2064–2089, 2013.

P. Deb, S. Sharma, and K. M. Hassan, “Pathophysiologic mechanisms of acute ischemic stroke: an overview with emphasis on therapeutic significance beyond thrombolysis,” Pathophysiology, vol. 17, no. 3, pp. 197–218, 2010.

T. Kalogeris, C. P. Baines, M. Krenz, and R. J. Korthuis, “Cell biology of ischemia/reperfusion injury,” International Review of Cell and Molecular Biology, vol. 298, pp. 229–317, 2012.

E. Taub, N. E. Miller, T. A. Novack et al., “Technique to improve chronic motor deficit after stroke,” Archives of Physical Medicine and Rehabilitation, vol. 74, no. 4, pp. 347–354, 1993.

G. Uswatte, E. Taub, D. Morris, M. Vignolo, and K. McCulloch, “Reliability and validity of the upper-extremity motor activity log-14 for measuring real-world arm use,” Stroke, vol. 36, no. 11, pp. 2493–2496, 2005.

D. M. Morris, E. Taub, and V. W. Mark, “Constraint-induced movement therapy: characterizing the intervention protocol,” Europa Medicophysica, vol. 42, no. 3, pp. 257–268, 2006.

M. Etoom, M. Hawamdeh, Z. Hawamdeh et al., “Constraint-induced movement therapy as a rehabilitation intervention for upper extremity in stroke patients: systematic review and metaanalysis,” International Journal of Rehabilitation Research, vol. 39, no. 3, pp. 197–210, 2016.

A. Abdullahi, “Effects of number of repetitions and number of hours of shaping practice during constraint-induced movement therapy: a randomized controlled trial,” Neurology Research International, vol. 2018, Article ID 5496408, 9 pages, 2018.

H. Cohen, Ed., Neuroscience for Rehabilitation, Lippincott-Williams & Wilkins, Philadelphia, 2nd ed edition, 1999.

B. T. Gillick and L. Zirpel, “Neuroplasticity: an appreciation from synapse to system,” Archives of Physical Medicine and Rehabilitation, vol. 93, no. 10, pp. 1846–1855, 2012.

E. Taub, G. Uswatte, and V. W. Mark, “The functional significance of cortical reorganization and the parallel development of CI therapy,” Frontiers in Human Neuroscience, vol. 8, 2014, 396.

S.-L. Liew, E. Santarnecchi, E. R. Buch, and L. G. Cohen, “Non-invasive brain stimulation in neurorehabilitation: local and distant effects for motor recovery,” Frontiers in Human Neuroscience, vol. 8, 2014.

Biomarkers Definitions Working Group, “Biomarkers and surrogate endpoints: preferred definitions and conceptual framework,” Clinical Pharmacology & Therapeutics, vol. 69, no. 3, pp. 89–95, 2001.

R. Huss, “Chapter 19. Biomarkers,” in Translational Regenerative Medicine, pp. 235–241, Academic Press, 2015.

L. A. Boyd, K. S. Hayward, N. S. Ward et al., “Biomarkers of stroke recovery: consensus-based core recommendations from the Stroke Recovery and Rehabilitation Roundtable,” International Journal of Stroke, vol. 12, no. 5, pp. 480–493, 2016.

B. Kim and C. Winstein, “Can neurological biomarkers of brain impairment be used to predict poststroke motor recovery? A systematic review,” Neurorehabilitation and Neural Repair, vol. 31, no. 1, pp. 3–24, 2016.

H. S. Markus, “Cerebral perfusion and stroke,” Journal of Neurology, Neurosurgery, and Psychiatry, vol. 75, no. 3, pp. 353–361, 2004.

P. Mergenthaler, U. Lindauer, G. A. Dienel, and A. Meisel, “Sugar for the brain: the role of glucose in physiological and pathological brain function,” Trends in Neurosciences, vol. 36, no. 10, pp. 587–597, 2013.

A. H. Goodman, R. Einstein, and H. J. Granger, “Effect of changing metabolic rate on local blood flow control in the canine hindlimb,” Circulation Research, vol. 43, no. 5, pp. 769–776, 1978.

A. Zauner and J. P. Paul Muizelaar, “Chapter 5. Brain metabolism and cerebral blood flow,” in Head Injury, Chapman & Hall, London, London, 1997.

L. Lin, A. Bivard, and M. W. Parsons, “Perfusion patterns of ischemic stroke on computed tomography perfusion,” Journal of Stroke, vol. 15, no. 3, pp. 164–173, 2013.

K. A. Hossmann, “Viability thresholds and the penumbra of focal ischemia,” Annals of Neurology, vol. 36, no. 4, pp. 557–565, 1994.

M. Könönen, J. T. Kuikka, M. Husso-Saastamoinen et al., “Increased perfusion in motor areas after constraint-induced movement therapy in chronic stroke: a single-photon emission computerized tomography study,” Journal of Cerebral Blood Flow & Metabolism, vol. 25, no. 12, pp. 1668–1674, 2005.

A. Shumway-Cook and M. H. Woollacott, Motor Control: Theory and Practical Applications, Lippincott Williams & Wilkins, Philadelphia, 2nd ed edition, 2001.

W. Wang, A. Wang, L. Yu et al., “Constraint-induced movement therapy promotes brain functional reorganization in stroke patients with hemiplegia,” Neural Regeneration Research, vol. 7, no. 32, pp. 2548–2553, 2012.

T. Ro, E. Noser, C. Boake et al., “Functional reorganization and recovery after constraint-induced movement therapy in subacute stroke: case reports,” Neurocase, vol. 12, no. 1, pp. 50–60, 2006.

L. Sawaki, A. J. Butler, Xiaoyan Leng et al., “Constraint-induced movement therapy results in increased motor map area in subjects 3 to 9 months after stroke,” Neurorehabilitation and Neural Repair, vol. 22, no. 5, pp. 505–513, 2008.

E.-J. Kong, K.-A. Chun, J.-H. Jeong, and I.-H. Cho, “Brain SPECT analysis after constraint-induced movement therapy in young children with hemiplegic cerebral palsy: case report,” Nuclear Medicine and Molecular Imaging, vol. 47, no. 2, pp. 119–124, 2013.

L. J. Lee, C. S. Kidwell, J. Alger, S. Starkman, and J. L. Saver, “Impact on stroke subtype diagnosis of early diffusion-weighted magnetic resonance imaging and magnetic resonance angiography,” Stroke, vol. 31, no. 5, pp. 1081–1089, 2000.

F. Li, K. F. Liu, M. D. Silva et al., “Transient and permanent resolution of ischemic lesions on diffusion-weighted imaging after brief periods of focal ischemia in rats: correlation with histopathology,” Stroke, vol. 31, no. 4, pp. 946–954, 2000.

A. W. Dromerick, C. E. Lang, R. L. Birkenmeier et al., “Very early constraint-induced movement during stroke rehabilitation (VECTORS). A single-center RCT,” Neurology, vol. 73, no. 3, pp. 195–201, 2009.

G. A. Dienel, “Fueling and imaging brain activation,” ASN Neuro, vol. 4, no. 5, p. AN20120021, 2012.

W. D. Heiss, H. G. Emunds, and K. Herholz, “Cerebral glucose metabolism as a predictor of rehabilitation after ischemic stroke,” Stroke, vol. 24, no. 12, pp. 1784–1788, 1993.

E. Rostami, “Glucose and the injured brain—monitored in the neurointensive care unit,” Frontiers in Neurology, vol. 5, 2014.

P. Ferdinand and C. Roffe, “Hypoxia after stroke: a review of experimental and clinical evidence,” Experimental & Translational Stroke Medicine, vol. 8, no. 1, 2016.

N. M. Robbins and R. A. Swanson, “Opposing effects of glucose on stroke and reperfusion injury: acidosis, oxidative stress, and energy metabolism,” Stroke, vol. 45, no. 6, pp. 1881–1886, 2014.

Y. Y. Li, B. Zhang, K. W. Yu et al., “Effects of constraint-induced movement therapy on brain glucose metabolism in a rat model of cerebral ischemia: a micro PET/CT study,” The International Journal of Neuroscience, vol. 128, no. 8, pp. 736–745, 2017.

L. Røhl, L. Østergaard, C. Z. Simonsen et al., “Viability thresholds of ischemic penumbra of hyperacute stroke defined by perfusion-weighted MRI and apparent diffusion coefficient,” Stroke, vol. 32, no. 5, pp. 1140–1146, 2001.

C. T. Wass and W. L. Lanier, “Glucose modulation of ischemic brain injury: review and clinical recommendations,” Mayo Clinic Proceedings, vol. 71, no. 8, pp. 801–812, 1996.

N. J. J. MacDougall and K. W. Muir, “Hyperglycaemia and infarct size in animal models of middle cerebral artery occlusion: systematic review and meta-analysis,” Journal of Cerebral Blood Flow & Metabolism, vol. 31, no. 3, pp. 807–818, 2010.

H. L. Qu, M. Zhao, S. S. Zhao et al., “Forced limb-use enhanced neurogenesis and behavioral recovery after stroke in the aged rats,” Neuroscience, vol. 286, pp. 316–324, 2015.

W. R. Schäbitz, T. Steigleder, C. M. Cooper-Kuhn et al., “Intravenous brain-derived neurotrophic factor enhances poststroke sensorimotor recovery and stimulates neurogenesis,” Stroke, vol. 38, no. 7, pp. 2165–2172, 2007.

M. Ploughman, V. Windle, C. L. MacLellan, N. White, J. J. Doré, and D. Corbett, “Brain-derived neurotrophic factor contributes to recovery of skilled reaching after focal ischemia in rats,” Stroke, vol. 40, no. 4, pp. 1490–1495, 2009.

D. K. Binder and H. E. Scharfman, “Brain-derived neurotrophic factor,” Growth Factors, vol. 22, no. 3, pp. 123–131, 2009.

N. Kuczewski, C. Porcher, and J. L. Gaiarsa, “Activity-dependent dendritic secretion of brain-derived neurotrophic factor modulates synaptic plasticity,” The European Journal of Neuroscience, vol. 32, no. 8, pp. 1239–1244, 2010.

H. Park and M. M. Poo, “Neurotrophin regulation of neural circuit development and function,” Nature Reviews Neuroscience, vol. 14, no. 1, pp. 7–23, 2013.

A. Arvidsson, T. Collin, D. Kirik, Z. Kokaia, and O. Lindvall, “Neuronal replacement from endogenous precursors in the adult brain after stroke,” Nature Medicine, vol. 8, no. 9, pp. 963–970, 2002.

S. W. Hou, Y. Q. Wang, M. Xu et al., “Functional integration of newly generated neurons into striatum after cerebral ischemia in the adult rat brain,” Stroke, vol. 39, no. 10, pp. 2837–2844, 2008.

A. Lasek-Bal, H. Jędrzejowska-Szypułka, J. Różycka et al., “Low concentration of BDNF in the acute phase of ischemic stroke as a factor in poor prognosis in terms of functional status of patients,” Medical Science Monitor, vol. 21, pp. 3900–3905, 2015.

N. Kuczewski, C. Porcher, V. Lessmann, I. Medina, and J. L. Gaiarsa, “Activity-dependent dendritic release of BDNF and biological consequences,” Molecular Neurobiology, vol. 39, no. 1, pp. 37–49, 2009.

C. C. Alcantara, L. F. García-Salazar, M. A. Silva-Couto, G. L. Santos, D. S. Reisman, and T. L. Russo, “Post-stroke BDNF concentration changes following physical exercise: a systematic review,” Frontiers in Neurology, vol. 9, 2018.

M. Niimi, K. Hashimoto, W. Kakuda et al., “Role of brain-derived neurotrophic factor in beneficial effects of repetitive transcranial magnetic stimulation for upper limb hemiparesis after stroke,” PLoS One, vol. 11, no. 3, article e0152241, 2016.

A. Ishida, S. Misumi, Y. Ueda et al., “Early constraint-induced movement therapy promotes functional recovery and neuronal plasticity in a subcortical hemorrhage model rat,” Behavioural Brain Research, vol. 284, pp. 158–166, 2015.

C. T. Shiner, K. D. Pierce, A. G. Thompson-Butel, T. Trinh, P. R. Schofield, and P. A. McNulty, “BDNF genotype interacts with motor function to influence rehabilitation responsiveness poststroke,” Frontiers in Neurology, vol. 7, 2016.

J. U. Blicher, J. Near, E. Næss-Schmidt et al., “GABA levels are decreased after stroke and GABA changes during rehabilitation correlate with motor improvement,” Neurorehabilitation and Neural Repair, vol. 29, no. 3, pp. 278–286, 2014.

N. J. Paik and E. J. Yang, “Role of GABA plasticity in stroke recovery,” Neural Regeneration Research, vol. 9, no. 23, pp. 2026–2028, 2014.

A. Floyer-Lea, M. Wylezinska, T. Kincses, and P. M. Matthews, “Rapid modulation of GABA concentration in human sensorimotor cortex during motor learning,” Journal of Neurophysiology, vol. 95, no. 3, pp. 1639–1644, 2006.

V. I. Skvortsova, K. S. Raevskii, A. V. Kovalenko et al., “Levels of neurotransmitter amino acids in the cerebrospinal fluid of patients with acute ischemic insult,” Neuroscience and Behavioral Physiology, vol. 30, no. 5, pp. 491–495, 2000.

J. N. Sanes and J. P. Donoghue, “Plasticity and primary motor cortex,” Annual Review of Neuroscience, vol. 23, no. 1, pp. 393–415, 2000.

C. J. Stagg, V. Bachtiar, and H. Johansen-Berg, “The role of GABA in human motor learning,” Current Biology, vol. 21, no. 6, pp. 480–484, 2011.

C. Alia, C. Spalletti, S. Lai, A. Panarese, S. Micera, and M. Caleo, “Reducing GABAA-mediated inhibition improves forelimb motor function after focal cortical stroke in mice,” Scientific Reports, vol. 6, no. 1, 2016.

A. Routtenberg, I. Cantallops, S. Zaffuto, P. Serrano, and U. Namgung, “Enhanced learning after genetic overexpression of a brain growth protein,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 13, pp. 7657–7662, 2000.

D. Gorup, I. Bohacek, T. Milicevic et al., “Increased expression and colocalization of GAP43 and CASP3 after brain ischemic lesion in mouse,” Neuroscience Letters, vol. 597, pp. 176–182, 2015.

Å. Sandelius, N. C. Cullen, Å. Källén et al., “Transient increase in CSF GAP-43 concentration after ischemic stroke,” BMC Neurology, vol. 18, no. 1, p. 202, 2018.

A. Routtenberg, D. M. Lovinger, and O. Steward, “Selective increase in phosphorylation of a 47-kDa protein (F1) directly related to long-term potentiation,” Behavioral and Neural Biology, vol. 43, no. 1, pp. 3–11, 1985.

S. Zhao, M. Zhao, T. Xiao, J. Jolkkonen, and C. Zhao, “Constraint-induced movement therapy overcomes the intrinsic axonal growth-inhibitory signals in stroke rats,” Stroke, vol. 44, no. 6, pp. 1698–1705, 2013.

S. E. Vermeer, A. Algra, C. L. Franke, P. J. Koudstaal, and G. J. E. Rinkel, “Long-term prognosis after recovery from primary intracerebral hemorrhage,” Neurology, vol. 59, no. 2, pp. 205–209, 2002.

A. Saleh, M. Schroeter, A. Ringelstein et al., “Iron oxide particle-enhanced MRI suggests variability of brain inflammation at early stages after ischemic stroke,” Stroke, vol. 38, no. 10, pp. 2733–2737, 2007.

C. Li, B. Zhang, Y. Zhu et al., “Post-stroke constraint-induced movement therapy increases functional recovery, angiogenesis, and neurogenesis with enhanced expression of HIF-1α and VEGF,” Current Neurovascular Research, vol. 14, no. 4, pp. 368–377, 2018.

H. Shi, “Hypoxia inducible factor 1 as a therapeutic target in ischemic stroke,” Current Medicinal Chemistry, vol. 16, no. 34, pp. 4593–4600, 2009.

B. D. Kelly, S. F. Hackett, K. Hirota et al., “Cell type-specific regulation of angiogenic growth factor gene expression and induction of angiogenesis in nonischemic tissue by a constitutively active form of hypoxia-inducible factor 1,” Circulation Research, vol. 93, no. 11, pp. 1074–1081, 2003.

C. W. Pugh and P. J. Ratcliffe, “Regulation of angiogenesis by hypoxia: role of the HIF system,” Nature Medicine, vol. 9, no. 6, pp. 677–684, 2003.

G. L. Semenza, “Regulation of mammalian O₂ homeostasis by hypoxia-inducible factor 1,” Annual Review of Cell and Developmental Biology, vol. 15, no. 1, pp. 551–578, 1999.

B. F. Palmer and D. J. Clegg, “Oxygen sensing and metabolic homeostasis,” Molecular and Cellular Endocrinology, vol. 397, no. 1–2, pp. 51–58, 2014.

Y. Zhao, J. Li, Q. Tang et al., “Regulation of extracellular signal-regulated kinase 1/2 influences hippocampal neuronal survival in a rat model of diabetic cerebral ischemia,” Neural Regeneration Research, vol. 9, no. 7, pp. 749–756, 2014.

N. Sawe, G. Steinberg, and H. Zhao, “Dual roles of the MAPK/ERK1/2 cell signaling pathway after stroke,” Journal of Neuroscience Research, vol. 86, no. 8, pp. 1659–1669, 2008.

J. Sun and G. Nan, “The extracellular signal-regulated kinase 1/2 pathway in neurological diseases: a potential therapeutic target (review),” International Journal of Molecular Medicine, vol. 39, no. 6, pp. 1338–1346, 2017.

A. Saleh, M. Schroeter, C. Jonkmanns, H. P. Hartung, U. Mödder, and S. Jander, “In vivo MRI of brain inflammation in human ischaemic stroke,” Brain, vol. 127, no. 7, pp. 1670–1677, 2004.

M. Schroeter, A. Saleh, D. Wiedermann, M. Hoehn, and S. Jander, “Histochemical detection of ultrasmall superparamagnetic iron oxide (USPIO) contrast medium uptake in experimental brain ischemia,” Magnetic Resonance in Medicine, vol. 52, no. 2, pp. 403–406, 2004.

C. J. S. Price, D. Wang, D. K. Menon et al., “Intrinsic activated microglia map to the peri-infarct zone in the subacute phase of ischemic stroke,” Stroke, vol. 37, no. 7, pp. 1749–1753, 2006.

F. Zhang, Y. Wu, J. Jia, and Y. S. Hu, “Pre-ischemic treadmill training induces tolerance to brain ischemia: involvement of glutamate and ERK1/2,” Molecules, vol. 15, no. 8, pp. 5246–5257, 2010.

B. Zhang, Q. He, Y.-Y. Li et al., “Constraint-induced movement therapy promotes motor function recovery and downregulates phosphorylated extracellular regulated protein kinase expression in ischemic brain tissue of rats,” Neural Regeneration Research, vol. 10, no. 12, pp. 2004–2010, 2015.

W. D. Hill, D. C. Hess, A. Martin-Studdard et al., “SDF-1 (CXCL12) is upregulated in the ischemic penumbra following stroke: association with bone marrow cell homing to injury,” Journal of Neuropathology and Experimental Neurology, vol. 63, no. 1, pp. 84–96, 2004.

C. Zhao, J. Wang, S. Zhao, and Y. Nie, “Constraint-induced movement therapy enhanced neurogenesis and behavioral recovery after stroke in adult rats,” The Tohoku Journal of Experimental Medicine, vol. 218, no. 4, pp. 301–308, 2009.

T. Bogoslovsky, M. Spatz, A. Chaudhry et al., “Stromal-derived factor-1α correlates with circulating endothelial progenitor cells and with acute lesion volume in stroke patients,” Stroke, vol. 42, no. 3, pp. 618–625, 2011.

E. J. Nestler, M. B. Kelz, and J. Chen, “ΔFosB: a molecular mediator of long-term neural and behavioral plasticity,” Brain Research, vol. 835, no. 1, pp. 10–17, 1999.

P. Angel and M. Karin, “The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation,” Biochimica et Biophysica Acta, vol. 1072, no. 2-3, pp. 129–157, 1991.

M. Werme, C. Messer, L. Olson et al., “ΔFosBRegulates wheel running,” Journal of Neuroscience, vol. 22, no. 18, pp. 8133–8138, 2002.

C. A. McClung, P. G. Ulery, L. I. Perrotti, V. Zachariou, O. Berton, and E. J. Nestler, “ΔFosB: a molecular switch for long-term adaptation in the brain,” Molecular Brain Research, vol. 132, no. 2, pp. 146–154, 2004.

J. Clarke, K. D. Langdon, and D. Corbett, “Early poststroke experience differentially alters periinfarct layer II and III cortex,” Journal of Cerebral Blood Flow & Metabolism, vol. 34, no. 4, pp. 630–637, 2014.

J. Liepert, W. H. R. Miltner, H. Bauder et al., “Motor cortex plasticity during constraint-induced movement therapy in stroke patients,” Neuroscience Letters, vol. 250, no. 1, pp. 5–8, 1998.

C. Boake, E. A. Noser, T. Ro et al., “Constraint-induced movement therapy during early stroke rehabilitation,” Neurorehabilitation and Neural Repair, vol. 21, no. 1, pp. 14–24, 2016.

K. C. Lin, H. Y. Chung, C. Y. Wu et al., “Constraint-induced therapy versus control intervention in patients with stroke: a functional magnetic resonance imaging study,” American Journal of Physical Medicine & Rehabilitation, vol. 89, no. 3, pp. 177–185, 2010.

M. Laible, S. Grieshammer, G. Seidel, M. Rijntjes, C. Weiller, and F. Hamzei, “Association of activity changes in the primary sensory cortex with successful motor rehabilitation of the hand following stroke,” Neurorehabilitation and Neural Repair, vol. 26, no. 7, pp. 881–888, 2012.

M. Könönen, I. M. Tarkka, E. Niskanen et al., “Functional MRI and motor behavioral changes obtained with constraint-induced movement therapy in chronic stroke,” European Journal of Neurology, vol. 19, no. 4, pp. 578–586, 2012.

C. Y. Wu, Y. W. Hsieh, K. C. Lin et al., “Brain reorganization after bilateral arm training and distributed constraint-induced therapy in stroke patients: a preliminary functional magnetic resonance imaging study,” Chang Gung Medical Journal, vol. 33, no. 6, pp. 628–638, 2010.

N. Bolognini, G. Vallar, C. Casati et al., “Neurophysiological and behavioral effects of tDCs combined with constraint-induced movement therapy in poststroke patients,” Neurorehabilitation and Neural Repair, vol. 25, no. 9, pp. 819–829, 2011.

M. R. El-Helow, M. L. Zamzam, M. M. Fathalla et al., “Efficacy of modified constraint-induced movement therapy in acute stroke,” European Journal of Physical and Rehabilitation Medicine, vol. 51, no. 4, pp. 371–379, 2015.

D. E. Bohning, A. Shastri, Z. Nahas et al., “Echoplanar BOLD fMRI of brain activation induced by concurrent transcranial magnetic stimulation,” Investigative Radiology, vol. 33, no. 6, pp. 336–340, 1998.

M. Rijntjes, F. Hamzei, V. Glauche, D. Saur, and C. Weiller, “Activation changes in sensorimotor cortex during improvement due to CIMT in chronic stroke,” Restorative Neurology and Neuroscience, vol. 29, no. 5, pp. 299–310, 2011.

E. A. Fridman, T. Hanakawa, M. Chung, F. Hummel, R. C. Leiguarda, and L. G. Cohen, “Reorganization of the human ipsilesional premotor cortex after stroke,” Brain, vol. 127, no. 4, pp. 747–758, 2004.

M. Lotze, J. Markert, P. Sauseng, J. Hoppe, C. Plewnia, and C. Gerloff, “The role of multiple contralesional motor areas for complex hand movements after internal capsular lesion,” The Journal of Neuroscience, vol. 26, no. 22, pp. 6096–6102, 2006.

N. S. Ward, M. M. Brown, A. J. Thompson, and R. S. J. Frackowiak, “Neural correlates of outcome after stroke: a cross‐sectional fMRI study,” Brain, vol. 126, no. 6, pp. 1430–1448, 2003.

A. K. Rehme, S. B. Eickhoff, L. E. Wang, G. R. Fink, and C. Grefkes, “Dynamic causal modeling of cortical activity from the acute to the chronic stage after stroke,” NeuroImage, vol. 55, no. 3, pp. 1147–1158, 2011.

A. C. Vidal, P. Banca, A. G. Pascoal et al., “Bilateral versus ipsilesional cortico-subcortical activity patterns in stroke show hemispheric dependence,” International Journal of Stroke, vol. 12, no. 1, pp. 71–83, 2016.

C. Brogårdh, M. Vestling, and B. H. Sjölund, “Shortened constraint-induced movement therapy in subacute stroke—no effect of using a restraint: a randomized controlled study with independent observers,” Journal of Rehabilitation Medicine, vol. 41, no. 4, pp. 231–236, 2009.

A. Abdullahi, “Movement Rehabilitation in Physiotherapy after Stroke: The Role of Constraint-Induced Movement Therapy,” in Different Areas of Physiotherapy, IntechOpen, London, 2019.

Z. Ni and R. Chen, “Short-interval intracortical inhibition: a complex measure,” Clinical Neurophysiology, vol. 119, no. 10, pp. 2175-2176, 2008.

J. C. Rothwell, B. L. Day, P. D. Thompson, and T. Kujirai, “Short latency intracortical inhibition: one of the most popular tools in human motor neurophysiology,” The Journal of Physiology, vol. 587, no. 1, pp. 11-12, 2009.

J. Liepert, F. Hamzei, and C. Weiller, “Lesion-induced and training-induced brain reorganization,” Restorative Neurology and Neuroscience, vol. 22, no. 3-5, pp. 269–277, 2004.

J. Liepert, “Motor cortex excitability in stroke before and after constraint-induced movement therapy,” Cognitive and Behavioral Neurology, vol. 19, no. 1, pp. 41–47, 2006.

P. K. Pal, D. K. Prashantha, S. J. Sriranjini, T. N. Sathyaprabha, and D. Nagaraja, “Evaluation of the motor cortical excitability changes after ischemic stroke,” Ann Indian Acad Neurol, vol. 16, no. 3, pp. 394–397, 2013.

V. Di Lazzaro, M. Dileone, F. Capone et al., “Immediate and late modulation of interhemispheric imbalance with bilateral transcranial direct current stimulation in acute stroke,” Brain Stimulation, vol. 7, no. 6, pp. 841–848, 2014.

D. A. Cunningham, N. Varnerin, A. Machado et al., “Stimulation targeting higher motor areas in stroke rehabilitation: a proof-of-concept, randomized, double-blinded placebo-controlled study of effectiveness and underlying mechanisms,” Restorative Neurology and Neuroscience, vol. 33, no. 6, pp. 911–926, 2015.

J. A. Williams, A. Pascual-Leone, and F. Fregni, “Interhemispheric modulation induced by cortical stimulation and motor training,” Physical Therapy, vol. 90, no. 3, pp. 398–410, 2010.

C. Yu, W. Wang, Y. Zhang et al., “The effects of modified constraint-induced movement therapy in acute subcortical cerebral infarction,” Frontiers in Human Neuroscience, vol. 11, p. 265, 2017.

L. Sawaki, A. J. Butler, X. Leng et al., “Differential patterns of cortical reorganization following constraint-induced movement therapy during early and late period after stroke: a preliminary study,” NeuroRehabilitation, vol. 35, no. 3, pp. 415–426, 2014.

S. Barbay, E. J. Plautz, K. M. Friel et al., “Behavioral and neurophysiological effects of delayed training following a small ischemic infarct in primary motor cortex of squirrel monkeys,” Experimental Brain Research, vol. 169, no. 1, pp. 106–116, 2006.

Z. Zhao, X. Wang, M. Fan et al., “Altered effective connectivity of the primary motor cortex in stroke: a resting-state fMRI study with Granger causality analysis,” PLoS One, vol. 11, no. 11, article e0166210, 2016.

P. Chouinard, G. Leonard, and T. Paus, “Changes in effective connectivity of the primary motor cortex in stroke patients after rehabilitative therapy,” Experimental Neurology, vol. 201, no. 2, pp. 375–387, 2006.

L. Jiang, H. Xu, and C. Yu, “Brain connectivity plasticity in the motor network after ischemic stroke,” Neural Plasticity, vol. 2013, Article ID 924192, 11 pages, 2013.

L. V. Gauthier, E. Taub, C. Perkins, M. Ortmann, V. W. Mark, and G. Uswatte, “Remodeling the brain: plastic structural brain changes produced by different motor therapies after stroke,” Stroke, vol. 39, no. 5, pp. 1520–1525, 2008.

R. J. Seitz and G. A. Donnan, “Recovery potential after acute stroke,” Frontiers in Neurology, vol. 6, 2015.