Buma 2013

Restorative Neurology and Neuroscience xx (20xx) x–xx 1
DOI 10.3233/RNN-130332
IOS Press
1 Review
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2 Understanding upper limb recovery
3 after stroke
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4 Floor Bumaa , Gert Kwakkela,b,∗ and Nick Ramseyc
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a Rudolph
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Magnus Institute of Neuroscience and Center of Excellence for Rehabilitation Medicine, University
Medical Center Utrecht and Rehabilitation Center de Hoogstraat, Utrecht, The Netherlands
b Department of Rehabilitation Medicine, VU University Medical Center, Amsterdam, The Netherlands
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c Department of Neurology and Neurosurgery, Rudolf Magnus Institute of Neuroscience, University Medical Center
9 Utrecht, The Netherlands

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10 Abstract. This review addresses what is currently known about the time course of skill reacquisition after stroke. There is growing
11 evidence that the natural logarithmic pattern of functional recovery can be modified by intensive task-oriented practice preferably
12 initiated within 6 months after stroke. However, the impact of practice on the learning-dependent and intrinsic spontaneous
13 mechanisms of neurological recovery is poorly understood. At least four probably interrelated mechanisms have been identified
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14 that drive motor and recovery after stroke: (1) salvation of penumbral tissue in the first days to weeks after stroke; (2) alleviation
15 of diaschisis; (3) homeostatic and learning-dependent (Hebbian) neuroplasticity; (4) behavioral compensation strategies. These
16 mechanisms underlying recovery are highly interactive, and operate in different, sometimes limited, time-windows after stroke
17 onset. In line with these mechanisms of improvement after stroke, we present a hypothetical phenomenological model for
18 understanding skill reacquisition after stroke. Translational research is important at this point to improve our knowledge about
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19 the neural correlates of what and how patients learn when they show functional improvement after stroke. This knowledge
20 should serve as a basis to optimize the timing, focus and intensity of evidence-based rehabilitation interventions and to design
21 innovative strategies to enhance motor recovery after stroke.
Keywords: Neuroplasticity, recovery, stroke, rehabilitation, paresis, hebbian learning

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23 1. Introduction or a Barthel Index (BI) below 12 points at 3 months 29
after after stroke (Heuschmann et al., 2011). In the 30
24 Stroke is the leading cause of disability in western United States, stroke has a mortality rate of 15%, and 31
25 society (Wardlaw, Sandercock, & Murray, 2009). The 26% of stroke survivors aged 65 years and older are 32
26 European Registers of Stroke (EROS) show that in a institutionalized at 6 months after stroke, while 50% 33
27 sample of 2,034 first-ever strokes, about 40% had a suffer from hemiparesis and 30% cannot walk with- 34
28 poor outcome in terms of death, institutionalization out assistance (Kelly-Hayes et al., 2003; Lloyd-Jones 35
et al., 2009). Although individual recovery patterns 36

∗ Corresponding author: prof. Gert Kwakkel (PhD), Department and outcome differ between patients, several prognos- 37
of Rehabilitation Medicine, VU University Medical Centre, de
Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. Tel.: +31 tic studies have shown that outcome at 3 or 6 months 38
204 440460; Fax: +31 204 44; E-mail: g.kwakkel@vumc.nl. is highly predictable for upper (Nijland et al., 2010; 39
0922-6028/13/$27.50 © 2013 – IOS Press and the authors. All rights reserved
2 F. Buma et al. / Understanding upper limb recovery after stroke
40 Stinear et al., 2012), and lower limb (Veerbeek et body segments in the same way as they did before their 87
41 al., 2011) as well as basic activities of daily living stroke. It is therefore essential to be explicit when talk- 88
(ADLs)in general (Kwakkel et al., 2006; Prabhakaran ing about recovery, and to refer to the different levels
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42 89
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43 et al., 2008). Almost all patients show a certain degree of the International Classification of Functioning, Dis- 90
44 of spontaneous neurological recovery, following a nat- ability and Health (ICF) as suggested by Levin and 91
45 ural logarithmic pattern (Langhorne et al., 2011). The colleagues (Levin et al., 2009). The ICF defines three 92
46 recovery rate is highest in the first months after stroke, levels of recovery: body structure and functions, activ- 93
47 after which recovery levels of and reaches a plateau ities and participation (Levin et al., 2009). In this Point 94
(Kwakkel et al., 2006; Langhorne et al, 2009; Ng et of View article we will focus on recovery of body
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48 95
49 al., 2007). Unfortunately, the underlying mechanisms functions and activities. We will distinguish neuro- 96
50 responsible for these spontaneous, natural logarith- logical recovery at the level of body functions such 97
51 mic changes in impairment in the first months after as strength, synergism and sensation, from improve- 98
52
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stroke are poorly understood and the subject of the
present review. We first introduce the theoretical phe-
nomenological model shown in Fig. 1 (Panel A), and
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ment at the level of activities such as dexterity and
gait after stroke. Although some impairments such as
synergies are poorly defined in the literature we prefer
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55 to explain processes involved in skill reacquisition. to define synergies according to Thomas Twitchell’s 102
56 This model summarizes the present body of knowl- work as “increased co-activation between muscles in 103
57 edge relating to the empirical observations of motor the paretic limb that can be elicited voluntarily or as 104
58 recovery after stroke in a way that is consistent with the a reflexive reaction” (Twitchell, 1951). As a conse- 105
more fundamental knowledge about underlying mech- quence, the joints that are coupled within a synergy
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59 106
60 anisms of brain plasticity after stroke. Subsequently, cannot be mastered in isolation (Twitchell, 1951). 107
61 we discuss the various underlying mechanisms that Skill reacquisition is defined as improvement on an 108
62 may explain the natural logarithmic time course of outcome measure either at the level of functions or at 109
63 recovery, and briefly discuss the specific timeframes the level of activities. Improvement after stroke encom- 110
64 in which these mechanisms may play a role after passes two distinct types of improvement: 1) True 111
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65 stroke. We then focus on the sizeable contribution (neurological) recovery reflects the return or restitution 112
66 of non-learning–dependent, spontaneous neurological (or repair) of body functions (or reduction of impair- 113
67 mechanisms and the possible influence of learning- ments), which results in the reappearance of the same 114
68 dependent mechanisms in the brain that might underlie end effectors during task performance (Krakauer et al., 115
the processes of skill reacquisition after stroke (Fig. 1, 2012). In this context, an end effector is defined as a
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69 116
70 Panel B). Finally, we define targets for translational body part, such as a hand or foot, that interacts with an 117
71 research with respect to motor recovery and neuroplas- object or the environment (Levin et al., 2009). And 2) 118
72 ticity mechanisms and discuss new opportunities for Skill reacquisition through motor compensation at an 119
73 rehabilitation interventions to enhance motor recovery activity level which can be defined as the appearance 120
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74 in patients after stroke. of ‘new’ motor patterns resulting from compensation 121
by the remaining intact motor elements at the level of 122
body function. However, skill reacquisition at an activ- 123

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75 2. Deﬁning stroke recovery ity level can also entail “take-over”, or substitution of 124
function by entirely different end effectors or body seg- 125
76 To understand recovery from stroke, it is important ments that accomplish the task (Cirstea & Levin, 2000; 126
77 to define what we mean by the terms recovery, restitu- Michaelsen et al., 2006). 127
78 tion, compensation and substitution, and their relation Obviously, both situations i.e., restitution and com- 128
79 to neuroplasticity and changes in the role of specific pensation (or substitution) mean that patients are able 129
80 brain regions (cortical map reorganization) (Dobkin, to accomplish the task, but they differ greatly in the 130
81 2009; Rothi & Horner, 1983). A number of recent lon- way the task is performed, in terms of quality of motor 131
82 gitudinal studies show that improvement at the level performance. An improvement in quality of movement 132
83 of activities after stroke, such as dexterity (Cirstea & after stroke in for example a reach to grasp task can be 133
84 Levin, 2000) is mainly driven by learning compensa- defined as approaching ‘normal performance’ when 134
85 tion strategies rather than by neural repair (Kwakkel compared to healthy individuals). Recent, intensive 135
86 et al., 2004) where patients learn to re-use the same repeated kinematic measurements early after stroke 136
F. Buma et al. / Understanding upper limb recovery after stroke 3
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Fig. 1. Proposed phenomenological model. Panel A) shows the processes underlying skill reacquisition after stroke and emphasizes the fact
that most evidence for skill improvement is due to compensatory mechanisms, partly driven by biomechanical changes and the interaction
with spontaneous and learning-dependent reorganization. Panel B refers to the underlying neuronal mechanisms influencing the process of skill
acquisition after stroke. Dashed lines represent connections for which there is as yet no direct evidence to be found in the literature, while
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bold lines represent connections for which there is considerable evidence. These lines represent the existence of a relationship between two
mechanisms, and do not necessarily refer to a causal relationship. The challenge in this field of research is represented by the red dashed lines and
question marks: can we modulate restitution of function after stroke? And can we understand the interaction between compensatory mechanisms
and true restitution of body functions after stroke. (The symbol represents change in this model).
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137 have shown that the normalization of movement per- distinguish restitution of function as a result of neuro- 153
138 formance in stroke recovery is accompanied with a logical repair from compensation strategies, especially 154
139 gradual increments in the number of degrees of free- when patients are using the same end effectors to 155
dom (DoF) to control for, as observed in healthy accomplish the specific task (Levin et al., 2009). Unfor-
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140 156
141 age-matched subjects (Kordelaar, 2013). In the same tunately animal studies have usually not focused on 157
142 vein, Duff and colleagues showed that normalization whether improvement of a particular activity with 158
143 of motor control of the upper paretic limb is signifi- the affected limb such as reaching for a food pellet 159
144 cantly accompanied with improvement in peak speed, is due to adaptive compensatory mechanisms or to 160
145 smoothness of movement, efficiency and consistency restitution of function. Some of the studies that did 161
146 of the trajectory of the hand to the target, reduced errors address this issue are those by Whishaw and colleagues 162
147 in placing the hand on the target as well as minimizing who demonstrated by video analysis that functional 163
148 compensation by shoulder and torso movements and recovery after stroke in rats involves mostly compen- 164
149 minimizing coupling in elbow and shoulder and wrist satory movements (Whishaw et al., 2000; Whishaw, 165
150 in completing the reaching task (Duff, 2013). 2008). Moon and colleagues found that rats showed 166
151 This also indicates that without quantifying the compensatory movement strategies during recovery 167
152 quality of task performance, it is not possible to after photothrombotic stroke (Moon et al., 2009). The 168
169 occurrence of compensatory mechanisms in animal but have been functionally impaired trough changes in 216
170 models after stroke suggests that this should not be metabolic activity. However, since true repair in the 217
overlooked when investigating the outcome in tasks brain might only be possible by replacing lost neurons
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172 such as reaching for food pellets (Metz et al., 2005). in the brain, neuroplasticity mechanisms in the brain 219
173 These findings are in line with a recent review by Kerr itself may always be viewed as compensatory (Levin 220
174 and colleagues who concluded that experience and et al., 2009). The functioning of these neurons will 221
175 behavioral interventions such as rehabilitative training always be in response to tissue loss and might interact 222
176 can drive functionally beneficial neural reorganiza- with changes in synaptic activity in the motor net- 223
tion in the injured adult hemisphere, but may also work. Compensatory mechanisms at a behavioral level
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178 have detrimental effects on neuroplasticity (Kerr et al., are thought to involve neuroplasticity mechanisms in 225
179 2011). the brain itself in order to develop and sustain these 226
180 In the same vein, clinical outcome measures that are compensatory strategies. Changes at the neural level 227
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used to assess activities in humans are not suitable to
assess the quality of motor performance and, with that,
to distinguish between restitution and compensation.
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(neuroplasticity) can be either adaptive or maladap-
tive to recovery and not all changes in the brain will
have functional significance for skill reacquisition after
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184 For example, most disability scales for activities of stroke. The precise way in which changes at a neuronal 231
185 daily living, such as the BI (Mahony & Barthel, 1965) level influence restitution as well as compensation is 232
186 and modified Rankin Scale (Banks & Marotta, 2007), still under investigation. 233
187 allow the use of the non-paretic hand to accomplish

tasks such as dressing, making the outcome of such
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189 scales almost independent of the amount of neurolog- 4. True neurological recovery in skill 234
190 ical “repair” of the paretic limb. In a less marked way, reacquisition after stroke 235
191 most clinical outcome measures of the upper paretic

192 limb do not account for trunk involvement in their final Apart from saving neural tissue by thrombolysis, 236
193 scoring system. An example is the Nine Hole Pegtest there is insufficient evidence that it is possible to 237
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194 (Chen et al., 2009), where the final score is based only modulate true recovery (i.e. restitution of function 238
195 on the accomplishment of the task. Some studies have or reduction of impairment) by specific rehabilita- 239
196 shown that even in grasping an object a number of tion interventions that start in the first weeks after 240
197 compensatory mechanisms might play a role in shap- stroke beyond spontaneous neurological recovery after 241
ing the hand around the object (Raghavan et al., 2010). stroke (Langhorne et al., 2009, 2011). Only a few
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198 242
199 Therefore, the mere accomplishment of grasping such randomized controlled trials have been designed to 243
200 as used in the Nine Hole Peg-test might not be suf- specifically study the restoration of body functions 244
201 ficient to reveal the use of these subtle compensatory by measuring motor impairment directly such as the 245
202 strategies. Hence, it remains unclear from the litera- motor part of the Fugl-Meyer arm test (FM-arm) (Wolf 246
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203 ture, both on animals and humans, to what extent the et al., 2006). Another way to assess improvement 247
204 improvement in motor performance at an activity level at the level of body functions is by using kinematic 248
205 by the affected arm itself is caused by true neurological analysis to establish whether therapeutic interventions 249
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206 repair or by learning compensation strategies. have an effect at the impairment level. Patterns of 250
improvement are often characterized by movements 251
in synergistic patterns (Cirstea & Levin, 2000). Syn- 252
207 3. Deﬁning neuroplasticity ergistic movement patterns have been described as 253
pathological couplings between, for example, shoulder 254
208 There are several definitions of neuroplasticity in and elbow movements by either voluntary of reflexive 255
209 the literature. Murphy & Corbett (2009) defined neu- co-contraction of muscles before isolated movement of 256
210 roplasticity as “Changes in the strength of synaptic the end-effectors is possible (Brunnström, 1970). How- 257
211 connections in response to either an environmental ever, most RCT’s have focused on improvement at the 258
212 stimulus or an alteration in synaptic activity in a net- level of activities after stroke and were therefore not 259
213 work” (Murphy & Corbett, 2009). True recovery at the designed to measure the quality of motor performance 260
214 level of the brain may be defined as restitution of the and to distinguish between restitution and compen- 261
215 function of the neurons that have escaped infarction sation strategies after stroke (Kwakkel et al., 2004). 262
263 Such a design is, however, necessary to understand compensatory motor strategies. Furthermore, since the 313
264 exactly what and how stroke patients learn during skill outcome in terms of body functions as well as activ- 314
reacquisition after stroke supported by rehabilitation ities in humans can be predicted with a very high
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266 interventions (Kwakkel & Wagenaar, 1996; Kwakkel degree of certainty in the first few weeks after stroke 316
267 et al., 2004; Kwakkel et al., 2006; Sunderland & (Kwakkel et al., 2006; Prabhakaran et al., 2008; Stin- 317
268 Tuke, 2006; Wolf et al., 2005). Longitudinal regres- ear et al., 2012), we hypothesize that true neurological 318
269 sion analysis of change scores suggests that progress of recovery is mainly defined by spontaneous, non- 319
270 time as a reflection of spontaneous neurological recov- learning-dependent mechanisms in the first weeks after 320
ery, rather than rehabilitative therapeutic interventions, stroke, such as salvation of penumbral tissue and alle-
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272 account for the majority of improvements contribut- viation of diaschisis or shock. The first evidence that 322
273 ing to restitution of function in the first weeks after both processes (compensation and restitution) emerge 323
274 stroke (Kwakkel et al., 2006). As a consequence, mere simultaneously early post stroke is shown by Korde- 324
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277
progress of time in the first three months after stroke is a
major confounder in understanding the effects of reha-
bilitation interventions, which further underlines the
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laar et al. (2013) in which the number of degrees of
freedom to control as reflected by synergism is almost
completed within the first 3 months post stroke (Korde-
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278 need for large, well-designed randomized controlled laar, 2013). This time window corresponds to enhanced 328
279 clinical trials. Such trials should preferably adhere to gene-expression profiles in the post-ischemic brain in 329
280 the CONSORT statement, an evidence-based set of animals (Ge et al., 2007), and this might be true for 330
281 minimum recommendations for reporting randomized human stroke as well. These findings have important 331
trials. It provides a tool to standardize reports and min- implications for the treatment of motor impairments
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283 imize bias in trial results, by clear and transparent after stroke. If there is a limited time window for plas- 333
284 reporting of findings (Kwakkel et al., 2004). ticity mechanisms, this suggests that it is critical to 334
285 The time window of neural mechanisms assumed to start rehabilitative interventions in the first weeks after 335
286 play a role in the natural logarithmic pattern of recov- stroke (Carmichael, 2006). Although this assumption 336
287 ery of body functions (or reduction of impairments) is not directly supported by evidence found in trials 337
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288 (Kwakkel et al., 2004; Levin et al., 2009) may further started in the first weeks after stroke in humans, several 338
289 underline the need for RCTs starting in the first weeks prognostic models for regaining dexterity after stroke 339
290 after stroke. As suggested by Murphy and Corbett after do suggest that the final outcome of upper limb function 340
291 stroke a number of neural mechanisms are operating at 6 months in terms of motor synergies can be max- 341
in different, partly overlapping time frames (Murphy imally predicted within the first 4 weeks after stroke
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292 342
293 & Corbett, 2009). In the first hours to days, the brain (Kwakkel et al., 2006; Prabhakaran et al., 2008; Stinear 343
294 is trying to limit tissue damage in the penumbra (the et al., 2012). In animal research, rats showed better out- 344
295 brain region that suffers from ischemia but in which comes in terms of upper limb reaching tasks, with more 345
296 the ischemic damage is potentially or at least par- dendritic outgrowth, when they received upper limb 346
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297 tially reversible) (Witte et al., 2000) and is thought to training in combination with an enriched environment 347
298 promote useful neuroplasticity by upregulating a num- within the first 28 days after stroke, than when the upper 348
299 ber of proteins (such as inflammatory cytokines, nerve limb training was delayed beyond 28 days (Biernaskie 349
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300 growth factors, and neurotransmitters) in the ischemic et al., 2004). In the latter case, training turned out to 350
301 core as well as the penumbra (Murphy & Corbett, be ineffective in resolving the forelimb impairment as 351
302 2009). In addition, alleviation of diaschisis (Feeney well as in promoting dendritic outgrowth (Biernaskie 352
303 & Baron, 1986) and Hebbian as well as non-Hebbian & Corbett, 2001). The challenge in this field thus lies in 353
304 learning mechanisms are thought to drive cortical map trying to influence the mechanisms that are active dur- 354
305 reorganization in the first weeks after stroke (Witte et ing neurological recovery in the first weeks after stroke, 355
306 al., 2000). either by targeting motor function at the impairment 356
307 Longitudinal studies in humans with repeated mea- level as a reflection of neural repair and/or by directly 357
308 surements over time show that the pattern of restitution targeting neurological repair itself. The question is, 358
309 of impairments is mainly seen within the first 10 weeks however, does allowing patients to use compensation 359
310 after stroke (Kwakkel et al., 2004). After this time strategies within the first 12 weeks prevent true neuro- 360
311 window, improvement of the outcome in terms of activ- logical repair? This latter question is unsolved by lack 361
312 ities is thought to be mainly defined by adaptation or of trials in this field.

362 5. Compensation strategies in skill (Mirbagheri et al., 2008, 2009). In some patients, 411
363 reacquisition after stroke intrinsic and reflex stiffness increases continuously 412
after stroke, while in other patients, intrinsic stiff-
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In humans, increased coupling between shoulder
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364 ness decreases continuously over a 12-month interval. 414
365 abduction and elbow flexion of the paretic limb, as The mere existence of these different and potentially 415
366 well as increased trunk involvement to improve accu- opposing processes suggests that global joint-stiffness 416
367 racy of reaching with the affected hand (Cirstea & measures may be misleading (Alibiglou et al., 2008). 417
368 Levin, 2000; Ellis et al., 2005; Lang et al., 2006; It therefore seems worthwhile for future studies to dis- 418
Michaelsen et al., 2004; Sukal et al., 2007), also known tinguish between neural resistance induced by reflex
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369 419
370 as synergistic movement, is often seen during skill activity and the increased non-neural passive resis- 420
371 reacquisition after stroke. This suggests that functional tance by changes in muscle and connective tissue 421
372 improvement is achieved by compensatory mecha- (Mirbagheri et al., 2008, 2009). A longitudinal study 422
373
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375
nisms using preserved descending motor pathways to
compensate for distal impairment through better trunk
control, as opposed to restitution of function (Lang et
or
suggested that muscle stiffness at 5 weeks is a bet-
ter predictor of arm function measured with the Fugl
Meyer arm test (FMA) at 6 months, than FMA score
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376 al., 2006). For instance, improvement after constraint itself at 5 weeks (Mirbagheri et al., 2012). These results 426
377 induced movement therapy (CIMT), where the unaf- suggest that muscle stiffness affects upper limb recov- 427
378 fected limb is being constrained to enforce the use of ery These peripheral biomechanical changes within the 428
379 the affected limb, is not merely based on overcoming neuromuscular system itself (i.e., neuromechanics) are 429
380 learned non-use, but also on adopting alternative move- an important, but so far neglected component in the
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381 ment strategies to accomplish upper limb tasks (Kitago study of skill reacquisition after stroke, and will allow 431
382 et al., 2012). Poor selectivity of motor control, defined better interpretation of neural dynamics in longitudinal 432
383 as the impaired ability to isolate activation of mus- fMRI and TMS studies (Buma et al., 2010). 433
384 cles in a selected pattern, is characterized by a reduced

385 number of degrees of freedom, reduced speed and a
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386 more proximal control of the affected arm and hand 6. Understanding non-learning- and 434
387 (Latash et al., 2007). One may argue that, from the per- learning-dependent mechanisms of skill 435
388 spective of controlling degrees of freedom, proximal reacquisition 436
389 control through the trunk and shoulder while fixating

the elbow is easier than controlling all joints simul- A number of mechanisms in the brain have been pro-
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390 437
391 taneously while performing a functional task (Latash posed to underlie sensorimotor recovery after stroke, 438
392 & Anson, 1996). Therefore, serial kinematic mea- as shown in Fig. 1, panel B. The following sections 439
393 surements in which the quality of motor performance first explain the spontaneous mechanisms shown in 440
394 is measured systematically in the first months after panel B. Starting from the ischemic cascade in the 441
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395 stroke are vital in explaining the dynamics of neural first minutes after stroke, there are mechanisms pro- 442
396 recovery. tecting neurons on the one hand, and mechanisms 443
397 The occurrence of compensatory movement strate- accommodating and driving spontaneous peri-infarct 444
gies suggests that this should be seen as an important

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398 neuroplasticity (Brouns & Deyn, 2009; Doyle et al., 445
399 confounder in understanding true motor recovery. This 2008) on the other. In addition, metabolic changes 446
400 finding underlines that limitations in terms of body (including diaschisis) take place around and distal to 447
401 functions and restrictions of activities are not the only the lesion site, which can last up to several weeks 448
402 parameters that should be measured to understand (Biernaskie & Corbett, 2001) or even months (Seitz 449
403 changes in motor performance. Moreover, one may et al., 1999). Subsequent sections then present the evi- 450
404 hypothesize that biomechanical changes in the muscu- dence for the learning-dependent mechanisms in panel 451
405 loskeletal system itself may contribute to a gradually C, introducing evidence to suggest that these sponta- 452
406 changing preferred performance during the execution neous mechanisms can be influenced by experience 453
407 of tasks (Latash et al., 2007). For example, recent stud- (Biernaskie & Corbett, 2001). First, however, we need 454
408 ies using electromyography (EMG) of the arm muscles to define what is meant by neuroplasticity after stroke 455
409 found that mechanical perturbations of the elbow angle and what its relationship with skill reacquisition is 456
410 resulted in two different temporal change patterns (through restitution or compensation).
457 7. Spontaneous (non-learning-dependent) influence of an upregulation of a number of growth 502
458 mechanisms of recovery promoting genes connectivity in surviving neurons is 503
restored. For example, in the first weeks after focal
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459 In the first weeks after stroke, a number of mecha- stroke in rats, growth promoting factors (such as brain- 505
460 nisms are hypothesized to be involved in spontaneous derived neurotrophic factor, BDNF and nerve growth 506
461 neurological recovery such as: (1) salvation of the factor, NGF) are expressed in waves by neurons in the 507
462 penumbra, (2) physiological and neuroanatomical peri-infarct area, creating a favorable environment for 508
463 reorganization, (3) alleviation of diaschisis, (4) and dendritic outgrowth and synaptogenesis (Carmichael, 509
reperfusion enhanced by post-stroke angiogenesis. 2006). Evidence for the involvement of these factors
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464 510
in recovery after stroke has been found in studies on 511
465 7.1. Salvation of the penumbra BDNF, where administering BDNF in rats promoted 512
the improvement of skilled reaching after stroke, as 513
466
467
468
Neurological recovery is assumed to be linearly
correlated with the volume of at-risk tissue in the
penumbra that escapes infarction, whether this is
or
well as dendritic outgrowth (Schäbitz et al., 2004).
There seems to be a change in the balance between the
excitation and inhibition of neurons, and this hyperex-
514
515
516
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469 spontaneous or enhanced by recombinant Tissue citability can be a signal of the resetting of neuronal 517
470 Plasminogen Activator (rTPA) (Baron, 2005). Two activity in the infarcted area due to homeostatic mech- 518
471 mechanisms underlie this correlation: (1) return of neu- anisms (Murphy & Corbett, 2009). This could provide 519
472 ral function (probably due to blood flow being reduced a favorable environment for the presence of waves of 520
but not below a certain threshold), within hours or days, depolarization in the infarct area, which are thought to
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473 521
474 and (2) gradual recovery over weeks through structural be a signal of axonal sprouting (Carmichael, 2006). 522
475 and functional plasticity in the infarct rim. Reperfusion At a later time point after upregulation of growth 523
476 after stroke can greatly reduce injury after ischemia and factors, outgrowth is modulated by inhibitory factors 524
477 can improve neurological outcome after stroke. Struc- (such as NOGO, chondroitin sulphate proteoglycan64, 525
478 tural damage to the dendrites can even be reversed eprhin A5, semaphoring 3A and neuropilin 1). These 526
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479 during reperfusion (Zhang et al., 2005). However, factors are expressed in a later stage after stroke in 527
480 reperfused tissue might still be at risk for inflamma- rats, probably to control axonal outgrowth and pre- 528
481 tion and selective neuronal death up to several days to vent overconnectivity (Murphy and Corbett, 2009; 529
482 weeks after stroke (Guadagno et al., 2008). Cellular Overman et al., 2012). Homeostatic plasticity mech- 530
events related to tissue inflammation and selective cell anisms might cause an initial overproliferation of new
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483 531
484 death during salvation of the penumbra are assumed to connections through axonal sprouting due to disinhi- 532
485 interact with plasticity mechanisms in the infarct rim, bition in the areas connected to the injury (Winship 533
486 which are therefore important when trying to model the & Murphy, 2009). These overconnections might be 534
487 mechanisms involved in recovery after stroke (Baron, pruned by Hebbian- and non-Hebbian like learning 535
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488 2005; van der Zijden et al., 2008). Subsequently the mechanisms in optimizing these adapted neural cir- 536
489 amount of recovery that a patient shows in this period cuits in response to relearning skills. Interestingly, both 537
490 might well be influenced by these mechanisms related Hebbian-like mechanisms in the peri-infarct area and 538
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491 to the survival of the penumbra. homeostatic synaptic neuroplasticity could be coordi- 539
nated by upregulation of factors such as BDNF (Pozo 540
492 7.2. Spontaneous neuroplasticity & Goda, 2010). 541
493 After injury, the areas around the lesion as well as 7.3. Alleviation of diaschisis 542
494 anatomically connected areas further away from the

495 lesion undergo substantial spontaneous physiological Spontaneous recovery after stroke is not restricted 543
496 and neuroanatomical changes. Homeostatic mecha- to the first hours after stroke, but may happen dur- 544
497 nisms ensure that activity in the surviving neurons is ing a longer period, even up to 10 weeks (Kwakkel 545
498 scaled to previous input, meaning that high levels of et al., 2006). The limited therapeutic window for 546
499 activation favor synaptic depression while low levels rTPA, three to four hours after stroke, suggests that 547
500 of activation (for example deafferentiation due to the other mechanisms, such as recovery from “cerebral 548
501 lesion) induce facilitation (Turrigiano, 2008). Under shock” or alleviation of diaschisis, may explain the 549
550 spontaneous neurological recovery that may continue priate therapeutic target in the penumbral area in the 598
551 for several weeks. Monakov first described the phe- first hours after stroke. Proteins associated with neu- 599
nomenon of diaschisis in 1914, and proposed that areas roplasticity and dendritic outgrowth in stroke, such as
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553 distant from the lesion could be functionally affected BDNF and transforming growth factor alpha (TGFa), 601
554 by neuronal damage. The term diaschisis is used today have also been associated with angiogenesis and are 602
555 for any “remote” effect initiated by a focal lesion or therefore referred to as angioneurins (Font et al., 2010). 603
556 ischemic event to the brain (Andrews, 1991; Seitz et Interestingly, these proteins are involved in learning- 604
557 al., 1999; Witte et al., 2000). Diaschisis is accompa- dependent neuroplasticity as well (Ploughman et al., 605
nied by depression of regional cerebral blood flow 2009).
P
558 606
559 extending beyond the anatomical lesion, as demon-

560 strated by a perfusion deficit in the region of cortical 7.5. Learning-dependent mechanisms of 607
561 diaschisis measured with rCBF-SPECT (Chu et al., neuroplasticity 608
562
563
564
2002; Komaba et al., 2004). Alleviation of the sup-
pression of brain areas anatomically related to the
lesion (i.e. reversal of diaschisis) is thought to con-
or
The synaptic scaling caused by homeostatic neu-
roplasticity seems to create a favorable environment
609
610
uth
565 tribute to motor recovery of neurological function and in which other forms of learning-dependent plastic- 611
566 motor control in the first months after stroke (Feeney ity (Hebbian-type synaptic strengthening and pruning) 612
567 & Baron, 1986; Seitz et al., 1999). While serial assess- can take place, and ensures that neurons in the peri- 613
568 ments of diaschisis have been scarce, the topographical infarct area continue to receive sufficient input. The 614
overlap between lesion-affected and recovery-related brain quickly adapts in response to a lack of input by
dA
569 615
570 brain networks supports the idea that reversal of the remapping the somatosensory cortex, as was shown 616
571 suppressed areas may play a significant role in skill in monkeys following deafferentiation (Clifford, 1998; 617
572 reacquisition after stroke (Chu et al., 2002; Seitz et al., Nudo & Milliken, 1996). If a single digit is removed 618
573 1999). However, its physiological aspects, as well as from an adult animal (a form of deafferentiation) the 619
574 its time window, are still largely unknown, and persis- cortical area connected to that digit rapidly remaps to 620
cte
575 tent remote effects of cortical injury are more complex represent the remaining intact digits that project to the 621
576 than previously thought (Gold & Lauritzen, 2002). For adjacent cortex (Nudo & Milliken, 1996). The forma- 622
577 example, diaschisis involves disinhibition of anatomi- tion of new cortical connections occurs in areas that are 623
578 cally related brain areas as well as hyperexcitability, not involved in the infarct itself and that start to receive 624
in addition to the well-known hypometabolism and input of information from the nearby cortex (Dancause
rre
579 625
580 inhibition of these areas (Andrews, 1991). et al., 2005). Strong excitatory or inhibitory NMDA 626
receptor-dependent postsynaptic changes may lead to 627
581 7.4. Non-neural forms of plasticity after stroke long-term potentiation (LTP) or long-term depression 628
(LTD), respectively (Cooke & Bliss, 2006). Further 629

co
582 New blood vessels are formed in the peri-infarct enhancement of the production of proteins involved 630
583 zone in the first days to weeks after stroke (Font et al., in synaptic neuroplasticity can be obtained through 631
584 2010). Recent research demonstrated that angiogenesis experience, including training and afferent stimulation 632
Un
585 and neurogenesis are coupled restorative mechanisms (Sawaki et al., 2006; Winship & Murphy, 2009). 633
586 that contribute to neurological recovery (Chopp et al., Animal studies have revealed a complex interplay 634
587 2007). between mechanisms of homeostatic and Hebbian- 635
588 For example, metalloproteinases (MMPs) released and non-Hebbian forms of plasticity, in which mecha- 636
589 in the penumbral area after stroke causes breakdown of nisms of neuroplasticity are not only dependent on the 637
590 the blood–brain barrier (BBB) and are therefore associ- amount of practice, but also on the type of training as 638
591 ated with edema and neuronal loss. However, MMP-9 well as its timing after stroke (Biernaskie & Corbett, 639
592 has also been suggested to be involved in revascular- 2001; Ploughman et al., 2009). For example, moderate 640
593 ization in the later stages after stroke (Zhao et al., 2006, treadmill training in rats was found to increase levels of 641
594 2007). Thus, downregulation of MMPs over a longer proteins such as BDNF, neurophysin-I and insulin-like 642
595 period might protect neurons in the first few hours but growth factor (IGF) type I. However, when these rats 643
596 might subsequently be detrimental to neuroplasticity. engaged in an intensive (60 minutes, forced) motorized 644
597 It seems that timing is important in finding an appro- running training, the elevation of growth factors was 645
646 more short-lived than after voluntary running initiated motor network (Dancause, 2006). In the early days 691
647 by the rats themselves (Ploughman et al., 2005). This most fMRI studies were performed on patients in the 692
finding suggests that frequent but low-intensity exer- chronic stage (>6 months) after stroke. These studies
f
648 693
roo
649 cise episodes (voluntary running over a 12 h period) found overactivations in a number of motor areas in 694
650 has a delayed but sustained effect on BDNF production patients who showed poor skill reacquisition compared 695
651 (Ploughman et al., 2007). The importance of therapy to control subjects. These over-activations were pre- 696
652 dosage is shown by MacLellan and colleagues who dominantly seen in the bilateral premotor cortex (PM), 697
653 found that voluntary reaching in rats needed to rise supplementary motor area, as well as parietal regions 698
above a certain threshold to cause improvement of (Seitz et al., 1998; Ward, Brown et al., 2003b). High
P
654 699
655 motor function at an activity level and to produce ele- scores on outcome measures in terms of body func- 700
656 vated levels of BDNF (MacLellan et al., 2011). There tions and activities is associated with preservation or 701
657 seems to be a critical time window when administering restoration of activity in the ipsilesional hemisphere, 702
658
659
660
rehabilative therapy in animals after stroke. An impor-
tant study showed that delaying rehabilative treatment
in a rodent stroke model for 30 days after stroke, led
or
rather than task-related recruitment of activity in the
non-affected hemisphere (Small et al., 2002; Ward et
al., 2003a). Recent serial fMRI and PET studies have
703
704
705
uth
661 to poor improvement of upper limb function as well a suggested that cortical reorganization over time (i.e. the 706
662 no change in dendritic outgrowth. Rehabilitation ther- amount of recruitment and activation of task-specific 707
663 apy administered in the first few weeks after stroke, areas in the unaffected and affected hemispheres) is 708
664 however, enhanced improvement on a reaching task as largely dependent on the intactness of the corticospinal 709
well as increasing dendritic outgrowth (Biernaskie et tract, which can be measured with TMS (Ward et
dA
665 710
666 al., 2004). al., 2003a, 2003b), or diffusion-tensor imaging (DTI) 711
(Newton et al., 2006). 712
667 7.6. Other forms of brainplasticity It is unlikely (from the perspective of regaining dex- 713
terity) that secondary motor areas are able to take over 714
668 Animal studies have shown that treadmill running the actions of the primary motor system (Maier et al., 715
cte
669 may also enhance the blood-vessel density in the 2002; Ward, 2007). Indeed, ipsilateral increments in 716
670 motor cortex, cerebellum and striatum thereby allow- cortical activation are correlated with poor skill reac- 717
671 ing increased metabolism in poorly perfused areas quisition in terms of body functions and activities 718
672 (Black et al., 1990; Ding et al., 2004; Kleim et al., (Buma et al., 2010). An increase in axial muscle con- 719
2002). In interaction with some of the above men- trol has recently been suggested to be accompanied by
rre
673 720
674 tioned forms of cortical reorganization around the an increase in ipsilateral cortical activity, whereas for 721
675 infarct rim, treadmill running therapy does indeed up- distal arm muscles, ipsilateral increases are correlated 722
676 regulate endothelial nitric oxide synthase (Endres et with moderate to severe impairment (Schwerin et al., 723
677 al., 2003), as well as reducing pro-coagulation factors 2010). These findings might suggest that an increase 724
co
678 and increasing factors associated with anticoagulation in the excitability of ipsilateral pathways projecting 725
679 (Wittenberg et al., 2003). Nevertheless, the exact role to the proximal upper arm may contribute to the con- 726
680 of angiogenesis evoked by training in the human brain trol of arm extension following stroke (Bradnam et al., 727
Un
681 is an unexplored area. 2012). Apparently, it is much more difficult to restore 728
the affected primary motor networks responsible for 729
distal multi-joint coordination than to use more proxi- 730
682 8. In vivo imaging of cortical map mal motor control in a sequential, fragmented type of 731
683 reorganization in humans movement (Cirstea & Levin, 2000). 732
The mechanisms of cortical reorganization are prob- 733
684 Cross-sectional and longitudinal fMRI, PET and ably stimulated by task-specific therapy. For example, 734
685 TMS studies suggest that the damaged adult human repeated TMS (Liepert et al., 2000), PET (Nelles 735
686 brain shows changes in activity patterns (Askim et al., et al., 2001) or fMRI (Johansen-Berg et al., 2002) 736
687 2008; Calautti & Baron, 2003; Johansen-Berg et al., measurements show that therapy-mediated improve- 737
688 2002; Nelles et al., 2001; Rehme et al., 2012; Ward ments by CIMT result in increased activity in the 738
689 et al., 2003a). These changes are thought to repre- affected hemisphere and decreased activity in the 739
690 sent remapping and vicarious functions of areas in the unaffected hemisphere while a motor task is being 740
741 performed with the affected hand. However, these proposed phenomenological model for understanding 788
742 macroscopic changes in cortical activation after arm skill reacquisition after stroke (Fig. 1). As discussed, 789
training or CIMT may reflect compensatory motor panel A illustrates that skill reacquisition through
f
743 790
roo
744 skill learning rather than restoration of lost repre- motor learning may take place in a number of steps. 791
745 sentations (Sunderland & Tuke, 2006). As mentioned At first, most patients suffer from a reduced abil- 792
746 above, it is of paramount importance to kinematically ity to modulate their movement apparatus due to 793
747 assess whether synergistic compensatory movement loss of somatosensory sensation, muscle strength and 794
748 patterns (such as trunk involvement) might be respon- selectivity in muscle recruitment. At the same time, 795
sible for the improved task performance and whether biomechanical changes occur as a result of loss of
P
749 796
750 these compensatory mechanisms are confounding the muscle fibers by orthograde degeneration, increased 797
751 relationship between skill reacquisition and brain acti- stiffness and velocity-dependent changes in myotatic 798
752 vation as measured with fMRI. stretch reflexes (spasticity). Patients with a poor prog- 799
753
754
755
Since improvement after stroke is time-dependent,
results of imaging studies are heavily influenced by
the moment of scanning after stroke, at least when
or
nosis will use compensatory movement strategies
to recover motor control, whereas patients with a
favorable prognosis will be able to restore impaired
800
801
802
uth
756 measuring during the first 6 months after stroke functions. Ultimately, the actual motor performance, 803
757 (Kwakkel, 2006). The great complexity of assess- and consequently the ability to accomplish a particu- 804
758 ing neural correlates of skill reacquisition after stroke lar task, will depend on the equilibrium between the 805
759 demands an appropriate study design taking account capacity for restitution versus compensation. 806
of the confounders often encountered in stroke imag- In the early stages after stroke, non-learning-
dA
760 807
761 ing research. Statistical, anatomical, experimental and dependent mechanisms such as spontaneous motor 808
762 task-dependent factors may confound results, lead- recovery (panel B) as well as learning-dependent 809
763 ing to interpretation problems in serial fMRI studies mechanisms (panel C) are responsible for changes in 810
764 (Buma et al., 2010, for a systematic review). Exam- cortical reorganization. The process of spontaneous 811
765 ples are: (1) using appropriate measures of functional recovery is defined by salvation of penumbral tis- 812
cte
766 improvement of the upper paretic limb, which measure sue by reperfusion, angiogenesis and “spontaneous” 813
767 improvement of body functions; (2) using quantitative alleviation of diaschisis or cerebral shock (panel 814
768 measures of the quality of performance in executing a B). Mechanisms related to spontaneous neurological 815
769 motor paradigm (e.g. strength, ROM, speed, attention recovery are mainly defined by progress of time and 816
and sensation), so that performance of the task can be restricted to the first 10 weeks after stroke (Dobkin,
rre
770 817
771 accounted for; (3) controlling for “mirror movements” 2005; Kwakkel et al., 2006). Simultaneously, and in 818
772 of the non-paretic limb to ensure proper interpretation interaction with spontaneous neurological recovery, 819
773 of activity in the unaffected hemisphere (Kim et al., experience through practice will also lead to corti- 820
774 2003). In addition it might be relevant to assess the cal reorganization, starting within minutes from stroke 821
co
775 influence of time-dependent neuromechanical changes onset (Panel C). Hebbian and non-Hebbian learning 822
776 in the arm itself in terms of increased stiffness and spas- mechanisms lead to LTP and LTD. Both mechanisms 823
777 ticity, to be able to understand the relationship between result in a change in interneuronal connectivity and 824
Un
778 task dependent changes in the brain and the possibly efficiency in the communication along existing neu- 825
779 increased non-neural passive resistance by changes in ronal networks (Cooke & Bliss, 2006). 826
780 muscle and connective tissue (for critical comments We argue that understanding skill reacquisition 827
781 see Dobkin, 2003). after stroke requires a translational, multidisciplinary 828
approach, with intensive measurements repeated over 829
time. In these time-series both motor performance and 830
782 9. Connecting the dots and targets for future changes in brain activity need to be measured simulta- 831
783 research neously during identical time frames after stroke. The 832
first measurements should preferably start in the first 833
784 The likelihood of regaining skills after stroke is days after stroke, and they should be repeated until skill 834
785 complex and determined by a number of learning- reacquisition has reached a plateau. In order to improve 835
786 and non-learning-dependent mechanisms. These are our understanding of skill reacquisition after stroke, 836
787 brought together and summarized in context in our serial assessments should investigate the relationships 837
838 between observed improvements in clinical measures, Latash et al., 2007), phenomena such as increased 888
839 kinematics, biomechanics and cortical map reorganiza- intrinsic stiffness and reflex stiffness need to be mea- 889
tion (Kollen et al., 2005; Kwakkel et al., 2008; Wagner sured to understand the observed changes in motor
f
840 890
roo
841 et al., 2007). Such serial measurements may enable us performance (Dewald et al., 2001; Mirbagheri et al., 891
842 to distinguish “true” neurological repair from learn- 2009). 892
843 ing to use compensation strategies. This goal does not As a consequence, our model of the processes and 893
844 seem to be sufficiently served merely by studying the mechanisms of skill reacquisition after stroke may be 894
845 changes in cortical map reorganization by fMRI or helpful in designing trials and selecting therapy. First, 895
PET in relation to the intactness of the corticospinal our model recommends that clinicians and researchers
P
846 896
847 tract system assessed by TMS or fiber tracking. Under- should distinguish between skill reacquisition result- 897
848 standing the meaning of changes in cortical activity as a ing from neurological repair and from compensation 898
849 function of time requires simultaneous measurements strategies (Fig. 1) (Levin et al., 2009). Second, the con- 899
850
851
852
of changes in motor performance, including kinematics
(Goodwin & Sunderland, 2003; Kwakkel & Wagenaar,
1996; Wagner et al., 2007).
or
tribution of non-learning-dependent mechanisms such
as spontaneous neurological recovery suggests that tri-
als should use appropriate randomization procedures
900
901
902
uth
853 The above phenomenological model currently when studying the impact of therapeutic interventions 903
854 serves as a template for the EXPLICIT-stroke program on skill reacquisition in the early stages after stroke 904
855 in the Netherlands (Kwakkel et al., 2008). EXPLICIT- (Kwakkel et al., 2006). This confirms the general rule 905
856 stroke is an acronym for ‘EXplaining PLastICIiTy that stroke outcome data should only be reported when 906
after stroke’. The EXPLICIT-stroke program is a 6- the observations of experimental and control groups
dA
857 907
858 year translational research program supported by the are made during the same time interval after stroke 908
859 The Netherlands Organisation for Health Research and onset. Third, our model supports the general conviction 909
860 Development (ZonMw). The main aim of EXPLICIT- that the selection of a type of therapy in the early stages 910
861 stroke is to investigate the effects of intensive after stroke, matters for the final outcome. For exam- 911
862 intervention to regain dexterity starting within 2 weeks ple, there is a longstanding debate in rehabilitation 912
cte
863 after stroke, and to explore the underlying mechanisms medicine whether specialists should aim for restitu- 913
864 involved in regaining upper limb function in the first 6 tion of body functions or should allow patients to adopt 914
865 months after stroke. For this purpose stroke patients compensation strategies (Kollen et al., 2005; Krakauer 915
866 are longitudinally investigated by applying a multi- et al., 2012). The current view is an extension of reports 916
modal approach in which clinical outcomes are related from longitudinal studies that suggest that restitution
rre
867 917
868 to observed changes measured with fMRI, TMS, DTI, and compensation complement each other in the pro- 918
869 kinematic assessments and haptic robotics after stroke. cess of skill acquisition that starts immediately after 919
870 The EXPLICIT-stroke program is expected to provide stroke onset. The question whether we should prevent 920
871 an answer to the key question how much of therapy- patients from adaptive motor learning in the first weeks 921
co
872 induced improvement is due to restitution of function after stroke to optimize normal movement remains 922
873 and how much to compensatory mechanisms (Kwakkel unsolved, through lack of proper randomized clinical 923
874 et al., 2008). trials (Kollen et al., 2005). 924

Un
875 In addition, future studies, including those con-

876 ducted in animals should measure the quality of
877 motor performance, by including kinematic analysis, 10. Limitations 925
878 in addition to outcome measures in terms of body func-

879 tions and activities. With that, research relating the The focus in the present Point of View has been 926
880 principles of cortical map reorganization to a better on bridging the gap between preclinical and clini- 927
881 understanding of what and how patients learn, instead cal research on skill reacquisition after stroke. We 928
882 of relating it to whether they learn, is expected to fur- have attempted to show where there are gaps in 929
883 ther enhance our understanding of the meaning of the our knowledge and have focused on constructing 930
884 neural dynamics in activation patterns after stroke. a phenomenological model for understanding stroke 931
885 Acknowledging that patients’ motor performance is recovery. While much can be learned from animal stud- 932
886 also determined by changes in the structure of the ies some caution must be taken in translating these 933
887 movement apparatus itself (Latash & Anson, 1996; results to humans. We suggest there are a number 934
935 of issues (1) Animal stroke models are mostly based ses derived from and founded on knowledge of basic 982
936 on cortical stroke, whereas subcortical stroke is much and preclinical science (Cheeran et al., 2009). The 983
more common in humans (Carmichael, 2005) (2) The research questions addressed will then lead to answers
f
937 984
roo
938 exercise therapy used in animal studies does not easily to clinically relevant problems that are perceived as 985
939 translate to human studies since (a) treadmill running critical for improving care for one of the most common 986
940 does not translate to task specific training used in reha- disabling diseases, stroke (Dong et al., 2006). 987
941 bilitative setting in humans (Hillman et al., 2008) (b)

942 the threshold dose for treatment of task-specific train-
ing in animal studies is found to be around a factor of
P
943
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945 tative setting (Krakauer et al., 2012; Lang et al., 2009; Alibiglou, L., Rymer, W.Z., Harvey, R.L. & Mirbagheri, M.M. 989
946 Remple et al., 2001) (3) The timeframe of recovery (2008). The relation between Ashworth scores and neu-
947
948
949
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952 ery that is aimed for is relearning a well-practiced task
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958 motor control is restored is mainly confined to a limited Biernaskie, J., Chernenko, G. & Corbett, D. (2004). Efficacy of reha- 1006
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975 drive “spontaneous” recovery after stroke and restitu- Calautti, C. & Baron, J.C. (2003). Functional neuroimaging studies 1025
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Restorative Neurology and Neuroscience xx (20xx) x–xx 1

9 Utrecht, The Netherlands

Keywords: Neuroplasticity, recovery, stroke, rehabilitation, paresis, hebbian learning

23 1. Introduction or a Barthel Index (BI) below 12 points at 3 months 29

after after stroke (Heuschmann et al., 2011). In the 30

et al., 2009). Although individual recovery patterns 36

by the remaining intact motor elements at the level of 122

body function. However, skill reacquisition at an activ- 123

function by entirely different end effectors or body seg- 125

187 allow the use of the non-paretic hand to accomplish

191 most clinical outcome measures of the upper paretic

improvement are often characterized by movements 251

in synergistic patterns (Cirstea & Levin, 2000). Syn- 252

pathological couplings between, for example, shoulder 254

312 ities is thought to be mainly defined by adaptation or of trials in this field.

after stroke, while in other patients, intrinsic stiff-

In humans, increased coupling between shoulder

384 cles in a selected pattern, is characterized by a reduced

388 spective of controlling degrees of freedom, proximal reacquisition 436

389 control through the trunk and shoulder while fixating

gies suggests that this should be seen as an important

398 neuroplasticity (Brouns & Deyn, 2009; Doyle et al., 445

457 7. Spontaneous (non-learning-dependent) influence of an upregulation of a number of growth 502

458 mechanisms of recovery promoting genes connectivity in surviving neurons is 503

restored. For example, in the first weeks after focal

in recovery after stroke has been found in studies on 511

the improvement of skilled reaching after stroke, as 513

nated by upregulation of factors such as BDNF (Pozo 540

492 7.2. Spontaneous neuroplasticity & Goda, 2010). 541

494 anatomically connected areas further away from the

nied by depression of regional cerebral blood flow 2009).

559 extending beyond the anatomical lesion, as demon-

561 diaschisis measured with rCBF-SPECT (Chu et al., neuroplasticity 608

receptor-dependent postsynaptic changes may lead to 627

(LTD), respectively (Cooke & Bliss, 2006). Further 629

587 2007). between mechanisms of homeostatic and Hebbian- 635

(Newton et al., 2006). 712

the affected primary motor networks responsible for 729

distal multi-joint coordination than to use more proxi- 730

683 reorganization in humans movement (Cirstea & Levin, 2000). 732

The mechanisms of cortical reorganization are prob- 733

approach, with intensive measurements repeated over 829

time. In these time-series both motor performance and 830

first measurements should preferably start in the first 833

842 to distinguish “true” neurological repair from learn- 2009). 892

874 et al., 2008). trials (Kollen et al., 2005). 924

875 In addition, future studies, including those con-

878 in addition to outcome measures in terms of body func-

941 bilitative setting in humans (Hillman et al., 2008) (b)

Baron, J. (2005). How healthy is the acutely reperfused ischemic 1000

upper limb following stroke. Cereb Cortex, 22(11), 2662-2671. 1015

measurement of upper limb recovery in the subacute phase 1111

exercise your heart: Exercise effects on brain and cognition. 1122

Brain, 125, 2731-2742. 1127

1074 99(22), 14518-14523. 1131

310-318. dependent neural plasticity in the adult damaged brain. J 1139

1088 306-315. 14(10), 1329-1332. 1144

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