Reflections on mirror therapy: a systematic review of the effect of mirror visual feedback on the...

Reflections upon mirror therapy!

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Reflections upon mirror therapy –!a systematic review of the effect of mirror

visual feedback on the brain

Deconinck FJA1,2,*(PhD), Smorenburg ARP3(PhD), Benham A4(PhD), Ledebt

A5(PhD), Feltham MG6(PhD), Savelsbergh GJP5(PhD)!

1 Ghent University (Belgium), Department of Movement and Sports Sciences!2 Manchester Metropolitan University (UK), School of Healthcare Sciences!3 Burke-Cornell Medical Research Institute (USA)!4 Bradford Institute for Health Research (UK)!5 VU University Amsterdam (The Netherlands), Research Institute MOVE!6 University of Birmingham (UK), Primary Care Clinical Sciences!

*Corresponding author:

Ghent University –!Faculty of Medicine and Health Sciences, Department of

Movement and Sports Sciences, Watersportlaan 2, 9000 Gent, Belgium!

Tel.: +32 (0)9 264 91 37!

E-mail: [email protected]!

!

This paper is published in Neurorehabilitation and Neural Repair.

The final publication is available at Sage via

http://dx.doi.org/[DOI:10.1177/1545968314546134]


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Abstract

Background: Mirror visual feedback (MVF), a phenomenon where movement of one

limb is perceived as movement of the other limb, has the capacity to alleviate

phantom limb pain or promote motor recovery of the upper limbs after stroke. The

tool has received great interest from health professionals, however, a clear

understanding of the mechanisms underlying the neural recovery owing to MVF is

lacking.!Objective: We performed a systematic review to assess the effect of MVF on brain

activation during a motor task. !Methods: We searched PubMed, CINAHL, and EMBASE databases for

neuroimaging studies investigating the effect of MVF on the brain. Key details for

each study regarding participants, imaging methods and results were extracted.!Results: The database search yielded 347 papers, of which we identified 33 suitable

for inclusion. Compared with a control condition, MVF increases neural activity in

areas involved with allocation of attention and cognitive control (dorsolateral

prefrontal cortex, posterior cingulate cortex, S1 and S2, precuneus). Apart from

activation in the superior temporal gyrus and premotor cortex, there is little evidence

that MVF activates the mirror neuron system. MVF increases the excitability of the

ipsilateral primary motor cortex (M1) that projects to the ‘untrained’!hand/arm. There

is also evidence for ipsilateral projections from the contralateral MI to the

untrained/affected hand as a consequence of training with MVF. !Conclusion: MVF can exert a strong influence on the motor network, mainly through

increased cognitive penetration in action control, though the variance in methodology

and the lack of studies that shed light on the functional connectivity between areas

still limit insight into the actual underlying mechanisms.!

Key words

systematic review, sensorimotor control, visual feedback, mirror, hemiparesis, stroke,

cerebral palsy !


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Introduction

Often a source of fascination, or perhaps frustration, optical illusions have captivated

people since ancient times. For instance, curved surfaces and the absence of right

angles in archaic Greek temples suggest that its architects attempted to optically

correct the illusion of slanted columns or curved tympanums; however, others believe

these features may serve engineering purposes or reflect aesthetic preference.1 As

much as they are a source of excitement, for neuroscientists optical illusions are

considered a backdoor into people’s mind and provide an excellent way to study the

neural mechanisms underlying perception and action.2

Interestingly, although optical illusions are known to deceive the individual, the

false reality may fool the brain, such that the outcome is beneficial. One such an

illusion is the mirror illusion, which has been found to have therapeutic benefits over

the past 2 decades. When a mirror is placed, along the midsagittal plane in between

the 2 limbs, the reflection of the limb in front of the mirror is superimposed on the

contralateral limb. Any motion of the limb in front of the mirror induces the illusion

of 2 synchronously moving limbs. After Ramachandran and his colleagues found that

this illusion could alleviate phantom pain in a proportion of the patients,3 mirror

visual feedback (MVF) was introduced as a neurorehabilitation tool to treat other

unilateral pain disorders, such as complex regional pain syndrome (CRPS). In

addition, the paradigm is now used to promote motor recovery (eg, in hemiparetic

patients or after hand surgery).

Despite its widespread use in neurorehabilitation and the claims that MVF

therapy would lead to neuroplastic changes, there is no consensus about the

underlying mechanism and speculation often lacks the neuroscientific proof. The

aim of this review is therefore to bring together current knowledge on the effect of

MVF on the brain as has been described in neuroimaging studies, in order to

explore potential processes underlying the beneficial clinical effects of MVF. To

acquaint the reader with MVF and its current applications, we will first revisit

Ramachandran’s rationale for MVF, followed by a narrative review of the clinical

neurorehabilitation research that followed in his footsteps. At the end of this

section, we introduce 3 hypotheses that have been proposed to explain the positive

effects related to MVF. Part 2 provides a systematic review and discussion of

studies that examined the effect of MVF on brain activation patterns using

neuroimaging or electrophysiological techniques. Finally, in Part 3 we discuss the


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findings of the systematic review in relation to the hypotheses introduced in Part 1

and we identify where further research is required.

Part 1: Mirror therapy – background, current applications, and potential

mechanisms

The idea of using MVF for the management of phantom limb pain was inspired by

early findings on the integration of perception and action, in particular the

principle of reafference.4,5 Reafference is afferent sensory information caused by a

motor command (eg, signals from muscle spindles in M. biceps brachii when the

arm is actively flexed), as opposed to exafferent information, which results from

factors outside the individual (eg, signals from muscle spindles in M. biceps

brachii when the arm is flexed passively). To distinguish between these 2 sensory

stimuli, it is maintained that the generation of a motor command is accompanied

by a parallel signal, termed efference copy, which contains the sensory feedback to

be expected due to this command. Comparison of all afferent signals with the

efference copy provides a way to separate signals that originate from bodily

movements and those from outside the individual. As a consequence, motor

commands that are not instantaneously followed by the expected reafferent

feedback will be modified in an attempt to evoke the expected sensory afference.5

It is this conflictive state that, according to some,6,7 may evolve into a form of

“learned paralysis” accompanied by a feeling of painful spasms,* as experienced

by a proportion of patients who have had an arm or leg amputated. The goal of

MVF is to restore the efference–afference loop that has been interrupted. MVF of

the intact limb deceives the individual and elicits the awareness that the amputated

limb is still intact, not at least due to the dominance of the visual system over

other modalities.8,9 Indeed, when the illusion was tested in arm amputees with

complaints of “clenching spasms” and phantom limb pain, the spasms were

&!In their recent review article, Ramachandran and Altshuler9 rec- ognize that the origin of phantom pain is still poorly understood and may be related to other factors, for example, persistence of preamputation pain and pathological “remapping” among others (see also Ramachandran and Hirstein6). The rationale to use MVF, however, is based on the notion of a mismatch between motor output and visual and/or proprioceptive feedback.!


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eliminated and the pain was relieved immediately after exposure to MVF in a

proportion of the sample.3

The novelty and simplicity of the idea, in combination with the far-reaching

potential of MVF, prompted clinicians and researchers to replicate the initial

findings of Ramachandran and colleagues. Consistent with the earlier

observations, follow-up studies have confirmed that MVF treatment has the

capacity to reduce phantom limb pain intensity and duration.10,11 Moreover, the

notion that many neurological disorders with unilateral pain and motor symptoms

may be (partly) caused by maladaptive cortical reorganization involving a

disruption of the efference–afference loop, led others to apply MVF to a wide

range of conditions. Hemiparesis after stroke is perhaps the most striking example.

In a proportion of the patients the paresis is thought to be a form of “learned

paralysis” due to a nonpermanent blocking of corticofugal fibers by swelling after

the trauma.12 A recent Cochrane Review exploring the effectiveness of MVF

therapy in patients after stroke (13 randomized controlled trials, 506 patients)

concluded that mirror therapy indeed might be more effective in promoting motor

function than a control intervention† when used as an adjunct to conventional

therapy.13 Furthermore, the meta-analysis indicated that the effects were retained,

up to 6 months after the intervention, and that MVF therapy had a significantly

greater effect than control interventions on activities of daily living and on pain,

though the latter was found only in a subgroup with CRPS after stroke.

To date, MVF is administered to treat various unilateral pain and/or motor

disorders, including CRPS,14-18 hemiparesis after stroke,19,20 reduced mobility after

wrist fracture,21 and spastic hemiparetic cerebral palsy (SHCP).22,‡ The findings of

these studies tend to corroborate the initial work, that is, a reduction in pain and

improvement in motor function. Still, it should be noted that publication bias toward a

selection of positive results may be likely and additional placebo-controlled studies

are needed for all conditions or symptoms. In this respect, it is worth mentioning that

Brodie et al found that the attenuating effect of MVF on pain was not stronger than a

control condition in lower limb amputees.23

(The effect of MVF therapy was significantly larger than control interventions.!!)See Ramachandran and Altschuler9 for a list of clinical cases where the use of MVF has been observed informally but has not been described in the literature.!


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Despite the fact that there appear to be parallels in the pathophysiology of unilateral

pain and motor disorders as described by Ramachandran and Altschuler,12 the 2

phenomena should be considered separately, hence the focus of this review will be on

the effects of MVF on sensorimotor control. To fully exploit the potential of MVF, a

better insight into the processes that underlie the beneficial effects on motor function

is required. Not only would this knowledge advance our theoretical understanding of

the brain, it may also provide guidelines as to when MVF may be useful and how it

should be applied.

When the individual is required to perform bilateral, symmetrical motor tasks,

MVF therapy may be considered a special form of bilateral training, and hence exploit

similar mechanisms (see Cauraugh and Summers for a review24). However, in search

of the added value of MVF researchers have invoked 3 (not mutually exclusive)

hypotheses to account for the positive effects of MVF on motor recovery. A first

hypothesis relates to the mirror neuron system.17,19,20 Mirror neurons fire both when

an individual observes an action and when he/she performs a similar action. The

network, including the premotor cortex, supplementary motor area, inferior frontal

gyrus, and inferior parietal lobule of the brain, is thought to play an important role in

action recognition and motor learning or rehabilitation.25 An observation/execution

matching mechanism, whereby action observation activates crucial parts of the motor

system, is hypothesized to induce motor learning.25,26 It is known that action

observation facilitates the corticospinal pathway and this paradigm is already used in

neurorehabilitation as mental practice aimed at improving motor function.27

According to this hypothesis, a “mirror box” is a means to facilitate action

observation and therefore MVF is thought to activate the mirror neuron system in a

similar way to action observation (Hypothesis 1). In line with this is the notion that

MVF may elicit or enhance motor imagery,28 that is, internal simulation of movement

without overt action. Just like action observation motor imagery has been attributed

therapeutic capacities because it activates neural circuits involved in motor control.29

Second, MVF might promote recruitment of ipsilateral motor pathways.30 These

motor pathways, originating in the unaffected hemisphere and projecting ipsilaterally

to the paretic body-side, have been attributed a nontrivial role in the restoration of

motor function in hemiparesis.31-34 It is hypothesized that MVF might facilitate the

unmasking of “dormant” ipsilateral projections, which are normally inhibited

(Hypothesis 2).


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Finally, MVF or the associated illusion is thought to increase an individual’s

(spatial) attention toward the unseen (affected) limb.35 It is known that hemiparetic

patients may end up in a state of “learned nonuse,” by continuously avoiding the use

of the paretic hand or by pathophysiological disruption of the efference–afference

loop.36 In keeping with the rationale for using constraint-induced movement therapy,36

the increased attention toward the affected limb, mediated by the illusory image of a

“healed” paretic limb, may activate motor networks (Hypothesis 3).

In sum, an increasing body of evidence underpins the potential of MVF to facilitate

recovery of motor function. Still, the neural mechanism of MVF, whether the

behavioral effect is accompanied by neuroplastic changes, and what this

reorganization would involve is unclear. The hypotheses invoked to explain MVF

effects are based on known concepts in neurorehabilitation, but they remain

speculative. Recent experimental neuroimaging research has begun to reveal the

extent of brain activation during movement with MVF, and its modulatory effects on

brain processes compared with normal visual conditions. In the following part of this

article, the findings of these studies will be systematically reviewed. This will serve as

a validity test of the proposed hypotheses.

Part 2: The neural correlates of mirror visual feedback

2.1. Purpose

The purpose of this systematic review was to identify the areas in the brain that are

differentially affected or modulated by MVF compared with a condition with normal

or without visual feedback.

2.2. Literature search

A literature search using the electronic databases PubMed, CINAHL, and EMBASE

(1972 to January 2014) was conducted. Search terms included “mirror therapy” or

“mirror visual feedback” combined with “functional magnetic resonance imaging

(fMRI),” “positron emission topography (PET),” “transcranial magnetic stimulation

(TMS),” “magnetoencephalography (MEG),” “electroencephalography (EEG),” or “near

infra-red spectrometry (NIRS).” In addition, we checked our personal database and the

reference list of included articles. Our search was restricted to peer-reviewed full articles

written in English.


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Inclusion criteria were the following:

• Experimental studies or clinical trials

• Normal and/or motor-impaired human participants

• Use of neuroimaging techniques (fMRI, PET, MEG, EEG, NIRS) or TMS to

study the effect of MVF§ on cortical activation (and related motor performance

or perceptual measures)

Exclusion criterion was the following:

• Studies that do not assess effect of MVF on sensorimotor control, but focus on

pain and/or tactile perception.

The records identified by this search were screened independently by 2 authors of

this systematic review (FD and AS) in 2 stages: a first stage screening of titles and

abstracts and a second stage using the full text of the remaining article. The lists of

eligible articles identified by the independent reviewers were compared, and any

disagreements were resolved through discussion (and referral to the text of the articles

in question).

2.3. Results

The electronic database search yielded 347 unique articles, of which 33 were

deemed eligible for this systematic review (see Figure 1 for an overview of the

selection process). Across the selected articles, the most commonly used scanning

technique was fMRI (12 studies).37-47 MEG was the neuroimaging modality in 5

article,48-52 EEG in 4,53-56 PET in 2,57,58 and NIRS in 2.59,60 Nine studies

investigated the effect of MVF on cortical activation with TMS47,61-68; 1 study

used both TMS and fMRI.47 In Tables 1 to 4, the included articles and their

methodologies are listed according to modality. The majority of the studies (n =

27) examined immediate modulatory effects when exposed to MVF, of which 22

focused on healthy individuals and 5 on stroke patients (Tables 1-3). In 16 studies,

MVF was provided in a bilateral fashion, that is, not obscuring the active hand.

Six studies assessed neuroplastic changes in response to a bout of practice or an

-Mirror visual feedback could be induced by a real mirror or using a virtual reality environment.!


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intervention in healthy individuals (n = 3) or stroke patients (n = 3). Here, bilateral

MVF was used in all but one study (Table 4 and Supplementary Material). The

variance in methodology and motor task, which may be unilateral or contralateral,

complicates the overall interpretation of the observations. A factor that adds to this

difficulty is the absence of a standard control condition. In some studies, MVF is

contrasted with normal full vision of the 2 limbs, whereas in others visual

feedback of the active or static limb only is used as a control. Furthermore, to

isolate the effect of MVF on brain activation it is crucial to keep the movement

(range, frequency, intensity) constant across MVF and control conditions, which a

number of studies have failed to do or to control for (see Table 1-4 for details).

Instant Neuromodulatory Effects of MVF. The neuromodulatory effects of MVF

refer to changes in activity or excitation that are evoked by MVF, that is, revealed

by direct comparison of MVF with a control condition (listed in Table 5). MVF

evokes a conflict between expected and actual feedback (cognitive conflict) and

between visual and kinaesthetic feedback (perceptual conflict). This conflict is

most obvious when performing unimanual or asymmetric bimanual tasks, although

even during symmetric bimanual actions, the perfect interlimb symmetry is

perceived as surreal. In this latter case, MVF is accompanied with an increase of

activity within the superior parietal lobe (precuneus [bilateral] and superior

posterior parietal cortex [contralateral]40), the posterior cingulate cortex,58 and

ipsilateral lateral sulcus51,52 compared to a condition with full vision of the 2

hands.

MVF inducing a more extreme conflict (during unimanual actions) stimulates

activity within primary visual and somatosensory areas, as well as higher order

processing areas in the occipital and parietal cortex ipsilateral to the moving

limb.38,39,42,43,46,60 In fact, the mirror inverts the lateralization that is normally

associated with the presentation of a right or left hand in these regions. Note,

however, that these observations stem from studies that contrasted virtual MVF of

the active hand with virtual VF displayed in the frontal plane (on a screen or onto

MRI-compatible goggles). Other studies show increased activation in the right

dorsolateral prefrontal cortex (DLPFC),58 the contralateral secondary sensory

cortex (SII),51 the ipsilateral superior temporal gyrus (STG),46 and the contralateral

insular cortex.52,57


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Finally, MVF modulates activity of the primary motor cortex, both ipsilateral and

contralateral to the active hand reflected into the mirror, though the findings are

somewhat inconsistent. The majority of the studies suggest an increase in ipsilateral

M1 excitability or increased ipsilateral activation as indicated by a change in laterality

index (vs a control condition).47,53,55,56,63,65-68 Hadoush et al claim that this effect is

more prominent for unimanual MVF, that is, when the active hand (reflected into the

mirror) is covered.48 Others show that the increase in excitability is observed

particularly when MVF and motor imagery are combined.66,68 Investigation of the

potential mediators of this effect suggests that MVF has the capacity to neutralize the

(interhemispheric) inhibition from contralateral to ipsilateral hemisphere. Still, it

should be noted that a number of studies could not find changes in activity within the

ipsilateral M1 evoked by MVF.39,60,64

Neuroplastic Effects Due to Practice or Intervention With MVF. Six studies have

examined the effect of a bout of practice or treatment with MVF on motor function

while also measuring the change in brain activity pre and post training (see Table 4

for details).44,45,54,61,62,69 Consistent with earlier reports training with MVF resulted in

a gain in motor function of the untrained or affected hand in all studies. This gain

seems to be related to an enhanced excitatory function of the (contralateral)

corticospinal pathway projecting to this hand (ie, decrease in motor threshold and

intracortical inhibition within M1 ipsilateral to the trained hand).61,62 After training the

activation balance when moving the affected hand has shifted toward M1 of the

affected hemisphere, indicating increased activation of the affected side and/or

decreased activation of the contralesional side.45,54,69 This would imply a

reestablishment the hemispheric balance that was disrupted by the insult. Another

study suggests, however, that the improvement of untrained hand is related to the

establishment of a functional connection between this hand and the ipsilateral motor

cortex (ie, M1 contralateral to the trained hand).44 Dynamic causal modeling and

functional connectivity analysis further indicates that this reorganization is mediated

by enhanced connectivity between the premotor cortices (both left and right) and the

ipsilateral supplementary motor area.

2.4. Discussion


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This systematic review aimed to identify instant and long-term neuromodulatory

effects associated with MVF. The findings of the 33 articles indicate that MVF

engages a distributed network within the brain, including regions related to

perceptual, motor, and higher cognitive functions, though it is important to

acknowledge a number of limitations. Clearly, the variety of methodologies impedes

the ability to draw firm conclusions. In addition, a large number of studies had

relatively small sample sizes (N ! 10 in 17 out of 33 studies) and a number of studies

fail to meet all methodological requirements, for example, equal performance across

experimental manipulations or adequate control intervention (see Tables 1-3 and

Supplementary Material). These limitations highlight that future research should

primarily focus on isolating the effect of MVF from the mechanisms associated with

bilateral training. Despite these limitations, this first systematic review of the effect of

MVF on the brain reveals useful information with respect to the underlying

mechanisms of MVF for both researchers and practitioners in neurorehabilitation.

Overall, the findings suggest that MVF may affect perceptuo-motor control

processes via (parts of) 3 functional networks. First, the increase in activity in primary

and secondary visual and somatosensory areas suggests a rise in attentional resources

to resolve the perceptual incongruence.51,52 This is associated with conscious

awareness of sensory feedback or control of agency, as observed in the activity within

the insular cortex,70 and enhanced monitoring of the movement, as found in the

involvement of the right DLPFC.58,71 Furthermore, greater activation of the posterior

aspect of the parietal and cingulate cortex supports the notion of greater attentional

demands. The posterior cingulate cortex, highly interconnected with various brain

regions, is considered a hub for information exchange72 and a prominent role in the

cognitive control of behavior is attributed to this region.73 The nearby superior

posterior parietal cortex and its medial extension (precuneus) are known to be

involved in visuospatial information processing and directing spatial attention,

especially during bimanual coordination tasks.74,75 This probably explains why the

effect of MVF on the precuneus is primarily observed in studies that use virtual MVF

of the hand in the frontal plane.38,39,42,43,60 Notably, a number of studies have shown

that the precuneus is particularly active during motor imagery,76 which may account

for the combined effect of imagery and MVF.


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Second, MVF seems to cause increased immediate activation of STG46 and

elevated engagement of PMC44 after training. Both areas have been associated with

the mirror neuron system. STG is often linked to its neighboring superior temporal

sulcus and is involved in the visual identification of biological motion.77 Combined

with the PMC, it forms a network that subserves the imitation of biological motion

and the acquisition of motor skills.25,78,79 The activation of PMC, especially at the side

of the lesion, is in keeping with earlier research that has attributed a prominent role to

this region in motor recovery after stroke.80,81

A third functional network on which MVF appears to exert a modulatory effect

is the motor network. The primary motor cortex (M1) ipsilateral to the active

(reflected) hand, that is, M1 projecting to the unseen hand behind the mirror, is

considered the final common pathway for the beneficial effect of MVF according

to various studies. A complete reversal of lateralization when moving a limb that

is reflected by a mirror (ie, the ipsilateral side taking over control), as put forward

by some,53,56,59 is unlikely; however, there is accumulating evidence that MVF

decreases the motor threshold and enhances corticospinal output of the ipsilesional

M1 in stroke patients.55,63,65-68 This is probably mediated through a reduction in

interhemispheric inhibition (from contralateral/lesional to ipsilateral/lesional)63

and/or a reduction of intracortical inhibition.61 In view of the notion that

functional recovery is correlated with the extent of involvement of the ipsilesional

(here: contralateral) motor network,82 this seems a promising therapeutic effect of

MVF. Other findings in healthy adults, however, indicate that improved motor

skill of the untrained hand is achieved by establishing a functional connection with

the ipsilateral motor cortex via MVF, a mechanism that has been associated with

poorer motor recovery compared with normalization of the hemispheric balance.83

This discrepancy might reflect 2 stages in the recovery process or a population-

specific response and warrants further investigation.

The effect of MVF on brain activation is likely dependent on the specific nature of

the feedback. In this respect it is remarkable that the effect on primary and secondary

visual processing areas is primarily related to unilateral MVF. Bimanual MVF, in

contrast, seems to engage more frontal and parietal regions related to higher cognitive

functions like attention and monitoring (see Table 5).

Finally, it is noteworthy that the findings for individuals with stroke are in

accordance with those for healthy people, insofar as the limited number of studies


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allows this comparison (see Table 5). There is evidence of increased activation of

higher order areas involved with attentional processes (precuneus and posterior

cingulate cortex) and the ipsilateral M1.

Part 3: Summary and future directions

Convergent evidence suggests that MVF may be used as a tool to promote

functional recovery in patients with unilateral motor impairments. A systematic

review of neuroimaging research was conducted to test the validity of the 3

hypotheses proposed to explain the positive effects associated with MVF. The

findings of this review, suggesting substantial overlap between MVF-related

activity and regions subserving attention-related processes, confirm that MVF

activates a broad network dedicated to attention and action monitoring (Hypothesis

3). This is consistent with known motor learning principles, which attribute

success of motor practice to attentional focus and cognitive processing.

Furthermore, the positive effect on motor function is associated with facilitation of

M1 contralateral to the affected or untrained hand (here: referred to as ipsilateral

to the moving hand that is mirrored). However, there is also evidence to support a

mechanism that exploits ipsilateral control of the affected limb, which has been

associated with suboptimal recovery after other therapeutic interventions

(Hypothesis 2). Regions that have been linked with the mirror neuron system

(PMC, STG) may play a mediating role in connecting perceptual and motor areas

(Hypothesis 1). Still, the current evidence indicates that MVF therapy is certainly

not a substitute for observational therapy or motor imagery, given that MVF

activates only isolated parts of the MNS. Future research using recent advances in

graph theory may elucidate functional connectivity within and between the

involved networks.84

To date the majority of evidence stems from studies in healthy adult

individuals and the few studies that have examined a patient population only

considered people who survived a stroke. It remains unclear to what extent these

hypotheses may be valid for other clinical conditions for which MVF has been

suggested an adjunct to conventional therapy (eg, SHCP22,85-87 and CRPS14-18).

The finding that MVF may have an impact on multiple functional networks may


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mean it can serve as a versatile tool to promote motor recovery, of which the

actual mechanism is dependent on the specific condition or damage. Large-scale

clinical trials that include measurement of brain function and structure are to

examine the efficacy and the underlying mechanisms of MVF in different

populations, and potential differences between them. Although further research is

warranted to fully understand and exploit the potential of MVF in

neurorehabilitation, it is indisputable that MVF can exert a strong modulatory

influence on the motor system.


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Acknowledgements

The authors wish to thank Prof. Karen Caeyenberghs and 2 anonymous reviewers for

their advice and suggestions.

Declaration of Conflicting Interest

The author(s) declared no potential conflicts of interest with respect to the research,

authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research,

authorship, and/or publication of this article: This work was partly supported by a

research grant from Sparks, registered charity 1003825 (England & Wales), to Geert

Savelsbergh and Frederik Deconinck (Grant 09MMU01).


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Reflections upon mirror therapy

! 22

Table 1. Outline of the Methodology, Type of MVF, Measures to Avoid Systematic Variation in Movement Across Conditions, and Known Potential

Confounds in All Experimental Studies Using fMRI Included in the Systematic Review.

Abbreviations: MVF, mirror visual feedback; VF, normal visual feedback. Bilateral MVF, active hand and its mirror reflection; Unilateral MVF, MVF of active hand only. MVF was generated by a mirror placed in between the arms in the sagittal plane, except when stated otherwise.

Study reference Participants Outline of experimental methodology relevant to this review Type of MVF

(a) Measures to avoid systematic variation (b) Potential confounds

Diers et al. (2010)37 9 healthy individuals aged 51.9±6.9

Repetitive clenching of the fist at dominant side with (1) normal VF, (2) MVF of active hand, or (3) during motor imagery.

Bilateral (a) Metronome paced (b) No statistical comparison between conditions

Dohle et al. (2004)38 6 healthy individuals aged 29.0±1.5

Static condition vs. finger-thumb opposition with (1) virtual VF of hand; (2) virtual MVF of hand

Unilateral (a) Metronome paced

Fritzsch et al. (2013)39 15 healthy individuals aged 22-56

Unilateral index finger-thumb opposition of either left or right hand with (1) virtual VF, (2) virtual MVF


Matthys et al. (2009)46 18 healthy individuals aged 22-48

Tapping right index finger with (1) VF active hand; (2) MVF active hand

Bilateral (a) None

Merians et al. (2009)47 3 healthy individuals aged 26.8 and 1 stroke patient aged 70.0

Finger tapping right hand with (1) virtual VF active hand; (2) virtual MVF active hand

Unilateral (a) None (b) Lack of control condition

Michielsen et al. (2011a)40 18 stroke patients aged 54.7±9.9

Unimanual (non-affected hand) and bimanual clenching movement with (1) VF; (2) MVF

Bilateral (a) Metronome paced

Shinoura et al. (2008)41 5 healthy individuals aged 21-57 and 2 patients with brain tumor aged 47 & 67

Unimanual and bimanual clenching of hand(s) with (1) eyes closed; (2) MVF of (one of the) active hand(s)

Bilateral (a) None (b) No statistical comparison between conditions

Wang et al. (2013a)42 15 healthy individuals aged 22-56

Movement performance task: Unilateral index finger-thumb opposition of either left or right hand with (1) virtual VF, (2) virtual MVF. Movement observation task: Observation of similar action on video

Unilateral (a) Number of repetitions counted post-hoc

Wang et al. (2013b)43 15 healthy individuals aged 22-56 and 5 stroke patients aged 50-72

Unilateral index finger-thumb opposition of either left or right hand with (1) virtual VF, (2) virtual MVF.



! 23

Table 2. Outline of the Methodology, Type of MVF, Measures to Avoid Systematic Variation in Movement Across Conditions, and Known

Potential Confounds in All Experimental Studies Using TMS Included in the Systematic Review.

Abbreviat

ions: MVF, mirror visual feedback; VF, normal visual feedback; AO, action observation; Exp, experiment. Bilateral MVF, active hand and its mirror reflection; Unilateral MVF, MVF of active hand only. MVF was generated by a mirror placed in between the arms in the sagittal plane, except when stated otherwise.



Carson & Ruddy (2012)63 12 healthy individuals aged 21.5±3.4

Exp1: Flexion-extension of left wrist with (1) VF of non-moving right hand; (2) MVF of moving left hand; (3) no VF.

Bilateral (a) Metronome paced, EMG recording

Fukumura et al. (2007)68 6 healthy individuals aged 20-39

Flexion-extension of left wrist with (1) VF left hand; (2) VF left + motor imagery right hand; (3) MVF left hand; (4) MVF left + motor imagery right hand; (5) MVF left + passive movement right hand; (6) MVF + passive movement and motor imagery right hand


Funase et al. (2007)64 12 healthy individuals aged 19-40

Flexion-extension left hand or left index finger & wrist with (1) VF left side; (2) MVF left side


Garry et al. (2005)65 8 healthy individuals aged 39.6±14.5

Finger-thumb opposition with (1) VF active hand; (2) VF inactive hand; (3) neutral VF; (4) MVF active hand


Kang et al. (2011)66 30 healthy individuals aged 28.0±2.4 and 30 stroke patients aged 66.0±11.0

Thumb abduction/adduction with (1) VF active hand + motor imagery; (2) MVF active hand + motor imagery inactive hand; (3) MVF active hand + motor imagery of asymmetric movements inactive hand. Passive task with (1) motor imagery of right hand; (2) AO other hand + motor imagery own right hand; (3) MVF + motor imagery other hand



Exp1: TMS across nondominant/affected hemisphere during unilateral flexion-extension of the dominant/unaffected wrist with (1) MVF, (2) virtual MVF, or during (3) relaxation. Exp2: TMS across nondominant/affected hemisphere during unilateral flexion-extension of the dominant/unaffected wrist with (1) continuous virtual MVF, (2) internmittent virtual MVF


Merians et al. (2009)47 1 healthy individual Finger tapping right hand with (1) virtual VF active hand; (2) virtual MVF active hand

Bilateral (a) None


! 24


Confounds in All Experimental Studies Using PET, MEG, EEG, and NIRS Included in the Systematic Review.

Study reference Modality Participants Outline of experimental methodology relevant to this review Type of MVF


Dohle et al. (2011)57 PET 10 healthy individuals aged 19-42

PET; Unilateral circular movement of left or right arm with (1) VF; (2) virtual MVF


Fink et al. (1999)58 PET 10 healthy individuals aged 20-73

PET; Luria’s bimanual circle drawing task: (1) in phase with VF; (2) in phase with MVF; (3) out-of-phase with VF; (4) out-of-phase with MVF

Bilateral (a) None

Hadoush et al. (2013)48 MEG 10 healthy individuals aged 22-35

MEG; Index finger extension with MVF of active hand, (1) with VF of active hand or (2) without VF of active hand

Bilateral (a) None

Tominaga et al. (2009)49 MEG 11 healthy individuals aged 19-34

MEG; Stimulation of right median nerve at wrist while holding a pencil with (1) MVF of right hand; (2) VF of right hand; (3) MVF of left hand; (4) VF of left hand.

Unilateral (a) N/A


MEG; Stimulation of right or left median nerve at wrist while holding a pencil with (1) MVF of right hand; (2) VF of right hand; (3) MVF of left hand; (4) VF of left hand.

Unilateral (a) N/A

Wasaka & Kakigi (2012a)52

MEG 10 healthy individuals aged 24-46

MEG; Stimulation of left median nerve at wrist while flexing-extending left thumb repetitively or at rest with (1) MVF of stationary right hand; (2) VF of both hands

Bilateral (a) None

Wasaka & Kakigi (2012b)51


MEG; Stimulation of left median nerve at wrist while flexing-extending left and right thumb repetitively symmetrically or asymmetrically with (1) MVF of right hand; (2) VF of both hands

Bilateral (a) None

Praamstra et al. (2011)55 EEG 9 healthy individuals aged 32±11

EEG; Extension-flexion right or left index finger with (1) VF active finger; (2) MVF active finger

Unilateral (a) Set number of trials, EMG recording

Touzalin-Chretien et al. (2008)56

EEG 11 healthy individuals aged 27.7

EEG; Key press with right hand [except (4)] with (1) VF of right hand; (2) MVF of right hand; (3) MVF of right hand in a frontal mirror; (4) VF of left hand




EEG; Key press with right hand [except (2)] with (1) VF of right hand; (2) VF of left hand; (3) MVF of right hand; (4,5) MVF of right hand with left hand in incongruent position; (6) MVF of right hand in a frontal mirror


Imai et al. (2008)59 NIRS 5 healthy individuals aged 21.1±1.1

NIRS; Unilateral grasping movements with right or left hand with (1) VF of non-moving hand (2) with MVF of moving limb


Mehnert et al. (2013)60 NIRS 22 healthy individuals aged 21-40

NIRS; Unilateral index finger-thumb opposition of either left or right hand with (1) virtual VF, (2) virtual MVF.



! 25

Abbreviations: MVF, mirror visual feedback; VF, normal visual feedback; PET, positron emission topography; MEG, magnetoencephalography; EEG, electroencephalography; NIRS, near infrared spectrometry.


"#!

Table 4. Outline of the Methodology in All Clinical or Training Studies Included in the Systematic Review.

Abbreviations: EEG, electroencephalography; fMRI, functional magnetic resonance imaging; TMS, transcranial magnetic stimulation; MG, mirror group; CG, control group; MVF, mirror visual feedback; VF, normal visual feedback; Exp, experiment; AO, action observation; MT, motor threshold; ICI, intracortical inhibition; ICF, intracortical facilitation; IHI, interhemispheric inhibition; cTBS, continuous theta burst stimulation. MVF was generated by a mirror placed in between the arms in the sagittal plane, except when stated otherwise.

Study reference Modality Participants Nature of training Frequency & duration

Outline of experimental methodology relevant to this review

Bae et al. (2012)54 EEG MG: 10 stroke patients aged 55.2±8.5 CG: 10 stroke patients aged 52.6±11.2

MG: bilateral movements with MVF CG: unilateral movements of paretic side with VF of two limbs

4 weeks, 5 sessions/week, 30’/session

Observation of hand movements during rest, while measuring µ- rhyrthm across left (C3), right (C4) and (Cz) central fissure prior to and after training.

Bhasin et al. (2012)69 fMRI MG: 20 stroke patients aged 28-62

Bilateral hand exercises with virtual MVF on laptop screen

8 weeks, 5 sessions/week, 30’-60’/session

Repetitive clenching/extension of fist at the affected side without VF pre and post training

Hamzei et al. (2012)44 fMRI MG: 13 healthy individuals aged 23.9 CG: 13 healthy individuals aged 25.5

MG & CG: 5 unimanual skills (RH only) with MVF or VF of RH only

4 days, 20’/day fMRI during (1) AO of grasping movement during rest (2) active imitation of grasping movement with left or right hand, pre and post training

Laeppchen et al. (2012)61

TMS MG & CG: 10 healthy individuals aged 24.1


4 days, 20’/day Test of TMS parameters (MT, ICI, ICF, IHI left hemisphere) pre and post training

Michielsen et al. (2011b)45

fMRI MG: 9 stroke patients aged 51.9±9.3 CG: 7 stroke patients aged 59.0±10.4

MG & CG: bimanual exercises with MVF or VF of two hands

6 weeks, 5 sessions/week, 60’/day

fMRI during clenching movement with affected hand without VF pre and post training

Nojima et al. (2012)62 TMS Exp1. MG & CG: 10 healthy individuals (young adults)

MG & CG: unimanual (RH only) ball handling task with MVF or VF of 2 hands

10 sets of 30’’ each

Test of TMS parameters (MT, SICI, IHI) pre and post practice

Exp2. MG1 and MG2: 8 healthy individuals (young adults)

MG1 = MG2: unimanual (RH only) ball handling task with MVF


Similar to Exp1. Practice was followed by cTBS over M1 (MG1) or occipital cortex (MG2)


! 22

















Bilateral (a) None

















! 23



Abbreviat























Bilateral (a) None


! 24










Bilateral (a) None



Bilateral (a) None



Unilateral (a) N/A



Unilateral (a) N/A




Bilateral (a) None




Bilateral (a) None



















! 25



"#!


































! 22

















Bilateral (a) None

















! 23



Abbreviat























Bilateral (a) None


! 24










Bilateral (a) None



Bilateral (a) None



Unilateral (a) N/A



Unilateral (a) N/A




Bilateral (a) None




Bilateral (a) None



















! 25



"#!


































"#!

Table 5. Brain Areas Differentially Activated With Mirror Visual Feedback (MVF)

Compared to Control Conditions, Corresponding Brodmann Area (BA) Where Known, Side

of Activation Listed According to Populationa,b.

!!!

Abbreviation: MNS, mirror neuron system. aThe 2 final columns indicate the type of MVF that elicits this observation and the network to which specific areas are considered to belong. bContralateral (contra) and ipsilateral (ipsi) are defined with respect to the (moving) limb that is reflected in the mirror. MVF indicates the type of MVF (unilateral or bilateral) that elicits this observation.

Population! Area! BA! Side! MVF! Network!

Healthy! Dorsolateral prefrontal cortex! 9/46! Right58! Bi! Attention!

Precentral gyrus (M1)! 4! Ipsi41,47,63,65-68! Uni & Bi! Motor!

Postcentral sulcus, posterior wall (S1/S2)! 2! Contra52! Uni & Bi! Attention!

Lateral sulcus, upper wall (S2)! Contra51,52! Bi! Attention!

Superior posterior parietal cortex! 7! Ipsi58! Bi! Attention!

Precuneus (V6)! 7! Ipsi38,42,43,60! Uni & Bi! Attention!

Superior temporal gyrus! 39! Ipsi46! Bi! MNS!

Cuneus/Lingual gyrus (V1/V2)! 17/18! Ipsi38,42! Uni! Attention!

Superior/Middle occipital gyrus (V2,3,5)! 19! Ipsi38,42,46! Uni & Bi! Attention!

Fusiform gyrus (V4)! 37! Ipsi38,42! Uni! Attention!

Insular cortex, posterior region! Contra57! Uni! Attention!

Stroke! Precentral gyrus (M1)! 4! Ipsi66,67! Bilateral! Motor!

Precuneus (V6)! 7! Contra40, Ipsi40,43! Uni & Bi! Attention!

Posterior cingulate cortex! 30! Contra40! Bi! Attention!


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Figure captions

Figure 1: Flow diagram of the article selection process.


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Supplementary material to Figure 1

List of all 8 references excluded in 2nd stage and the reason for exclusion.

Full bibliographic details of all 8 excluded references: • Egsgaard LL, Petrini L, Christofferson G, Arendt-Nielsen L. Cortical responses to the mirror box

illusion: a high-resolution EEG study. Exp Brain Res. 2011;215:345-57. • Llobera J, González-Franco M, Perez-Marcos D, Valls-Solé J, Slater M, Sanchez-Vives MV.

Virtual reality for assessment of patients suffering from chronic pain. A case study. Exp Brain Res. 2013;225:105-17.

• Nojima I, Koganemaru S, Fukujama H, Kawamata T, Mima T. Effect of mirror visual feedback on human motor plasticity. Neurosci Res. 2011;71S:e253.

• Nojima I, Oga T, Fukuyama H, Kawamata T, Mima T. Mirror visual feedback can induce motor learning in patients with callosal disconnection. Exp Brain Res. 2013;227:79-83.

• Ohtsuka H, Matsuzawa D, Numata K, Yoshida S, Nakazawa K, Shimizu E. Reduced transcallosal inhibition during watching unilateral movement through mirror. Neurosci Res. 2009;65:S217.

• Papeo L, Longo MR, Feurra M, Haggard P. The role of the right temporoparietal junction in intersensory conflict: detection or solution? Exp Brain Res. 2010;206:129-39.

• Ro T, Wallace R, Hagedorn J, Farnè A, Pienkos E. Visual enhancing of tactile perception in the posterior parietal cortex. J Cog Neurosci. 2004;16:24-30.

• Seidel S, Kasprian G, Furtner J, Schöpf V, Essmeister M, Sycha T, Auff E, Prayer D. Mirror therapy in lower limb amputees – A look beyond primary motor cortex reorganization. Fortschr Röntgenstr. 2011;183:1051-57.

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Study reference Imaging modality

Reason for exclusion

Egsgaard et al. (2011) EEG Examines effect of MVF on tactile perception, not on motor control Llobera et al. (2013) EEG EEG used to control brain computer interface, not to examine effect of MVF Nojima et al. (2011) TMS Conference proceeding. Full paper is included (Nojima et al. 2012) Nojima et al. (2013) TMS Neuroimaging used for diagnostic purposes, not to examine effect of MVF Ohtsuka et al. (2009) TMS Conference proceeding, limited data. Papeo et al. (2011) EEG Examines effect of MVF on tactile perception, not on motor control Ro et al. (2004) TMS Examines effect of MVF on tactile perception, not on motor control Seidel et al. (2011) fMRI Examines effect of MVF on pain, not on motor control


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Supplementary material to Table 1d - Outline of the type of MVF, and measures to

avoid systematic variation across conditions in all clinical or training studies included

in the systematic review.

Abbreviation: Bilateral MVF = active hand and its mirror reflection; Unilateral MVF = MVF of active hand only.

Study reference Type of MVF (a) Measures to avoid systematic variation across conditions (b) Potential confounds

Bae et al. (2012)54 Bilateral (a) no measures taken (b) task in sham and mirror condition is different

Bhasin et al. (2012)69 Unilateral (a) visual monitoring of movement in fMRI (b) no control group

Hamzei et al. (2012)44 Bilateral (a) set number of trials + EMG recording of movement


Bilateral (a) set number of trials + EMG recording


Bilateral (a) movement is metronome paced

Nojima et al. (2012)62 Bilateral (a) set number of trials + EMG recording

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Reflections on mirror therapy: a systematic review of the effect of mirror visual feedback on the...

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