Noninvasive Cortical Stimulation in Neurorehabilitation: A Review

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Noninvasive Cortical Stimulation in Neurorehabilitation: A Review Michelle L. Harris-Love, PT, PhD, Leonardo G. Cohen, MD ABSTRACT. Harris-Love ML, Cohen LG. Noninvasive cortical stimulation in neurorehabilitation: a review. Arch Phys Med Rehabil 2006;87(12 Suppl 2):S84-93. The purpose of this special communication is to provide an overview of noninvasive cortical stimulation techniques, the types of mechanistic information they can provide, and the ways their use is contributing to our understanding of current models of neurorehabilitation. The focus is primarily on studies using noninvasive cortical stimulation techniques in the human motor system. Noninvasive cortical stimulation techniques are useful tools in the field of neurorehabilitation that are being actively used to test proposed models of functional recovery after neurologic injury. They can provide insight into the physiologic mechanisms of functional recovery and are under investigation as a possible auxiliary intervention to modulate cortical excitability and enhance training effects. Key Words: Neuronal plasticity; Rehabilitation; Transcranial magnetic stimulation. © 2006 by the American Congress of Rehabilitation Medicine ITH THE DEVELOPMENT of techniques for noninvasive cortical stimulation it has become possible to evalW uate and influence cortical activity in awake, behaving humans. Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (TDCS) can contribute to the understanding of mechanisms of rehabilitative processes and may lead to the generation of new therapeutic strategies in neurorehabilitation. Here we review applications of noninvasive transcranial stimulation and recent findings using these techniques as they relate to larger concepts in the field of neurorehabilitation. NONINVASIVE CORTICAL STIMULATION: PRINCIPLES, TECHNIQUES, AND APPLICATIONS Transcranial Magnetic Stimulation TMS and more recently TDCS1 are 2 approaches that allow noninvasive and painless central nervous system (CNS) stimulation in living and awake humans. TMS uses a rapidly changing magnetic field to elicit electric currents running parallel to the cortical surface via electromagnetic induction (fig 1).2 A very brief high-intensity electric current is passed

From the Human Cortical Physiology Section, National Institute of Neurological Disorders and Stroke, Bethesda, MD. Supported by the National Institute of Neurological Disorders and Stroke (competitive postdoctoral fellowship and intramural program). No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the author(s) or upon any organization with which the author(s) is/are associated. Reprint requests to Michelle Harris-Love, PT, PhD, Human Cortical Physiology Section, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892. 0003-9993/06/8712S-10984$32.00/0 doi:10.1016/j.apmr.2006.08.330

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through a wire coil held over the scalp, setting up a perpendicularly directed magnetic field, which passes relatively unimpeded through the layers of tissue and bone over the cortex. The small electric field that flows around the magnetic field results in currents that excite cortical neurons, causing them to fire. Unlike electric stimulation, which can excite neuronal axons by directly, TMS stimulates neurons indirectly via interneurons and can therefore elicit responses that reflect cortical excitability.3 In most of the studies discussed below the TMS coil is held over the primary motor cortex (M1) in the optimal position for eliciting a response in the muscle of interest. The resulting motor evoked potential (MEP) is recorded using surface electromyography. TMS is delivered in the form of single, paired, and repetitive pulses, each of which can be applied for different experimental purposes. Single-pulse TMS. Single-pulse TMS provides information about corticospinal excitability by measuring variables such as motor threshold (the threshold stimulation intensity at which an MEP can be elicited), MEP amplitudes, and latencies. Additionally, the recruitment curve (the slope of the increase in MEP amplitude with increasing stimulation intensity) and the motor map area (size of the scalp area over which an MEP can be elicited) convey information on corticospinal excitability.4 A single-pulse TMS can also disrupt sustained electromyographic activity, and the resulting “silent period” is often used as a measure of corticospinal inhibition.5 Single-pulse TMS is also used to measure transcallosal inhibition via the ipsilateral silent period.6 This technique uses a single TMS pulse to M1 to interrupt ongoing muscle activation in the ipsilateral hand. In this paradigm, transcallosal inhibition is characterized by the latency, duration, and depth of the ipsilateral silent period.7 Abnormalities in ipsilateral silent period have been shown in patients with multiple sclerosis,8-10 schizophrenia,11,12 focal hand dystonia,13 parkinsonian syndromes,14 and attention deficit disorder.15 Besides providing measures of corticospinal excitability and inhibition, single-pulse TMS can also be used to disrupt a particular cortical area at a precise point during planning or performance of a motor task. The resulting decrement in motor performance is evaluated to determine the behavioral consequences of the cortical disruption.16,17 Because of its highly precise time resolution (on the order of milliseconds), single-pulse TMS used in this way can provide detailed information on the neural substrates underlying performance of a particular task.18 Paired-pulse TMS. In these protocols, paired pulses are delivered through 1 or 2 separate magnetic coils at varying interstimulus intervals to elicit measurable inhibition or facilitation. Paired-pulse TMS can be applied to 1 hemisphere through the same coil in order to measure intracortical inhibition or facilitation,19 or 1 pulse can be delivered to each hemisphere through 2 separate magnetic coils to measure interhemispheric inhibition20 or facilitation.21-23 For paired pulses delivered to the same hemisphere at short interstimulus intervals (1⫺4ms), the MEP produced by a suprathreshold test stimulus preceded by a subthreshold conditioning stimulus is smaller than that produced by an unconditioned test stimulus. The magnitude of this short latency intracortical inhibition is

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Fig 1. In TMS, (A) a brief strong electric current traveling through the coil (B) results in a magnetic field that passes through (C, D) the skull to produce electric currents in the cortex. The magnetic coil is positioned in this example using a frameless stereotactic device on the scalp overlying the target cortical site on the subject’s own MRI. Reprinted with permission of Jarmo Ruohonen.

quantified as the MEP amplitude produced by the conditioned test stimulus expressed as a percentage of that produced by the test stimulus alone. Another form of intracortical inhibition, long latency intracortical inhibition, occurs at interstimulus intervals of 50 to 200ms when both the conditioning stimulus and test stimulus are suprathreshold.24-26 Short-latency and long-latency intracortical inhibition convey information on intracortical inhibitory mechanisms predominantly mediated by ␥-aminobutyric acid (GABA)A and GABAB receptors, respectively.27-29 At interstimulus intervals of 6 to 20ms, a subthreshold conditioning stimulus facilitates the MEP produced by the test stimulus, providing a measure of intracortical facilitation, which is influenced by glutamatergic activity.30,31 For paired-pulse measurement of interhemispheric inhibition, the first pulse is a suprathreshold conditioning stimulus applied to one M1 followed at interstimulus intervals of 6ms or greater by a suprathreshold test stimulus delivered to the opposite homologous M1 area.20 As with other paired-pulse techniques, interhemispheric inhibition is expressed as the amplitude of the conditioned MEP relative to the test MEP. Paired-pulse measurement of interhemispheric inhibition is thought to convey information on interhemispheric glutamatergic pathways that target GABAergic neurons before reaching pyramidal tract cells.20 Studies using paired-pulse interhemispheric inhibition have suggested diminished inhibition in patients with schizophrenia32 and epilepsy.33 Interhemispheric inhibition can be studied at rest20,34 and in the process of generation of specific voluntary movements.35-37 In a reaction time paradigm, single and paired pulses are delivered at evenly spaced time points in the 100 to 200ms between the “go” signal and the onset of the motor response. In this way it is possible to obtain information on the

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evolution of interhemispheric interactions immediately preceding movement onset. For instance, in healthy volunteers, interhemispheric inhibition decreases progressively and reverses to facilitation as movement onset approaches (fig 2).37 Besides interhemispheric inhibition, interhemispheric facilitation can also be elicited by using interstimulus intervals of 4 to 8ms with low, subthreshold conditioning stimulus intensities and test stimulus intensities that induce low-amplitude MEPs.21,22 Repetitive. Repetitive TMS (rTMS) is used to purposefully modulate excitability in the cerebral cortex under the stimulating coil and also in distant regions transynaptically.38 This modulation often exceeds the stimulation period for varying periods of time. The characteristics of the modulatory effect depend on the frequency, intensity, and duration of the rTMS trains. When applied to the motor cortex, low-frequency rTMS (⬇1Hz) results in decreased cortical excitability that outlasts the period of stimulation,39,40 whereas at higher frequencies (⬎5Hz), rTMS can increase cortical excitability.41 Applied in this way, rTMS may be used to try to enhance certain cognitive processes42,43 or to downregulate activity in specific brain regions,44-47 in the process providing information on the role of these cortical sites in behavioral performance. Additionally, rTMS applied during motor training can enhance use-dependent plasticity,48 a finding of particular importance for the field of neurorehabilitation. This tool has been used to try to improve specific conditions, such as depression, Parkinson’s disease, dystonia, and even motor disability resulting from brain lesions.49-53 One study applied low-frequency rTMS to decrease excitability in the motor cortex of 1 hemisphere in healthy volunteers and found improved motor performance in a sequential key press task performed with the hand ipsilateral to the stimulation.54 The authors attributed this finding to reduced interhemispheric inhibition from the stimulated to the unstimulated hemisphere. Recent studies have begun to examine the effects of rTMS applied to the motor cortex in patients with stroke. Low-frequency rTMS applied to the nonlesioned

Fig 2. Schematic of premovement interhemispheric inhibition (IHI) in a healthy volunteer performing a reaction time task. Note the initial deep inhibition from the resting to the active hemisphere that reverses into facilitation close to movement onset. Abbreviation: EMG, muscle activity measured by electromyography.

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hemisphere53 and high-frequency rTMS applied to the affected hemisphere52 were associated with improvements in motor performance in the paretic hand. Theta burst. In animal studies, electric stimulation delivered in a theta burst paradigm has been found to induce synaptic long-term potentiation and depression.55-57 In this paradigm, 3 to 5 pulses are delivered at 100Hz, and this is repeated at a rate of 5Hz. Recently, a modified version of this theta burst pattern has been applied in humans using rTMS.58 The basic pattern of stimulation was 3 pulses delivered at 50Hz, repeated at a rate of 5Hz. This approach has shown long-lasting modulation of cortical excitability (up to 1h) after short periods of stimulation (20⫺190s). Theta burst rTMS may therefore provide a noninvasive strategy to modulate synaptic activity in intact humans. Transcranial Direct Current Stimulation Instead of a brief magnetic pulse, TDCS uses more prolonged, low-intensity electric current applied over the scalp to alter activity in the underlying neurons. This form of brain polarization is applied using a stimulating device commonly used for iontophoresis.59-61 This form of stimulation, older but less tested than TMS, has been successfully used to influence cognitive processes.62-64 To stimulate the primary motor cortex, 1 electrode is placed on the scalp over M1 and the other on the contralateral supraorbital area. Similar to TMS, TDCS can be used to up- or downregulate neural activity in the stimulated regions. Increased excitability of the underlying neurons occurs with anodal stimulation and decreased excitability with cathodal stimulation.65,66 TDCS is usually applied for 5 to 20 minutes with the effects on neural excitability outlasting the period of stimulation by up to an hour.66 Relative to TMS, brain polarization with TDCS elicits fewer perceptual sensations but has lesser temporal and spatial resolution. Additionally, it is a technique that is only recently attracting active interest in the field of neurorehabilitation, and more data are required to fully assess its value. There seems to be a general consensus that the changes in excitability elicited by TDCS are due to changes in resting membrane potentials, which lead to changes in spontaneous firing rates and N-methyl-D-aspartate (NMDA)–receptor activation.67,68 Importantly, NMDA-receptor antagonists seem to prevent the aftereffects of both anodal and cathodal TDCS, suggesting similar mechanisms to those involved in neuroplasticity.67,68 Recent reports suggest that the changes in cortical excitability due to TDCS are associated with changes in the excitability of inhibitory and facilitatory intracortical circuits as well. Anodal TDCS resulted in decreased intracortical inhibition and increased intracortical facilitation, and cathodal stimulation resulted in the reverse.69 It is likely that the mechanisms underlying the effects of TDCS vary from those of TMS, and more work is needed to sort out optimal safe parameters of administration.70 TDCS has been used to examine the effects of altering the excitability of different brain areas on learning and memory tasks. Anodal TDCS to prefrontal cortical areas has been shown to improve implicit learning,63 sleep-dependent declarative memory,64 and working memory.62 In the motor domain, cathodal TDCS was shown to dampen the increase in cortical excitability that occurs with motor imagery.71 Most notably for the field of neurorehabilitation, TDCS also seems to influence motor learning processes. Early motor memory encoding is disrupted when TDCS is applied during motor training in healthy volunteers.72 On the other hand, TDCS applied over M1 enhanced implicit learning of a serial reaction time task73 and applied over V5 (a middle temporal region associated with motion perception) improved early learning of a visuomotor Arch Phys Med Rehabil Vol 87, Suppl 2, December 2006

tracking task.74,75 TDCS has also been examined in combination with interventions other than motor training, such as peripheral nerve stimulation76 and rTMS77,78 to examine the enhancement effects of combined treatments and to evaluate the recently proposed concept of metaplasticity, according to which synapses are more susceptible to a facilitatory input if they first undergo inhibition, and vice versa.77,78 Overall, these findings indicate that, like TMS, TDCS can be used to modulate cortical activity in healthy volunteers and patients with different motor disorders. These properties could potentially be used to enhance the beneficial effects of training and rehabilitative treatments. Examples of such use include recent studies in stroke patients.52,53,79,80 In one of these studies, it was shown that anodal TDCS over the lesioned hemisphere in people with chronic stroke can induce a significant, though transient, improvement in paretic hand function.79 Because of its cost effectiveness and ease of use, as well as the limited perceptual sensations it elicits, TDCS could evolve into a valuable tool in neurorehabilitation. Applications Noninvasive cortical stimulation techniques are usually used for 3 different purposes: (1) to modulate cortical excitability, (2) to evaluate the behavioral or physiologic consequences of disruption of focal brain regions, and (3) to measure various aspects of brain function such as intracortical inhibition, intracortical facilitation, interhemispheric inhibition, and cortical excitability. In the first approach, TMS or TDCS is used to modulate the excitability of a particular cortical area. It should be kept in mind that changes in the excitability of 1 cortical site may elicit additional changes in activity in distant cortical regions anatomically connected through transynaptic mechanisms.81-84 Therefore, the behavioral or physiologic consequences of such modulation could theoretically be attributed to changes in the stimulated area and/or in the physiologically interconnected regions. In the second approach, rTMS, singlepulse TMS, and/or TDCS are used to transiently disrupt activity in a cortical area of interest in order to determine its effects on the planning, execution, or learning of a movement.72,85-91 Finally, single- and paired-pulse TMS are used to measure corticospinal excitability, intracortical inhibition and intracortical facilitation, and/or interhemispheric inhibition. These measures contribute to the understanding of the physiologic underpinnings of certain disorders11,92-97 and of specific interventions in neurorehabilitation.98-101 NEUROPLASTICITY AFTER BRAIN LESIONS Understanding how the CNS recovers from injury is an important step to formulate effective strategies to promote functional recovery.102 Through neuroimaging techniques like functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and spectroscopy and through electrophysiologic studies using magnetoencephalography, electroencephalography, TMS, TDCS, electromyography, and evoked potentials, new and useful information has arisen regarding how the nervous system recovers from injury such as that due to stroke. Vicariation The initial idea of a vicariation process is attributed to Munk in 1881,103 and the term refers to the proposal that new cortical regions take over the function previously performed by the damaged site. For instance, after a stroke involving M1, different cortical areas could take over some of the roles of the motor cortex in the lesioned hemisphere. One possible cortical area contributing to recovery processes after stroke is the contralesional M1. Animal

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studies have shown that a lesion induced in the sensorimotor cortex of 1 hemisphere results in morphologic and physiologic changes in the sensorimotor cortex of the contralateral hemisphere.104,105 The best example of this phenomenon is provided by hemispherectomized rats, who can recover almost full motor function after a short time period.106 In this case it is quite clear that the remaining hemisphere mediates recovery. In humans, M1 has been shown to participate in performance of complex ipsilateral hand tasks.107 Studies of disruption of activity with TMS in healthy volunteers raised the hypothesis of the ability of 1 hemisphere to functionally compensate for disruption induced in the other hemisphere.85,86 In patients with stroke, neuroimaging studies often show enhanced nonlesioned hemisphere activation during motor tasks performed with the paretic hand.108-113 Based on these neuroimaging findings, it has been proposed that the nonlesioned M1 may take over functions previously performed by the lesioned motor areas after stroke.110 This form of compensation could occur via unmasking of the few uncrossed, ipsilateral motor pathways from the contralesional hemisphere to the affected paretic limb, a proposal supported by the finding of ipsilateral MEPs in the paretic hand in response to stimulation of the nonlesioned hemisphere M1.114 When present, this effect is more prominent in proximal and midline muscles, which are thought to exhibit a more bilateral organization than distal muscles.115 Additionally, studies using TMS have shown less intracortical inhibition in the nonlesioned hemisphere of patients with good recovery, an effect not observed in patients with poor recovery.116 It is possible that the intact hemisphere contributes to higher aspects of motor function in patients with stroke and more disability.117-119 However, other findings suggest that the nonlesioned hemisphere does not contribute fundamentally to the recovery process. For example, ipsilateral MEPs in the paretic hand are sometimes seen in patients with more prominent impairment but are usually not seen in well-recovered patients.120,121 Similarly, better recovery is seen in people in whom the fMRI shows very little activity in the nonlesioned hemisphere during simple paretic hand movements, similar to patterns seen in healthy volunteers.111 In addition, TMS disruption of nonlesioned M1 activity did not influence paretic hand simple reaction time measurements in patients with good or moderate recovery. However, disruption of M1 in the lesioned hemisphere delayed paretic hand reaction time much more than in healthy controls,88 showing reliance on lesioned hemisphere activation for good task performance. There is, therefore, some agreement that the nonlesioned M1 is unlikely to completely take over the functions previously performed by the lesioned hemisphere; however, it could contribute to some extent to higher-level organizational aspects of motor control in the paretic hand117 and to control of more complex motor tasks,119 and it may even have a role in simple motor tasks in stroke patients with more substantial impairment. It is also possible that nonprimary motor areas could contribute to the recovery process. For example, the dorsal premotor cortices of both hemispheres have been implicated in the recovery process after stroke. It has been proposed that patients with more prominent disability may engage to a larger extent the nonlesioned hemisphere dorsal premotor cortices,118 whereas those with lesser impairment engage the lesioned hemisphere dorsal premotor cortices102,122 when performing voluntary movements with the paretic hand. These studies showed that focal TMS disruption of dorsal premotor cortices resulted in characteristic behavioral changes like delayed reaction times. This suggests that the dorsal premotor cortices of both hemispheres may perform a new, behaviorally relevant function that it had not performed before the stroke.

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Another potential area for vicariation is within the M1 perilesional area. Monkeys undergoing rehabilitative training after a focal M1 lesion in the digit area recover finger function and show a shift of the digit representation into former elbow and shoulder representations.123,124 After motor training in humans with chronic stroke, TMS motor maps increase in size (an indication of increased excitability) and undergo a nonspecific shift in location, suggesting recruitment of areas adjacent to the lesion for motor performance.100 A recent imaging study of patients with lesions localized to M1 showed a progressive dorsal shift in activation over the course of their successful recovery,125 again suggesting other M1 areas may have taken over lesioned-area functions. Contralesional Hemisphere Overexcitability Hypothesis Although the question of nonlesioned hemisphere vicariation remains controversial, it is generally accepted that activity in the nonlesioned hemisphere changes after stroke. There is evidence of disinhibition (ie, decreased intracortical inhibition) of the contralesional M1 in patients with postacute stroke.116,126-129 It has been proposed that the 2 cortical hemispheres maintain a balance of excitability via interhemispheric inhibition (fig 3A).102 According to this model, when a lesion occurs in 1 hemisphere, the contralateral counterparts of the affected areas are released from inhibition originating in the affected hemisphere. Under certain circumstances, overactivity of these areas in the nonlesioned cortex may result in excessive interhemispheric inhibition from these areas back to their contralateral counterparts in the lesioned hemisphere (fig 3B), as has been shown to occur in the motor domain.35,37 Support for this hypothesis has come from physiologic and imaging studies showing disinhibition and increased activity of the contralesional hemisphere after stroke in the motor116 and language domains.130 Martin et al130 suggested this may be maladaptive “overactivation.” In 4 people with poststroke aphasia, they showed improved language function after 10 treatments of rTMS to downregulate activity in the right (nonlesioned) inferior frontal gyrus (Broca’s area). However, Winhuisen et al131 used rTMS coregistered with PET images to examine the functional relevance of right hemisphere activation in patients with poststroke aphasia. They concluded that right inferior frontal gyrus activation may contribute to residual language function in some patients, but its compensatory potential is limited compared with the recovery associated with return of some left (ie, lesioned hemisphere) inferior frontal gyrus function. In the motor domain, most studies show no differences in markers of overall corticospinal excitability (eg, motor threshold, recruitment curves, MEP amplitudes) in the nonlesioned hemisphere versus that in age-matched controls.116,128,129,132 However, a decrease in nonlesioned hemisphere intracortical inhibition has been reported after stroke.116,128,129 Using paired-pulse TMS, Shimizu et al129 showed a decrease in contralesional intracortical inhibition in the subacute period after cortical stroke. As discussed in the vicariation section above, the significance of increased activity and disinhibition in the nonlesioned hemisphere remains to some extent unclear at this time. It could potentially contribute to functional recovery,116,119,133,134 it could play a maladaptive role,129,130 it could be superfluous, or it could even play different roles according to individual patient characteristics like lesion site, level of recovery, or other factors.102 In the lesioned hemisphere, motor excitability is decreased early on and increases over time, as expressed by increasing TMS motor map area135 and MEP amplitudes136,137 and decreasing intracortical inhibition.138 The progressive increase in excitability in the affected hemisphere appears to correlate with progressive Arch Phys Med Rehabil Vol 87, Suppl 2, December 2006

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ation between increasing lesioned hemisphere activity and motor function is consistent with the idea that it is beneficial to reestablish the balance of excitability between the 2 hemispheres.102 Interhemispheric Inhibition These findings support the view that certain aspects of motor control of the paretic hand may be influenced by a balance of interactions between the 2 hemispheres that changes over time after stroke. In patients with subcortical stroke, transcallosal inhibition (measured either as pairedpulse interhemispheric inhibition140 or ipsilateral silent period129) from the lesioned to the nonlesioned hemisphere at rest is not different from healthy volunteers, but it is reduced140 or absent129 in patients with cortical involvement. However, interhemispheric inhibition from the nonlesioned to the lesioned hemisphere when a stroke patient moves the paretic hand is abnormally high, not changing to facilitation around movement onset, as it does in healthy volunteers (see fig 2).35,37,102 The magnitude of interhemispheric inhibition abnormality in disorders such as stroke and multiple sclerosis correlates with the degree of impairment resulting from these disorders, supporting the possibility of a causative link.10,37 If this were the case, one would predict that downregulation of activity in the intact hemisphere or upregulation of activity in the affected hemisphere could contribute to improve certain aspects of motor function in the paretic hand,102 possibly through a correction of imbalances in interhemispheric inhibition.47 As reviewed in the previous section, evidence supporting this view has begun to emerge. Increasing activity in the lesioned hemisphere with either TDCS79,80 or TMS52 can lead to quantifiable performance improvements in the paretic hand of patients with chronic stroke, as can decreasing activity in the nonlesioned hemisphere.53 These studies provided support for disbalance in interhemispheric inhibition as a factor contributing to motor disability after stroke.102 Additionally, they suggest that noninvasive cortical stimulation with TMS or TDCS, in association with rehabilitation training interventions, could enhance motor recovery after stroke.

Fig 3. (A) A hypothesis emerging from recent investigations is that normal motor control results from a proper balance of inhibitory and excitatory interactions between both hemispheres. (B) After subcortical stroke (represented by circle with cross hatching), this balance of inhibition is disrupted, such that the inhibition from the nonlesioned to the lesioned hemisphere is more prominent when the patient moves the paretic hand. Noninvasive cortical stimulation has been used in initial studies to enhance activity in the lesioned hemisphere or to downregulate activity in the nonlesioned hemisphere.

clinical motor improvement in the paretic hand.136,138 Similarly, TMS measurements before and after constraint-induced movement therapy (CIMT) have shown increased MEP amplitudes and motor map area in the affected hemisphere, changes that are also correlated with improved motor function.100,101,139 Other training interventions focused on the paretic arm have similarly shown increased TMS map area for the muscles involved in the training, decreased motor threshold, and increased MEP amplitude from the lesioned hemisphere, associated with improvement in motor function.98,99 Recently, Hummel79 and Khedr52 and colleagues used TDCS and rTMS, respectively, to upregulate activity in the lesioned hemisphere. Both interventions were associated with improved paretic arm and hand motor performance. This associArch Phys Med Rehabil Vol 87, Suppl 2, December 2006

Cortical Stimulation and Training in Neurorehabilitation New rehabilitative interventions based on behavioral and neurophysiologic principles have been recently proposed. CIMT, for instance, consists of focused training of the paretic hand while restraining the nonparetic arm during waking hours, so that daily tasks are performed with the paretic arm alone. Some studies using TMS showed that CIMT-dependent improvements in paretic arm function are accompanied by increased size of motor map areas in the lesioned hemisphere, as well as a shift in the location of the motor map, suggesting increased recruitment of adjacent motor areas,100,101,139 although results have been heterogeneous141 and more studies are needed. Because patients usually eligible for CIMT should have residual wrist and finger extension and sufficient balance, a large proportion of patients who have greater poststroke motor deficits may not be eligible for CIMT. One approach to retraining arm function in patients with more severe poststroke impairments is bilateral arm training.142-144 The rationale for bilateral arm training is based in part on the behavioral phenomenon of interlimb coupling, in which the movement patterns of the arms tend toward similarity when moving simultaneously, and producing independent movements with each arm is difficult.145 Indeed, even after chronic stroke, interlimb coupling effects persist during reaching movements and can benefit paretic arm reaching

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performance.146 A recent imaging study showed that behavioral improvements after bilateral arm training with rhythmic auditory cueing144 were related to increased activation in the nonlesioned hemisphere during paretic arm movements.133 Another study using TMS in healthy volunteers examined changes in intracortical inhibition and intracortical facilitation after a single session of unilateral and bilateral arm exercise.147 After a unilateral training session, there was increased intracortical facilitation and decreased intracortical inhibition in the cortex contralateral to the trained arm and increased intracortical inhibition in the cortex ipsilateral to the trained arm. After a bilateral training session, there was increased intracortical facilitation and decreased intracortical inhibition in both hemispheres. These results show that bilateral arm training modulates activity in both motor cortices. It is also conceivable that alterations in interhemispheric inhibition could occur after bilateral arm training.143 Other types of motor training, and even motor imagery,148,149 have shown similar changes in cortical excitability and motor map shifts.98,99,150 Cortical stimulation provides information on the mechanisms underlying beneficial effects of rehabilitative interventions and may also be used to enhance the beneficial effects of particular training modalities. CONCLUSIONS Noninvasive cortical stimulation, TMS and TDCS, are techniques useful in testing mechanisms of recovery and evaluating interventional strategies to enhance the beneficial effects of motor training after stroke and enhance neuroplasticity. Use of TDCS and TMS is starting to shed light on the roles of vicariation and interhemispheric interactions in motor recovery. These techniques may also be used to enhance the effects of rehabilitative interventions by strategic modulation of cortical excitability, a possibility that is now under active investigation. References 1. Gandiga PC, Hummel FC, Cohen LG. Transcranial DC stimulation (tDCS): a tool for double-blind sham-controlled clinical studies in brain stimulation. Clin Neurophysiol 2006;117:845-50. 2. Roth BJ, Saypol JM, Hallett M, Cohen LG. A theoretical calculation of the electric field induced in the cortex during magnetic stimulation. Electroencephalogr Clin Neurophysiol 1991;81:4756. 3. Day BL, Dressler D, Maertens de Noordhout A, et al. Electric and magnetic stimulation of human motor cortex: surface EMG and single motor unit responses [published erratum in: J Physiol (Lond) 1990;430:617]. J Physiol 1989;412:449-73. 4. Cohen LG, Roth BJ, Wassermann EM, et al. Magnetic stimulation of the human cerebral cortex, an indicator of reorganization in motor pathways in certain pathological conditions. J Clin Neurophysiol 1991;8:56-65. 5. Chen R, Lozano AM, Ashby P. Mechanism of the silent period following transcranial magnetic stimulation. Evidence from epidural recordings. Exp Brain Res 1999;128:539-42. 6. Chen R, Yung D, Li JY. Organization of ipsilateral excitatory and inhibitory pathways in the human motor cortex. J Neurophysiol 2003;89:1256-64. 7. Garvey MA, Ziemann U, Becker DA, Barker CA, Bartko JJ. New graphical method to measure silent periods evoked by transcranial magnetic stimulation. Clin Neurophysiol 2001;112: 1451-60. 8. Boroojerdi B, Hungs M, Mull M, Topper R, Noth J. Interhemispheric inhibition in patients with multiple sclerosis. Electroencephalogr Clin Neurophysiol 1998;109:230-7. 9. Meyer BU, Roricht S, Schmierer K, et al. First diagnostic applications of transcallosal inhibition in diseases affecting callosal

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