Contribution of transcranial magnetic stimulation to the understanding of mechanisms of functional recovery after stroke

doi:10.1177/1545968309345270

Neurorehabil Neural Repair. Author manuscript; available in PMC 2010 September 25.

Published in final edited form as:

Neurorehabil Neural Repair. 2010 February; 24(2): 125–135.

Published online 2009 September 18. doi: 10.1177/1545968309345270

PMCID: PMC2945387

NIHMSID: NIHMS178007

Contribution of transcranial magnetic stimulation to the understanding of mechanisms of functional recovery after stroke

Michael A. Dimyan, MD and Leonardo G. Cohen, MD

Human Cortical Physiology and Stroke Neurorehabilitation Section, NINDS, NIH

Correspondence to: Michael A. Dimyan, MD (Email: dimyanm/at/mail.nih.gov) or Leonardo G Cohen, MD (Email: cohenl/at/ninds.nih.gov) 10 Center Dr MSC1428, Bldg 10, Rm 7D50, Bethesda MD 20892-1428, 301-402-1011

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Abstract

Motor disability continues to be a major cause of morbidity after stroke. The neural underpinnings of disability and of functional recovery are still unclear. Here, we review recent evidence obtained using transcranial magnetic stimulation (TMS) that provides new insight into these mechanisms. We briefly discuss the use of TMS in the diagnosis, prognosis, and therapy of post-stroke motor disability. Differently from previous reviews, particular emphasis is placed in the discussion of the use of TMS as a tool to explore in detailed mechanisms of neuroplasticity during spontaneous and treatment-induced recovery of motor function. TMS can be used to acquire the understanding of these mechanisms required for the development of more rational and clinically useful interventions in stroke neurorehabilitation.

Introduction

The problem

Stroke continues to be the leading cause of long term disability in the U.S. [1] Primarily due to a loss of motor abilities and subsequent impairment in activities of daily living, stroke is estimated to cost the U.S. over two trillion dollars in the next fifty years[2]. These economic and social costs are not restricted to the intensive acute care that occurs with stroke, but rather is outweighed by later outpatient costs and is highly correlated with the level of disability [3]. Taken together, these statistics emphasize the need for interventions designed to improve post-stroke neurorehabilitation [4]. While recent advances in stroke care have primarily been concentrated on the neuroprotective and neurovascular fronts [5, 6], tools used to study and alter cortical function have played a significant role in all parts of post-stroke care: diagnostic, prognostic, and interventional. In this review, we will examine how transcranial magnetic stimulation (TMS) can be used to dissect the physiologic mechanisms underlying motor deficits, spontaneous motor recovery, and the beneficial effects of therapeutic interventions. An understanding of these neurobiological foundations will likely enhance our abilities to diagnose, prognosticate, and treat post-stroke motor disabilities.

TMS as a technical tool

Since the first reported use of TMS in humans[7], it has been clear that this tool would enhance understanding of the nervous system and find application in medical treatment of nervous system disorders. Working via the principles of electromagnetic induction, standard TMS instruments consist of a high voltage capacitor which can be discharged through an insulated coil of wires [8-10]. The rapid, time-varying magnetic field created around the coil, which passes unchanged through electrically-resistant structures such as the skull, can be used to induce an electrical current in human brain tissue. When a TMS coil is placed on the scalp over primary motor cortex (M1), the induced electrical current stimulates the neurons of the cortex [11]. When first applied to stroke patients, TMS was envisioned as a less painful alternative to transcranial electrical stimulation for the assessment of the impaired corticomotoneuronal pathways [12], however it soon became clear that fundamental differences in the physiological effects of TMS compared to electrical stimulation could allow more elaborate investigations [13, 14].

Electrophysiological measurements available with TMS

TMS activates a mixed population of inhibitory and excitatory cortical interneurons which can affect local and remote pyramidal tract neurons. The frequency, intensity and coil orientation at which TMS pulses are delivered to the cortex significantly affect its consequences and its uses. Generally, when TMS pulses are delivered at frequencies less than 0.3Hz, it is for measurement purposes and has not been found to alter motor cortical excitability for prolonged periods of time as long as the motor system is at rest at the time of stimulus delivery [15, 16]. However TMS stimuli applied to resting M1 at or above 0.3Hz [17] and paired pulses 1.5ms apart given in trains of at least 0.2Hz [18] have been found to alter cortical excitability beyond the period of stimulation. All of these and other forms of repetitive TMS (rTMS) can be used in an interventional manner to purposely alter cortical excitability both in a facilitatory and inhibitory way, in an attempt to change function of the underlying stimulated cortical tissues . The following represent some of the most common TMS measures used after stroke to dissect the physiologic mechanisms underlying motor deficits, spontaneous motor recovery, and the beneficial effects of therapeutic interventions.

Motor evoked potentials (MEP)

When TMS is applied at intensities above motor threshold, the activation of excitatory interneurons can result in volleys of upper motor neuron activity which subsequently activate alpha motor neurons of the spinal cord. The summed activity, an MEP, is measured via electromyography (EMG) from surface or needle electrodes over or in the muscles of interest [19], or as descending volleys of direct (D) or indirect (I) waves recorded directly from epidural electrodes over the spinal cord, close to the pyramidal tract [20, 21]. The amplitude, area under the curve, and latency of MEPs are all used in various ways to measure motor cortical excitability.

Resting motor threshold (rMT) is defined as the intensity of stimulation required to produce an MEP of small amplitude in 5 out of 10 trials [19].

Stimulating M1 at different stimulus intensities (relative to rMT intensity or maximum stimulator output) creates an input/output or recruitment curve of MEP amplitudes [22, 23] that is usually sigmoidal in shape. rMT is predominantly influenced by mechanisms of neuronal membrane excitability, evidenced by its alteration in the presence of pharmacological modifiers of sodium and calcium channels and relative stability in the presence of modifiers of synaptic transmission [24-26]. rMT also correlates with measures of white matter microstructure [27]. In contrast, recruitment curves are contributed to by changes in synaptic excitability, as evidenced by their alteration in the presence of pharmacological modifiers of synaptic transmission [23, 28].

Short-interval intra-cortical inhibition (SICI) and facilitation (SICF)

Exploiting TMS’ preferential activation of interneurons and transsynaptic activation of pyramidal tract cells has allowed for a better characterization of inhibitory and facilitatory mechanisms operating within M1. Paired pulse stimulation delivered through the same magnetic coil over M1, where a suprathreshold test stimulus (TS) is preceded by a sub- or supra-threshold conditioning stimulus (CS), can be used to gain insight into the relative contribution of local inhibitory and excitatory inputs to M1 pyramidal tract cells. The CS can cause an increase in MEP amplitude (facilitation, SICF) or decrease in MEP amplitude (inhibition, SICI) compared to the MEP evoked by the TS alone. Inter-stimulus intervals of approximately 1.5-3ms cause attenuation of MEP amplitudes or SICI [29], which seems to be at least partially GABA-A receptor mediated [21, 30-33]. With longer inter-stimulus intervals (~6-10ms) it is possible to observe a facilitation of MEP amplitudes, referred to as SICF [34], a more heterogeneous measurement that may have a significant spinal component [35]. One additional measurement that has been proposed as useful has been the determination of recruitment curves of SICI, a method perhaps underutilized that is likely to call for more attention in the future[36, 37].

Another test of intracortical inhibition is the contralateral cortical silent period (CSP), a drop in background voluntary EMG activity which occurs when a suprathreshold TMS pulse is delivered to the M1 contralateral to a muscle that is voluntarily activated. It has been proposed that the later part of the contralateral CSP [38] is a GABA-B receptor mediated cortical phenomenon [24], and hence likely represents a separate inhibitory network or mechanism within M1 relative to SICI [30].

Inter-hemispheric inhibition (IHI)

The inhibitory interactions between the two M1s can be evaluated using a paired pulse technique [39], where a suprathreshold CS is applied over the conditioning M1 at about 10ms prior to the TS applied to the conditioned M1. While other inter-stimulus intervals have been used, the 10ms interval has been the most widely studied (IHI₁₀). IHI₁₀ is likely mediated via transcallosal glutamatergic neurons from the conditioning M1 interacting with local GABA-B receptor mediated inhibitory interneurons within the target M1 [40, 41]. Another form of measuring interhemispheric inhibition is the ipsilateral CSP, evidenced as the suppression of voluntary EMG activity in one muscle via ipsilateral M1 stimulation [39, 42-44]. While both IHI₁₀ and ipsilateral CSP are forms of transcallosal inhibition, they are likely mediated by different subsets of transcallosal neurons and different interactions with local inhibitory circuits as evidenced by the lack of correlation in input/output curves between the two measures. Also, the current direction of the CS influences the level of ipsilateral CSP induced, unlike IHI₁₀ [44, 45]. While both can be considered complementary measurements, ipsilateral CSP can be especially useful in stroke patients who may not have measurable MEPs in the paretic limb after stimulation of the ipsilesional M1, but can produce voluntary EMG activity. Measures of ipsilateral CSP in the paretic limb can reveal the level of transcallosal inhibition targeting ipsilesional M1 [46].

Inter-regional interactions

Paired pulse and rTMS methods have also been used to evaluate the influence of non-primary motor areas within the same and opposite hemispheres on M1, including dorsal premotor (PMd)[47-53], supplementary motor (SMA)[47, 54], parietal [55], and cerebellar areas [56-60].

Motor mapping

A cortical map of a target muscle’s representation can be rendered by measuring MEP amplitudes evoked in that target muscle by TMS applied to different scalp positions [61-64]; by weighting each point by some measure of the overall map, a center of gravity for a particular muscle representation can also be determined. Motor mapping using TMS has some similarities with mapping using functional neuroimaging in that the size of the map depends to some extent on the intensity of stimulation used and in that an increase in map size may be due to either increased excitability of an unchanged cortical representation or of an actual centrifugal increase in motor map size [65]. Alternatively, motor maps may show well characterized topographic displacement of the center of gravity, as for example what occurs after amputation, where a nearby representation expands consistently over the deafferented representation [66], indicating real representational plasticity.

Central motor conduction (CMC)

The latency of MEP onsets can be used to measure nervous system conduction time. When peripheral conduction time is also known, via magnetic stimulation of the cervical roots or F-wave testing, then a central motor conduction time can be calculated [67, 68]. Abnormalities in central motor conduction time may be due to axonal or demyelinating lesions of the corticospinal tract.

This brief introduction intended to define some of the most common TMS measurements and their proposed mechanisms as they have been applied across healthy volunteers and post-stroke populations. For a more detailed description of these measurements and their impact on motor control, please refer to more thorough reviews [33]. Overall, these techniques allow detailed analysis at various levels of interactions within and across cortical areas in health and disease.

Contribution of TMS to the study of stroke rehabilitation

Diagnostic

One area in which TMS has contributed to the neurobiological basis of motor disorders has been when considering the evaluation and diagnosis of psychogenic paralysis. TMS may play a role by identifying normal MEPs and CMC, ruling out corticospinal tract neurophysiological damage [69], and in investigating the nervous system mechanisms behind motor conversion disorder[70]. Liepert et al reported the existence of decreased excitability during motor imagery in patients with this psychogenic paralysis. Such a finding may result in more objective diagnostic criteria for this disorder. Theoretically, a thorough characterization of neurophysiologic abnormalities in this disorder may lead to interventions targeting those abnormalities, and hence better treatment.

Prognostic

One of the major concerns in stroke rehabilitation is prognosis. Previous work demonstrated that high motor thresholds or a complete absence of MEPs in the paretic hand after subacute stroke are associated with poorer prognosis in terms of motor recovery [71-73]. On the other hand, the presence of MEPs, even with prolonged CMC time, may predict better prognosis [72-78]. Functional measurements of corticospinal integrity as provided by TMS can complement data on anatomical integrity as measured by diffusion tensor imaging (DTI). A recent report showed that, consistent with the previous literature, paretic limb MEP presence predicted meaningful gains in chronic stroke patients receiving motor rehabilitation [79]. Within the subgroup of patients in whom MEPs could not be evoked in the paretic hand (theoretically predicting poor prognosis), functional outcome was poorer in patients with greater posterior internal capsule fiber disruption, as measured by DTI. Using these methods together can fine tune our ability to generate more accurate prognostic evaluations [79]

Understanding mechanisms of motor deficits

Using TMS as a complex probe into the neurophysiologic underpinnings of motor function allows researchers to comment about specific mechanisms of behavior and plasticity. Application of these techniques to patients with impaired nervous system will likely reveal more regarding the mechanisms of both injury and recovery after stroke. These measures have potential not only to improve diagnosis and prognosis, as discussed above, but even more intriguingly, to reveal new unpredicted targets for therapy.

Primary motor cortex

One of the early intriguing findings in the application of TMS to stroke patients was the presence of ipsilateral MEPs within the paretic limb [71, 80-84], which are otherwise rarely found in healthy subjects at rest. This also seemed to correlate with other measures of increased excitability in the contralesional M1 [85-87]. Interestingly, ipsilateral MEPs have been reported more frequently in poorly recovered stroke patients [71], a finding interpreted as indicating that contralesional facilitation of excitability may not be a marker of good recovery [80]. Based on these reports, much interest was triggered regarding to what extent alterations in excitability in contralesional M1 influence recovery of motor function in the paretic arm, and what mechanisms may be involved. In subacute severely paretic stroke patients, Liepert et al reported decreased SICI in contralesional M1 as compared to age-matched controls [88]; a finding subsequently replicated in more acute patients [36, 89-92]. Also, decreases in SICI in ipsilesional M1 have been consistently reported in the literature, both in the acute and chronic periods after stroke [37, 90, 93-95]. When assessing changes longitudinally, it does seem that acute disinhibition may, especially contralesionally, normalize over time [92, 96]. However, how measures of intracortical inhibition or its changes correlate with function at any particular time-point may be highly dependent on initial patient characteristics [36, 92, 96]. Another issue that is presently under investigation is the extent to which decreased inhibition in contralesional M1 is present in patients with both cortical and subcortical lesions [36, 91], perhaps explaining the relative variance in reproducibility [94, 95]. Finally, intense scrutiny is necessary to determine how these electrophysiological abnormalities relate to previously reported abnormalities in metabolic activity of both the ipsilesional and contralesional hemisphere of patients with stroke [97-104].

Beyond investigation of the local changes in excitability of both M1s in stroke patients, it should be kept in mind that functional recovery is likely related to changes in distributed neuronal networks rather than in individual regions. Studies have begun to investigate the alteration in transcallosal neurophysiology after stroke. IHI₁₀ between the two M1s is likely altered after stroke, possibly in a lesion-location dependent manner [105]. Examining whether changes in IHI₁₀ and SICI after stroke may be related, Butefisch and colleagues have shown that the attenuation of SICI in ipsilesional M1 is not accompanied by a change in resting IHI₁₀ from contralesional to ipsilesional M1. In contrast, disinhibition of contralesional M1 is accompanied but not completely correlated with a decrease in IHI₁₀ from ipsilesional to contralesional M1s [37]. Together, these findings may imply that at rest, local modulation of inhibition within ipsilesional M1 is prominent. However, a thorough investigation of the resting interactions between SICI and IHI₁₀, which has begun in healthy individuals [40, 106], will need to be carried in stroke patients, at various time points and levels of recovery, before more fundamental conclusions can be made. It should also be kept in mind that neurophysiological abnormalities may be more prominent when patients intend to use the paretic hand, rather than when they remain at rest.

Much of these basic cortical physiology measures have been most thoroughly examined at rest. Clearly, extending such measures to active behavior will add significant insight into post-stroke mechanisms of paralysis. For example, the phenomenon of facilitation of M1 excitability by forceful or complex activity of the ipsilateral limb has been explored in the healthy brain [106-111]. How modulations in SICI & IHI₁₀ and their interactions may contribute to this facilitation has also been investigated in healthy subjects [106]. Understanding of these interactions in stroke patients would raise the possibility that non-paretic limb activity could change the physiology of the ipsilesional M1, as proposed in neurorehabilitative interventions like bilateral arm training [112] or mirror therapy [113]. However, with isometric force production, non-paretic arm activity in stroke patients does not lead to as much ipsilateral M1 facilitation as seen in healthy controls [114, 115]. Perhaps this lack of task-dependent modulation in ipsilesional M1 is due to abnormalities in IHI₁₀ after stroke [116]. Studies have begun to address this question by looking at premovement IHI₁₀. In chronic, relatively well recovered stroke patients, initially normal levels of IHI₁₀ from the contralesional to the ipsilesional M1 remain abnormally deep at the onset of paretic hand movement, in contrast to the disinhibition that accompanies non-paretic hand movement and movement in age matched controls [117, 118] during a simple reaction time task (Figure 1).

Figure 1

Intra- and inter-hemispheric excitability within M1 in the healthy (A) and stroke affected (B) brain

Expanding this line of research to encompass measures of both local and transcallosal neurophysiology and apply them to different motor tasks will allow us to more broadly characterize the neurophysiologic underpinnings of motor deficits after stroke. Clearly, more work is required to fully elaborate these findings.

Non-primary motor regions

Understanding that recovery processes are likely to rely on changes in neurophysiological interactions between different nodes in distributed networks led to the investigations of specific interregional interactions. Investigation of premotor cortex contributions to stroke recovery using TMS have revealed a role for both ipsilesional [119] and contralesional [103] dorsal premotor cortices to the functioning of the paretic hand after stroke, with a trend towards contralesional PMd contributing more effectively in patients with more marked impairment, while ipsilesional PMd could be more active in patients with lesser impairment. A prominent possibility for translation of these findings will be investigations into how purposeful modulation of premotor cortical excitability may influence functional recovery after stroke.

It should be kept in mind that identification of neurophysiological abnormalities in patients with stroke is not an easy task. There are technical challenges, as well as a marked heterogeneity in patients’ characteristics that makes generalizations risky. For these reasons, careful manipulation of the various technical tools available is of the utmost importance. It is expected that these new investigations, many presently under way, will in the future allow greater generalizability by fleshing out the details regarding each technique and each subgroup of patients to which they are applied.

Understanding mechanisms underlying the beneficial effects of intervention and therapy

Just as TMS measurements can be used to investigate pathophysiology, they can also be used to gain insight into the mechanisms underlying the beneficial effects of therapeutic interventions. For example, using TMS measures of local inhibition and non-concurrent functional magnetic resonance imaging (fMRI), Hamzei and colleagues demonstrated in chronic subcortical stroke patients that functional improvement from constraint-induced (CI) therapy was accompanied by decreased fMRI activity and decreased SICI in the ipsilesional M1, while the opposite effects were found in patients with lesions in M1 or the corticospinal tract [120]. This study suggested that the beneficial effects of CI therapy might be mediated at least partially by modulation of intracortical inhibition within ipsilesional M1, perhaps accompanied by some level of morphological changes as well[121]. We now know that the benefits of a single session of reaching practice in moderately impaired chronic stroke patients is accompanied by decreased transcallosal inhibition (ipsilateral CSP) [46] only in the trained muscles, implying a specific and differential change in physiology that may contribute to the behavioral gains.

Attempts to enhance rehabilitation by application of different forms of non-invasive electrical and magnetic stimulation to the nervous system have increased [122-125]. Interestingly, TMS can be used not only to carry out the stimulation, but to investigate the mechanisms by which it may be having its effects. For example, it was found that the beneficial effects of applying anodal transcranial direct current stimulation (tDCS) to ipsilesional M1 correlated with a decrease in SICI in this same cortical area [126]. Using an alternative approach, it has been proposed that the beneficial effects of downregulating excitability in the contralesional M1 by cathodal tDCS are associated with a normalization in the abnormal IHI₁₀ from the contralesional to the ipsilesional M1 (Hummel et al, unpublished observations), perhaps contributing to clinically significant effects [127-130].

TMS has also been used to evaluate the mechanisms underlying the beneficial effects of somatosensory input modulation in patients with chronic stroke. Specifically, it has been reported that the beneficial effects on paretic hand motor function caused by cutaneous anesthesia of the non-paretic hand are associated with decreased IHI₁₀ from contralesional to ipsilesional M1, which may be an underlying mechanism of action of the post-stroke functional improvements seen with this and similar methods targeting the non-paretic limb, like limb immobilization [131]. When applying somatosensory stimulation to a paretic hand in an attempt to facilitate motor function[132-134], it was found that better baseline motor function was correlated with deeper SICI in the contralesional hemisphere[135]. Also behavioral gains in motor function induced by somatosensory stimulation of the paretic hand were accompanied by a reduction in SICI and SICF in the ipsilesional M1 in patients with chronic stroke [134].

As examination of the physiologic mechanisms underlying the beneficial effects of therapeutic interventions has expanded, so has the desire to use such measures as surrogate markers [136, 137]. While changes in TMS measured cortical excitability and motor maps can be seen after various forms of neurorehabilitative treatments [138-145], and correlations can be found with various functional measures, there are significant hurdles to be managed before these measures become useful in the clinical setting. Particularly, all of these measures need to be better standardized to make them consistent and easily reproducible across laboratories [146]. Such standardization would be an important step towards developing these measurements as useful markers of recovery.

Finally, one of the most sought out applications of TMS, as well as other noninvasive stimulation techniques like tDCS, is as an adjuvant strategy for rehabilitation of both motor [123]and cognitive [147] impairment after stroke, an issue that has been thoroughly reviewed recently in this journal [148].

Conclusions and future

While we have summarized the several ways in which TMS can be used to gain insight into the physiological mechanisms underlying motor deficits and neurorehabilitation after stroke, it is clear that one technique alone cannot provide a full mechanistic picture of such a multifaceted problem. Combinations of TMS with other techniques are bound to lead to a more sophisticated understanding. For instance, brain-derived-neurotrophic-factor (BDNF) has been implicated as an important biochemical modulator of neural plasticity[149], and its relationship to physiology as measured by brain stimulation is beginning to be investigated[150-152], although much less is known in terms of its relation to motor learning. It is also being appreciated that in vitro and non-human investigations of nervous system stimulation and physiology have great potential to elucidate some of the complexities that cannot be approached through human TMS work [153, 154]. Finally, though it has yet to be applied to stroke patients, concurrent TMS with various forms of metabolic functional imaging [155-157] and other neurophysiologic measures [158] has potential to further elucidate changes in network connectivity after stroke and during rehabilitation. In summary, TMS represents a unique tool for probing the sophisticated physiologic mechanisms underlying motor and non-motor network activity mediating normal and impaired behavior after stroke and other brain lesions. And from a more sophisticated understanding of the underlying physiology, so will come more sophisticated and effective interventions.

Footnotes

This version of the manuscript is an early version that was altered significantly by the time of publication. The final, definitive version of the article is available at http://online.sagepub.com/.’

References

[1] Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB, Flegal K, et al. Heart Disease and Stroke Statistics--2009 Update. A Report From the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2008 December 15; 2008:CIRCULATIONAHA.108.191261.

[2] Flynn RW, MacWalter RS, Doney AS. The cost of cerebral ischaemia. Neuropharmacology. 2008 Sep;55(3):250–6. [PubMed]

[3] Spieler JF, Lanoe JL, Amarenco P. Costs of stroke care according to handicap levels and stroke subtypes. Cerebrovasc Dis. 2004;17(2-3):134–42. [PubMed]

[4] Cheeran B, Cohen L, Dobkin B, Ford G, Greenwood R, Howard D, et al. The future of restorative neurosciences in stroke: driving the translational research pipeline from basic science to rehabilitation of people after stroke. Neurorehabil Neural Repair. 2009 Feb;23(2):97–107. [PMC free article] [PubMed]

[5] Fisher M. Advances in Stroke 2007: introduction. Stroke. 2008 Feb;39(2):250–1. [PubMed]

[6] Quinn TJ, Lees KR. Advances in emerging therapies 2007. Stroke. 2008 Feb;39(2):255–7. [PubMed]

[7] Barker AT, Jalinous R, Freeston IL. Non-invasive magnetic stimulation of human motor cortex. Lancet. 1985 May 11;1(8437):1106–7. [PubMed]

[8] Roth BJ, Saypol JM, Hallett M, Cohen LG. A theoretical calculation of the electric field induced in the cortex during magnetic stimulation. Electroencephalography and Clinical Neurophysiology/Evoked Potentials Section. 1991;81(1):47–56. [PubMed]

[9] Wagner T, Gangitano M, Romero R, Theoret H, Kobayashi M, Anschel D, et al. Intracranial measurement of current densities induced by transcranial magnetic stimulation in the human brain. Neurosci Lett. 2004 Jan 9;354(2):91–4. [PubMed]

[10] Wagner TA, Zahn M, Grodzinsky AJ, Pascual-Leone A. Three-dimensional head model simulation of transcranial magnetic stimulation. IEEE Trans Biomed Eng. 2004 Sep;51(9):1586–98. [PubMed]

[11] Cohen LG, Roth BJ, Nilsson J, Dang N, Panizza M, Bandinelli S, et al. Effects of coil design on delivery of focal magnetic stimulation. Technical considerations. Electroencephalogr Clin Neurophysiol. 1990 Apr;75(4):350–7. [PubMed]

[12] Homberg V, Stephan KM, Netz J. Transcranial stimulation of motor cortex in upper motor neurone syndrome: its relation to the motor deficit. Electroencephalogr Clin Neurophysiol. 1991 Oct;81(5):377–88. [PubMed]

[13] Amassian VE, Quirk GJ, Stewart M. A comparison of corticospinal activation by magnetic coil and electrical stimulation of monkey motor cortex. Electroencephalogr Clin Neurophysiol. 1990 Sep-Oct;77(5):390–401. [PubMed]

[14] Day BL, Dressler D, de Noordhout A Maertens, Marsden CD, Nakashima K, Rothwell JC, et al. Electric and magnetic stimulation of human motor cortex: surface EMG and single motor unit responses. J Physiol. 1989 May;412:449–73. [PubMed]

[15] Ziemann U, Corwell B, Cohen LG. Modulation of plasticity in human motor cortex after forearm ischemic nerve block. J Neurosci. 1998 Feb 1;18(3):1115–23. [PubMed]

[16] Ziemann U, Hallett M, Cohen LG. Mechanisms of deafferentation-induced plasticity in human motor cortex. J Neurosci. 1998 Sep 1;18(17):7000–7. [PubMed]

[17] Cincotta M, Borgheresi A, Gambetti C, Balestrieri F, Rossi L, Zaccara G, et al. Suprathreshold 0.3 Hz repetitive TMS prolongs the cortical silent period: potential implications for therapeutic trials in epilepsy. Clin Neurophysiol. 2003 Oct;114(10):1827–33. [PubMed]

[18] Thickbroom GW, Byrnes ML, Edwards DJ, Mastaglia FL. Repetitive paired-pulse TMS at I-wave periodicity markedly increases corticospinal excitability: A new technique for modulating synaptic plasticity. Clinical Neurophysiology. 2006;117(1):61–6. [PubMed]

[19] Rossini PM, Barker AT, Berardelli A, Caramia MD, Caruso G, Cracco RQ, et al. Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application. Report of an IFCN committee. Electroencephalogr Clin Neurophysiol. 1994 Aug;91(2):79–92. [PubMed]

[20] Amassian VE, Cracco RQ, Maccabee PJ. Focal stimulation of human cerebral cortex with the magnetic coil: a comparison with electrical stimulation. Electroencephalogr Clin Neurophysiol. 1989 Nov-Dec;74(6):401–16. [PubMed]

[21] Di Lazzaro V, Oliviero A, Profice P, Saturno E, Pilato F, Insola A, et al. Comparison of descending volleys evoked by transcranial magnetic and electric stimulation in conscious humans. Electroencephalography and Clinical Neurophysiology/Electromyography and Motor Control. 1998;109(5):397–401. [PubMed]

[22] Devanne H, Lavoie BA, Capaday C. Input-output properties and gain changes in the human corticospinal pathway. Exp Brain Res. 1997 Apr;114(2):329–38. [PubMed]

[23] Boroojerdi B, Battaglia F, Muellbacher W, Cohen LG. Mechanisms influencing stimulus-response properties of the human corticospinal system. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology. 2001 May;112(5):931–7. [PubMed]

[24] Ziemann U. TMS and drugs. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology. 2004 Aug;115(8):1717–29. [PubMed]

[25] Ziemann U, Lönnecker S, Steinhoff BJ, Paulus W. Effects of antiepileptic drugs on motor cortex excitability in humans: A transcranial magnetic stimulation study. Annals of Neurology. 1996;40(3):367–78. [PubMed]

[26] Chen R, Samii A, Caños M, Wassermann EM, Hallett M. Effects of phenytoin on cortical excitability in humans. Neurology. 1997;49(3):881–3. [PubMed]

[27] Klöppel S, Bäumer T, Kroeger J, Koch MA, Büchel C, Münchau A, et al. The cortical motor threshold reflects microstructural properties of cerebral white matter. Neuroimage. 2008;40(4):1782–91. [PubMed]

[28] Paulus W, Classen J, Cohen LG, Large CH, Di Lazzaro V, Nitsche M, et al. State of the art: Pharmacologic effects on cortical excitability measures tested by transcranial magnetic stimulation. Brain Stimulation. 2008;1(3):151–63. [PubMed]

[29] Kujirai T, Caramia MD, Rothwell JC, Day BL, Thompson PD, Ferbert A, et al. Corticocortical inhibition in human motor cortex. The Journal of physiology. 1993 Nov;471:501–19. [PubMed]

[30] Ilic TV, Meintzschel F, Cleff U, Ruge D, Kessler KR, Ziemann U. Short-interval paired-pulse inhibition and facilitation of human motor cortex: the dimension of stimulus intensity. J Physiol. 2002 Nov 15;545(Pt 1):153–67. [PubMed]

[31] Nakamura H, Kitagawa H, Kawaguchi Y, Tsuji H. Intracortical facilitation and inhibition after transcranial magnetic stimulation in conscious humans. J Physiol. 1997 Feb 1;498(Pt 3):817–23. [PubMed]

[32] Ziemann U, Steinhoff BJ, Tergau F, Paulus W. Transcranial magnetic stimulation: its current role in epilepsy research. Epilepsy Res. 1998 Mar;30(1):11–30. [PubMed]

[33] Reis J, Swayne OB, Vandermeeren Y, Camus M, Dimyan MA, Harris-Love M, et al. Contribution of transcranial magnetic stimulation to the understanding of cortical mechanisms involved in motor control. J Physiol. 2008 January 15;586(2):325–51. 2008. [PubMed]

[34] Ziemann U, Rothwell JC, Ridding MC. Interaction between intracortical inhibition and facilitation in human motor cortex. The Journal of physiology. 1996 Nov 1;496(Pt 3):873–81. (Pt 3) [PubMed]

[35] Di Lazzaro V, Pilato F, Oliviero A, Dileone M, Saturno E, Mazzone P, et al. Origin of facilitation of motor-evoked potentials after paired magnetic stimulation: direct recording of epidural activity in conscious humans. J Neurophysiol. 2006 Oct;96(4):1765–71. [PubMed]

[36] Butefisch CM, Netz J, Wessling M, Seitz RJ, Homberg V. Remote changes in cortical excitability after stroke. Brain. 2003 February 1;126(2):470–81. 2003. [PubMed]

[37] Butefisch CM, Wessling M, Netz J, Seitz RJ, Homberg V. Relationship between interhemispheric inhibition and motor cortex excitability in subacute stroke patients. Neurorehabil Neural Repair. 2008 Jan-Feb;22(1):4–21. [PubMed]

[38] Fuhr P, Agostino R, Hallett M. Spinal motor neuron excitability during the silent period after cortical stimulation. Electroencephalography and Clinical Neurophysiology/Evoked Potentials Section. 1991;81(4):257–62. [PubMed]

[39] Ferbert A, Priori A, Rothwell JC, Day BL, Colebatch JG, Marsden CD. Interhemispheric inhibition of the human motor cortex. J Physiol. 1992;453:525–46. 1992. [PubMed]

[40] Daskalakis ZJ, Christensen BK, Fitzgerald PB, Roshan L, Chen R. The mechanisms of interhemispheric inhibition in the human motor cortex. J Physiol. 2002 Aug 15;543(Pt 1):317–26. 2002. [PubMed]

[41] Chen R. Interactions between inhibitory and excitatory circuits in the human motor cortex. Exp Brain Res. 2004 Jan;154(1):1–10. [PubMed]

[42] Wassermann EM, Fuhr P, Cohen LG, Hallett M. Effects of transcranial magnetic stimulation on ipsilateral muscles. Neurology. 1991 Nov;41(11):1795–9. [PubMed]

[43] Meyer BU, Roricht S, Woiciechowsky C. Topography of fibers in the human corpus callosum mediating interhemispheric inhibition between the motor cortices. Ann Neurol. 1998 Mar;43(3):360–9. [PubMed]

[44] Chen R, Yung D, Li J-Y. Organization of Ipsilateral Excitatory and Inhibitory Pathways in the Human Motor Cortex. J Neurophysiol. 2003 March 1;89(3):1256–64. 2003. [PubMed]

[45] Trompetto C, Bove M, Marinelli L, Avanzino L, Buccolieri A, Abbruzzese G. Suppression of the transcallosal motor output: a transcranial magnetic stimulation study in healthy subjects. Exp Brain Res. 2004 Sep;158(2):133–40. [PubMed]

[46] Harris-Love ML, Perez MA, Morton S, Kapteyn R, Cohen LG. Neural mechanisms of practice-induced improvement in functional reaching after moderate severity stroke. Poster presented at: Neuroscience 2008 Abstracts of the 38th annual meeting of the Society for Neuroscience; Washington, DC, USA. 2008, Nov 15-19.2008.

[47] Civardi C, Cantello R, Asselman P, Rothwell JC. Transcranial magnetic stimulation can be used to test connections to primary motor areas from frontal and medial cortex in humans. Neuroimage. 2001 Dec;14(6):1444–53. [PubMed]

[48] Gerschlager W, Siebner HR, Rothwell JC. Decreased corticospinal excitability after subthreshold 1 Hz rTMS over lateral premotor cortex. Neurology. 2001 Aug 14;57(3):449–55. [PubMed]

[49] Munchau A, Bloem BR, Irlbacher K, Trimble MR, Rothwell JC. Functional Connectivity of Human Premotor and Motor Cortex Explored with Repetitive Transcranial Magnetic Stimulation. Journal of Neuroscience. 2002 Jan 15;22(2):554–61. [PubMed]

[50] Mochizuki H, Huang YZ, Rothwell JC. Interhemispheric interaction between human dorsal premotor and contralateral primary motor cortex. J Physiol. 2004 Nov 15;561(Pt 1):331–8. [PubMed]

[51] Rizzo V, Siebner HR, Modugno N, Pesenti A, Munchau A, Gerschlager W, et al. Shaping the excitability of human motor cortex with premotor rTMS. The Journal of Physiology. 2004;554(2):483–95. [PubMed]

[52] Baumer T, Bock F, Koch G, Lange R, Rothwell JC, Siebner HR, et al. Magnetic stimulation of human premotor or motor cortex produces interhemispheric facilitation through distinct pathways. The Journal of Physiology. 2006;572(3):857–68. [PubMed]

[53] Koch G, Franca M, Del Olmo MF, Cheeran B, Milton R, Sauco M Alvarez, et al. Time course of functional connectivity between dorsal premotor and contralateral motor cortex during movement selection. J Neurosci. 2006 Jul 12;26(28):7452–9. [PubMed]

[54] Matsunaga K, Maruyama A, Fujiwara T, Nakanishi R, Tsuji S, Rothwell JC. Increased corticospinal excitability after 5 Hz rTMS over the human supplementary motor area. J Physiol. 2005 Jan 1;562(Pt 1):295–306. [PubMed]

[55] Koch G, Del Olmo M Fernandez, Cheeran B, Ruge D, Schippling S, Caltagirone C, et al. Focal stimulation of the posterior parietal cortex increases the excitability of the ipsilateral motor cortex. J Neurosci. 2007 Jun 20;27(25):6815–22. [PubMed]

[56] Meyer BU, Roricht S, Machetanz J. Reduction of corticospinal excitability by magnetic stimulation over the cerebellum in patients with large defects of one cerebellar hemisphere. Electroencephalogr Clin Neurophysiol. 1994 Oct;93(5):372–9. [PubMed]

[57] Ugawa Y, Uesaka Y, Terao Y, Hanajima R, Kanazawa I. Magnetic stimulation over the cerebellum in humans. Ann Neurol. 1995 Jun;37(6):703–13. [PubMed]

[58] Werhahn KJ, Taylor J, Ridding M, Meyer BU, Rothwell JC. Effect of transcranial magnetic stimulation over the cerebellum on the excitability of human motor cortex. Electroencephalogr Clin Neurophysiol. 1996 Feb;101(1):58–66. [PubMed]

[59] Pinto AD, Chen R. Suppression of the motor cortex by magnetic stimulation of the cerebellum. Exp Brain Res. 2001 Oct;140(4):505–10. [PubMed]

[60] Daskalakis ZJ, Paradiso GO, Christensen BK, Fitzgerald PB, Gunraj C, Chen R. Exploring the connectivity between the cerebellum and motor cortex in humans. J Physiol. 2004 Jun 1;557(Pt 2):689–700. [PubMed]

[61] Cohen LG, Hallett M, Lelli S. Noninvasive mapping of the human motor cortex with transcranial magnetic stimulation. In: Chokroverty S, editor. Magnetic stimulation in clinical neurophysiology. Butterworth Publishers; Boston: 1989. pp. 113–20.

[62] Wassermann EM, McShane LM, Hallett M, Cohen LG. Noninvasive mapping of muscle representations in human motor cortex. Electroencephalography and Clinical Neurophysiology/Evoked Potentials Section. 1992;85(1):1–8. [PubMed]

[63] Thickbroom GW, Sammut R, Mastaglia FL. Magnetic stimulation mapping of motor cortex: factors contributing to map area. Electroencephalography and Clinical Neurophysiology/Electromyography and Motor Control. 1998;109(2):79–84. [PubMed]

[64] Corneal SF, Butler AJ, Wolf SL. Intra- and intersubject reliability of abductor pollicis brevis muscle motor map characteristics with transcranial magnetic stimulation. Arch Phys Med Rehabil. 2005 Aug;86(8):1670–5. [PMC free article] [PubMed]

[65] Ridding MC, Rothwell JC. Stimulus/response curves as a method of measuring motor cortical excitability in man. Electroencephalogr Clin Neurophysiol. 1997 Oct;105(5):340–4. [PubMed]

[66] Karl A, Birbaumer N, Lutzenberger W, Cohen LG, Flor H. Reorganization of motor and somatosensory cortex in upper extremity amputees with phantom limb pain. J Neurosci. 2001 May 15;21(10):3609–18. [PubMed]

[67] Barker AT, Freeston IL, Jabinous R, Jarratt JA. Clinical evaluation of conduction time measurements in central motor pathways using magnetic stimulation of human brain. Lancet. 1986 Jun 7;1(8493):1325–6. [PubMed]

[68] Samii A, Luciano CA, Dambrosia JM, Hallett M. Central motor conduction time: reproducibility and discomfort of different methods. Muscle Nerve. 1998 Nov;21(11):1445–50. [PubMed]

[69] Cantello R, Boccagni C, Comi C, Civardi C, Monaco F. Diagnosis of psychogenic paralysis: the role of motor evoked potentials. J Neurol. 2001 Oct;248(10):889–97. [PubMed]

[70] Liepert J, Hassa T, Tuscher O, Schmidt R. Abnormal motor excitability in patients with psychogenic paresis : A TMS study. J Neurol. 2009 Jan 29; [PubMed]

[71] Turton A, Wroe S, Trepte N, Fraser C, Lemon RN. Contralateral and ipsilateral EMG responses to transcranial magnetic stimulation during recovery of arm and hand function after stroke. Electroencephalography and Clinical Neurophysiology/Electromyography and Motor Control. 1996;101(4):316–28. [PubMed]

[72] Catano A, Houa M, Caroyer JM, Ducarne H, Noel P. Magnetic transcranial stimulation in non-haemorrhagic sylvian strokes: interest of facilitation for early functional prognosis. Electroencephalogr Clin Neurophysiol. 1995 Dec;97(6):349–54. [PubMed]

[73] Pennisi G, Rapisarda G, Bella R, Calabrese V, De Noordhout A Maertens, Delwaide PJ. Absence of response to early transcranial magnetic stimulation in ischemic stroke patients: prognostic value for hand motor recovery. Stroke. 1999 Dec;30(12):2666–70. [PubMed]

[74] Heald A, Bates D, Cartlidge NE, French JM, Miller S. Longitudinal study of central motor conduction time following stroke. 1. Natural history of central motor conduction. Brain. 1993 Dec;116(Pt 6):1355–70. [PubMed]

[75] Heald A, Bates D, Cartlidge NE, French JM, Miller S. Longitudinal study of central motor conduction time following stroke. 2. Central motor conduction measured within 72 h after stroke as a predictor of functional outcome at 12 months. Brain. 1993 Dec;116(Pt 6):1371–85. [PubMed]

[76] Escudero JV, Sancho J, Bautista D, Escudero M, Lopez-Trigo J. Prognostic Value of Motor Evoked Potential Obtained by Transcranial Magnetic Brain Stimulation in Motor Function Recovery in Patients With Acute Ischemic Stroke. Stroke. 1998 September 1;29(9):1854–9. 1998. [PubMed]

[77] Rapisarda G, Bastings E, de Noordhout AM, Pennisi G, Delwaide PJ. Can Motor Recovery in Stroke Patients Be Predicted by Early Transcranial Magnetic Stimulation? Stroke. 1996 December 1;27(12):2191–6. 1996. [PubMed]

[78] Thickbroom GW, Byrnes ML, Archer SA, Mastaglia FL. Motor outcome after subcortical stroke: MEPs correlate with hand strength but not dexterity. Clinical Neurophysiology. 2002;113(12):2025–9. [PubMed]

[79] Stinear CM, Barber PA, Smale PR, Coxon JP, Fleming MK, Byblow WD. Functional potential in chronic stroke patients depends on corticospinal tract integrity. Brain. 2007 January 1;130(1):170–80. 2007. [PubMed]

[80] Palmer E, Ashby P, Hajek VE. Ipsilateral fast corticospinal pathways do not account for recovery in stroke. Annals of Neurology. 1992;32(4):519–25. [PubMed]

[81] Caramia MD, Iani C, Bernardi G. Cerebral plasticity after stroke as revealed by ipsilateral responses to magnetic stimulation. Neuroreport. 1996 Jul 29;7(11):1756–60. [PubMed]

[82] Netz J, Lammers T, Homberg V. Reorganization of motor output in the non-affected hemisphere after stroke. Brain. 1997 September 1;120(9):1579–86. 1997. [PubMed]

[83] Trompetto C, Assini A, Buccolieri A, Marchese R, Abbruzzese G. Motor recovery following stroke: a transcranial magnetic stimulation study. Clinical Neurophysiology. 2000;111(10):1860–7. [PubMed]

[84] Werhahn KJ, Conforto AB, Kadom N, Hallett M, Cohen LG. Contribution of the ipsilateral motor cortex to recovery after chronic stroke. Ann Neurol. 2003 Oct;54(4):464–72. [PubMed]

[85] Traversa R, Cicinelli P, Bassi A, Rossini PM, Bernardi G. Mapping of motor cortical reorganization after stroke. A brain stimulation study with focal magnetic pulses. Stroke. 1997 Jan;28(1):110–7. [PubMed]

[86] Cicinelli P, Traversa R, Rossini PM. Post-stroke reorganization of brain motor output to the hand: a 2-4 month follow-up with focal magnetic transcranial stimulation. Electroencephalography and Clinical Neurophysiology/Electromyography and Motor Control. 1997;105(6):438–50. [PubMed]

[87] Delvaux V, Alagona G, Gérard P, De Pasqua V, Pennisi G, de Noordhout AM. Post-stroke reorganization of hand motor area: a 1-year prospective follow-up with focal transcranial magnetic stimulation. Clinical Neurophysiology. 2003;114(7):1217–25. [PubMed]

[88] Liepert J, Hamzei F, Weiller C. Motor cortex disinhibition of the unaffected hemisphere after acute stroke. Muscle Nerve. 2000 Nov;23(11):1761–3. [PubMed]

[89] Nardone R, Tezzon F. Inhibitory and excitatory circuits of cerebral cortex after ischaemic stroke: prognostic value of the transcranial magnetic stimulation. Electromyogr Clin Neurophysiol. 2002 Apr-May;42(3):131–6. [PubMed]

[90] Manganotti P, Patuzzo S, Cortese F, Palermo A, Smania N, Fiaschi A. Motor disinhibition in affected and unaffected hemisphere in the early period of recovery after stroke. Clin Neurophysiol. 2002 Jun;113(6):936–43. [PubMed]

[91] Shimizu T, Hosaki A, Hino T, Sato M, Komori T, Hirai S, et al. Motor cortical disinhibition in the unaffected hemisphere after unilateral cortical stroke. Brain. 2002 Aug;125(Pt 8):1896–907. [PubMed]

[92] Manganotti P, Acler M, Zanette GP, Smania N, Fiaschi A. Motor cortical disinhibition during early and late recovery after stroke. Neurorehabil Neural Repair. 2008;22(4):396–403. [PubMed]

[93] Liepert J, Storch P, Fritsch A, Weiller C. Motor cortex disinhibition in acute stroke. Clin Neurophysiol. 2000 Apr;111(4):671–6. [PubMed]

[94] Cicinelli P, Pasqualetti P, Zaccagnini M, Traversa R, Oliveri M, Rossini PM. Interhemispheric asymmetries of motor cortex excitability in the postacute stroke stage: a paired-pulse transcranial magnetic stimulation study. Stroke. 2003 Nov;34(11):2653–8. [PubMed]

[95] Wittenberg GF, Bastings EP, Fowlkes AM, Morgan TM, Good DC, Pons TP. Dynamic course of intracortical TMS paired-pulse responses during recovery of motor function after stroke. Neurorehabil Neural Repair. 2007 Nov-Dec;21(6):568–73. [PubMed]

[96] Swayne OB, Rothwell JC, Ward NS, Greenwood RJ. Stages of motor output reorganization after hemispheric stroke suggested by longitudinal studies of cortical physiology. Cereb Cortex. 2008 Aug;18(8):1909–22. [PubMed]

[97] Ward NS, Newton JM, Swayne OBC, Lee L, Frackowiak RSJ, Thompson AJ, et al. The relationship between brain activity and peak grip force is modulated by corticospinal system integrity after subcortical stroke. European Journal of Neuroscience. 2007;25(6):1865–73. [PubMed]

[98] Hodics T, Cohen LG, Cramer SC. Functional Imaging of Intervention Effects in Stroke Motor Rehabilitation. Archives of Physical Medicine and Rehabilitation. 2006;87(12, Supplement 1):36–42. [PubMed]

[99] Takahashi CD, Der Yeghiaian L, Cramer SC. Stroke recovery and its imaging. Neuroimaging Clin N Am. 2005 Aug;15(3):681–95. xii. [PubMed]

[100] Saur D, Lange R, Baumgaertner A, Schraknepper V, Willmes K, Rijntjes M, et al. Dynamics of language reorganization after stroke. Brain. 2006 Jun;129(Pt 6):1371–84. [PubMed]

[101] Small SL, Hlustik P, Noll DC, Genovese C, Solodkin A. Cerebellar hemispheric activation ipsilateral to the paretic hand correlates with functional recovery after stroke. Brain. 2002 Jul;125(Pt 7):1544–57. [PubMed]

[102] Gerloff C, Bushara K, Sailer A, Wassermann EM, Chen R, Matsuoka T, et al. Multimodal imaging of brain reorganization in motor areas of the contralesional hemisphere of well recovered patients after capsular stroke. Brain. 2006 Mar;129(Pt 3):791–808. [PubMed]

[103] Johansen-Berg H, Rushworth MF, Bogdanovic MD, Kischka U, Wimalaratna S, Matthews PM. The role of ipsilateral premotor cortex in hand movement after stroke. Proc Natl Acad Sci U S A. 2002 29;99(22):14518–23. [PubMed]

[104] Calautti C, Naccarato M, Jones PS, Sharma N, Day DD, Carpenter AT, et al. The relationship between motor deficit and hemisphere activation balance after stroke: A 3T fMRI study. NeuroImage. 2007;34(1):322–31. [PubMed]

[105] Boroojerdi B, Diefenbach K, Ferbert A. Transcallosal inhibition in cortical and subcortical cerebral vascular lesions. J Neurol Sci. 1996 Dec;144(1-2):160–70. [PubMed]

[106] Perez MA, Cohen LG. Mechanisms Underlying Functional Changes in the Primary Motor Cortex Ipsilateral to an Active Hand. Journal of Neuroscience. 2008 May 28;28(22):5631–40. 2008. [PMC free article] [PubMed]

[107] Muellbacher W, Facchini S, Boroojerdi B, Hallett M. Changes in motor cortex excitability during ipsilateral hand muscle activation in humans. Clinical Neurophysiology. 2000;111(2):344–9. [PubMed]

[108] Hess CW, Mills KR, Murray NMF. Magnetic stimulation of the human brain: Facilitation of motor responses by voluntary contraction of ipsilateral and contralateral muscles with additional observations on an amputee. Neuroscience Letters. 1986;71(2):235–40. [PubMed]

[109] Stedman A, Davey NJ, Ellaway PH. Facilitation of human first dorsal interosseous muscle responses to transcranial magnetic stimulation during voluntary contraction of the contralateral homonymous muscle. Muscle & Nerve. 1998;21(8):1033–9. [PubMed]

[110] Hortobagyi T, Taylor JL, Petersen NT, Russell G, Gandevia SC. Changes in Segmental and Motor Cortical Output With Contralateral Muscle Contractions and Altered Sensory Inputs in Humans. J Neurophysiol. 2003 October 1;90(4):2451–9. 2003. [PubMed]

[111] Tinazzi M, Zanette G. Modulation of ipsilateral motor cortex in man during unimanual finger movements of different complexities. Neurosci Lett. 1998 Mar 20;244(3):121–4. [PubMed]

[112] Waller S McCombe, Forrester L, Villagra F, Whitall J. Intracortical inhibition and facilitation with unilateral dominant, unilateral nondominant and bilateral movement tasks in left- and right-handed adults. J Neurol Sci. 2008 Jun 15;269(1-2):96–104. [PMC free article] [PubMed]

[113] Altschuler EL, Wisdom SB, Stone L, Foster C, Galasko D, Llewellyn DM, et al. Rehabilitation of hemiparesis after stroke with a mirror. Lancet. 1999 Jun 12;353(9169):2035–6. [PubMed]

[114] Woldag H, Lukhaup S, Renner C, Hummelsheim H. Enhanced Motor Cortex Excitability During Ipsilateral Voluntary Hand Activation in Healthy Subjects and Stroke Patients. Stroke. 2004 November 1;35(11):2556–9. 2004. [PubMed]

[115] Renner CIE, Woldag H, Atanasova R, Hummelsheim H. Change of facilitation during voluntary bilateral hand activation after stroke. Journal of the Neurological Sciences. 2005;239(1):25–30. [PubMed]

[116] Ward NS, Cohen LG. Mechanisms Underlying Recovery of Motor Function After Stroke. Archives of Neurology. 2004 December 1;61(12):1844–8. [PubMed]

[117] Murase N, Duque J, Mazzocchio R, Cohen LG. Influence of Interhemispheric Interactions on Motor Function in Chronic Stroke. Annals of Neurology. 2004;55(3):400–9. [PubMed]

[118] Duque J, Hummel F, Celnik P, Murase N, Mazzocchio R, Cohen LG. Transcallosal inhibition in chronic subcortical stroke. NeuroImage. 2005;28(4):940–6. [PubMed]

[119] Fridman EA, Hanakawa T, Chung M, Hummel F, Leiguarda RC, Cohen LG. Reorganization of the human ipsilesional premotor cortex after stroke. Brain. 2004 Apr;127(Pt 4):747–58. 2004. [PubMed]

[120] Hamzei F, Liepert J, Dettmers C, Weiller C, Rijntjes M. Two different reorganization patterns after rehabilitative therapy: an exploratory study with fMRI and TMS. Neuroimage. 2006 Jun;31(2):710–20. [PubMed]

[121] Gauthier LV, Taub E, Perkins C, Ortmann M, Mark VW, Uswatte G. Remodeling the brain: plastic structural brain changes produced by different motor therapies after stroke. Stroke. 2008 May;39(5):1520–5. [PMC free article] [PubMed]

[122] Alonso-Alonso M, Fregni F, Pascual-Leone A. Brain stimulation in poststroke rehabilitation. Cerebrovasc Dis. 2007;24(Suppl 1):157–66. [PubMed]

[123] Hummel FC, Cohen LG. Non-invasive brain stimulation: a new strategy to improve neurorehabilitation after stroke? Lancet Neurol. 2006 Aug;5(8):708–12. 2006. [PubMed]

[124] Brown JA, Lutsep HL, Weinand M, Cramer SC. Motor cortex stimulation for the enhancement of recovery from stroke: a prospective, multicenter safety study. Neurosurgery. 2006 Mar;58(3):464–73. [PubMed]

[125] Fregni F, Pascual-Leone A. Hand motor recovery after stroke: tuning the orchestra to improve hand motor function. Cogn Behav Neurol. 2006 Mar;19(1):21–33. [PubMed]

[126] Hummel F, Celnik P, Giraux P, Floel A, Wu WH, Gerloff C, et al. Effects of non-invasive cortical stimulation on skilled motor function in chronic stroke. Brain. 2005 Mar;128(Pt 3):490–9. [PubMed]

[127] Fregni F, Boggio PS, Mansur CG, Wagner T, Ferreira MJ, Lima MC, et al. Transcranial direct current stimulation of the unaffected hemisphere in stroke patients. Neuroreport; Neuroreport. 2005 Sep 28;16(14):1551–5. [PubMed]

[128] Fregni F, Boggio PS, Valle AC, Rocha RR, Duarte J, Ferreira MJ, et al. A sham-controlled trial of a 5-day course of repetitive transcranial magnetic stimulation of the unaffected hemisphere in stroke patients. Stroke; a journal of cerebral circulation. 2006 Aug;37(8):2115–22. [PubMed]

[129] Vines BW, Nair DG, Schlaug G. Contralateral and ipsilateral motor effects after transcranial direct current stimulation. Neuroreport; Neuroreport. 2006 Apr 24;17(6):671–4. [PubMed]

[130] Boggio PS, Nunes A, Rigonatti SP, Nitsche MA, Pascual-Leone A, Fregni F. Repeated sessions of noninvasive brain DC stimulation is associated with motor function improvement in stroke patients. Restor Neurol Neurosci. 2007;25(2):123–9. [PubMed]

[131] Floel A, Hummel F, Duque J, Knecht S, Cohen LG. Influence of somatosensory input on interhemispheric interactions in patients with chronic stroke. Neurorehabil Neural Repair. 2008 Sep-Oct;22(5):477–85. [PubMed]

[132] Conforto AB, Kaelin-Lang A, Cohen LG. Increase in hand muscle strength of stroke patients after somatosensory stimulation. Annals of Neurology. 2002;51(1):122–5. [PubMed]

[133] Wu CW, Seo HJ, Cohen LG. Influence of electric somatosensory stimulation on paretic-hand function in chronic stroke. Arch Phys Med Rehabil. 2006 Mar;87(3):351–7. [PubMed]

[134] Celnik P, Hummel F, Harris-Love M, Wolk R, Cohen LG. Somatosensory stimulation enhances the effects of training functional hand tasks in patients with chronic stroke. Archives of Physical Medicine and Rehabilitation. 2007 Nov;88(11):1369–76. [PubMed]

[135] Conforto AB, dos Santos RL, Farias SN, Marie SK, Mangini N, Cohen LG. Effects of somatosensory stimulation on the excitability of the unaffected hemisphere in chronic stroke patients. Clinics. 2008 Dec;63(6):735–40. [PMC free article] [PubMed]

[136] Richards LG, Stewart KC, Woodbury ML, Senesac C, Cauraugh JH. Movement-dependent stroke recovery: a systematic review and meta-analysis of TMS and fMRI evidence. Neuropsychologia. 2008 Jan 15;46(1):3–11. [PMC free article] [PubMed]

[137] Milot MH, Cramer SC. Biomarkers of recovery after stroke. Curr Opin Neurol. 2008 Dec;21(6):654–9. [PMC free article] [PubMed]

[138] Liepert J, Miltner WH, Bauder H, Sommer M, Dettmers C, Taub E, et al. Motor cortex plasticity during constraint-induced movement therapy in stroke patients. Neurosci Lett. 1998 Jun 26;250(1):5–8. [PubMed]

[139] Liepert J, Graef S, Uhde I, Leidner O, Weiller C. Training induced changes of motor cortex representations in stroke patients. Acta Neurologica Scandinavica. 2000;101(5):321–6. [PubMed]

[140] Wittenberg GF, Chen R, Ishii K, Bushara KO, Eckloff S, Croarkin E, et al. Constraint-induced therapy in stroke: magnetic-stimulation motor maps and cerebral activation. Neurorehabil Neural Repair. 2003 Mar;17(1):48–57. [PubMed]

[141] Yen CL, Wang RY, Liao KK, Huang CC, Yang YR. Gait training induced change in corticomotor excitability in patients with chronic stroke. Neurorehabil Neural Repair. 2008 Jan-Feb;22(1):22–30. [PubMed]

[142] Stinear JW, Byblow WD. Rhythmic bilateral movement training modulates corticomotor excitability and enhances upper limb motricity poststroke: a pilot study. J Clin Neurophysiol. 2004 Mar-Apr;21(2):124–31. [PubMed]

[143] Sawaki L, Butler AJ, Xiaoyan L, Wassenaar PA, Mohammad YM, Blanton S, et al. Constraint-induced movement therapy results in increased motor map area in subjects 3 to 9 months after stroke. Neurorehabil Neural Repair. 2008 Sep-Oct;22(5):505–13. [PMC free article] [PubMed]

[144] Butler AJ, Page SJ. Mental Practice With Motor Imagery: Evidence for Motor Recovery and Cortical Reorganization After Stroke. Archives of Physical Medicine and Rehabilitation. 2006;87(12, Supplement 1):2–11. [PMC free article] [PubMed]

[145] Butler AJ, Kahn S, Wolf SL, Weiss P. Finger extensor variability in TMS parameters among chronic stroke patients. J Neuroeng Rehabil. 2005 May;31(2):10. [PMC free article] [PubMed]

[146] Butler AJ, Wolf SL. Transcranial magnetic stimulation to assess cortical plasticity: A critical perspective for stroke rehabilitation. Journal of Rehabilitation Medicine. 2003;(41):20–6. Supplement. [PubMed]

[147] Lefaucheur JP. Stroke recovery can be enhanced by using repetitive transcranial magnetic stimulation (rTMS) Neurophysiol Clin. 2006 May-Jun;36(3):105–15. [PubMed]

[148] Hiscock A, Miller S, Rothwell J, Tallis RC, Pomeroy VM. Informing dose-finding studies of repetitive transcranial magnetic stimulation to enhance motor function: a qualitative systematic review. Neurorehabil Neural Repair. 2008 May-Jun;22(3):228–49. [PubMed]

[149] Kleim JA, Chan S, Pringle E, Schallert K, Procaccio V, Jimenez R, et al. BDNF val66met polymorphism is associated with modified experience-dependent plasticity in human motor cortex. Nature Neuroscience. 2006;9(6):735–7. [PubMed]

[150] Cheeran B, Talelli P, Mori F, Koch G, Suppa A, Edwards M, et al. A common polymorphism in the brain-derived neurotrophic factor gene (BDNF) modulates human cortical plasticity and the response to rTMS. J Physiol. 2008 Dec 1;586(Pt 23):5717–25. [PubMed]

[151] Zhang X, Mei Y, Liu C, Yu S. Effect of transcranial magnetic stimulation on the expression of c-Fos and brain-derived neurotrophic factor of the cerebral cortex in rats with cerebral infarct. J Huazhong Univ Sci Technolog Med Sci. 2007 Aug;27(4):415–8. [PubMed]

[152] Lang UE, Hellweg R, Gallinat J, Bajbouj M. Acute prefrontal cortex transcranial magnetic stimulation in healthy volunteers: no effects on brain-derived neurotrophic factor (BDNF) concentrations in serum. J Affect Disord. 2008 Apr;107(1-3):255–8. [PubMed]

[153] Maggiolini E, Viaro R, Franchi G. Suppression of activity in the forelimb motor cortex temporarily enlarges forelimb representation in the homotopic cortex in adult rats. Eur J Neurosci. 2008 May;27(10):2733–46. [PubMed]

[154] Karayannis T, Huerta-Ocampo I, Capogna M. GABAergic and Pyramidal Neurons of Deep Cortical Layers Directly Receive and Differently Integrate Callosal Input. Cereb Cortex. 2007 May 1;17(5):1213–26. 2007. [PubMed]

[155] Paus T, Jech R, Thompson CJ, Comeau R, Peters T, Evans AC. Transcranial magnetic stimulation during positron emission tomography: a new method for studying connectivity of the human cerebral cortex. J Neurosci. 1997 May 1;17(9):3178–84. [PubMed]

[156] Fox P, Ingham R, George MS, Mayberg H, Ingham J, Roby J, et al. Imaging human intra-cerebral connectivity by PET during TMS. Neuroreport. 1997 Aug 18;8(12):2787–91. [PubMed]

[157] Bohning DE, Shastri A, Nahas Z, Lorberbaum JP, Andersen SW, Dannels WR, et al. Echoplanar BOLD fMRI of brain activation induced by concurrent transcranial magnetic stimulation. Invest Radiol. 1998 Jun;33(6):336–40. [PubMed]

[158] Ilmoniemi RJ, Virtanen J, Ruohonen J, Karhu J, Aronen HJ, Na?a?ta?nen R, et al. Neuronal responses to magnetic stimulation reveal cortical reactivity and connectivity. Neuroreport. 1997;8(16):3537–40. [PubMed]