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Transcranial Magnetic Stimulation as anInvestigative Tool for Motor Dysfunction andRecovery in Stroke: An Overview forNeurorehabilitation CliniciansMar Cortes, MD*, Randie M. Black-Schaffer, MD †, Dylan J. Edwards, PhD* ‡§

Rationale: An improved understanding of motor dysfunction and recovery after stroke has important clinical implications thatmay lead to the design of more effective rehabilitation strategies for patients with hemiparesis.

Scope: Transcranial magnetic stimulation (TMS) is a safe and painless tool that has been used in conjunction with other existingdiagnostic tools to investigate motor pathophysiology in stroke patients. Since TMS emerged more than two decades ago, itsapplication in clinical and basic neuroscience has expanded worldwide. TMS can quantify the corticomotor excitability propertiesof clinically affected andunaffected muscles andcanprobelocal cortical networksas well as remote but functionally related areas. This provides novel insight into the physiology of neural circuits underlying motor dysfunction and brain reorganization duringthe motor recovery process. This important tool needs to be used with caution by clinical investigators, its limitations need to beunderstood, and the results should to be interpreted along with clinical evaluation in this patient population.

Summary: In this review, we provide an overview of the rationale, implementation, and limitations of TMS to study stroke motorphysiology. This knowledge may be useful to guide future rehabilitation treatments by assessing and promoting functionalplasticity.

Keywords: Motor recovery, stroke rehabilitation, transcranial magnetic stimulation

Conict of Interest: The authors have no conict of interest in the submission of this manuscript.

MOTOR RECOVERY IN STROKE AND THE GAPIN KNOWLEDGE

Stroke remains a leading cause of serious long-term disability in theUnitedStates (1).Thisdisabilityis in mostcases relatedto incompleterecovery of motor function on the hemiparetic side (2). Whetherpatients are performing at their full potential in the years followingstrokeis inuenced bya host of personal andenvironmental factors,includingage, premorbidmedical and functional status, motivation,andaccess to rehabilitation services (3,4). However, even with state-of-the-art medical and rehabilitation care, full recovery is often notachieved(5). Standardrehabilitation interventionstypicallycorrelatewith modest rather than marked improvements in motor function(6). This speaks to ourlimited understanding of thebiologyof motordysfunction and recovery. In order to develop ways to optimizerehabilitation interventions and improve function, a more completeunderstanding of biologic restoration is needed. Transcranial mag-netic stimulation(TMS),now well into itsthirddecadeofexperimen-tation in humans, has proven to be a useful tool to safely andpainlessly examine cortical and corticospinal physiology (7). Thismethod can complement existing and emerging technologies toenable us to better understand motor dysfunction. When physi-ologic data are correlated with clinical function, they can providepowerful insight to biologic processes that underlie movement dys-function (8,9). In addition, TMS can be a surrogate marker of reco-very that is both sensitive and quantitative (10).

This article aims to provide an overview of the rationale, imple-mentation, considerations, and limitations of TMS for studies inmotor recovery following strokeand to demystify this technique forclinicians interested in stroke motor physiology. While TMS can beused to assess nonmotor areas of the brain, this article will focus onthemotor systems, using theevoked muscle responseas theoutputmeasure from corticospinal stimulation.

Address correspondence to: Dylan J. Edwards, PhD, Non-Invasive Brain Stimula-tion and Human Motor Control Laboratory, Burke Medical Research Institute,785 Mamaroneck Avenue, White Plains, NY 10605, USA. Email: [email protected]

* Department of Neurology & Neuroscience, Winifred Masterson Burke MedicalResearch Institute, White Plains, NY, USA;

† Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, MA, USA;‡ Berenson-Allen Center for Noninvasive BrainStimulation, Beth Israel Deaconess

Medical Center, Harvard Medical School, Boston, MA, USA; and§ Centre for Neuromuscular and Neurological Disorders, University of Western

Australia, Nedlands, Western Australia, Australia

For more information on author guidelines, an explanation of our peer reviewprocess, and conict of interest informed consent policies, please go to http://www.wiley.com/bw/submit.asp?ref = 1094-7159&site = 1Source of nancialsupport:The development of thisarticle was supportedby NIHgrant R21HD060999 for DJE and by the New York State Center of Research Excel-lence in Spinal Cord Injury Grant CO19772 for MC.

Neuromodulation: Technology at the Neural Interface

Received: October 11, 2011 Revised: February 22, 2012 Accepted: March 28, 2012

(onlinelibrary.wiley.com) DOI: 10.1111/j.1525-1403.2012.00459.x

www.neuromodulationjournal.com Neuromodulation 2012; ••: ••–••© 2012 International Neuromodulation Society



TMS AS AN INVESTIGATIVE TOOL INMOTOR DYSFUNCTION

Since the inception of TMS in 1985, there have been a number of published reports attesting to the safety of the technique in healthand disease, within recommended operation guidelines (11,12) aswell as theputativemechanisms(13–15).TMS is typicallyperformedin a designated hospital room or university laboratory, the formerbeing preferred for stroke studies for safety reasons. Clinicians andresearchers using TMS should have suitably screened patients toexclude for all TMS risk factors (see TMS safety guidelines). TMSalters brain excitability, and while single- and paired-pulse stimula-tion is considered safe, even in patient populations, there stillremains a theoretical risk. Particularly with the development of stronger stimulators (use of higher frequency stimulation protocolssuch as theta burst stimulation) and a greater range of patient clini-cal states being studied (from acute to chronic), new investigationsshould be carefully considered by the institutional review boardweighing the risk/benet. Suitably trained personnel should apply TMS, and adverseevent monitoringand safety plan should be put inplace. If adverse events occur, theyshould be carefullydocumented,

as well as the medications and dose, together with other comorbidand medical history details to aid with data interpretation. Formotor studies, surface electromyography (EMG) is used to measurethemuscle response in a sensitivemanner. EMGsignal analysis soft-ware is used to quantify the response during and after the TMSsession. Pragmatic and safety reasons for excluding patients from TMS studies include: 1) Seizure history and presence of metalimplants.TMS can inducetensional headaches, neck pain, andothersymptoms, yet the most clinically signicant is considered to beseizure. TMS can and has caused seizures, as the safety guidelineshave been developed in healthy subjects even with single andpaired pulses. Seizures have been predominantly reported withhigh-frequencytrains of pulses (repetitiveTMS [rTMS])and are infre-quent when single or paired pulses are used for investigative pur-poses (11). TMS in subjects with brain metal implants or cochlearimplants should be avoided because of multiple possible unsafeinteractions between the TMS pulse and the implants (16); 2) Medi-cations. Drugs can be potentially hazardous (depending on thestimulation protocol used—high or low frequency rTMS/number of pulses, as well as the characteristics of the patient), or may substan-

tially inuence the motor-evoked potential (MEP) response. Of thevarious medications prescribed to stroke patients, there are nonereported where investigative TMS (single and paired pulse) is con-traindicated. Several antidepressants (including imipramine, ami-triptyline, and doxepine) and neuroleptics (for example,chlorpromazine, clozapine, and haloperidol) increase seizure risk bylowering the seizure threshold ; and some other drugs can changecortical excitability (such as dopaminergic and gamma-

aminobutyric [GABA]ergic drugs); 3) Inability to sit still for the dura-tion of the experiment and maintain stable arousal ; and 4) Inabilityto generate an MEP using TMS; because the MEP is the outcomemeasure, the inability to detect an MEP means that the subtlechanges cannot be detected. It is possible, however, that early afterinjury there is no MEP, but with evolution of motor recovery, an MEPreturns; this could be useful in longitudinal studies.

Machines and CoilsA variety ofTMS machinesand coils are commerciallyavailable, withspecications obtainable on the company website of each. Anincrease in the intensity of stimulator output (from 0 to 100%, with

intensity range varying by manufacturer) will elicit a larger muscleresponse when the coil is held over the optimal cortical location fora given target muscle. Also, a larger diameter coil (circular, gure-8or cone-shaped) and a biphasic pulse shape can all increase theevoked response at a given scalp location (17). TMS users shouldnote that the response in one person to one machine and set of stimulation parameters is likely to be different from that of anotherdevice using the same stimulation parameters, even if the percent-age of the stimulator output is the same.

What Is an MEP? The MEP is the standard measure of motor response to TMS. It isimportant to have an understanding of the characteristics of theMEP in order to correctly interpret studies using this as an outcomemeasure (Fig. 1) (18–20). It is an electrical potential differencedetected using bipolar surface EMG over the target muscle. Mostcommonly for TMS, the intrinsic hand muscles (the rst dorsalinterosseous and abductor pollicis brevis muscles) have beenstudied, because distal muscles more readily evoke a response rela-

Figure 1. TMS-derived measures of cortical excitability. Schematic of motor-evoked potential characteristics, when a single TMS pulse is recorded from a musclewith a slight contraction. a. Background EMG; b. latency; c. peak-to-peak amplitude; d. silent period.TMS, transcranial magnetic stimulation; EMG, electromyography.

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tive toproximal muscles (inhealthy subjects), likelydue to thelargercortical representation and lower activation thresholds (21,22).Other muscles canalso be studied byTMS, because theactivation of muscles is detected by surface EMG, and the reliability of the signalis determined by the relative isolation of the targeted muscle. Manymuscles have been tested, including the face, jaw, neck, arm,forearm, hand, paraspinal muscles, respiratory muscles, thigh, andleg muscles (23–25). The latency of conduction increases with dis-

tance, and not all pathways are precisely understood. The responseis typically biphasic, comprising a negative deection (upward) fol-lowed by a positive deection (downward), before a return baseline(if at rest) or short period of EMG silence and return to low-levelactivity (ifduringan isometric contraction of thetarget muscle).Thetypical measures of the MEP are resting motor threshold (RMT),latency of onset, peak-to-peak amplitude, area under thecurve, andsilent period (SP) (if performed during contraction) and areexplainedbelow. Themagnitude of theMEP response (amplitude orarea) and the threshold of activation (minimum stimulation inten-sity to elicit an MEP)areconsidered corticospinal (or“corticomotor”)excitability measures. In lay terms, these parameters may bethought of as the ease with which a responsecanbe elicited andthestrength of the response. These measures therefore provide impor-tant information on the physiologic integrity of the corticospinalpathway from the primary motor cortex, and the areas feeding intoit, to the spinal motor neurons, and to the electrical potential inmuscle that leads to contraction (excitation–contraction coupling).Unlike the response to a supramaximal peripheral nerve stimulus(inuenced only by nerve conduction neuromuscular transmissionand muscle excitation), and which generates consistent responses,the MEP is inherently variable (26–28). This may be in part becauseof multiple converging inhibitory, and inputs onto corticospinalcells and alpha motoneurons, and in part because of subtle coilmovements as the experimenter balances the small contact area of the coil on the patient’s approximately spherical scalp, thus subtlychanging the trajectory of the magnetic pulse. For these reasons,

successive pulses yield varying sized responses. This varianceshould be minimized as much as possible by maintaining a steadyarousal of the patient (no talking/interaction, minimal environmen-tal stimulation but also regular pauses to ensure the patient doesnotfall asleep). Also,it is important for theexperimenter tomaintainconsistent positioning of the coil regarding its location, tilt, androtation.

How Is an MEP Generated? TMS PhysiologyA single pulse of sufficient strength TMS, with the coil held againstthe scalp approximately over the primary motor cortex, can gener-atea transient current in thecortex in the opposite direction to thatin the coil (typically posterior to anterior across the precentral gyrusfor monophasic pulse and both directions for biphasic pulse, result-ing in greater neuronal recruitment and larger MEP).

The current is thought to activate horizontal interneurons in cere-bral cortex (7,29,30) that subsequently depolarizes the corticospinalcell and leads to waves of descending action potentials (“volleys” inthe TMS literature). These are known as indirect waves, or I-waves,with three predominant waves separated by 1.5 ms. This is impor-tant, because different interventions may affect different I-waves,and thus give us better insight into the mechanism of action of theinterventions. The I-waves depolarize motoneurons in the anteriorhorn of the spinal cord, relating to the somatotopic organization of the cortical area stimulated (8,31). If these motoneurons are suffi-ciently depolarized (and this is inuenced by converging excitatory

and inhibitory drive, such as from afferent signals from musclespindles as well as presynaptic inhibitory mechanisms), then effer-ent motor unit activity occurs causing a muscle twitch. EMG is moresensitive than observation, because a very small muscle twitch maybe insufficient to transfer force through a compliant tendon andovercome inertia of the body part to generate movement. It is diffi-cult to activate a singlemuscle with TMS, thetypical responsebeingmultiple adjacent muscles activated in concert. This leads to a net

activation that causesa slight“jump”of thebody part in a reproduc-ible direction (32). This is partly because of the low resolution orrelatively large stimulation area (low focality) of conventional TMScoils and partly because the representation for anatomically adja-cent muscles has overlapping projections from primary motorcortex (33).The fact that many synapses areinvolved to produce theMEPmeansthat theMEP represents thenet effect of multiple neuralelements along the pathway. Stated differently, the MEP can beinuenced by many physiologic (cortical and spinal) and technical(TMS coil position and movement, electrodes position) factors (34).Both physiologic and technical aspects should be well controlled sothat changes in MEP response can be attributed to real biologicchanges attributed to recovery or intervention.This means thatelec-trode position should remain xed in place if the intervention isshort term(suchas singledose, short time frame),or if theelectrodesare to be moved, then a control measure should be done, such as amaximal M-response (that represents the muscle response to asupramaximal peripheral nerve stimulus, uninuenced by centralnervous system changes) or recording from another muscle notinuenced by the intervention if that is possible. The coil should bekept in a consistent location (historically using a cap with surfacemarkings) and the wings of the coil (if gure-8 coil) maintainedtangential to the scalp as best as possible (35). This is part of the skillof theexperimenter that takes practiceandis quitecrucial toobtain-ing reliable data. Using neuronavigation systems helps (indepen-dent of whether an anatomic magnetic resonance imaging [MRI] isused to target specic anatomy), because real-time feedback about

coil position is then provided to the experimenter (36) (Fig. 2).Other factors that can modify TMS response and might be a limi-

tation in the result interpretation are previous voluntary activation/movement, age, time of the day, aerobic exercise, attention,genetics, and medication (37); these should be suitably controlledfor. Because arousal can be a major problem in patients with acutestoke because of their inability to keep thesame concentration levelduring the duration of the TMS session, it may be necessary toconduct the study more than two or more sessions, making sure tomaximize reliability and account for changes in baseline because of recovery. At present, there are few studies early after stroke, andmore work needs to be done in this time period.

TMS responses are highly variable between subjects (healthy orwith neurologic diseases) (38,39). Thesource of this variability is notwell understood but it seems to be multifactorial, and it may limitthe interpretation of the results as well as its therapeutic use inpatients with disabilities. Other TMS limitations include: low spatialresolution,which canbe improved by pairing it with a sophisticatedneuronavigation system; the possibility of false negative resultsbecause of high threshold in paralyzed muscles or at early stagesafter stroke; the inability ofTMS to explore beyond thecorticospinalpathway, when additional pathways may involved in motor reco-very; and thefact that thetechnique cannotexplore themotortractat subcortical level (40).

Considering all the above, what does it mean if you detect areliable change in MEP? If the data are real, an increase in the MEPmeans that corticospinal (“corticomotor”) excitability has increased,

TMS IN MOTOR DYSFUNCTION AND RECOVERY IN STRO




andif theMEP hasdecreased, thismeans thatcorticomotorexcitabil-ity has decreased. Again, this means that the net effect of all theinhibitory and excitatory processes feeding into the pyramidal cellsandthemotoneuronshas increased ordecreased.For example,if theMEPresponseis reducedafter an intervention,it doesnot necessarilymean that there is more inhibition, because it could also result fromless excitatory or“facilitatory” activity. Furthermore, it does not nec-essarily mean that something has happened in thebrain, because itcould also have occurred in the spinal cord. When interpreting the

results of TMS studies in stroke patients or other neurologic disor-ders, or when navigating the literature in this eld, care should betaken to appreciate that the MEP is a result of many interactingfactors. So is the MEP useful? Yes, the MEP can provide valuableinformation about the state of the corticomotor projection. As well,the MEP can be related to clinical data, or more precise physiologycan be probed further using the eloquent paired stimulation para-digms. In addition, the presence of contralateral MEP early afterstroke may indicate a better prognosis with a favorable recovery,whilethe absence ofMEP hasbeenrelated toa poor recovery (41,42).

In summary, the MEP is a valuable tool for clinical research, whenconclusions are drawn in the context of the reliability of MEP mea-sures and the understanding of the factors that comprise the MEP.

THE MEP IN STROKE AND ITS RELATIONSHIPTO RECOVERY

TMS outcome measures after stroke vary with the stage of recovery(acute, subacute, and chronic) and the degree of motor function(43). In general, higher motor threshold (MT) smaller MEP ampli-tude, prolonged latency, and longer SP have been associated withthe affected hemisphere in stroke patients. These changes may beattributed to some of the following: loss of neurons, altered mem-brane excitability in the remaining cells, increased cortical inhibi-tion, compromised conduction, and dispersion of the excitatoryvolleys onto motoneurons (21,44,45).

TMS Measures: Single-Pulse Stimulation

MTWhen the TMS is applied in the motor cortex, the threshold isdened as the lowest intensity needed to elicit an MEP response of at least 50 mV amplitude with the muscle at rest and that has beenelicited in 50% of ten successive trials (46). This is the most basicmeasurement of excitability within the corticospinal system.Recently, a more efficient method to determine MT has beendescribed by using Bayesian adaptive technique, a method

that shortens the MT estimation without compromising accuracyby using fewer pulses than other MT determination methods(47).

In muscles with lack of motor control—as in stroke patients—theMT is elevated (a greater percentage of maximal stimulator output[MSO] is needed to elicit a response). An absent TMS response (or aweak response—small amplitude, delayed, and polyphasic) can befound in paralyzed or severelyaffected muscles, that is, musclewith0, 1, or 2 out of maximum possible 5 points in Medical ResearchCouncil Scale(MRC) formuscle strength, even usinghigh intensities.In order to get some insight into the pathophysioloy of the studiedmuscle, the active MT can be calculated by asking the patient to doan attempted contraction of the muscle in order to facilitate theevokedresponse. Lower MTs in theaffected limb are associated with

better motor function in upper extremity in both subacute andchronic patients (48).

MEP Amplitude The size of the peak-to-peak amplitude of the MEP represents thestrength or the integrity of the corticospinal pathway (18). In strokepatients, with lack of voluntary motor control, the size of the TMSresponse is smaller than in healthy subjects with normally function-ing muscles. Rehabilitation strategies as well as spontaneous motorrecovery promote restoration toward the normal values of the MEP. The absence of MEP response in early stages after the injury inhemiplegic limbs has been proposed as a negative predictor ormotor recovery, while a presence of a response is a positive predic-tor (49).

Figure 2. Diagram of experimental setup used for neuronavigation-guided TMS. An example of how neuronavigation can be used to guide TMS in stroke studies(with permission). Using either direct anatomic targets or a superimposed reference grid, real-time experimenter feedback is given regarding coil position in relationto the targets during the study. Precise coil position is recorded concurrently with the evoked motor response (MEP) associated with every stimulus.

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MEP Latency This is the period of time, in milliseconds, from the onset of thestimulation to the start of the motor-evoked response. Longer MEPlatencies are common in stroke patients compared with healthysubjects and are more evident in the early stages after the injury.

Silent PeriodWhen a single-pulse TMS is applied during a constant muscle con-

traction, there is an interruption of the electromyographic signal,which is called the SP. This neurophysiologic phenomenon is due toinhibition mechanisms of the motor cortex mediated through theGABAergic system. This suppression of muscle activation or SP ismore pronounced in the acute phase after an injury and it normal-izes in conjunction with the improvement in clinical outcomes (50–52). Prolonged SP duration is found in subacute and chronicpatients,althoughits relationship with motorfunctionhasnotbeenwell described in the literature (53). In stroke patients with motorneglect, motor dysfunction appears because of an increased inhibi-tion rather than an alteration of the corticospinal tract (51).

Motor Cortex MappingMotor cortex mapping can be studied by investigating the MEP

responses in themotorcortex area of a target muscle (54). Map areaand volume, center of gravity, and optimal site are the parametersthat will help to elucidate how the cortex is reorganized after injuryand how the restoration of the corticospinal pathway leads toregaining motor function after stroke (28,55,56). An enlargement of the motor area representation and an increase of the MEP havebeen shown a positive correlation with motor recovery (33).

Paired-Pulse Techniques: What Are They, What Do TheyTell Us? Thepaired-pulsetechnique consistsof aTMSprocedure in whichtwomagneticstimuliaredelivered inclosesequence,wherethe principal TMS pulse (the test pulse) is conditioned by an earlier pulse (theconditioning pulse). The conditioning pulse activates a range of intracortical neurons that inuence the response to the test pulse. The modulatory effects can be facilitatory or inhibitory dependingon the interval between the stimuli and the intensity of the condi-tioningpulse(belowor above threshold).The conditioningpulsecanbe in the same cortical location, a different cortical location (usingaseparate coil) that projects to the primary motor cortex where thetest pulse is delivered, or from a peripheral nerve (delivered byperipheral electrical stimulation). The location of the conditioningpulse (sameor differentlocation as test pulse), theintensityof stimu-lation, and the interval between thepulses has a signature effect onthe test stimulus (TS) response (known as the “conditioned MEP”). Achange in the conditioned MEP amplitude can be examined during

motor recovery after neurologic injury, or in relation to a well-controlled intervention to identify corresponding changes in physi-ology intercortical (across hemispheres) or intracortical excitability(57,58). Commonmeasures in stroke include: transcallosal inhibitionand intracortical inhibition and facilitation.

Paired-Pulse One Location (Intracortical Facilitation [ICF] andInhibition) The imbalance between the both hemispheres can be investigatedby using a paired pulse with a unique TMS coil (59,60). A subthresh-old conditioning stimulus (CS) will be elicited from 2 to 7 ms beforethesuprathresholdTS, at 130% of RMTusually, to examine theshortintracortical inhibition. In the same way, separating both stimuli7–10 ms, the ICF will be studied. Lately, numerous studies have

adjusted the CS to a pre-established value, for example, 0.5 or 1 mVto avoid interindividual variability and to facilitate the comparisonpre and post any given intervention (61).

With this paired-pulse paradigm, the interaction between theaffected and unaffected hemisphere can be investigated in strokepatients, where the current thinking establishes that there is anincrease of excitability in the healthy hemisphere that is sendinginhibitory signals to the affected hemisphere (62,63). Patients with

hemiparetic stroke usually present exaggerated inhibition withinthe primary motor cortex (51).Several studies support a disruption of interhemispheric excit-

ability balance that occurs withunilateral lesion, thought to contrib-ute to functional motor decit. A reduction in excessive unaffectedhemisphere excitability has been achieved experimentally usingnoninvasive brain stimulation (low frequency rTMS and cathodaltranscranial direct current stimulation [tDCS]) as well as increasedexcitability in the affected hemisphere (high frequency rTMS, oranodal stimulation) (64–66). Functional gain and improved inter-hemispheric excitability balance has also been demonstrated withbehavioral therapy (constraint induce movement therapy), withconstraint of the unaffected arm, and force use of the affected arm.

Paired Pulse—Two Regions (Transcallosal Inhibition) Transcallosal inhibition (TCI) is measured by the MEP response froma test pulse delivered over theprimarymotorcortex, conditionedbya single pulse over the same site on the opposite hemisphere. Bothpulses are typically above threshold. The conditioning pulse isthought to exert an inhibitory effect on the contralateral cortex viathe corpus callosum when the interstimulus interval is approxi-mately 12 ms. This inhibitory effect can be disrupted following aunilateral lesion, setting up a putative interhemispheric imbalancethat is pathophysiologic, and is commonlyinvestigated in strokestudies. Whether this effect persists or remains altered in chronicpatients is controversial (67,68). Several stroke studies havereported a reduction in TCI from the intact to the affected hemi-sphere associated with behavioral gains, as measured by the Fugl-Meyer Scale (69).

TMS TO INDEX CORTICAL EXCITABILITY

The current reasoning for use of TMS information is as follows. If weidentify specic excitability decits (deviance from what is estab-lished in healthy—preferably age-matched—controls), and weknow that they are correlated (orat least associated) with a decit infunctional output (as observed in a change in behavior), then byinference we can target interventions that alter specic aspects of physiology (such as pharmacologic agents) in order to restorephysi-ology and by consequence improve behavior (70,71). Furthermore,we can use TMS to identify the specic physiologic effects of con-temporary, well-described interventions to establish specic

aspects of physiology that they are modulatingoreven to reneanddevelop therapies to have the desired effect (72). These mightinclude interventions that act on very specic functional networks,such as behavioral training and therapies (focus network, lowpotency), or grossly targeted therapies such as CNS drugs or nonin-vasive brain stimulation, including tDCS or rTMS (low focus, highpotency specicity).This can be taken one step further to purpose-fully generate an interaction and is being tested in many laborato-ries presently.

Optimal TMS Study DesignDepending on the hypothesis to test, a different research studymethod will be chosen. One method is to take a cross-sectional





snapshot of neurophysiology in relation to known motor decits,and use this in conjunction with other clinical data includingmedical exam and radiologic/stroke related biomarkers. The neuro-physiology data are typically compared with normative data, butcan also be correlated with specic clinical ndings (39). Anothermethod is the longitudinal study approach, where TMS is used totrack the course of recovery during conventional standard of care(orintervention, such as rTMS, tDCS plasticity-enhancing drugs, or a

novel training paradigm), actingas a probe to disrupted andchang-ing physiology in the living human. This also complements existingclinical tools. Like most interventions given early after stroke, it canbe difficult to determine the degree of change caused by naturalrecovery vs. intervention-induced recovery. Suitable controls needto be built-in experimentally, such as recording TMS response froma body part not engaged in the training; this could be the contralat-eral hand in a unilateral training paradigm. If bilateral effects aresuspected from a unilateral intervention, then a proximal contralat-eral muscle could be chosen, or even a lower limb muscle. The ideais to ensure MEP stability (experimental reliability) in muscle/s thatyou would not hypothesize to be affected by the intervention. Thiscan be done in addition to having a sham-controlled group thatdoes not receive real intervention.

Reducing TMS Response VariabilityMuscle responses to brain stimulation are inherently variable (ascompared with peripheral nerve stimulation response), which iswhy recording only one response may be unreliable and why mul-tiple evoked responses (usually 4–20 MEPs) should be reported by ameasure of central tendency such as the mean or median . Formapping studies, as few as 2–4 stimuli per site may be necessary,while for pre–post intervention comparisons at a single site, 10–20stimuli are collected (73). This is partly due to the converging inu-ence on spinal motor neurons and cortical pyramidal cells that canchange excitability properties from moment to moment. This

becomes a challenge for the investigator during a session andbetween sessions for the collection of reliable data.

MEPvariabilityfrompulse-to-pulse may bedueto theconverginginuence on spinal motor neurons and cortical pyramidal cells thatcan change excitability properties from moment to moment. Thisbecomes a challenge for the investigator during a session andbetween sessions for the collection of reliable data.

There are many interacting and potentially controllable factorsthat can inuence the MEP response over a session or betweensessions, and some remain to be formally tested for impact onexperimental results.However, someideas forconsiderationprior tostarting an experimental session would include: testing at the sametime of day (circadian rhythms), ensuring that patients arenot inu-enced by nicotine or caffeine, not testing immediately after a largemeal, and waiting prior to the start of an experiment if the patienthas rushed to attend the clinic.

In addition, patient arousal and certain aspects of cognition cansubstantially affect MEP response. It is therefore prudent to try tomaintain stable experimental conditions, such that arousal is notaffected (74), for example, by minimizing talking/interacting withthe patient while recording MEPs, either from the investigator or asignicant other of the patient. While some laboratories allow thepatient to fall asleep, this shouldbe avoided forarousal changes andpractical test reasons (especially if in a seated position). A low-levelisometric contraction is sometimes performed to stabilize theresponse (75). If this is done, biofeedback should be providedregarding contraction level (either force or rectied and smoothed

EMG) in order to avoid uctuations that might inuence MEPresponse. A window of 10–20% maximal voluntary isometric con-traction is often used, or greater if patients have difficulty with necontrol contraction strength.

Furthermore, the prolonged length of an experiment caused bycollection of many TMS variables can be detrimental for the qualityof the data, and should be avoided. Many laboratories aim to keepexperimental sessions under two hours.

Where Does TMS Fit With Existing Clinical Tools?Over the last century, rapid technological advancement in medicalinvestigative tools such as imaging and brain plasticity biomarkeranalysis (such as brain-derived neurotrophic factor [BDNF]) has pro-foundly inuencedour understandingof the historically rened andrigorousclinical information determinedat the bedside (76–78).Yet,there remain large gaps in knowledge about mechanisms underly-ing specic clinical presentations. Assessment tools in studies of thestroke motor system as with other clinical and investigative tools inmedicine can be thought of to lie on a biology-function continuum(Fig. 3).Tools that tell us muchabout function/dysfunction, typicallytell us little about biology or mechanism of the dysfunction. Con-versely, tools that inform of biology and mechanism may be corre-lated with function, but they do not usually inform of function. Forexample, a clinical scale such as theFugl-Meyer Assessment informsof voluntary motor control decit, with the biologic cause specula-tive and nonspecic. On the other hand, the anatomic MRI providesa clear indication of the disrupted anatomy, though predictions of inuence of voluntary control based on the images are not alwaysaccurate. Thus, both types of information are useful and comple-mentary. Moving forward in the eld of stroke motor recovery, weneed to have a strong understanding of functional decit as well asthe biologic mechanism; and similarly for intervention studies instable or recovering patients, we need to understand the biologicand functional effects of well-dened interventions in well-

characterized patients (79). Assessment tools or outcome measurescan be described in terms of sensitivity (degree of precision todetect a change afforded by a measurement instrument), reliability (condence to rule out equipment, technique, or rater error when achange is detected), and functional relevance .

The schematic highlights that when functional relevance is high(such as with ambulatory measures, or upper limb movementgrading), then reliability is low(due to factors such as rater error andpatient effort variation) and sensitivity is low (scales are necessarilyordinal, and therefore only gross changes can be detected). Thebenet of using assessment tools at this end of the continuum isthat change is considered to be meaningful because it has clearpersonal and socioeconomic benet, and this becomes highlyimportant for clinical decision making as well as for determiningintervention efficacy and recovery. However, little can be learned asto why patients recover or respond to interventions the way theydo, unless we have more information about biology (80). The bio-logic assessments typically have the advantage of high precision(sensitivity) and high reliability. While they do not have high func-tional relevance alone, when combined with functional tools, theycan provide powerful insight into mechanism. We suggest that TMSis an important tool that ts toward the middle of the functionalbiology continuum for assessment tools in stroke motor recovery. This technique assesses the functional biology of the nal outputfrom thebrain to themuscle.It represents thefunctional integrity of the pathway used to control voluntary movement and real-timeassessment of its inuence at spinal and supraspinal level of net-

CORTES ET AL.




works that feed into it (45,81). It has the advantage of being argu-ably more functionally relevant than other biologic measures (suchas computed tomography [CT] scan and blood analysis), yet moresensitive and less inuenced than by human factors than clinicalscales. It is acknowledged that while biomarkers may presently notrelate directly to specic functional characteristics, this may be pos-sible in the future. Furthermore, the position of individual outcomeson the continuum is a schematic representation only and may not

represent their true position. TMS has limitations that are discussed elsewhere in this article,

but it can be an important complement to the other available tools.It may be considered close to functional magnetic resonanceimaging (fMRI) or electroencephalograpy (EEG) on the continuum(albeit quite different in information gathered), but it is also close tohighly quantitative assessment of limb/body motion, forces, andmuscle activity, such as can be captured with rehabilitation robotics(82,83). The importance of these measures should be underscored,because they represent highly quantitative assessment of voluntarymotor control that is sensitive, reliable, and relevant. Of key impor-tance is the precision of the robotic sensors (sensitivity) to detectsubtle changes in function, such as during a short period of earlypoststroke hospitalization, or a short exposure to a novel trainingintervention in chronic stroke. Especially for the latter, it is notprudent to launch into long clinical training studies using gross butrelevant clinical outcome measures without the condence that asmall clinical change can be detected with a small dose. Stateddifferently, highly sensitive measures of motor control may capturesubtle but important changes associated with a short exposure tonew interventions being tested (not identied with more coarseand subjective clinical scales). Furthermore, these methods canuncover individual elements of movement generation or appear-ance that can focus rehabilitation interventions to target specicdecits. Similarly, TMS can uncover functional pathways that cannotbe detected clinically, and thus provide biologic substrate for TMS-guided rehabilitation interventions. Taken together, sensitive and

reliable tools testing outputof functional pathways (such asTMS) aswell as specic test of anatomy and physiology of motor control(such as fMRI/EEG/magnetoencephalography) can be powerfulcomplements to understanding motor recovery and intervention instroke because the types of questions answered by these tech-niques are different (84–86). For example, fMRI has excellent spatialresolution but poor temporal resolution, because it is trackingblood-ow changes secondary to neuronal activity, while EEG has

excellent temporal resolution but arguably less spatial resolution. These techniques can be powerful complements to understand-

ingmotorrecovery and intervention in stroke, when combined withinformation from highly sensitive motor control assessment toolssuch as rehabilitation robots (82,87–89).

LIMITATIONS AND CAVEATS

This represents an exciting time where physiologic ndings relatedto clinical function in stroke, as well as what physiologic effectstherapies are causing, are slowly being uncovered, providing abetter understanding of stroke motor dysfunction physiology inhumans and of motor recovery. This may ultimately lead to target-ing specic therapies for specic patients at specic and importanttime points postinjury (90–92). Consumers of this expanding litera-ture and clinicians need to take care in interpreting thisliterature.

Because the primary determinant of outcome in TMS motorstudies is subtlechanges in theMEP, thequality and reliabilityof theMEP is of critical importance. This has experimental implicationsbecause the presence and quality of MEPs in stroke patients isdiminished. This is important, because reduced corticomotoroutput in response to TMS is associated with poor motor function,highlighting one aspect of the underlying pathophysiology(41,93,94). However, to run more elegant physiologic paradigmssuch as paired-pulse techniques, then strong changes in a poor

Figure 3. The biology-function continuum for assessment tools in stroke motor recovery. Following stroke, investigative tools, and clinical evaluations are selecteddepending on many factors to inform of clinical status, prognosis, treatment planning, recovery, and treatment outcome. The selection of a given tool maycompromise on sensitivity,reliability, or functional relevance, but in combination theycan provide powerful insight intofunctionand mechanism.In our opinion,TMSfalls in a midpoint, having aspects of biologic and functional insight. When used in conjunction with other measures, it can be an important complement to enhanceour understanding of motor recovery. TMS, transcranial magnetic stimulation; CT, computed tomography; MRI, magnetic resonance imaging; MEG, magnetoen-cephalography; EEG, electroencephalograpy; fMRI, functional magnetic resonance imaging; EMG, electromyography.





quality test pulse (minimal presence, and unreliable) are difficult tond or believe. The original TMS physiology studies were often per-formed in young healthy adults, by experienced investigators. Forexample, with short-latency intracortical inhibition, a strong TMSresponse for an intrinsic hand muscle of around 0.5–1.5 mV mightbe observed with a supra-thresholdTMS pulse at around 120–130%RMT. A subthreshold conditioning pulse (preceding pulse) exertinga net inhibitory effect on the test pulse might reduce the amplitude

of the test pulse around 50%. When unconditioned (test responsealone) and conditioned MEPs are averaged, the change is clear andvalid, with normalized or ratio data that do not mask effects of apoor quality MEP. However, in a stroke patient, there may be “oor”effects whereby a poor MEP response (i.e., barely detectable,50–100 mV) could arguably show only a small reduction when con-ditioned by a test pulse (interestingly, a small reduction from 100 to50 mV would have the same 50% normalized reduction as a healthysubject reducing from 1000 to 500 mV). These types of difference inaltered ability to run protocols in patients as is done in healthysubjects, makes interpretation problematic. That is, the differencebetween patients and healthy subjects is intriguing, but to examineeffects of intervention on a measure that is itself potentially awedor limited is questionable. The point to be taken from this is not that TMS in stroke patients is questionable, but rather, that data need tobe carefully interpreted, even in the most well conducted clinicalexperiments. There is still the potential to extract rich and meaning-ful data, and many laboratories successfully do this. The practicalimplication is that more technically demanding measures of pairedpulse lend themselves well to patients with a higher level of func-tion, where a stronger MEP is more likely seen. Muscles that arecompletely accid are difficult to elicit an MEP, and it would not bereasonable to expect to conduct pair-pulseparadigms in suchcases.For this reason, manyTMS studies focus on higher level functioningpatients (95–98) (often stable chronic patients), or even the unaf-fected hemisphere,which canprovide rich data andwhereMEPs aremore readily accessible. Another method that has been attempted

is to perform a low-level muscle contraction, which facilitates theMEP response (and has the benet of obtaining an SP). Otherproblem is the high MT in patients. Typically, to elicit an MEP, thestimulator intensity is set to around 120% of MT or 20%of MSOabove RMT. If the threshold is 84% or higher, which is often the casefor resting state TMS in elderly stroke patients (older subjects havehigher RMT) (99), then TMS simply cannot deliver the requiredexperimental intensity. The consequence is that each patient istested at a different percentage above MT (and at a different part of theslopeon therecruitment curve), which makesdrawing compari-sons between patients less robust.

CONCLUSION

TMS is a remarkable contemporary tool to understand and ulti-mately promotemotor recovery in stroke patients.When studies areproperly conducted and results were suitably interpreted, TMSinformationcan be a powerful adjunct to existing clinical and inves-tigative information.More work is needed in this area,particularlyinthe subacute phase, and we can anticipate insightful data beinggenerated over the coming years.

Acknowledgements The authors would like to thank Roch M. Comeau for assistance withthe neuro-navigation gure.

Authorship statementAll the authors have contributed equally in the preparation of thismanuscript.

How to Cite this Article:

Cortes M., Black-Schaffer R.M., Edwards D.J. 2012. Tran-scranial Magnetic Stimulation as an Investigative Toolfor Motor Dysfunction andRecovery in Stroke: An Over-view for Neurorehabilitation Clinicians.Neuromodulation 2012; e-pub ahead of print. DOI:10.1111/j.1525-1403.2012.00459.x

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