Transcranial Magnetic Stimulation: A Possible Treatment for TBI

LWW/JHTR LWWJ264-07 August 31, 2006 9:6 Char Count= 0

J Head Trauma RehabilVol. 21, No. 5, pp. 437–451c© 2006 Lippincott Williams & Wilkins, Inc.

Transcranial MagneticStimulationA Possible Treatment for TBI

Theresa Louise-Bender Pape, DrPH, MA, CCC-SLP/L;Joshua Rosenow, MD; Gwyn Lewis, PhD

The purpose of this article is to outline the principles of transcranial magnetic stimulation (TMS), tosummarize the existing use of TMS as a prognostic indicator and as a therapeutic device in clinicalpopulations, and to highlight the potential of repetitive TMS (rTMS) as an intervention for traumaticbrain injury. TMS is a painless method to stimulate the human brain. Repeated applications of TMScan influence brain plasticity and cortical reorganization through stimulation-induced alterationsin neuronal excitability. Existing evidence has demonstrated positive outcomes in people withmotor disorders and psychiatric conditions who have received rTMS as a therapeutic intervention.These findings suggest that rTMS may be a promising treatment for people with traumatic braininjury. Key words: transcranial magnetic stimulation, traumatic brain injury, treatment

Review Article

TRANSCRANIAL MAGNETIC STIMULA-TION (TMS) was introduced in 1985

From the Department of Veterans Affairs (VA),Research Service, Edward Hines Jr. VA Hospital,Hines, Ill, the Marianjoy Rehabilitation Hospital,Wheaton, Ill, the Department of Physical Medicineand Rehabilitation, Northwestern University,Department of Physical Medicine and Rehabilitation,Office of Medical Education (1574), Chicago, Ill, andthe Institute for Health Services Research and PolicyStudies, Northwestern University Feinberg School ofMedicine, Chicago, Ill (Dr Pape); the Department ofNeurosurgery, Northwestern University FeinbergSchool of Medicine, Chicago, Ill, and FunctionalNeurosurgery Program, Northwestern MemorialHospital, Chicago, Ill (Dr Rosenow); and the SensoryMotor Performance Program, The RehabilitationInstitute of Chicago, Chicago, Ill (Dr Lewis).

Funding for this study was provided by the Departmentof Veterans Affairs (VA), Veterans Health Affairs, Reha-bilitation Research and Development Service, throughan advanced research career development award toDr Theresa Pape (B3302K). The Phase I clinical trialdescribed in this article is also supported by the Gen-eral Clinical Research Center (GCRC) of NorthwesternUniversity’s Feinberg School of Medicine. The GCRC issupported by grant M01 RR-00048 from the NationalCenter for Research Resources, National Institutes ofHealth. In-kind contributions from Marianjoy Rehabil-itation Hospital, Northwestern Memorial Hospital, andThe Rehabilitation Institute of Chicago also support thework described in this article. Dr Pape’s research insevere traumatic brain injury is also supported phi-

as a noninvasive and painless method ofstimulating the cerebral cortex.1 Over thepast decade, it has been shown that repeatedapplications of TMS can induce changes inneural excitability that outlast the period ofstimulation. The relatively focal nature of theapplied stimulation provides the potentialto up- or downregulate neuronal activityin specific areas of the cortex. RepetitiveTMS (rTMS) therefore holds promise asan experimental treatment for a variety ofneurological and psychiatric conditions. Thisarticle explains the principles and biophysicsof TMS, describes pulse delivery patternsand stimulation parameters, outlines safetyissues related to TMS, and summarizes theevidence indicating the potential of rTMSas a treatment option for traumatic braininjury (TBI). At present, magnetic stimulationdevices have approval from the Food andDrug Agency (FDA) for use over the spinalcord and the periphery. Magnetic stimulation

lanthropically by the Nick Kot Charity, a not-for-profitorganization.

Corresponding author: Theresa Louise-Bender Pape,DrPH, MA, CCC-SPL/L, Department of Veterans Affairs(VA), Research Service, Edward Hines Jr. VA Hospital,PO Box 5000 (M/C 151H), Hines, IL 60141 (e-mail:[email protected]).

437


438 JOURNAL OF HEAD TRAUMA REHABILITATION/SEPTEMBER–OCTOBER 2006

over the brain is considered investigationaland requires approval from the local HumanSubjects Institutional Review Board andthe FDA through an Investigational DeviceExemption.

PRINCIPLES OF TMS

Neural stimulation using TMS is achievedvia the principles of electromagnetic induc-tion. A stimulating coil is placed and heldover the surface of the scalp (Fig 1). If theinvestigator is concerned about his/her abil-ity to hold the coil in the selected scalp po-sition for the duration of the stimulation ses-sion, then it is recommended that a coil holder(Fig 1b) be used to avoid inadvertent coilmovement during stimulation. When the stim-ulator unit is discharged, a large current istransferred into the coil. The current flow-ing around the coil generates a surroundingmagnetic field, which, in turn, induces a cur-rent within proximate electrically conductivetissues. The magnetic field is able to passthrough the scalp and generate action poten-tials in cortical neurons that lie beneath the

Figure 1. Coil orientation and stabilization: Illustration of figure-of-eight coil. (a) Figure-of-eight coil located

over the right dorsolateral prefrontal cortex. The coil is oriented such that the induced current flow will

be in a posterior-anterior direction, perpendicular to the presumed orientation of the underlying neurons.

(b) Custom-built coil holder (white arrow) to stabilize/maintain coil position for 25 to 30 minutes.

coil. The depth and focality of stimulation isinfluenced by the size and shape of the stim-ulating coil (Fig 2). In general, a larger coilwill provide a greater depth of stimulation.The first coils used in TMS were round, con-sisting of a single coil of wire (Fig 2a). Thesecoils give rise to a rather nonfocal magneticfield that peaks around the circumference ofthe coil. Subsequently, a coil that consists of2 round coils wound together has been devel-oped. This is known as the “figure-of-eight,”“double”or “focal”coil (Fig 2b). The magneticfield of these coils peaks along the intersec-tion of the 2 windings, thereby providing amore focal area of peak intensity. Another coildeveloped later that is in use is the double-cone coil (Fig 2c). This is similar to the figure-of-eight coil with the exception that the 2windings are angled inwards. The angular na-ture of the windings gives rise to a magneticfield that peaks a further distance from thecoil intersection, resulting in a greater depthof stimulation. The double-cone coil is use-ful for activating areas of the motor cortex lo-cated deeper within the central sulcus, suchas the trunk and lower limb representations.


Transcranial Magnetic Stimulation 439

Figure 2. Shapes and sizes of coils. (a) 90-mm circular coil where peak strength (2.0 Tesla) occurs around

the circumference of the inner turn (black arrow). (b) 70-mm double coil/figure-of-eight where peak

strength (2.2 Tesla) occurs at intersection of the 2 circles (white arrow). (c) Double-cone coil where two

angled windings improve coupling to the head and lower limb areas.

There are 2 quite distinct applications ofTMS in basic and clinical research. The firstis the use of cortical stimulation as a measure-ment device. For example, TMS can be used todetermine the excitability of the corticospinalpathway or to map cortical representations.TMS can also be implemented as an inter-vention to manipulate cortical excitability orto disrupt cortical activity. Although distinct,these 2 applications are often used in conjunc-tion. For example, one may make premeasure-ments and postmeasurements of corticospinalexcitability to a specific muscle after a mag-netic stimulation intervention designed to al-ter activity in the cortical representation ofthat muscle.

TYPES OF STIMULATION

Delivery of magnetic stimuli is generally de-scribed in the published literature as single-

pulse, paired-pulse, or repetitive (rTMS). Eachof these designs specifies or defines the num-ber of stimuli applied to the cortex. Sincethe majority of TMS investigations examinethe motor cortex, the types of TMS stimu-lation and rTMS stimulation parameters aredescribed in this article according to the cor-ticomotor pathway. The application of TMS toother cortical regions is discussed later in thisarticle.

Single-pulse TMS indicates that the mag-netic stimuli are delivered individually andnot coupled with another pulse. Single-pulseTMS is generally used to measure aspects ofcorticomotor excitation and inhibition. It canalso be used to map cortical representation,2,3

examine central motor conduction time,4 orprobe cortical movement encoding.5 In thesecircumstances, responses to TMS (motor-evoked potentials [MEPs]) are recorded pe-ripherally using electromyography. The size

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and latency of the MEP provide informationregarding the integrity of the corticomotorpathway to the target muscle. Single-pulseTMS can also be used to create temporary vir-tual lesions to disrupt ongoing or upcomingcortical activity. Studies involving the creationof virtual lesions are more common in cogni-tive neuroscience, including research in areasof memory, learning, and speech.6

Paired-pulse TMS refers to 2 stimuli thatare delivered within a short period of time.Paired-pulse designs are typically used toevaluate the effects of the first (condition-ing) pulse on the size of the evoked po-tential elicited by the second (test) pulse.This technique is often implemented to mea-sure intracortical inhibition and intracorticalfacilitation.7 To evaluate intracortical inhibi-tion or intracortical facilitation, a submotor-threshold conditioning pulse is able to acti-vate low-threshold inhibitory and facilitatoryinterneurons that synapse onto corticospinalneurons. Since the time courses of these in-terneuron action potentials vary, it is possi-ble to inhibit or facilitate the test response bymanipulating the interval between the con-ditioning and test stimuli. The extent of in-hibition or facilitation elicited by the con-ditioning stimulus provides an indication ofthe excitability of the intracortical interneu-rons. Paired-pulse TMS can also be used toinvestigate interhemispheric interactions pro-vided by transcallosal fibers.8 In this case,2 separate coils are used to provide condi-tioning and test stimuli over the 2 corticalhemispheres. The effects of the condition-ing stimulus reflect activity of transcallosalfibers that pass between homologous motorrepresentations.

In rTMS designs, a repeated train of pulses(usually 1–20 Hz) is delivered. These trainsmay only be a few seconds in duration butare repeated multiple times within one ses-sion. Repetitive stimulation is generally imple-mented as an intervention to alter neuronalexcitability of a specific region of the cor-tex. Repetitive TMS interventions may be ap-plied on their own or in combination with asecondary input to influence cortical plastic-

ity. Further details of rTMS protocols are dis-cussed in following sections.

rTMS STIMULATION PARAMETERS

The effects of rTMS on cortical excitabil-ity are dependent upon the stimulation pa-rameters applied, including the stimulus in-tensity, frequency, and duration.9 rTMS hasbeen dichotomized in the published litera-ture into low- or high-frequency stimulation.Wasserman10 defined low frequency as stimu-lation rates of 1 Hz or less and high frequencyas stimulation rates of more than 1 Hz. Thisdivision is based on the different physiologi-cal effects associated with stimulation at thesefrequencies. Initially, there is a direct effectupon the neuron (ie, axons, dendrites, andcell bodies) by the electrical currents inducedwithin the brain tissue by the magnetic fields.Indirect effects then result from synaptic ac-tions of the neuronal elements that have beenaltered (excited or inhibited).11 Although cur-rent models of stimulators can deliver pulsesat up to 100 Hz, high-frequency stimulation inhumans is most commonly applied at rates of5 to 20 Hz.

When performing TMS, it is necessary tofirst define the optimal site for stimulation(“hot spot”) given the target cortical region.For the motor cortex, this is the region overthe scalp that gives rise to the largest MEPin the muscle of interest with the lowestamount of magnetic stimulation. Sinceeven slight changes in coil orientation andlocation can give rise to marked variations inthe area of cortical stimulation, it is extremelyimportant to mark this spot on the scalp afterit is located so that the exact coil positionis maintained throughout a session and thesite is reproducible during multiple sessionsin the same subject. Devices to maintain thecoil in constant position (Fig 1b) coupledwith image-guidance systems can assist inthis endeavor.

The intensity of the applied cortical stimu-lation can be defined using a number of meth-ods. It is commonly reported according to(1) the percentage of maximum stimulator



output (MSO), (2) the percentage of MSOrequired to elicit an MEP of a certain size,or as (3) a percentage of the resting or ac-tive motor threshold. Percentage of MSO isdevice-specific and allows for defining inten-sity within the context of the equipment used.This is useful when the same intensity leveland equipment is suitable for all subjects,12

but may not be ideal when investigating neu-rological conditions where the subject popu-lation is more heterogeneous (eg, TBI). Set-ting the stimulator intensity (percent MSO)to elicit a response (MEP) of a certain sizeis most often used when analyzing responsesto paired-pulse TMS.13 Often, the effects ofa conditioning stimulus on the effects of atest stimulus will vary with the size of thetest MEP. Therefore, it is important to adopta stimulation intensity that gives rise to anMEP of a specific amplitude in all subjects andconditions.

Determining stimulation intensity as a per-centage of the stimulation-evoked motorthreshold is more individually precise becauseit better reflects each subject’s unique cor-tical physiology. Resting motor threshold isdefined as the lowest stimulus intensity thatgives rise to an evoked response (50 μV am-plitude or greater) in the relaxed target mus-cle 50% of the time following a train of atleast 6 stimuli.14 Motor thresholds are lowestfor the intrinsic muscles of the hands and fin-gers, primarily due to the large area of themotor cortex devoted to distal upper limbmusculature and the relatively superficial lo-cation of the hand area in the motor homuncu-lus. An active motor threshold can also bedefined using a similar technique while thetarget muscle is minimally activated. In gen-eral, the increased excitability of the depolar-ized motoneurons will mean that the activemotor threshold is 70% to 90% of the rest-ing motor threshold. Defining the intensity ofstimulation relative to motor threshold is ad-vantageous because it reduces the effectsof individual variability of motor cortexexcitability.15 A drawback of using magnet-ically evoked motor threshold is that it as-sumes a relationship between the excitabil-

ity of the motor cortex and the cortical sitewhere the repetitive stimulation is to be pro-vided, if this site is not the primary motorcortex. Often studies involving rTMS will in-corporate stimulation of cortical regions re-mote from the primary motor cortex, suchas prefrontal,16,17 occipital,18 or speech andlanguage corticies.19 Benchmarking stimula-tion intensity using a percentage of motorthreshold may be inappropriate in these sit-uations given the possibility of differential ex-citability thresholds across cortical locations.Therefore, the advantages and limitations ofeach method of determining TMS intensityshould be considered when designing a re-search study.

Stimulation frequency for rTMS designs isdefined as the number of magnetic pulses pro-vided within 1 second. This parameter doesnot apply to single-pulse TMS and is the in-verse of the interpulse interval in paired-pulseTMS. The frequency of stimulation is the mostinfluential determinant of the effect of rTMSon cortical excitability. Low-frequency rTMS(∼1 Hz) applied at the motor threshold orslightly suprathreshold intensities give rise toa suppression of cortical excitability.20–22 Thetime duration of this inhibitory effect is similarto the duration of application (eg, 30 minutesof stimulation may induce a 30-minute periodof depressed cortical excitability). High-frequency (ie, 5 Hz or above) suprathresholdstimulation, however, results in increasedcortical excitability.23 This period of elevatedcortical excitability may last for minutes.24

Subthreshold high-frequency stimulationgenerally requires longer time periods of ap-plication (ie, longer than 2 minutes) to inducelasting effects; however, the lower risk ofadverse effects associated with subthresholdstimulation enables the provision of theselonger stimulation periods. Peinemann andcolleagues, for example, reported an increasein corticospinal excitability that lasted atleast 40 minutes following repeated trainsof 5-Hz subthreshold stimuli delivered overa 10-minute interim.25 The precise neuralmechanisms associated with the inducedchanges in cortical excitability by stimulation




at different frequencies are not definitivelyknown. It is thought that the effects may arisethrough induction of long-term potentiationand long-term depression-like mechanismsin horizontal intracortical cells.9 There isalso evidence that repeated applications ofrTMS may give rise to cumulative effects overtime.26

TMS: A USEFUL TOOL IN TBI?

Diagnostic applications of TMS

Responses to TMS can provide useful diag-nostic and prognostic information in a vari-ety of motor disorders. For example, strokeresults in an increase in motor thresholdand reduced MEP amplitude in the affectedlimb.27–31 These findings reflect reduced cor-ticomotor excitability due to ischemia. In ad-dition, the presence of ipsilateral responsesto TMS in the affected side of acute strokepatients (ie, MEPs elicited following stimula-tion of the nonaffected hemisphere) has beenlinked to a poor functional recovery.29,32

Focal hand dystonia is characterized bya lack of cortical inhibition and abnormallylarge and/or irregularly shaped maps of mo-tor representation as determined by TMS.33,34

These features correlate well with the clini-cal presentation of tonic muscle contractionwithout differentiation in hand motor con-trol. It is also possible to detect reorganiza-tion of motor representations and excitabilitymeasures in patients with dystonia after treat-ments such as botulinum toxin injections.In the weeks to months following injection,cortical parameters begin to resemble thoseof healthy subjects in parallel with clinicalimprovements.33,35

It has also been shown that responses toTMS are useful in determining the degreeof spinal cord injury.36 McKay et al have re-ported that the presence of MEPs in spinalcord injury is positively related to the qualityof voluntary motor function.37

Measures of central motor conductiontime (the time taken for TMS-generatedresponses to reach the spinal cord and

discharge the target motoneurons), motorthresholds, and cortical inhibition using TMShave proven valuable in diagnosing and as-sessing a number of disorders of the cen-tral and peripheral nervous system, includ-ing multiple sclerosis,38,39 myelopathy,40,41

and amyotrophic lateral sclerosis.42,43 Cervi-cal spondylotic myelopathy, for example, is adegenerative mechanical compression of thecervical cord. It is a gradual process and priorto TMS there was conflicting evidence re-garding diagnosing the level of cord compres-sion. Lo and colleagues40 demonstrated, how-ever, a significant correlation of central mo-tor conduction time recordings, elicited viaTMS, from upper and lower limb muscles withanatomical findings from magnetic resonanceimaging (MRI) in patients with CSM, indicat-ing that TMS is an effective screening tool forcervical cord abnormalities prior to MRI.

Finally, diagnostic applications for TMS arealso promising for accurate mapping of thefunctional cortex preoperatively and intra-operatively. Preoperative mapping superim-poses blood flow and electrical activation dataon 3-dimensional matrices created by MRI andimage processing. The criterion standard, atpresent, is direct cortical stimulation, whichcan identify primary motor, sensory, speech,and visual cortices. TMS may provide a non-invasive means for cortical mapping preoper-atively and intraoperatively when combinedwith imaging systems.44

There have been a few studies describ-ing the use of TMS in patients with TBI.Two studies by Chistayakov and colleaguesreported significant elevations in the motorthreshold in patients with mild to moderatehead injury, indicating a reduction in corti-cospinal excitability.45,46 Furthermore, the de-gree of threshold elevation was found to be di-rectly related to the severity of head injury.46

Single-pulse TMS has also been employed toinvestigate corticomotor excitability in per-sons who have not regained consciousness.Moosavi et al47 and Rhode et al48 studied atotal of 71 persons with severe brain injury.Overall, the studies indicated that MEPs couldbe elicited in upper and lower limb muscles



in the majority of subjects. Rhode’s study re-ported that responses to TMS early in comarecovery could predict the presence of post-coma motor deficit, but did not relate to theseverity of that motor deficit.48 These findingspoint to the survival of populations of corti-cospinal neurons in vegetative and minimallyconscious patients and the ability of TMS toprovide predictive information regarding mo-tor recovery.

Therapeutic applications of TMS

It has been demonstrated in healthy con-trols and in persons with neurological andpsychiatric disorders that high- and low-frequency rTMS can induce changes incortical excitability that exist beyond theperiod of stimulation. This is an importantfactor for incorporating rTMS as a therapeu-tic intervention as it indicates the inducementof an environment supportive of neural plas-ticity and/or of neural adaptation via TMS.49

There is also evidence that the effects of corti-cal stimulation propagate to secondarily con-nected cortical areas. These factors have ledto the application of rTMS as a treatment forseveral disorders.

Low-frequency rTMS, due to its result-ing suppression of cortical excitability, hasbeen investigated as a potential treatmentfor disorders characterized by cortical hy-perexcitability. There have been reports ofmoderate improvements in motor function inpatients with Tourettes syndrome50 and fo-cal hand dystonia51 following low-frequencyrTMS. Conversely, high-frequency rTMS hasbeen investigated as a potential treatmentfor motor and psychiatric disorders charac-terized by reduced cortical excitability. Im-provements in clinical ratings and motor taskshave been noted in patients with stroke andParkinson’s disease who have been treatedwith high-frequency rTMS.52–56 Although lim-ited in number, these studies have demon-strated that rTMS can induce lasting effects onmotor pathways and mood regulation.

A preponderance of literature on therapeu-tic effectiveness of high-frequency rTMS re-

lates to treatment of major depression (sum-marized in Table 1). A large number of thesestudies involve stimulation of the left dor-solateral prefrontal cortex (DLPFC) becauseearly rTMS investigations suggested a relation-ship between major depression and relativeunderactivity of the left DLPFC (eg, Georgeet al57). Hence, it was hypothesized that high-frequency rTMS directed over the left DLPFCwould increase excitability of this region andrestore a balanced interhemispheric activ-ity. Subsequent investigations suggest involve-ment of the right and left DLPFC in majordepression.80

Multiple trials have reported clinical im-provements following rTMS treatment target-ing the left DLPFC in major depression81,82; al-though these differences did not always reachstatistical significance, the effects were typi-cally equivalent to effects of electroconvulsivetherapy (eg, Grunhaus et al79). These trialshave not routinely compared rTMS with medi-cations because the subjects are typically per-sons with medication-resistant depression.

TMS has not previously been examined as atherapeutic intervention after TBI. Therefore,the most clinically effective rTMS parametersand the optimal site for stimulation in TBIare not currently known. The target area ofcortical stimulation for any TMS study shouldbe determined according to the theorized un-derlying neurophysiology and the treatmentgoal. Ideally, the most effective stimulationparameters would result in the maximizationof long-term synaptic potentiation. In prac-tice, determining these parameters is chal-lenging, given the relative lack of informa-tion on the specific neurophysiologic deficitsin TBI and the marked heterogeneity of thepopulation. Previous studies have demon-strated suppression of corticomotor thresh-old and excitability in patients following TBI,although even in severe TBI the integrity ofthe corticomotor system was preserved tosome extent. Since high-frequency rTMS hasshown positive effects in other populationswith decreased corticomotor excitability, itwould suggest that the application of rTMSover cortical motor regions may be beneficial




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for patients with TBI, given this similarity.However, in this population, the restorationof consciousness may take precedence overthe restoration of voluntary motor functionas the primary rehabilitation goal. Therefore,it may be more relevant to target alterna-tive cortical areas, such as the prefrontal cor-tex, to stimulate awareness. Activity of thecerebral cortex is dependent upon both spe-cific sensory input and nonspecific activat-ing impulses from the brainstem. The sourceof these activating impulses is the reticu-lar formation of the brainstem (ie, medulla,pons, and midbrain). Although the ascend-ing and descending reticular activating sys-tems are well integrated, the latter tendsto be centered in the medulla, whereas theformer is found more in the pons and themidbrain. The ascending reticular system is“connected” to the DLPFC as well as the en-tire cortex via thalamic relay nuclei and theraphe nucleus.

In addition to studying the effects of TMS inpersons who remain unconscious for longerthan 3 to 4 months, the effects of TMS couldbe examined in persons with mild TBI whocontinue to demonstrate depression 6 monthsafter injury. Basic science safety studies areneeded to examine the physiological effectsof TMS on mild, moderate, and moderate-severe TBI as early as 3 to 4 months afterinjury. Subsequent to these safety studies, clin-ical efficacy studies should be conducted toexamine the usefulness of TMS in facilitat-ing recovery of executive functioning skillsas well as medication-resistant spasticity. Ul-timately, Phase II randomized clinical trialscomparing the effectiveness of TMS withother established treatments and rehabilita-tions are also indicated.

Safety of TMS with TBI

The risks associated with TMS to personswith TBI include seizure induction, a tempo-rary increase in the auditory threshold, andmild headache. There are no known clinicaltrials that have examined the safety aspectsof TMS as a treatment for TBI. Therefore, therisks and the probability of these risks de-

scribed in this article reflect the publishedliterature relating to animal studies, healthycontrols, and persons with other neurologicaldisorders (ie, stroke, epilepsy, Parkinson’s dis-ease, and multiple sclerosis).10,20,83–85

Magnetic stimulation should not be pro-vided to persons with implanted objectswith electrically conductive properties (eg,cardiac pacemakers, intracranial metal clips,cochlear implants, neurostimulators, and/orheart valves with metallic materials) becausethere is the potential that the stimulus willdislodge the objects or induce electrical cur-rents in them. Ventriculoperitoneal shuntsare commonly inserted after severe TBI.Programmable ventriculoperitoneal shuntsrely on transcutaneous magnetic program-ming. The shunts need to be interrogatedand reprogrammed, if needed, after each TMSsession.

The risk of provoking a seizure with anytype (ie, single-pulse, paired-pulse, repetitive)of TMS in healthy persons (ie, persons whoare not predisposed) is low, but unplannedseizures temporally related to TMS have beenreported (eg, Wasserman 199810). Seizuresoccur because of an imbalance between exci-tatory and inhibitory postsynaptic potentials.A seizure would occur if there is faster con-duction along the myelinated monosynapticexcitatory collaterals, resulting in net excita-tion of neighboring pyramidal cells and hor-izontal spread of excitation. Therefore, TMSat a high enough frequency could result inhorizontal excitation that may develop into aseizure.

The risk of seizure induction is consideredto be low with single-pulse TMS relative topaired-pulse TMS and rTMS, but seizure in-duction with single-pulse TMS has been re-ported for 2 persons who had first incurreda stroke86,87 and for one person with bipo-lar disorder.88 Safety guidelines were devel-oped after the occurrence of seizures withsingle-pulse TMS in the persons who had suf-fered a stroke86,87 and after Pascual-Leone andcolleagues examined the safety of rTMS inhealthy subjects.84 This safety study led tothe 1993 safety parameter guidelines being

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developed according to the number of pulsesat a given intensity and frequency of stim-ulation. Seizures were avoided in the Na-tional Institute of Neurological Disorders lab-oratory for 3 years by adhering to the 1993guidelines.85 In the subsequent years, how-ever, there were 2 cases of seizures inhealthy female volunteers following high-frequency stimulation provided within therecommended guidelines. Two follow-up re-ports identified intertrain intervals as a fur-ther parameter that may be related to the in-duction of seizures.20,83 Following this, theNational Institutes of Health National Insti-tute of Neurological Disorders and Strokeconvened an international workshop on therisk and safety of rTMS.10 The conferencerevealed that, as of June 1996, there hadbeen 7 seizures produced by high-frequencyrTMS in 6 different studies worldwide. Theconference proceedings led to the consen-sus that short intertrain intervals permit a cu-mulative buildup of excitability in the cor-tex, resulting in a lowered seizure threshold.The 1993 guidelines were subsequently re-vised to include recommendations for inter-train intervals. The guidelines cover the eth-ical issues, recommended limits on stimula-tion parameters, monitoring of subjects, ex-pertise and function of the TMS team, med-ical and psychosocial management of un-planned seizures, and contraindications torTMS (Wasserman10,89). Since the adoption ofthese more stringent stimulation parametersin 1996, no seizures have been reported to oc-cur in the National Institute of NeurologicalDisorders and Stroke laboratory.85

There may also be other neurological con-ditions and medications that result in a low-ered seizure threshold. Neurological damagesecondary to TBI can include ischemic in-farcts. Two case reports have indicated thatpeople with large ischemic infarcts may beat the greatest risk for incurring seizures dur-ing brain stimulation.86,87 However, Kandlerreported no evoked seizures after more than800 TMS studies on controls and patientswith neurological conditions.90 Given the lim-ited knowledge regarding the side effects of

TMS, Kandler sent a health survey to 218 sub-jects who had been tested with TMS. Of the154 patients who responded, 2 people withmultiple sclerosis reported seizures within1 month of TMS. Kandler considered thetiming of the seizures worrisome and sug-gested that patients with certain neurolog-ical conditions might have a lower seizurethreshold.90

Procedures can be implemented to mon-itor for early detection of seizures and/orminimize risk of seizures as well as otheradverse events with patients with TBI. Elec-troencephalography and/or electromyogra-phy monitoring can be used to check for signsof spread of excitation and after-discharges,which may be a precursor for a seizure.84 Itis possible that a patient with TBI who re-ceives rTMS may experience a mild headacheafter the treatment session due to magneticstimulation of the temporalis, frontalis, andoccipitalis muscles. Therefore, proceduresshould also include plans for providing ac-etaminophen or a similar pain reliever. Thecoil discharge noise creates a risk of tem-porary mild hearing loss due to its substan-tial volume. Even though this risk is verysmall, foam earplugs should be placed in thesubject’s ears throughout the period of stim-ulation to minimize acoustic conduction.91

There may be other unknown and/or unantic-ipated side effects that could occur. A com-prehensive safety monitoring plan includingprescreening,92 tracking of adverse events,and response plans for unanticipated adverseevents should be developed for any investiga-tions of TMS with TBI.

Proposed use of rTMS in TBI

Published evidence suggests that rTMS mer-its investigation as an intervention for TBI.The first and second authors, at the time ofwriting this article, are implementing a varia-tion of the rTMS design in a Phase I clinicaltrial of TMS as a treatment for impairment ofconsciousness following severe TBI. This vari-ation of the rTMS design is referred to by theauthors as repetitive paired-pulse TMS (Fig 3).The repetitive paired-pulse design is similar




Figure 3. Repetitive paired-pulse design. Simulation parameters: frequency: 2 Hz; intensity: 110% MT;

number of trains per session: 300; and total number of sessions: 30.

to standard rTMS protocols except that pairsof stimuli pulses are repeated in lieu of multi-ple single pulses. The time between each re-peated pair (interpair interval) is longer thanthe time period normally separating a train ofsingle pulses. The benefit of this design is thatit incorporates the aspects of rTMS neededto induce cortical plasticity (high-frequencytrains of stimulation), while also including pe-riods of cortical rest (ie, interpulse and in-terpair intervals) needed to enhance safety.The effective stimulation frequency in the re-peated paired-pulse design is not as high astraditional rTMS protocols, due to the long in-terpair interval, therefore the risk of adverseevents is reduced. The stimulation will be di-rected over the right dorsolateral prefrontalcortex, with the aim of remote activation ofthe reticular activating system. Several neuro-physiological, reflex, and behavioral repeatedmeasures will be recorded and monitored dur-ing the trial. Approvals from the FDA for anInvestigational Device Exemption (FDA IDE# G040195) and from the local Human Sub-ject Institutional Review Boards have beenobtained.

SUMMARY

The studies above report that MEPs can besuccessfully induced in most patients withTBI and that these responses may be usefulin providing prognostic information on mo-tor recovery. The presence of MEPs also pro-vides evidence of cortical neuronal integrity,at least in motor regions of the brain after TBI.It is more difficult to assess the effectiveness

of TMS applied over nonmotor regions of thecortex, particularly in subjects who lack con-sciousness. Despite this, evidence from otherpopulations continue to suggest that rTMSmay be an effective therapeutic interventionfor inducing an environment supportive ofneural plasticity49 and/or enhancing neuraladaptation for recovery of functional skills.

While we are conducting the first eversafety and efficacy study of repeated paired-pulse TMS during coma recovery, additionalPhase I clinical trials may be indicated. Re-search designs could subsequently be ad-vanced to Phase II randomized clinical trialswhere the initial goal could be to enhance cor-tical excitability. It is recommended that ini-tial treatment intervention studies employ therepeated paired-pulse or similar designs thatmaximize patient safety. It is also suggestedthat early treatment intervention studiesfocus on determining the optimal stimulationparameters of rTMS treatments.

ACKNOWLEDGMENTS

Dr Pape appreciates the “out-of-the-box”thinking of the engineers within the Buildingsand Grounds Department of Marianjoy Reha-bilitation Hospital for designing and buildingthe coil holder illustrated in Figure 1b ofthis article. In particular, the efforts of JackDerose, Terry Higgins, and Tom Brandeis aregreatly appreciated. Drs Pape and Rosenowalso appreciate Dr Gwyn Lewis’s willingnessto share her knowledge about transcranialmagnetic stimulation. The authors appreciatethe suggestions made by Dr Leonardo

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Cohen and the subscribers of the TMSlistserv (tms [email protected]), whichhas approximately 127 members from 21countries representing about 30 laboratories.Dr Pape also acknowledges and thanks herVA advanced research career developmentcomentors, Drs Gwendolyn Kartje and Allen

Heinemann, for their dedication, time, andcarefully considered insights. Dr Pape alsoappreciates the ongoing guidance providedby Dr Frances Weaver. Drs Kartje, Heine-mann, and Weaver’s steadfast dedicationand guidance allowed Dr Pape to realizepossibilities.

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Transcranial Magnetic Stimulation: A Possible Treatment for TBI

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