Epilepsy: A Comprehensive Textbook
2nd Edition
© 2008 Lippincott Williams & Wilkins
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Chapter 88
Transcranial Magnetic Stimulation
Charles M. Epstein
Roberto Michelucci
Mark Hallett
Introduction
Transcranial magnetic stimulation (TMS) depolarizes neural elements through electromagnetic induction. It might more properly be called “transcranial electromagnetic stimulation.” However, emphasizing the magnetic component distinguishes TMS more clearly from direct electrical stimulation and highlights the easy penetration of the magnetic field through skin, skull, and cerebrospinal fluid. TMS provides unique, non-invasive measures of neurologic function, along with the possibility of focally augmenting or inhibiting cortical activity.
Principles of Transcranial Magnetic Stimulation
The fundamental principles of electromagnetic induction are that an electric current produces a magnetic field B and a changing magnetic field induces a flow of electric current in nearby conductors— including human tissue. A static magnetic field, however large, produces no current in the brain. Thus, the key parameter for a magnetic stimulator is not the absolute magnetic field strength in teslas but its first time derivative, dB/dt, combined with the duration of the stimulating pulse. Typical magnetic stimulators operate at a few thousand volts and several thousand amperes per pulse. Peak power output is measured in megawatts and lasts a few score microseconds. The very high peak currents are obtained by discharging a large capacitor directly into the stimulation coil (Fig. 1).
The resulting pulse waveforms are determined by the resonant frequency of the capacitor plus coil. These waveforms fall into two categories: (a) monophasic and (b) biphasic. “Monophasic” magnetic pulses have the general shape illustrated in FIGURE 2A, with a large initial peak and a much smaller, longer-lasting tail that presumably has no biologic effect. Biphasic pulses form a cosine wave, as shown in FIGURE 2B, with the later peaks smaller than the first because of energy losses in the circuitry.
These induced voltage waveforms mirror the voltage across the stimulation coil during the course of the discharge cycle. They do not reflect the actual coil current, which lags the coil voltage by 90°. The biphasic waveform appears to stimulate neurons maximally at the second (downgoing) shaded region, which represents the longest epoch of induced voltage across neuronal membranes.
Monophasic pulses have prominent directional effects, which may be important for some applications. They can be produced with circuitry that is lighter and cheaper than that needed for biphasic pulses. However, simple monophasic stimulators dissipate the entire capacitor charge with every pulse, incurring a high energy cost. This power loss translates into additional heating of the stimulation coil and other components, making monophasic stimulators more difficult to adapt for sustained repeat stimulation. Biphasic stimulators conserve energy by recapturing much of the original charge in the capacitor, and the biphasic wave shape has somewhat greater biologic effect for a given output voltage. This makes biphasic stimulators three to four times more efficient than monophasic devices, and the most practical choice for rapid repetitive stimulation.
TMS pulses may be single, paired, or repetitive (rTMS). rTMS can be fast (more frequently than once per second) or slow (less than once per second). Paired-pulse TMS most commonly involves passing two separate pulses through the coil within a few milliseconds. The large capacitors used for TMS cannot be recharged that rapidly, so paired-pulse stimulation requires two separate power modules coupled to a single coil.
Transcranial Magnetic Stimulation Coils
Circular Transcranial Magnetic Stimulation Coils
The simplest TMS coil is a circular loop. As shown in FIGURE 3, the changing current in the coil loop induces an antiparallel current flow of opposite direction in the underlying brain. Although the magnetic field is maximum directly under the center of the coil, the induced current is maximum near the outer edge of the coil. This discrepancy is an occasional source of confusion and may lead to the erroneous assumption that the site of magnetic stimulation is beneath the coil center.
Large circular TMS coils have good penetration to the cerebral cortex. They are commonly placed at the cranial vertex, where they can stimulate both hemispheres simultaneously. However, the effect on motor cortex tends to be asymmetric, especially with monophasic pulse waveforms. The main drawback of circular coils is their lack of focality. Not only does the circumference of the coil overlie a large area of brain, but in addition the radius of strongest stimulation is difficult to specify.
Figure 8 Transcranial Magnetic Stimulation Coils
If two round coils are placed side by side so that the currents flow in the same direction at the junction point, the induced electric fields will add together and be maximum below the junction (Fig. 4). This design, known as a “figure-8,” “butterfly,” or “double-D” coil, allows focal stimulation at a limited and clearly definable location. Because of this greater focality, figure-8 coils are chosen much more often than round coils for research and clinical applications. In typical use, the area of stimulated cerebral cortex is several square centimeters and its contours resemble an oval or rounded rectangle. The long axis of the rectangle parallels the junction of the two coils.
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FIGURE 1. Simplified transcranial magnetic stimulation (TMS) circuit. The capacitor is first charged to a high voltage and then is discharged into the inductor (the stimulation coil) when the switch is closed. Additional components are needed to shape monophasic TMS pulses and to stop biphasic TMS pulses after a single cycle.
FIGURE 2. Monophasic (A) and biphasic (B) transcranial magnetic stimulation waveforms. Darker curves represent the induced voltage in the brain, and lighter curves the simultaneous current in the stimulation coil. Shaded areas are the periods of highest induced voltage, when neuronal membranes are most likely to be depolarized.
FIGURE 3. Round transcranial magnetic stimulation coil. Small dark arrows show the primary current in the coil. Large arrows show the path of maximum induced current, which lies below the outer coil edge.
FIGURE 4. Figure-8 type transcranial magnetic stimulation coil. Small dark arrows show the primary current in the coil. Very small gray arrows (forming loops and penetrating into the brain) show the position and orientation of the maximum magnetic field, which lies perpendicular to the coil junction. Larger gray arrows show the position and orientation of the maximum electric field, which lies parallel to the junction and largely tangent to the cortical surface.
Iron-core Transcranial Magnetic Stimulation Coils
The efficiency of energy transfer from TMS coils to tissue is extremely small, on the order of 0.0001%. This striking inefficiency is responsible for the high power requirement of magnetic stimulation, bulky power supplies, and an annoying tendency to overheat with repeated firing. Ferromagnetic cores have much greater magnetic permeability than air, and consequently produce equivalent magnetic fields with much lower coil currents, increasing efficiency by a factor of four and reducing heat production by a factor of 5 to 10. In return for this improved performance, iron-core coils may be several pounds heavier.
Sham Transcranial Magnetic Stimulation Coils
The need for placebo stimulation in TMS research has led to the development of sham TMS coils, which are intended to prevent the subject and even the operator from knowing whether a given session involves real or sham stimulation. Ideally, sham stimulation should reproduce the external appearance of the coil and lead wires, the auditory click and mechanical tapping when it fires, and the complex sensations of scalp muscle contraction and electrical paresthesias that accompany real TMS, without actually projecting a magnetic field into the brain. The most advanced sham coils are integrated with scalp electrodes, which deliver a small current and produce subjective scalp paresthesias at the moment of sham stimulation. Most
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placebo coils have been less complex. Properly designed experiments rely in part on presenting real and sham stimulation to different subjects, or at widely separated times to the same subjects, so that any difference is difficult to detect.
The Site of Transcranial Magnetic Stimulation Activation
The electric currents induced by TMS in brain are strongly constrained to lie parallel to the superficial surface of the cerebral cortex. Evidence from varied sources suggests that TMS induces depolarization of myelinated axons that are aligned parallel to the cortical surface, and lie near the gray–white matter junction. The sites of activation are likely to be branch points or bends, where induced transmembrane currents will be largest. In motor cortex the depolarized axons belong primarily to interneurons, although the axons of large motor neurons can be activated directly in some experimental paradigms.
Transcranial Magnetic Stimulation and the Neurophysiology of Epilepsy
A large number of studies have investigated cortical excitability in epilepsy by means of TMS to gain new insight into the physiopathology of this disorder. As discussed in a subsequent section, however, antiepileptic drugs (AEDs) can influence TMS parameters. Therefore, the optimal methodologic approach to investigating epileptic processes by TMS is to evaluate untreated patients or, if this first-choice approach is not possible, design TMS studies to evaluate at best the possible effects of AED treatment. In this section the results of TMS studies investigating cortical excitability are separated into two main subsections according to the generalized or focal nature of the epilepsies included in the TMS trials.
Generalized Epilepsies
In a group of untreated patients with IGE, Reutens et al.72,73 found an abnormal motor threshold (MT) reduction. This finding was interpreted as an index of motor cortical hyperexcitability due to the epileptic process. In contrast, Gianelli et al.39 reported increased MT in untreated patients suffering from idiopathic generalized epilepsy (IGE) with typical absence seizures. Another group found no MT abnormality in IGE patients.7,52
Finally, MT increase has been reported in a group of untreated patients who experienced a first generalized tonic–clonic seizure in the previous 48 hours, this finding having been interpreted as a postictal “protective effect.”21 The differences reported in these studies may be related to the clinical heterogeneity of IGE patients. In accordance with this view, Reutens et al.73 found that MT was lower in patients with myoclonic seizures than in patients suffering from absence seizures. In an unusual group of patients with IGE and versive, circling seizures, the interhemispheric difference of the MT was significantly higher than in IGE patients without circling and in normal controls, suggesting an explanation for the clinical phenomena.3 The cortical silent period (CSP) was found to be increased or normal in untreated patients with IGE.21,54,63
According to the finding of increased excitability as demonstrated by MT in generalized myoclonic seizures, an abnormal intracortical inhibition (ICI) reduction and a normal intracortical facilitation (ICF) were found in both treated and untreated patients with juvenile myoclonic epilepsy (JME).10,42,56 ICI suppression suggests impaired functioning of inhibitory circuits in JME, which may result in hyperexcitability of the corticospinal pathways. Increased facilitation at interstimulus intervals of 200 to 300 msec, but not at 100 to 150 msec, corresponds to the mean interdischarge interval of spike-wave activity on the electroencephalogram (EEG).7,54 Patients with progressive myoclonus epilepsies (PMEs) have reduced long-ISI paired-pulse inhibition47,94 as well as exaggerated facilitatory effect of peripheral stimulation on motor-evoked potential (MEP), suggesting a markedly increased influence of afferent input on motor cortical excitability.73 Digital stimulation markedly facilitated conditioned MEPs, suggesting cortical and subcortical components of abnormal sensorimotor integration in addition to hyperexcitability of the sensory and motor cortex.54
Focal Epilepsies
Normal MT was reported in untreated patients with benign rolandic epilepsy (BRE)53 and cryptogenic focal epilepsy (FE),61 as well as in a group of patients with focal seizures in which AED treatment was discontinued at least 48 hours prior to TMS as part of an evaluation for epilepsy surgery.103
Alterations in MT and CSP prolongation have been reported, mostly in patients suffering from seizures involving the motor cortex. In these cases, CSP prolongation may indicate that the mechanisms underlying CSP contribute to the compensatory phenomena in the interictal phase. In contrast, CSP has been shown to be usually normal in FEs localized outside the motor cortex.8,15,17,103 Nevertheless, in a patient with FE due to a lesion within the supplementary motor area19 and in two patients with FE secondary to cortical dysgenesis not involving the motor cortex,16 the CSP was greatly lengthened in the contralateral hand, this effect being more likely related to the structural brain lesions rather than to the epileptic process. One study reported a shortened CSP after high-intensity TMS of the affected hemisphere in a group of patients with cryptogenic focal epilepsy, whose characteristics indicated that the epileptogenic area did not correspond to the motor cortex.14 More recently, a single- and paired-pulse TMS study performed in 23 patients with focal epilepsies not including the primary motor area disclosed that CSP was shorter in epileptic hemispheres of extratemporal epilepsies than in controls, suggesting that FEs chronically influence distant cortex, leading to decrease inhibition in the ipsilateral motor cortex even when the epileptogenic zone is apart from it.42
In FE, studies of ICI and ICF have led to inconsistent findings that may be due to subject heterogeneity and AED fluctuations. Overall, most studies have reported ICI reduction and ICF increase in FEs involving or not the motor cortex but without any clear lateralization value.8,37,95,103,104
Studies Performed by Stimulating During the Seizures
Single-pulse TMS performed during the seizures captured by long-term EEG monitoring may disclose a variety of alterations of MT and MEP amplitudes, which are likely to reflect the influences of different seizure types on the motor system.86 In four IGE patients, Gianelli et al.39 compared the size of MEPs following test magnetic pulses delivered during normal EEG segments and during typical 3-Hz spike-and-wave EEG complexes. MEP size was reduced when TMS was time-locked to the slow-wave component, suggesting a transient decrease in excitability of corticospinal pathways.
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In a group of BRE patients presenting extreme somato-sensory-evoked potentials, an abnormal MEP facilitation was seen when the test magnetic pulse was delivered during the ascending phase and the peak of the spike evoked by electrical digital nerve stimulation.54 In contrast, peripheral nerve stimulation produced no abnormality of MEP size modulation in IGE patients.74
Effects of Anticonvulsants
Although TMS can be a useful method for evaluating a patient with epilepsy, it is crucial to note that anticonvulsants have a major influence on brain excitability and, therefore, TMS effects. Hence, it is necessary to understand these effects in order to interpret TMS studies. In fact, some of the information on mode of action of anticonvulsants was actually determined in part from TMS studies.
Before looking at anticonvulsant effects, we review the types of information that can be obtained from TMS studies. Virtually all the data come from stimulation of the primary motor cortex, where TMS produces MEPs in muscles topographically related to the site of stimulation.1,41,88 Stimulation can excite the descending axons from M1 directly, called the D-wave, and indirectly by a series of intracortical synaptic influences that produce a number of indirect or I-waves.23 At lowest stimulation intensity, typically the earliest effect comes from the first I-wave, I1.
The threshold for producing an MEP reflects the excitability of a central core of neurons that arises from the excitability of individual neurons and their local density. It can be influenced by drugs that affect Na and Ca channels, and must indicate membrane excitability. Because the MEP is small, the threshold measure reflects the influence of mainly the I1 wave. Threshold can be measured with the muscle at rest, rMT, or with an active background contraction of the muscle, aMT.
The recruitment curve is the growth of MEP size as a function of stimulus intensity and/or background contraction force. This measurement is less well understood because there are many effects, but it must involve neurons in addition to the core region activated at threshold. These neurons have higher threshold for activation because either they are intrinsically less excitable or they are spatially further from the center of activation by the magnetic stimulus. These neurons would be part of the “subliminal fringe” and contribute to I2 and later I-waves. D-waves are also recruited with higher intensities of stimulation.
Intracortical inhibition and facilitation are obtained with paired-pulse studies and reflect interneuron influences in the cortex.108 In such studies, an initial conditioning stimulus is given, enough to activate cortical neurons but small enough that no descending influence on the spinal cord can be detected. A second test stimulus at suprathreshold level follows at a short interval (Fig. 5). Intracortical influences initiated by the conditioning stimulus modulate the amplitude of the MEP produced by the test stimulus. At very short intervals, <5 msec, there is inhibition, and at intervals between 8 and 30 msec, there is facilitation. ICI is likely largely a GABAergic effect, specifically γ-aminobutyric acid A (GABAA).24 This type of inhibition is also referred to as “short ICI” or SICI to contrast it with ICI studied at longer time intervals, called LICI.78
FIGURE 5. Intracortical inhibition and facilitation with paired-pulse stimulation. The first, conditioning pulse is just below motor threshold; the second, stimulating pulse, is just above. Depending on the time interval between the two pulses, the recorded compound muscle action potential (CMAP) may be (A) normal, (B) facilitated, or (C) inhibited.
The silent period (SP) (or cortical silent period, CSP) is a pause in ongoing voluntary EMG activity produced by TMS. Although the first part of the SP is due in part to spinal cord refractoriness, the latter part is entirely due to cortical inhibition. There is evidence that this type of inhibition is mediated by GABAB receptors.102 SICI and the SP reflect different aspects of cortical inhibition.
Intracortical inhibition can also be assessed with paired suprathreshold TMS pulses at intervals from 50 to 200 msec. This is called LICI to differentiate it from SICI as noted previously. LICI and SICI differ, as demonstrated by the facts that with increasing test pulse strength, LICI decreases but SICI tends to increase, and that there is no correlation between the degree of SICI and that of LICI in different individuals.78 In addition, LICI appears to inhibit SICI and shows some interaction of inhibitory mechanisms within the human motor cortex.78 The mechanisms of LICI and SP may be similar.
Short afferent inhibition (SAI) is produced at short latency by somatosensory stimulation of the hand.24 This has been demonstrated to be mediated by muscarinic synapses because it is selectively blocked by scopolamine.
The data on the influence of anticonvulsant drugs on TMS measures were reviewed in depth by Ziemann.106 Only the highlights are addressed here and summarized in Table 1. As he noted, the literature is not completely consistent, and the acute and chronic effects of these agents may differ, which makes the interpretation of the literature a bit more complex.
Certain anticonvulsants affect mainly Na channels and thus should influence the threshold for the MEP selectively. This is true of carbamazepine (CBZ),106 phenytoin (PHT),11 and la-motrigine (LTG).106 These agents do not affect MEP recruitment, SP, SICI, or ICF.
Some anticonvulsants, such as lorazepam107 and diazepam,67 appear to facilitate the action of GABAA in a straightforward fashion. These drugs do not influence the motor threshold, but they suppress MEP recruitment, increase SICI, and depress ICF. On the other hand, a more recent finding is that these two agents have different effects on SAI.26,27 Lorazepam decreases SAI and diazepam increases it. This result shows how complex interneuronal networks are and that even similar compounds might have differing effects.
Other anticonvulsants that are supposed to facilitate GABA do not have the fully expected effect. Valproate was initially reported to elevate MT in patients with primary generalized epilepsy,73 but in subsequent studies it had no clear influence on any measure.109 In one study, vigabatrin suppressed ICF but did not affect SP or SICI.106 In another study, vigabatrin increased LICI and SP but not SICI.70 This result would be compatible with a selective effect on GABAB receptors. Tiagabine has paradoxical effects in suppressing SICI and facilitating ICF, but it does lengthen the SP.102 This suggests that its inhibitory effect is also mediated largely by GABAB effects.
Table 1 Effects of AEDs on TMS Measures
AED MT SICI LICI SAI ICF REC sp
Carbamazepine ↑            
Lamotrigine ↑            
Phenytoin ↑            
Levetiracetam (↑)         ↓  
Lorazepam   ↑   ↓ ↓ ↓  
Diazepam   ↑   ↑ ↓ ↓  
Tiababine   ↓     ↑   ↑
Gabapentin   ↑     ↓   ↑
Vigabatrin     ↑   ↓   (↑)
Valproate   (↑)          
Topiramate   ↑          
Some anticonvulsants have unknown, incompletely known, or multiple modes of action. In this situation, the TMS studies can give some information about how they might have
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their most important actions. Gabapentin has several modes of action, including increasing GABA synthesis, and its effect is consistent with facilitating GABA effects in that it increases both the SP and SICI and suppresses ICF but has no effect on threshold.106 Topiramate also has several modes of action, but its effect on TMS measures is limited to increasing SICI, which likely indicates a prominent GABAA influence.
Levetiracetam has an uncertain mode of action, although some basic studies suggest an effect at the GABA synapse. Multiple TMS measures in one study revealed only a suppression of MEP recruitment and no effect on threshold, SP, ICI, or ICF.81 As noted earlier, this is difficult to interpret in isolation. Another study, however, did find an elevation in rMT.71 Levetiracetam was also studied in a special way, via a motor learning task, which might be a method for assessing long-term potentiation.82 Pinch force and acceleration and motor cortex excitability were studied before and after 30 minutes of pinch practice at 0.5 Hz. Either 3,000 mg of levetiracetam or placebo was administered 1 hour before the experiment. After practice, pinch acceleration was significantly increased with placebo but not with levetiracetam. All other measures showed no significant change. The finding is consistent with a negative influence on long-term potentiation.
Given the influence of anticonvulsants on the brain, it should be possible to use TMS as a functional measure of drug levels. In some ways, this makes more sense than just the serum level of a drug. On the other hand, there needs to be some caution because the anticonvulsant efficacy may not be linearly related to a TMS effect. This has been attempted in several studies. For example, the relationships among LTG oral doses, serum levels, and rMT were assessed by TMS.90 With a single dose, rMT elevation showed a poor but significant correlation with serum levels, but with a graded dose, serum levels as well as rMT increased in a dose-dependent fashion with significant linear correlation. However, there was a high interindividual variability in the relationship, resembling a sigmoid correlation.
Another study investigated the correlation between serum levels of CBZ and several different measures of motor excitability in patients at the beginning of antiepileptic treatment.93 Recording sessions were performed before treatment and after 7, 15, and 60 days. There was a progressive increase in rMT and aMT until the serum levels of CBZ reached a steady-state condition. On the other hand, no significant changes were observed in MEP amplitude, SP, SICI, and ICF. This study confirms both the selective effect of CBZ as well as the correlation with serum levels. A third study examined TMS measures and relationship to serum levels with both LTG and CBZ during drug administration and withdrawal.51 rMT increased with increasing total and free CBZ and LTG levels during drug administration. After acute drug withdrawal, rMT elevation persisted in most individuals with CBZ despite undetectable plasma levels, whereas there was a rapid normalization with LTG. Another interesting finding was that acute drug withdrawal resulted in a transient decrease in rMT in 3 of 10 individuals with CBZ and 2 of 10 with LTG. The authors concluded that plasma levels provide information on motor cortical function during active treatment phases but not during drug withdrawal, and noted that the transient decrease in rMT associated with acute drug withdrawal could represent a physiologic substrate contributing to drug withdrawal seizures.
Induction and Inhibition of Seizures
The potential role of TMS in inducing or inhibiting seizures has long been debated, and a number of experimental studies have been devoted to this issue. In this section we discuss the induction and inhibition properties of TMS separately, as well as the effects of single-pulse (sp), paired-pulse (pp), and repetitive (r) TMS.
Transcranial Magnetic Stimulation and Induction of Seizures
Single-pulse and Paired-pulse Transcranial Magnetic Stimulation
At the time of its introduction in clinical practice, the use of sp TMS was limited by the hypothetical risk of inducing epileptic seizures.2 However, there are only a few reports dealing with the accidental induction of seizures in patients with neurologic disorders of the brain, while the causative role of TMS remains questionable in most of these cases.34,43,50 Only Homberg and Netz43 reported a stroke patient who had his first tonic–clonic seizure during the stimulation procedure.
Table 2 Maximum safe duration (in seconds) of single trains of repetitive transcranial magnetic stimulation based on the National Institute of Neurological Disorders and Stroke experience
Frequency (Hz) Intensity (% of motor-evoked potential threshold)
100 110 120 130 140 150 160 170 180 190 200 210 220
1 >1,800 >1,800 360 >50 >50 >50 >50 27 11 11 8 7 6
5 >10 >10 >10 >10 7.6 5.2 3.6 2.6 2.4 1.6 1.4 1.6 1.2
10 >5 >5 4.2 2.9 1.3 0.8 0.9 0.8 0.5 0.6 0.4 0.3 0.3
20 2.05 1.6 1.0 0.55 0.35 0.25 0.25 0.15 0.2 0.25 0.2 0.1 0.1
25 1.28 0.84 0.4 0.24 0.2 0.24 0.2 0.12 0.08 0.12 0.12 0.08 0.08
Numbers preceded by > are the longest durations tested. No afterdischarge or spread of excitation has been encountered with single trains of repetitive transcranial magnetic stimulation at these combinations of stimulus frequency and intensity.
From Wassermann EM. Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5–7, 1996. Electroencephalogr Clin Neurophysiol. 1998;108(1):1–16.
Single-pulse TMS has not been shown to induce seizures consistently in epileptics.58,59 In 1990, Tassinari et al.85 studied 58 patients with recurrent seizures (either partial or generalized) resistant to AEDs. The patients were subdivided into three groups according to seizure frequency (rare, weekly, or daily seizures). Each patient received an average of 25 stimuli, ranging in intensity from 50% to 90% of the maximum stimulator output, with a rate not exceeding one shock every 10 seconds. Neither the short-term (for 2 hours after TMS) or long-term (for 2 months after TMS) clinical monitoring disclosed any
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TMS seizure-triggering effect in any group of patients. Only one patient with 5 to 10 complex partial seizures (CPS) a day experienced one of his habitual seizures during the TMS investigation. Similarly, Hufnagel et al.45 reported that 2 of 53 patients with three to five spontaneous CPS a day had a typical seizure during the course of the TMS investigation. Other cases of seizures temporally related to sp TMS in epileptics have been reported,29,44,46 but these ictal events may have been coincidental. For at least one patient, however, there is clear-cut evidence of focal seizures triggered consistently and reproducibly by single-pulse TMS.19 Recently, Schrader et al.,79 reviewing published data and their own experience with three additional seizures in epilepsy patients, estimated that the crude risk of a TMS-associated seizure ranges from 0.0% to 2.8% for sp TMS and from 0.0% to 3.6% for pp TMS in patients with epilepsy. Medically intractable epilepsy and lowering AEDs were associated with increased incidence. In most cases, however, the patients experienced their characteristic seizure semiology, and doubt was expressed in the original reports as to whether the seizures were induced or merely coincidental.
Repetitive Transcranial Magnetic Stimulation
By the end of 1996, six seizures had been elicited by rTMS in 6 nonepileptic individuals (5 volunteers and 1 with depression). Four of these seizures occurred in 4 of 250 volunteers studied at the National Institute of Neurological Disorders and Stroke (NINDS) during the program of clinical development of the technique.68,97,99 On the basis of these induced seizures and safety studies that monitored the occurrence of post-TMS EMG activity and spread of excitation,12 limits of stimulation parameters were recommended and proposed for a correct and safe use of the technique in clinical practice (Table 2). These safety margins supplemented and outweighed those previously published by Pascual-Leone et al.69 on the basis of their studies on spread of cortical excitation along the motor cortex.
Although high-frequency rTMS may induce accidental seizures in normal subjects, it has been rarely associated with seizures in epileptics. So far, only three epileptic patients have been reported to experience a seizure during rapid rTMS procedures (Dhuna et al.22; Cohen, personal communication; Michelucci, Valzania, and Tassinari, personal communication). In view of the seizures occurring in normal subjects, the difficulty of producing seizures in epileptic patients seems paradoxical, especially given that many studies used combinations of settings that were outside of the safe zone (Table 2). A possible explanation is that all of the epileptic subjects were treated with anticonvulsants at the time of stimulation. Special epileptic conditions, however, seem more prone to develop seizures following rTMS. Of 60 patients with various types of epilepsy studied by means of rTMS, Tassinari et al.87 observed apparently rTMS-induced seizures in 2 of 10 patients with PME and in 1 of 4 patients with epilepsia partialis continua. Persistent jerking of the contralateral arm following cessation of motor cortex rTMS, indicating the presence of afterdischarges, was reported by Michelucci et al.60 in 2 patients with cryptogenic FE.
Transcranial Magnetic Stimulation and Inhibition of Seizures
In normal subjects, application of low-frequency trains of rTMS produces a relatively long-lasting suppression of cortical excitability.13 In addition, 0.5-Hz rTMS prolonged the latency for development of pentylenetetrazol-induced seizures in rats.4 These data provide a rationale for using low-frequency rTMS to treat patients affected by epilepsy and epileptic myoclonus.
In an open pilot study, Tergau et al.89 investigated the effects of 0.33-Hz rTMS delivered on five consecutive days in nine patients with drug-resistant FE (two temporal, seven extratemporal). Each day, two trains of 500 pulses at 100% of the RMT were applied by means of a large circular coil placed over the vertex. During the follow-up period (4 weeks before and 4 weeks after the rTMS application) the AED treatment was kept constant. Seizure frequency was significantly reduced in the postintervention period compared with the preintervention period.
In a patient with intractable partial seizures due to a focal cortical dysplasia in the left parasagittal parietal region, Menkes and Gruenthal57 used 0.5-Hz trains of 100 subthreshold magnetic stimuli twice a week for four consecutive weeks. rTMS was delivered by a round coil. During the month of observation, the seizure frequency and the interictal spikes were reduced by 70% and 77%, respectively. Similarly, Fregni et al.38 observed a significant antiepileptic effect after one session of 0.5-Hz trains of 600 pulses in eight patients with refractory epilepsies due to malformations of cortical development.
These effects of 0.3- to 0.5-Hz rTMS on seizure frequency have yet to be replicated in randomized, blinded trials. In contrast, a controlled study was performed to assess the therapeutic potential of 1-Hz rTMS.91 Twenty-four FE patients were randomized to blinded active or placebo stimulation delivered
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for 15 minutes twice daily for 1 week. Active stimulation was administered at 120% of MT using a figure-8 coil placed over the EEG focus. For the “placebo” stimulation, the coil was angled at 90 degrees away from the scalp. A trend toward a short-term reduction of seizure frequency was observed in the active group, whereas placebo stimulation had no effect. However, this difference was not significant. These findings do not necessarily indicate that the seizure reduction observed in the previous reports was merely due to observer expectations and placebo effects. For instance, distinct effects of different rTMS frequencies (0.3–0.5 vs. 1 Hz) could also explain this discrepancy. Cincotta et al.18 provided evidence that suprathreshold 0.3-Hz rTMS but not 0.9- to 1-Hz rTMS produces a relatively long-lasting enhancement of the inhibitory mechanisms responsible for CSP.
A preliminary report suggested that low-frequency rTMS could reduce epileptic cortical myoclonus.101 However, the same group performed a sham-controlled study of a larger case series and found no significant beneficial effect with 10 days of 1-Hz rTMS of the motor cortex.100 In patients with epilepsia partialis continua due to cortical dysplasia, 0.5- to 1-Hz rTMS applied over the motor area induced a marked reduction or temporary disappearance of the jerks.62,75 In conclusion, the available data are too preliminary to establish whether low-frequency rTMS may be an effective adjunctive treatment in epileptic processes. Randomized trials with realistic shams reproducing as far as possible the physical sensation of the active stimulation should test different rTMS parameter combinations (frequency and intensity of stimulation, train duration, number and frequency of applications, focal vs. nonfocal stimulation). Larger and homogeneous case series are essential to increase sensitivity and to identify the specific epileptic conditions that could be alleviated by rTMS. Finally, appropriate endpoints and long-term follow-up are necessary to evaluate the clinical relevance of the results.
Mapping Speech, Language, and Memory
From the time of its introduction, many researchers in TMS have focused on replicating or replacing the intracarotid amobarbital test (Wada test).96 The requirements for doing so are straightforward. The new procedure should be safe, tolerable, and robust, producing obvious effects in virtually all subjects and allowing test paradigms that epilepsy patients can comply with in the face of anxiety, medications, and structural encephalopathies. Finally, of course, the new procedure should have excellent concordance with Wada test results, and when discordant, should be at least as good at predicting surgical outcomes. TMS has provided a wealth of information about language and memory mechanisms but has not yet fully satisfied the requirements for a clinical language test.
Initial attempts to affect language with rTMS were hampered by the use of round stimulation coils and colored by the belief that stimulation parameters should match those used in operative electrocorticography. Prior to the existence of safety guidelines,99 stimulation frequencies ranged up to 50 Hz; stimulator output was commonly set between 80% and 100% of maximum, with stimulus trains up to 10 seconds in duration. Pain, crying, and even seizure were among the outcomes.20,35,48,60,69 Pascual-Leone et al.68 reported lateralized interference with speech output using TMS in 6 of 6 epilepsy patients; all results matched the Wada test. Others found speech disruption difficult to induce with round TMS stimulation coils. Jennum et al.48 achieved complete speech arrest in only 7 of 14 subjects, whereas Michelucci et al.61 reported 14 of 21. Epstein et al.,30 using a more focal figure-8 coil, induced speech arrest with frequencies as low as 4 Hz and train durations of 5 seconds or less. These stimulation parameters produced more consistent results while reducing the discomfort of rTMS and allowing compliance with safety guidelines.
TMS-induced speech arrest is now safe and robust enough to produce obvious effects in almost all epilepsy patients and normal volunteers. However, it appears to represent a disruption of motor speech output rather than a true aphasia and to occur in the vicinity of facial motor cortex.32 Like simple speech arrest in the Wada test itself, it is not fully accurate for language lateralization.6 Jennum et al.48 and Epstein et al.32 each reported a patient with left hemisphere language lateralization by Wada testing but apparent right lateralization by rTMS speech arrest. We have encountered a third such patient in the course of additional testing. When compared directly in 17 epilepsy surgery candidates, rTMS showed a significant correlation with the Wada test but also showed a significant bias toward right hemisphere or bilateral lateralization.32 Most patients in this series underwent resection of the epileptic focus; the Wada results corresponded more closely than TMS with postoperative language deficits.
In retrospect, it might have been predicted that TMS speech effects would be obtained most easily over motor cortex. Ojemann’s classic studies of verbal interference sites during electrocorticography show the most common locus to lie at the foot of the precentral sulcus.66 In these studies, there is no evidence for a more anterior cluster of speech arrest sites corresponding to Broca’s area. Furthermore, despite occasional observations of transient aphasic phenomena, it has not been possible for TMS to produce consistent Broca’s or Wernicke’s aphasia.
Stewart et al.84 demonstrated in normal volunteers that magnetic stimulation of two different, nonoverlapping inferior frontal sites could result in speech arrest. Stimulation of the more posterior site was accompanied by mentalis muscle activity; stimulation of the more anterior site was not. The anterior, nonmotor site was more clearly lateralized to the left hemisphere but was also more uncomfortable and more difficult to activate in all subjects. The finding of two separate sites for TMS speech interference has been replicated,5 but it is not yet clear whether the anterior site represents interference with language as opposed to simply motor speech.
A large number of studies have in fact demonstrated TMS effects on language function. Most of these effects have been subtle, however, consisting of group changes in reaction time rather than accuracy of performance. Picture naming and a variety of other language tasks can be both delayed and facilitated by rapid rTMS over left posterior temporal, left superior temporal, dorsal frontal, and inferior frontal lobes.9,28,63,76,77,83,92 It is interesting that some of the facilitatory effects can be obtained from stimulation of the nondominant hemisphere65,100 and can be demonstrated in aphasic patients.64
In the present era, lateralization of memory function probably has greater practical importance than lateralization of speech. A few TMS studies have shown interference with verbal memory by TMS over the temporal lobe.29,40,69 However, the hippocampus represents a daunting target for TMS. Focal stimulation of such deep structures without overstimulation of overlying cortex remains a technical challenge. The granular cortex of the prefrontal lobe is now known to be intimately involved in both working memory and encoding of novel stimuli and represents a far more accessible target. Several reports have described interference or facilitation of episodic memory encoding by TMS over dorsolateral prefrontal cortex. In general, the results are consistent with classic models of hemispheric specialization: Verbal encoding is disrupted by stimulation over the left prefrontal region, and nonverbal encoding is impaired by right prefrontal stimulation.9,33,36,49,63,77,80 Virtually all of these studies have been carried out in normal volunteers, for
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which the required intensity of stimulation is generally quite tolerable.
New, noninvasive techniques for determining the lateralization of memory function remain desirable for epilepsy practice and research. Recent approaches to memory testing with TMS show promise of eventual clinical application.
Summary and Conclusions
Most of our understanding about the mechanisms of TMS comes from studies of the motor cortex, where the major site of activation appears to be myelinated axons of cortical interneurons, aligned parallel to the cortical surface. TMS findings in different epileptic phenotypes are complex and sometimes contradictory, with the most consistent being decreased MT and ICI in some forms of IGE. Such studies are complicated by time of testing in relation to seizures, the possibility that patients with similar clinical conditions may have different underlying disorders, and the independent effects of AEDs. The AED effects, while occasionally inconsistent, are sufficiently reliable that they can be helpful in exploring AED mechanisms of action and tracking central nervous system changes over time. Application of TMS to mapping language and memory is promising, but not yet sufficiently robust and accurate for general clinical application. Preliminary reports of TMS efficacy in activating and suppressing seizures have yet to be substantiated in clinical trials.
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