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1. Noninvasive Brain Stimulation
Noninvasive magnetic and electrical stimulation of cerebral cortex is an evolving field that includes a range of diagnostic and therapeutic protocols for conduction or induction of electrical current in the brain. Among clinical applications for these methods are electrical brain stimulation for intraoperative monitoring of the motor pathways, extraoperative assessment and mapping of motor and language cortical regions, and several techniques aimed at measuring or modifying cortical excitability. While the most mature and most widely tested techniques in this field are transcranial electrical stimulation (TES), transcranial direct current stimulation (tDCS), and transcranial magnetic stimulation (TMS), other protocols, such as transcranial alternating current stimulation, transcranial random noise stimulation, and low-field magnetic stimulation, are also in early testing phases. In this chapter, we focus on TES, tDCS, and TMS as examples of noninvasive brain stimulation techniques that are already in wide clinical and experimental use.
TES and TMS both rely on pulsatile stimulation with electrical current intensities sufficient to trigger action potentials within the stimulated cortical volume. In practical applications, TES, especially if delivered in brief trains of stimulus pulses, is most useful for intraoperative monitoring in an anesthetized patient , while single-pulse TMS is more useful for extraoperative diagnostic motor evoked potential (MEP) studies in awake subjects, as well as for research applications aimed at establishing and mapping causal brain–behavior relations in non-motor cortical areas. tDCS and TMS, particularly if delivered in repetitive trains (repetitive TMS [rTMS]), also share a capacity to modulate cortical excitability for prolonged periods and thus are either in active clinical use or in advanced stages of clinical trials for common neurological and psychiatric disorders such as major depression and other psychiatric disorders, post-stroke motor and language deficits, and epilepsy [2,3,4].
2. TES and Insights from Electrical Motor Cortex Stimulation
Applied to the motor cortex, a single electrical stimulus can produce multiple volleys within the descending motor tracts that can be recorded with epidural electrodes placed over the spinal cord. Studies in experimental animals have elucidated the mechanisms underlying this  (Fig. 28.1). The first volley reflects direct stimulation of the pyramidal neuron axons that leave cerebral cortex and make up the corticobulbar and corticospinal tracts; this volley has been labeled the D-wave (“D” for “Direct”). Subsequent volleys, labeled I-waves (“I” for “Indirect”), derive from activation of the pyramidal neurons via excitatory synaptic input from other cortical neurons that were themselves activated, either directly or indirectly, by the externally applied stimulus. The delay from that stimulus to an I-wave reflects the time required for the intervening synaptic transmission(s), and thus is the sum of an integral number of cortical synaptic transmission delays. This accounts for the relatively consistent intervals between the D-wave and the first I-wave and between successive I-waves (e.g., see Fig. 28.1A). Since the production of I-waves depends on cortical synaptic transmission, factors that depress cortical synaptic function will reduce or eliminate the I-waves (see Fig. 28.1B). Most anesthetic agents depress cortical synaptic function, and will reduce or eliminate the I-waves [6,7,8] (Fig. 28.2).
In TES, stimulating current passes between an anode and a cathode that are at different locations on the scalp. With electrical stimulation of peripheral nerves, the action potential volleys are predominantly initiated under the cathode , whereas with TES the D-waves are predominantly initiated under the anode  (Fig. 28.3). Why is this? Outward transmembrane current depolarizes the neuronal membrane and is excitatory, whereas inward transmembrane current hyperpolarizes the neuronal membrane and is inhibitory. When stimulating peripheral nerve, the outward transmembrane current depolarizes the axonal membrane and initiates the action potential under the cathode (Fig. 28.4). When stimulating cerebral cortex, it is the action potentials that are propagating in the corticofugal motor tracts that generate the MEPs, and these action potentials are initiated at the axon hillocks of the cortical pyramidal neurons. Current flows under the scalp anode result in inward (inhibitory) transmembrane current in the superficial portion of the pyramidal neuron but outward (excitatory) current at the axon hillock  (Fig. 28.5), which produces the D-waves that can be recorded with epidural electrodes over the spinal cord. Current flows under the TES cathode are opposite in direction; they may excite the superficial portion of the pyramidal neuron as well as cortical interneurons, but the hyperpolarization at the axon hillock may block the initiation or propagation of action potentials along the motor tracts that would give rise to D-waves. Under surgical anesthesia, when I-waves are largely suppressed and the MEPs are predominantly generated by D-waves, the myogenic MEPs elicited by TES are predominantly recorded from muscles contralateral to the TES anode (Fig. 28.6).
While I-waves are mediated by cortical synaptic activity, D-waves can be elicited by stimulation of corticospinal tract axons within the white matter (see Fig. 28.1A, 28.1C). As the TES stimulus intensity is increased, intraparenchymal current densities capable of stimulating these axons are produced farther and farther away from the surface of the head, and may be able to stimulate them as far caudally as the medulla . During intraoperative monitoring of the brainstem and of the corticospinal tracts within the cerebrum, this could prevent recognition of surgery-related motor tract compromise if the motor tracts were stimulated caudal to that dysfunction.
Due to the relatively high impedance of the skull, high-intensity electrical stimuli (hundreds of volts, and currents of the order of magnitude of 100 mA) must be applied to the surface of the scalp in order to effectively stimulate brain tissue. These current levels powerfully stimulate pain fibers in the scalp. Thus, while TES has been performed on conscious subjects as part of a research protocol , it is not practical for use as a neurodiagnostic tool in awake patients. It is, however, the procedure of choice for eliciting MEPs for intraoperative monitoring .
In awake subjects TES (as well as TMS, see below) will produce a series of volleys, derived from D-waves and I-waves, in the corticospinal tract. The postsynaptic potentials that these produce will summate to bring the lower motor neurons to threshold, causing muscle contractions and allowing the recording of myogenic MEPs, also called M-waves. Under anesthesia, a single TES pulse will most likely produce a single D-wave, which may not be sufficient to fire the anterior horn cells and produce reliable M-waves. Multiple stimuli will produce multiple D-waves; these will produce multiple excitatory postsynaptic potentials that will summate in the lower motor neurons, causing them to fire (Fig. 28.7) and producing muscle contractions (Fig. 28.8, right side). When stimulated repetitively, cerebral cortex may also produce I-waves , providing further excitatory drive to the anterior horn cells (see Fig. 28.8, left side). The development of stimulators capable of delivering brief trains of high-intensity electrical stimuli with short inter-stimulus intervals (ISIs) has permitted the recording of myogenic MEPs suitable for intraoperative monitoring in most patients.
The repetition rate of the pulses within the train has a marked influence on the size of the M-wave, as demonstrated by a paired-pulse experiment  (Fig. 28.9). If the ISI is too short, pulses after the first may not effectively stimulate the corticospinal tract axons due to their refractory periods (note the falloff of both the M-waves and of the second D-waves, “D2,” at the shortest ISIs). If the interval between the pulses is too long, the excitatory postsynaptic potentials within the alpha motor neurons will decay during the intervals between successive pulses, losing the benefit of the temporal summation (note the falloff of the M-waves at the longest ISIs as well). ISIs of 2 to 3 msec are typically used for intraoperative MEP monitoring. As needed, multiple stimulation trains can also be delivered to enhance the MEP size .
Even with high-intensity, short-ISI pulse train TES, only a small fraction of the motor neuron pool fires each time an MEP is recorded—and it is a different subset of the motor neuron pool each time, similar to the situation with F-waves to peripheral nerve stimulation. Thus, even though the stimulus is unchanged, successive M-wave recordings may differ markedly in amplitude and wave shape (Fig. 28.10), just as F-waves do. Because of this variability, signal averaging should not be applied to M-waves. However, these myogenic signals are usually sufficiently large that averaging is not necessary. D-waves can also be monitored using electrodes placed near the spinal cord; they are smaller than M-waves and more consistent in amplitude and wave shape (Fig. 28.11), so it is appropriate to use signal averaging (usually with a small number of sweeps per average) when recording D-waves.
The difficulty of activating the anterior horn cells under surgical anesthesia, even with repetitive train stimulation, makes myogenic MEPs highly susceptible to anesthetic effects, more sensitive than the sensory evoked potentials that are also used for intraoperative monitoring (Fig. 28.12). The choice of the anesthetic regimen is particularly critical when M-waves are being monitored. Halogenated inhalational agents prominently suppress them, and are best avoided. Intravenous anesthetics such as propofol and ketamine also affect MEPs, but to a lesser extent. Opioids have only minor effects on MEPs. Nitrous oxide produces marked changes in MEPs, but myogenic MEPs can be successfully recorded using a “nitrous-narcotic” technique. Total intravenous anesthesia using propofol and opioid infusions is an optimal anesthetic regimen for monitoring myogenic TES-MEPs. Complete neuromuscular blockade must obviously be avoided. If partial neuromuscular blockade is used, it should be maintained with a continuous infusion of muscle relaxant titrated to maintain a consistent degree of neuromuscular blockade, rather than with intermittent bolus doses, since the latter could cause misleading fluctuations in the degree of neuromuscular blockade and thus in the MEPs .
The electrical stimuli for TES are most often delivered using paired corkscrew electrodes inserted into the scalp, though alternative configurations such as a distributed or “ring” cathode covering a large region of the head have also been used. Electrode pairs Fz (anode)/Cz (cathode), C1/C2, and C3/C4 (Fig. 28.13) are most often used. The Fz/Cz electrode pair predominantly stimulates the corticospinal tracts to the legs, while C3/C4 preferentially stimulates the corticospinal tracts to the arms; stimulation between C1 and C2 may produce MEPs in both upper and lower extremities (see Figs. 28.6, 28.10). TES between electrodes Fz and Cz will stimulate the corticospinal tracts to the legs bilaterally. If M-waves are being monitored, this will permit assessment of the motor pathways to both legs simultaneously. However, if D-waves recorded from the spinal cord are being monitored, simultaneous bilateral stimulation may prevent recognition of unilateral corticospinal tract compromise. Use of laterally displaced electrode pairs permits selective stimulation of the hemisphere under the anode (see Fig. 28.6).
3. Neuromodulation and Seizure Suppression by tDCS
In contrast to high-voltage/high-current pulsatile stimulation in TES, neuronal activity in cerebral cortex may also be modulated by low-amplitude (typically 1–2 mA) transcranial direct current (DC) delivered by scalp electrodes. tDCS is based on decades-old observations that neuronal firing is modulated by low-amplitude electrical DC  that is, in contrast to TES, beneath the threshold necessary to trigger cortical action potentials. Specifically, when applied at the pial surface or at the scalp, anodal DC facilitates neuronal firing whereas cathodal DC inhibits neuronal firing. The mechanisms by which anodal tDCS facilitates neuronal firing likely relate to depolarization of the axon hillock cell membrane, which occurs when the dendrites of a neuron are oriented toward the anode in a constant electric field (see Fig. 28.5). The reverse may occur with cathodal tDCS with the axon hillock becoming hyperpolarized, inhibiting neuronal firing. This mechanism is supported by in vitro studies in isolated brain slices where the direction of change in regional excitability, whether toward activation or depression, is dependent on the orientation of the axonal input into that area relative to the anodal or cathodal terminal of the DC field .
Notably, the change in cortical excitability outlasts the duration of a tDCS stimulus (typically 10–30 minutes), and enables tDCS applications as a neuromodulation tool in disorders where regional over-activation or under-activation of the cortex is part of the pathophysiology. The mechanisms by which tDCS produces lasting changes in cortical excitability are not fully understood, though preclinical data indicate involvement of both glutamatergic and GABAergic signaling [18,19].
The practical application of tDCS is simple: low-amplitude DC is administered via broad scalp electrodes (typically saline-saturated sponges) such that the cortical target is exposed to either anodal or cathodal DC beneath one of the electrodes, while one or more electrodes of the opposite polarity are positioned elsewhere on the head or on an extracephalic site such as the shoulder. In some indications, such in neuromodulation aimed to facilitate motor or expressive language recovery after stroke, paired anodal and cathodal tDCS administered to both sides of the head may be useful because, in patients with lateralized strokes, the facilitatory effect of anodal tDCS on the lesioned cortex and the inhibitory effect of cathodal tDCS over the homologous area in the unlesioned hemisphere may both be beneficial .
In epilepsy, the capacity of cathodal tDCS to reduce cortical excitability has prompted research into its antiepileptic potential . Clinical tDCS experience in epilepsy is limited, but published reports suggest a realistic role for tDCS in seizure suppression . In one randomized controlled study of adults with intractable epilepsy (N = 19) referable to malformations of cortical development, interictal epileptiform discharges on EEG were reduced for up to 30 days followed one 20-minute application of 1 mA cathodal tDCS over the seizure focus . In a pediatric controlled trial (N = 36), 1-mA cathodal tDCS for 20 minutes corresponded to a significant decrease in the EEG spike frequency for up to 48 hours after stimulation. Clinical seizure reduction in the active cohort of this cohort was small (~5%), but also statistically significantly different from control, and supports continued efforts to test whether multiple tDCS courses will result in a meaningful antiepileptic effect . Another small (N = 12) crossover controlled trial identified an antiepileptic effect with active (2-mA cathodal tDCS for 30 minutes) stimulation over the seizure focus in a cohort of patients with temporal lobe epilepsy with hippocampal sclerosis .
As with other noninvasive brain stimulation protocols, the incomplete efficacy of human tDCS trials underscores the value of preclinical studies, the results of which can help to optimize future clinical tDCS study designs. Some preclinical studies underscore the antiepileptic potential of tDCS and demonstrate increased seizure thresholds in focal electroshock and amygdala seizure kindling models [26,27], as well as a neuroprotective effect in a rat pup pilocarpine-induced status epilepticus model . In a more recent experiment, cathodal tDCS electrographic seizure suppression was seen within minutes of stimulation in a rat pentylenetetrazole status epilepticus model. Of translational relevance for plausible clinical tDCS application, cathodal tDCS in this experiment worked synergistically with lorazepam to suppress seizures . These data underscore an important direction for translational neuromodulation research toward systematic testing of combination drug and device therapy in epilepsy [18,19].
4. TMS: Technical Aspects
During TMS, high-intensity current pulses are passed through a coil that is held in close proximity to the patient’s head. The magnetic field produced by this coil passes through the skull without significant attenuation and induces rotatory currents within the patient’s brain that flow in the opposite direction to the current in the stimulating coil  (Fig. 28.14). In essence, this system functions as a transformer, with the brain parenchyma acting as the secondary coil. It is the current induced by the time-varying magnetic field within the brain that stimulates the neurons. Thus, TMS is a form of electrical brain stimulation, though the delivery of electromagnetic energy to the head is via a rapidly changing magnetic field pulse rather than by directly conducted currents. The advantage of TMS is that it does not activate scalp pain fibers as strongly as TES, and it is therefore useful for assessing central motor pathways in conscious subjects. TMS can also be applied to non-motor regions in the brain convexity. Depth penetration is limited, as the magnetic field strength decreases as a cube of the distance and is always maximal closer to the stimulation coil. Therefore, while relatively broad stimulation is possible with specialized H-coil TMS arrays , selective stimulation of deep brain structures is not possible.
Pyramidal tract axons are most effectively stimulated by radial currents, those flowing normal to the cortical surface (see Fig. 28.5). Depending on the position and orientation of the coil, the intraparenchymal currents induced by TMS may be largely tangential in orientation (see Fig. 28.14), preferentially stimulating horizontally coursing neurites within the cortical neuropil rather than the axon hillocks of pyramidal neurons (Fig. 28.15). Thus, when monitored by epidural spinal cord recordings, TMS often produces predominantly I-waves rather than D-waves [30,31] (Fig. 28.16). Since the I-waves are suppressed by surgical anesthesia (see Fig. 28.2), anesthesia may also markedly suppress the MEPs elicited by TMS. In addition, small changes in the position and orientation of the stimulating coil may produce dramatic changes in TMS-MEPs , and it is difficult to maintain the coil in the exact same position relative to the patient’s head during operations lasting several hours. In addition, the magnetic field-pulse induced by TMS can affect other equipment in the operating room, necessitating appropriate placement and shielding of equipment. For these practical considerations, TES (see above), rather than TMS, is the procedure of choice for eliciting MEPs for intraoperative monitoring .
With a circular TMS coil, the intraparenchymal current density is relatively consistent within the torus of brain tissue underlying the coil (see Fig. 28.14). To obtain more focal stimulation of cerebral cortex, a figure-of-eight coil or other noncircular coil geometries may be used to obtain a focally higher current density within a more restricted volume [33,34,35] (Fig. 28.17). During diagnostic TMS-MEP studies, maintenance of a mild degree of tension in the muscle group(s) from which the MEPs are being recorded can augment the MEPs and decrease their onset latencies, or cause previously absent MEPs to appear [12,36]. This is most likely due to the voluntary contraction maintaining the spinal motor neurons in a partially depolarized state .
Single-pulse TMS can elicit an immediate MEP but does not induce changes in cortical excitability lasting more than a few milliseconds after the stimulus. rTMS, in contrast, induces changes in cortical excitability that outlast the stimulation . Although the precise mechanisms by which rTMS alters cortical excitability are not completely understood, they resemble those of long-term-potentiation and long-term depression of excitatory synaptic strength that can be induced by high (≥10 Hz) or low (≤1 Hz) repetitive electrical stimulation of the cortex or hippocampus [38,39,40,41]. It is this capacity to produce a durable and focal change in cortical excitability that appears to be the basis of the therapeutic effect of rTMS, which is supported by favorable clinical trials in several prevalent neuropsychiatric diseases states such as major depression, chronic pain, and epilepsy [3,42,43].
5. TMS as a Diagnostic and Therapeutic Tool
In clinical applications, TMS is unique among the neurostimulation methods in its realistic roles as both a therapeutic intervention and a diagnostic tool. As diagnostic procedures, single-pulse TMS and paired-pulse TMS may be used to noninvasively map cortical function and to measure regional cortical excitability [44,45], as underscored by U.S. Food and Drug Administration (FDA) clearance of one device for this indication. In therapeutic applications, the capacity of rTMS to induce a lasting change in cortical excitability has been tested in several disease states, including epilepsy [46,47,48,49]. The 2008 FDA clearance of a first device and protocol for treatment of some patients with medication-resistant major depression as well as subsequent clearance of several rTMS devices via the FDA 510k (equivalence to previously approved technology) mechanism indicates acceptance of rTMS in the clinical setting.
In most common protocols, TMS is coupled with surface electromyelography (TMS-EMG) such that the motor cortex is stimulated and the magnitude of the evoked muscle contraction in a contralateral limb (typically a hand muscle) can be quantified by skin electrodes and the recording of an MEP . From the MEP, a number of measures can be derived to probe cortico-spinal excitability, and a number of them characterize cortical and intracortical excitation/inhibition balance. One is the threshold to muscle activation, or motor threshold (MT). The MT, obtained by single-pulse TMS, appears to reflect largely sodium channel–mediated membrane excitability in efferent pyramidal cells, and is increased by anticonvulsants, such as phenytoin and carbamazepine, that inhibit voltage-gated sodium channels. Additionally, paired-pulse TMS (Fig. 28.18) provides measures of γ-aminobutyric acid (GABA)-mediated cortico-cortical inhibition and glutamate-dependent cortico-cortical excitability. In the most common paired-pulse TMS protocols, a subthreshold conditioning stimulus is delivered before each succeeding TMS pulse [43,49]. Short ISIs (1–5 msec) lead to reduction of the MEP, and likely reflect GABAA receptor–mediated short-interval intracortical inhibition. Slightly longer ISIs (6–20 msec) augment the MEP, reflecting glutamate-mediated intracortical facilitation. Benzodiazepine (GABAA receptor agonist) anticonvulsants such as diazepam and lorazepam enhance short-interval intracortical inhibition and suppress intracortical facilitation . Still longer ISIs (50–300 msec) paired-pulse TMS-EMG protocols can also measure GABAB receptor–mediated long-interval intracortical inhibition, which is enhanced by the GABAB receptor agonist baclofen [51,52]. The extent of cortical inhibition may also be measured by the cortical silent period, a transient EMG silence observed when TMS is delivered to the motor cortex during an active motor contraction. The cortical silent period too appears mediated by GABA receptors, although the contributions of GABAA and GABAB receptors to the cortical silent period are less defined than for paired-pulse measures [50,53,54].
These single-pulse TMS and paired-pulse TMS measures appear useful in detecting abnormalities in the excitation:inhibition (E:I) ratio in patients with epilepsy. Although findings vary between studies, published reports where parameters derived from TMS-EMG in patients with epilepsy were compared to values obtained from nonepileptic controls indicate that either primary or compensatory abnormalities in the cortical E:I ratio can be measured by TMS. In particular, pathologic suppression of intracortical inhibition as detected by paired-pulse stimulation appears to be a common finding in patients with epilepsy.
Detection of abnormalities in cortical inhibition by TMS-EMG data suggests its possible utility in epilepsy but also underscores a limitation, as global cortical excitability must be inferred from stimulation of the motor cortex. However, this anatomic limitation may be overcome by coupling TMS and EEG (TMS-EEG) such that TMS-evoked surface potentials can be recorded with scalp electrodes and used to estimate regional excitability of the areas of cerebral cortex other than motor cortex [55,56]. As a number of TMS-EMG experiments show motor cortex abnormalities in patients with extra-motor and generalized epilepsies, further studies will be required to test whether interrogating focal cortical excitability outside of the motor cortex by TMS-EEG is of any greater clinical value than checking TMS-EMG measures [57,58,59,60].
6. TMS in Presurgical Functional Mapping
In presurgical motor cortex mapping, TMS, delivered by a figure-of-eight coil, is coupled with magnetic resonance imaging (MRI)-guided frameless stereotaxy to record the coil position over the stimulated cortex, while MEPs are recorded by skin surface electrodes from selected muscle groups (Fig. 28.19). The TMS operator, guided by the patient’s brain MRI, thus tests whether stimulation of a specified brain region evokes an MEP from a specific muscle. These data are then registered to the patient’s MRI to generate a precise motor map. TMS motor map spatial resolution approximates that which can be obtained by intraoperative cortical electrical stimulation and monitoring of the MEP . In addition to motor mapping, TMS offers a unique tool for mapping the language cortex .
For language mapping, rTMS in short (~1 sec) 5- to 10-Hz trains is delivered repetitively to potential cortical language areas while a subject performs a linguistic task such as object naming, and the operator then identifies regions where stimulation interrupts the task performance. As with motor maps, the cortical region where stimulation produced a language error is documented and forms the basis of a functional language map [63,64]. Although language lateralization by rTMS-induced speech arrest shows a fairly high concordance with the results of intra-carotid amytal (Wada) testing in epilepsy patients [65,66,67], caution is warranted when administering rTMS for cortical mapping of linguistic functions. Early reports indicated relatively poor rTMS sensitivity for determination of language dominance, as some studies reported difficulties in obtaining speech arrest in more than one third of all tested patients [66,68]. Even when rTMS parameters are adjusted to reliably induce speech arrest, rTMS showed a relatively poor prognostic value for postoperative language deficits. Compared to the Wada test, the results of rTMS-induced speech arrest more often favor the right hemisphere and match less often the postoperative outcome with respect to language deficits . This is most likely accounted for by the fact that speech arrest is obtained most easily over facial motor areas, where true aphasia is rarely observed . Speech arrest might thus not represent an optimal marker for language lateralization. In future studies, rTMS protocols will have to be adapted in order to target aspects of language other than speech production, if online rTMS is to become a useful tool in presurgical evaluation of epileptic patients [69,71]. Of special interest in this respect is a study on the susceptibility of Wernicke’s area to rTMS-induced language disruption (in a picture–word matching task) and the relationship to language lateralization in the same, healthy subjects as assessed through functional MRI [72,73].
7. Seizure Suppression by rTMS
Encouraging open-label trials show a potential for seizure reduction by rTMS when applied over the epileptogenic region, or even when applied in a neutral scalp location, such as over the vertex. The positive response of some patients to stimulation outside of the epileptogenic zone, and in one series a favorable response of patients with primary generalized seizures to rTMS [3,21], raises the possibility that the antiepileptic mechanism of rTMS is not just local suppression of intracortical excitability but rather a network effect, where excitability is modulated at sites distal to the locus of stimulation [74,75,76].
In contrast to the open-label data, placebo-controlled rTMS trials have yielded inconsistent results. The first trial, in patients with temporal lobe epilepsy, did not reveal an antiepileptic benefit . A second trial showed a significant reduction in seizures and improvement of the interictal electroencephalogram (EEG) in patients with intractable seizures attributable to cortical dysplasia . The third, which investigated rTMS in a mixed group of patients with either focal or primary generalized seizures, found that rTMS was no better than placebo for seizure reduction but that active treatment significantly reduced epileptiform abnormalities in the interictal EEG . However, the most recent large randomized, single-blinded controlled clinical trial (N = 60) reveals a substantial antiepileptic capacity. In subjects randomized to a 2-week high-intensity treatment group (90% resting motor threshold), 0.5-Hz rTMS over the epileptogenic focus showed an 80% reduction in mean seizure frequency along with decreased interictal EEG discharges as compared to the low-intensity (20% resting motor threshold) control group, with a mean seizure reduction of 2%. The antiepileptic effects were relatively long-lasting and maintained up to 2 months after treatment .
In some clinical circumstances, such as treatment of ongoing seizures, TMS-EEG can be applied in the ictal state to identify real-time EEG changes induced by rTMS. Here, TMS-EEG may be of use to detect either improvement or exacerbation of seizures—both potentially valuable findings in the clinical setting. In patients with frontal lobe epilepsy and frequent interictal EEG spikes, TMS-EEG can demonstrate relative shortening of bursts of epileptiform activity . In a small number of cases of epilepsia partialis continua, TMS-EEG has been used to detect seizure suppression as well as to exclude seizure exacerbation during rTMS . Encouragingly, seizure exacerbation by rTMS was not seen, while seizure suppression was detected in some instances. A representative EEG obtained from a patient with epilepsia partialis continua undergoing 1-Hz rTMS is shown in Figure 28.20. In realistic applications, similar techniques for real-time EEG during therapeutic rTMS may be of use to monitor for epileptiform activity when rTMS is administered to treat nonepileptic symptoms such as mood disorder, motor dysfunction, or chronic pain in seizure-prone patients, such as those with recent stroke, neurodegenerative disease, or underlying epilepsy.
8. Safety Concerns
Among the safety concerns when stimulating the brain are physical damage to brain tissue, triggering of seizures or creation of an epileptic focus, and persistent changes in brain functions such as memory. Neuronal damage due to toxic electrochemical and electrolytic reactions at the electrode–tissue interface are a concern with direct electrical brain stimulation, but not with noninvasive brain stimulation protocols. On the other hand, TES and tDCS can induce similar skin reactions on the skin and lead to burns due to edge effects at the border of the electrodes.
Energy delivery to brain tissue and tissue heating are also negligible with all three techniques. The total charge and total charge density produced in brain tissue are less than those produced by direct cortical stimulation and by electroconvulsive therapy. Even in the relatively high-voltage TES protocols, the amount of current conducted to the cortex is orders of magnitude less than those values that have been found to be thresholds for tissue damage in animal experiments using 50-Hz stimulus trains sustained for several hours [81,82,83]. The major concern is with neuronal damage due to excitotoxicity. However, TES should not be performed with stimulating electrodes over a skull breach or a metal plate in the skull, lest unusually high current levels reach the brain.
Yet stimulation levels that do not produce histological damage in these animal studies can nonetheless produce seizures . Seizures have occurred following both TES (Fig. 28.21) and TMS . MacDonald  reported five seizures in a series of 15,000 patients having intraoperative MEP monitoring using TES, though it is not clear that the TES itself caused the seizures. In rTMS, seizure risk has been estimated in two patient populations: patients with major depression and patients with epilepsy. In patients with major depression, without epilepsy, the risk of seizure is less than 1 in 30,000 treatment sessions or less than 1 in 1,000 persons with a Neuronetis Neurostar device, and approximately 6 in 5,000 with the Brainsway Deep TMS device .
In patients with epilepsy, the crude per-subject risk of a seizure in patients with epilepsy during single- and paired-pulse TMS is estimated at 1.7% and 1.8%, respectively, and it has not been associated with a long-term adverse outcome . Encouragingly, the risk of TMS-induced seizures is not appreciably higher in patients with epilepsy who receive rTMS. Pereira et al. [87a], in a recent meta-analysis, estimated the per-subject risk at 2.9% (CI 1.3–4.4%), which includes the risk estimated previously by Bae et al.  of approximately 0.5% per 1,000 rTMS stimuli (0.41± 0.08% mean weighted by stimulus number). Further, seizures during low-frequency rTMS appear to be identical to the patients’ habitual seizures , and thus the causal relationship between stimulation and the documented seizures could not be ascertained in all cases.
The safety of TMS has been the focus of a number of studies as well as several consensus conferences. Safety recommendations and precautions have been developed by panels of experts and endorsed by the International Federation of Clinical Neurophysiology. The most recent of these consensus conferences took place in 2008, and the conclusions are summarized by Rossi et al. . These include specific discussion of applications of the various forms of TMS in the population with epilepsy who are, by definition, seizure-prone. In general, the side effects of TMS in patients with epilepsy are mild and short-lived. They include headache and scalp pain that result from direct activation of the pericranial scalp muscles. However, in some instances, seizures have been induced by rTMS in patients with epilepsy.
Beyond seizures, the side effects associated with TES, TMS, and tDCS are mild and short-lived. With TES, high current levels are delivered to the scalp, which may cause strong contractions of the temporalis muscle and forceful jaw closure. In MacDonald’s study of 15,000 cases of intraoperative MEP monitoring using high-intensity pulse train TES , the most common adverse effect was mouth injury, with several tongue or lip lacerations and one case of mandibular fracture. The use of soft bite blocks can help to prevent these complications.
Transient headache is commonly reported following rTMS [85,89]. Higher stimulus intensities and frequencies worsen the headaches, but they typically respond to simple analgesics . rTMS can also alter mood in non-depressed subjects . However, rTMS has been reported to induce mania or a hypomanic state in some subjects .
The safety profile of tDCS is overall favorable. Skin irritation has been reported as a rare mild adverse event after tDCS [24,91]. However, a review of safety reports from trials of conventional tDCS settings (≤40 min, ≤4 mA, ≤7.2 Coulombs) did not identify any reports of a serious adverse event or an irreversible injury across >33,200 sessions and in 1,000 subjects with repeated tDCS sessions .
Additional safety concerns related to the high magnetic fields produced during TMS and rTMS, which are of the order of magnitude of 2 Tesla, are the possibility that metallic objects nearby will be moved. This could produce a dangerous projectile if an object of the proper shape (the worst would be a ring of approximately the same dimensions as the coil) were close to the coil. Forces on small objects, such as an aneurysm clips and titanium skull plates and screws, are miniscule and not of clinical concern [80,93,94]. Eddy currents in nearby conductors can produce heating during repetitive TMS; a scalp burn in a patient with a scalp electrode has been reported .
The high-intensity and rapidly varying magnetic field in TMS causes a transient deformation of the stimulating coil, producing an audible and at times loud click [96,97]. With rTMS, transient increases in the hearing threshold can occur ; if ear protection is not used, permanent hearing loss can even be possible under certain circumstances . In animal studies, the hearing loss could be prevented with earphones that blocked external noise , suggesting that it is a noise-induced hearing loss rather than the result of direct effects of the pulsed magnetic field on the inner ear or the auditory pathways. Therefore, subjects receiving repetitive TMS, and personnel administering it, should wear earphones [85,98].
Implanted electronics such as cochlear prostheses and deep brain stimulators are considered contraindications to the performance of both TES and TMS. However, TMS is well tolerated in patients with extracranial stimulators such as a vagal nerve stimulator.
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