Cortical threshold and excitability measurements

Clinical Neurophysiology of Motor Neuron Diseases Handbook of Clinical Neurophysiology, Vol. 4 A. Eisen (Ed.) q 2004 Elsevier B.V. All rights reserved

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CHAPTER 17

Cortical threshold and excitability measurements Ulf Ziemann* Department of Neurology, Johann Wolfgang Goethe University of Frankfurt, Schleusenweg 2-16, D-60528, Germany

This chapter provides a reference text on motor cortical excitability as measured by single and paired pulse transcranial magnetic stimulation (TMS). The focus is on methodology, physiological mechanisms and pathophysiology of the various measures. It is the aim of this chapter to help the reader in understanding why and how these measures might be applicable to the neurophysiological assessment of patients with motor neuron disease while a detailed pathophysiological account of these measures in motor neuron disease will not be given here but in the clinical chapters. 17.1. Single pulse measures 17.1.1. Motor threshold 17.1.1.1. Methodology Motor threshold (MT) should always be determined with the stimulating coil placed at the “hot spot”, i.e. the optimal position for eliciting motor responses in the target muscle. MT has been defined in various ways by different authors. According to the IFCN recommendation, MT is the minimum intensity that is sufficient to produce a small motor-evoked potential (MEP . 50 mV) in at least half of the trials in the resting (resting MT) or contracting (active MT) target muscle (Rossini et al., 1999). A slightly different approach determines the maximum stimulus intensity, which has a probability of zero to elicit an MEP in the target muscle (lower threshold) and the minimum stimulus intensity, which has a probability * Correspondence to: Ulf Ziemann, Department of Neurology, Johann Wolfgang Goethe University of Frankfurt, Schleusenweg 2-16, D-60528 Frankfurt am Main, Germany. E-mail address: [email protected] (U. Ziemann). Tel.: þ49-69-6301-5739; fax: þ49-69-6301-6842.

of one to elicit an MEP (upper threshold) (Mills and Nithi, 1997). Alternatively, MT can be defined as the x-axis intercept of the peak slope tangent of the MEP intensity curve (Carroll et al., 2001). Finally, MT was defined as the intensity that produces the halfmaximum MEP amplitude on a Boltzmann fit of the sigmoid MEP intensity curve (Kammer et al., 2001). It is not clear if any one of these protocols is superior to the others, but the method according to the IFCN recommendation is certainly the least time-consuming. Within-subject variability of MT is low so that longitudinal measurements are feasible (Ziemann et al., 1996c; Mills and Nithi, 1997; Carroll et al., 2001). In contrast, between-subject variability is high for largely unexplained reasons (Cicinelli et al., 1997; Mills and Nithi, 1997). Active MT is on average 25% lower than resting MT. Therefore, it is important to monitor complete voluntary muscle relaxation for measurements at muscle rest. This can be achieved by audiovisual feedback of the EMG at high gain (50 mV/Div) of the EMG recording device. Automatic trial rejection is a helpful tool when voluntary EMG activity contaminates the pre-stimulus EMG period (Kaelin-Lang and Cohen, 2000). 17.1.1.2. Physiology MT is lowest for hand muscles and higher for proximal muscles of the arm (Brouwer and Ashby, 1990; Macdonell et al., 1991; Chen et al., 1998), trunk and lower limb (Chen et al., 1998). Most likely, these differences reflect differences in the density of the corticomotoneuronal projection, which is highest for intrinsic hand muscles. MT of hand muscles was slightly lower for the dominant hand (Macdonell et al., 1991; Triggs et al., 1994) and the degree of this asymmetry correlated with inter-hand differences in finger tapping speed and performance in a peg-board dexterity test (Triggs et al., 1997). This suggests that the corticomotoneuronal representation of the dominant hand is more excitable compared with the

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non-dominant one. MT is lower when a monophasic current in the brain runs from posterior to anterior than in the opposite direction (Niehaus et al., 2000; Kammer et al., 2001). Furthermore, after normalization to the square root of the maximum stored energy of the magnetic stimulator, biphasic current waveforms are more effective than monophasic waveforms (Niehaus et al., 2000; Kammer et al., 2001). In the case of a biphasic current waveform, MT is lower if the first quartercycle of the cosine waveform is directed from anterior to posterior in the brain (Kammer et al., 2001). Most likely, the first quartercycle hyperpolarizes the axons, which are then depolarized by the following halfcycle. These properties are the same as in magnetic stimulation of a peripheral nerve preparation (Maccabee et al., 1998). This suggests that MT reflects the excitability of axons in the motor cortex. Which are the axons directly excited by TMS? At threshold, TMS with the monophasic current in the brain directed from posterior to anterior does not activate corticomotoneuronal axons directly (Di Lazzaro et al., 1998a). In contrast, it is most likely that horizontally oriented cortico-cortical or thalamo-cortical axons, which run in the deep cortical layers or at the cortical – subcortical border, are directly excited by this form of TMS (Amassian et al., 1987; Epstein et al., 1990). Axon excitability is regulated mainly by voltagegated sodium channels (Hodgkin and Huxley, 1952). Consequently, voltage-gated sodium channel blocking drugs, such as carbamazepine, phenytoin or lamotrigine, elevate MT (Mavroudakis et al., 1994; Ziemann et al., 1996c; Chen et al., 1997; Boroojerdi et al., 2001). This effect correlates with the drug serum level (Chen et al., 1997). In contrast, a single dose of neurotransmitter (gamma-amino butyric acid (GABA), glutamate, dopamine (DA), serotonin (5-HT), norepinephrine (NE), acetylcholine) modulating drugs does not affect MT (Ziemann et al., 1995, 1996a –c, 1997, 1998a; Inghilleri et al., 1996; Liepert et al., 1997; Mavroudakis et al., 1997; Werhahn et al., 1998, 1999; Schwenkreis et al., 1999, 2000; Boroojerdi et al., 2001; Liepert et al., 2001; Plewnia et al., 2001; Sohn et al., 2001; Ilic et al., 2002a, 2003; Korchounov et al., 2003). These findings strongly suggest that MT reflects primarily ion-channel dependent excitability of axons, which are directly excited by TMS in motor cortex. However, recent findings provided some indirect evidence that neurotransmission through non-N-methyl- D -aspartate

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(NMDA) glutamate receptors, such as the AMPA receptor, may also influence MT (Di Lazzaro et al., 2003). This may be expected because the axons directly excited by TMS connect to the population of corticomotoneuronal cells via glutamatergic synapses. Finally, MT does not correlate with TMS excitation thresholds of other cortical areas, such as the phosphene threshold of the visual cortex (Stewart et al., 2001). Therefore, the measurement of MT cannot be used to make predictions about excitability of other areas of the brain. 17.1.1.3. Pathophysiology The main causes of a pathological increase in MT are: (1) significant axonal damage of the corticomotoneuronal tract; (2) treatment or intoxication with voltage-gated sodium channel blocking drugs. In contrast, a pathological decrease of MT may occur in certain states of cortical hyperexcitability, such as in certain forms of epilepsy, or in glutamate-driven excitotoxicity. 17.1.2. Motor-evoked potential intensity curve 17.1.2.1. Methodology The MEP intensity curve describes the increase in MEP amplitude (or MEP area) with stimulus intensity. It is generally recommended to measure MEP amplitude peak-to-peak, i.e. as the amplitude difference between the two maximum peaks of opposite polarity, or as area under the MEP curve (Rossini et al., 1999). MEP amplitude should always be related to the amplitude of the maximum M-wave (Rossini et al., 1999). The maximum M-wave is obtained by supramaximal electrical stimulation of the peripheral nerve. The ratio of MEP amplitude over maximum M-wave allows better than the MEP amplitude per se to differentiate between lesions of the upper versus lower motoneurons. For small hand muscles and at maximum stimulus intensity, this ratio is typically 0.5– 0.6, but there is large inter-individual variability. As a consequence, only a ratio , 0.15 can be safely regarded as pathological (Hess et al., 1987b). Therefore, the MEP/M-wave ratio is rather insensitive to detect conduction failure along the corticomotoneuronal tract. This can be improved by the recently developed triple-stimulation technique (Magistris et al., 1998, 1999; see also Chapter 16 in this volume). Typically, the increase in MEP amplitude with stimulus intensity is non-linear (Hess et al., 1987a;

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Kiers et al., 1995) and described best by a sigmoid function (Devanne et al., 1997; Carroll et al., 2001; Kammer et al., 2001; Fig. 1). MEPðRÞ ¼ MEPmax =1 þ eðR0 2R=dRÞ : where MEPðRÞ is the MEP amplitude (or MEP area) at a given stimulus intensity ðRÞ, MEPmax the maximum MEP, dR the slope parameter of the function, and R0 is the stimulus intensity at which MEP size is 50% of MEPmax. Stimulus intensity can be set as a percentage of maximum stimulator output (MSO). This is recommended when the primary interest is to compare MEP elicited by the same physical stimulus intensities, for instance in longitudinal comparisons. The alternative possibility is to set stimulus intensity as a percentage of MT. This is a more biological protocol, which, for instance, would adjust for possible MT differences between groups. Voluntary contraction of the target muscle shifts the MEP intensity curve towards lower intensities (decrease in MT) and increases the slope (Devanne et al., 1997; Fig. 1). 17.1.2.2. Physiology The MEP intensity curve is steeper to intrinsic hand muscles compared with muscles of the proximal arm or lower limb (Brouwer and Ashby, 1990; Devanne et al., 1997; Chen et al., 1998; Fig. 1). This reflects the density of the corticomotoneuronal projection, which is highest to the hand muscles. In order to understand the physiology of the MEP intensity curve, it is necessary to recognize that TMS usually elicits a complex corticospinal volley, which results from

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direct (D-wave) and indirect (I-waves) activation of the corticomotoneuronal cells (Amassian et al., 1987; Day et al., 1989; Di Lazzaro et al., 1998a). Near threshold, the corticospinal volley typically consists of a sole I1-wave while at higher intensity later I-waves are also recruited, which follow the I1-wave at intervals of approximately 1.5 ms (Di Lazzaro et al., 1998a). Therefore, the steepest part and the plateau of the MEP intensity curve are dominated by late I-waves. It is not entirely clear how the late I-waves are being generated but much evidence is in favor of the idea that the late I-waves originate through a chain of excitatory interneurons projecting onto the corticomotoneuronal cells (Amassian et al., 1987; Ziemann and Rothwell, 2000). If so, MEP amplitude should be influenced by neurotransmitters, which control the excitability of this neural circuitry. Indeed, the amplitude of the late I-waves, and in turn MEP amplitude, is easily modified by drugs that affect neurotransmission in the cortex. Anesthetics, which enhance neurotransmission through the GABAA receptor, lead to suppression of the late I-waves (Hicks et al., 1992). Similarly, antiepileptic drugs with agonistic properties at the GABAA receptor (Inghilleri et al., 1996; Di Lazzaro et al., 2000a; Boroojerdi et al., 2001) and the NE antagonist guanfacine (Korchounov et al., 2003) decrease MEP amplitude. In contrast, the indirect AMPA receptor agonist ketamine (Di Lazzaro et al., 2003), NE agonists (Boroojerdi et al., 2001; Plewnia et al., 2001, 2002; Ilic et al., 2003) and the 5-HT reuptake inhibitor sertraline (Ilic et al., 2002a) increase MEP

Fig. 1. MEP intensity curves from two different healthy subjects in the first dorsal interosseus (FDI, right panel) and tibialis anterior (TA, left panel) during muscle rest (black squares) and during 10% (open circles), 20% (black circles) and 40% (crosses) of maximum voluntary contraction. Note the sigmoid increase in MEP amplitude ( y-axis, in mV s) with stimulus intensity (x-axis, in percentage of MSO). Note further the shift towards lower intensities with voluntary contraction and the steeper intensity curve in the FDI compared with the TA (with permission, from Devanne et al., 1997).

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amplitude. Most of these changes in MEP amplitude occur without changes in MT. This confirms that the physiology of MT and MEP amplitude (steep part of the MEP intensity curve and MEP plateau) is different. MEP amplitude is a rather sensitive measure to detect changes in neurotransmission and may be the only TMS measure that is affected by a drug under study, as shown for the novel antiepileptic drug levetiracetam (Sohn et al., 2001). 17.1.2.3. Pathophysiology The main reasons for a pathological decrease in MEP amplitude (or better, MEP/M wave ratio) are: (1) increased phase cancellation due to increased temporal dispersion of the descending corticomotoneuronal volley in demyelinating diseases of the central nervous system; (2) complete or incomplete conduction failure of the corticomotoneuronal tract due to demyelinating or axonal lesion; (3) severe depression of axon or synaptic excitability due to treatment or intoxication with voltage-gated sodium channel blocking drugs or agonists at the GABA receptor. In contrast, a pathological increase in MEP amplitude (MEP intensity curve) may occur in certain states of motor cortical hyperexcitability, such as in glutamate-driven excitotoxicity. 17.1.3. Motor-evoked potential mapping 17.1.3.1. Methodology An MEP map is the area on the scalp surface from which MEP can be elicited in a given target muscle. Focal TMS is delivered to multiple scalp sites by moving the stimulating coil, ideally a small eightshaped coil, along a grid. MEP mapping is a timeconsuming procedure that is not suitable for the clinical-neurophysiological routine setting. The coordinates of the grid should be referenced relative to standard landmarks, such as Cz according to the International 10 –20 electrode system (Jasper, 1958). Mapping can be done either along grids with coordinates 0.5 – 2 cm apart (Cartesian co-ordinate system) (Brasil-Neto et al., 1992; Wassermann et al., 1992; Classen et al., 1998), or grids with co-ordinates based on a latitude – longitude system, which form a more general frame of reference by taking into account head curvature (Wilson et al., 1993b; Thickbroom et al., 1998). MEP mapping guided by online co-registered MRI shows significantly improved precision of coil placement compared

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with conventional “blind” MEP mapping (Gugino et al., 2001). Mapping should be performed with a moderate stimulation intensity of 110 – 120% MT determined at the optimal site for eliciting an MEP in the target muscle. To account for the considerable trial-to-trial variability in MEP amplitude, which even increases with distance from the optimal site (Brasil-Neto et al., 1992), about 10 trials need to be applied to a given co-ordinate (Classen et al., 1998). It is recommended to start MEP mapping at the optimal site (hot spot) and to continue until effective stimulation sites are completely surrounded by noneffective sites. A non-effective stimulation site is always defined by a threshold criterion, for example no MEP . 10 mV in any of the trials at this site (Wassermann et al., 1992). A restriction to those sites in proximity to the optimal site may degrade map accuracy considerably (Classen et al., 1998). With an optimal mapping technique, good reliability (Mortifee et al., 1994) and a spatial resolution in the order of 0.5 cm (Brasil-Neto et al., 1992) can be achieved. MEP maps can be characterized by three properties: extent, location and shape. Map extent is expressed as the number of effective stimulation sites (Wassermann et al., 1992; Classen et al., 1998). Map extent is a direct function of the excitability of the stimulated corticomotoneuronal cells, as shown by a close correlation between map extent and the slope of the MEP intensity curve (Ridding and Rothwell, 1997). Current spread and the distance of the stimulated corticomotoneuronal cells from the scalp surface contribute to map extent, i.e. the map is always larger than the actual extent of the population of stimulated corticomotoneuronal cells (Thickbroom et al., 1998). One way to overcome this overestimation of map extent is to measure MEP intensity curves from several stimulation sites to determine stimulator intensities that elicit half-maximal MEP (Thielscher and Kammer, 2002). Based on these stimulator intensities, the field distribution on the individual cortical surface can be calculated as rendered from anatomical MR data (Ilmoniemi et al., 1999; Thielscher and Kammer, 2002). The region on the cortical surface in which the different stimulation sites produce a minimal variance of the electrical field strength is the most likely stimulation site on the cortex. For a hand muscle, it was located consistently at the lateral part of the hand knob of the precentral gyrus (Thielscher and Kammer, 2002). Comparisons of model calculations with the solutions obtained in

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this manner reveal that the stimulated area of the motor cortex innervating the target muscle is substantially smaller than the extent of the electric field induced by the coil (Thielscher and Kammer, 2002). Map location is often expressed as the site of the maximum MEP in the map, but it is better to use the center of gravity (COG), which is the sum of all map co-ordinates weighted by MEP amplitude at that co-ordinates divided by the sum of all MEP amplitudes (map volume) (Wassermann et al., 1992). The weight at any scalp co-ordinate can be interpreted as the proportion of the map volume contributed by that co-ordinate. The COG corresponds to the scalp location at which the greatest number of the most excitable corticomotoneuronal cells can be stimulated (Classen et al., 1998; Thickbroom et al., 1998). MEP map shape is a descriptive property. Maps are usually ellipsoid with the long axis parallel to the direction of the induced current in the brain (Wilson et al., 1996). Voluntary contraction of the target muscle results in a slight medial shift of the MEP map when compared with the rest (Wilson et al., 1995). MEP mapping has confirmed a rough somatotopical order of motor representations in human motor cortex with the face, hand, upper arm, neck /trunk and leg MEP located along a lateral-to-medial axis (Wassermann et al., 1992; Metman et al., 1993; Thompson et al., 1997; Classen et al., 1998; Krings et al., 1998). Maps for different muscles of the hand and arm overlap, but representations of hand muscles are located slightly more laterally than representations of arm muscles (Wassermann et al., 1992). MEP mapping was referred to the underlying anatomy (Levy et al., 1991; Wang et al., 1994; Krings et al., 1997, 1998; Singh et al., 1997), and multi-modal approaches combined the results of MEP mapping with functional activation studies using positron emission tomography (Wassermann et al., 1996; Classen et al., 1998) and functional magnetic resonance imaging (Krings et al., 1997; Bastings et al., 1998; Terao et al., 1998; Boroojerdi et al., 1999). These studies showed consistently that the MEP maps project onto the precentral gyrus and largely overlap with the functional activation areas. MEP map reorganization in neurological disease is demonstrated best by changes in map location while changes in map extent are confounded by corticospinal excitability (Ridding and Rothwell, 1997).

17.1.3.2. Pathophysiology Changes in MEP map location very likely indicate true reorganization of motor cortical representations. This may be a consequence of many different causes, such as motor learning in health and disease, or substitution of function after lesion of the corticomotoneuronal system. 17.1.4. Cortical silent period 17.1.4.1. Methodology The cortical silent period (CSP) is defined as interruption of tonic voluntary EMG activity in the target muscle contralateral to the stimulated motor cortex, which is usually preceded by a MEP (Cantello et al., 1992; Wilson et al., 1993a; Fig. 2). It is recommended to define CSP onset as the time of MEP onset. Defining CSP onset as the time of MEP offset is discouraged to eliminate variability of MEP duration as a confounding factor of CSP onset and duration. CSP offset is defined as the resumption of sustained voluntary EMG activity, and CSP duration is the difference between CSP offset and onset. Automatic determination of CSP duration is possible by various analytical and statistical procedures, which compare the post-stimulus EMG with the pre-stimulus EMG (Nilsson et al., 1997; Garvey et al., 2001; Daskalakis et al., 2003). The CSP is longest in the intrinsic hand muscles where it may easily exceed 200 ms (Cantello et al., 1992; Fig. 2). CSP duration correlates roughly linearly with stimulus intensity (Cantello et al., 1992; Haug et al., 1992; Inghilleri et al., 1993; Triggs et al., 1993; Wilson et al., 1993a; Fig. 2). Stimulus intensity should be related to CSP threshold, not to MEP threshold as MEP and CSP may be differentially affected by disease (Chistyakov et al., 2001). CSP threshold was defined as the minimum intensity that produces a CSP . 50 ms in three consecutive trials in a hand muscle (Chistyakov et al., 2001). The level of muscle contraction either does not affect CSP duration (Haug et al., 1992; Triggs et al., 1992; Inghilleri et al., 1993; Roick et al., 1993), or the CSP shortens slightly with increasing contraction (Cantello et al., 1992; Wilson et al., 1993a; Mathis et al., 1998). CSP duration may be affected by the specifics of the motor instruction, e.g. to prepare for contraction, or to maintain isotonic versus isometric contraction (Mathis et al., 1998, 1999; Hoshiyama and Kakigi, 1999). This indicates that there is a significant contribution of motor attention to the

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Fig. 2. Increase in CSP duration with stimulus intensity (given as percentage of MSO above the CSP threshold) in the abductor pollicis brevis muscle of a healthy subject whilst maintaining 50% of maximum voluntary contraction. In each diagram, the EMG was single-trial rectified and averaged over 20 trials. TMS is applied at 100 ms into the sweep. The MEP preceding the CSP is truncated. CSP onset was set to MEP onset, CSP offset was determined automatically according to the protocol described by Garvey et al. (2001). In each diagram, filled circles denote CSP onset and offset, and CSP duration is indicated (in ms) above each trace.

CSP duration. Between-subject variability is high, while the within-subject inter-hemispheric difference between homologous muscles is low (Cicinelli et al., 1997; Fritz et al., 1997). 17.1.4.2. Physiology The late part of the CSP originates mainly or exclusively at the level of the motor cortex while the early part is mainly due to inhibition of the spinal alpha-motoneuron (Fuhr et al., 1991; Cantello et al., 1992; Inghilleri et al., 1993; Ziemann et al., 1993; Davey et al., 1994; Chen et al., 1999). During the late part of the CSP, the excitability of the spinal alphamotoneurons has fully recovered (Fuhr et al., 1991;

Inghilleri et al., 1993; Ziemann et al., 1993). The CSP threshold is usually below active MT, which strongly suggests that the CSP does not depend on activation of the corticomotoneuronal system (Davey et al., 1994). The usual difference of 25% between resting and active MT disappears during the CSP, supporting the idea that the CSP may be explained by a removal of central voluntary motor drive from the corticomotoneuronal system (Tergau et al., 1999). Alternatively, but not mutually exclusively, the duration of the CSP may be conceived as a measure of motor cortical inhibition (Hallett, 1995). The duration of the CSP in hand muscles is similar to the duration of a long-lasting inhibitory post-synaptic potential (IPSP)

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in slice preparations, which is mediated through the GABAB receptor (Connors et al., 1988; Avoli et al., 1997). Whether the CSP is a GABAB receptormediated cortical inhibition is currently uncertain. A single oral dose of baclofen, a GABAB receptor agonist, did not lengthen the CSP in healthy subjects (Inghilleri et al., 1996; Ziemann et al., 1996c). However, the applied dosages were probably too low to result in effective drug concentrations across the blood – brain barrier. One patient with generalized dystonia who was treated with incremental doses of intrathecal baclofen showed a significant lengthening of the CSP starting at a dose of 1.000 mg per day (Siebner et al., 1998). One problem with this study is that a contribution by changes in spinal excitability was not ruled out. The GABA reuptake inhibitor tiagabine also resulted in a significant increase of CSP duration, which indirectly supports the hypothesis that the CSP is mediated through the GABAB receptor (Werhahn et al., 1999). Neuromodulators may also influence CSP duration. In particular, levodopa and DA receptor agonists lengthen the CSP (Priori et al., 1994). In summary, it is currently thought that the CSP reflects removal of voluntary motor drive from the corticomotoneuronal system and/or a long-lasting cortical inhibition, which most likely is mediated through the GABAB receptor. 17.1.4.3. Pathophysiology The usefulness of CSP measurements in neurological disease is at present not entirely clear. From the current physiological concepts (see Section 17.1.4.2), it may be expected that disorders of the GABA system lead to a pathological decrease in CSP duration. This was confirmed for the stiff-person syndrome, which is an autoimmune-mediated dysfunction of GABAergic cortical interneurons (Sandbrink et al., 2000), and in a patient with an intracortical ischemic infarct in motor cortex, which most likely affected predominantly inhibitory cortical interneurons (Schnitzler and Benecke, 1994). Another example is the absence of the CSP in a patient with generalized tetanus, which is compatible with a presynaptic block of GABA release from GABAergic interneurons in the motor cortex caused by the tetanus toxin (Warren et al., 1999). The shortened CSP in Parkinson’s disease may be related to a pathologically reduced post-synaptic sensitivity to GABA due to cortical DA depletion. In contrast, there is no direct evidence as yet for a role of excitatory

neurotransmitters, in particular glutamate, in the generation of the CSP. 17.1.5. Ipsilateral MEP 17.1.5.1. Methodology Ipsilateral corticospinal projections withdraw in an activity-dependent process during the first years of life (Eyre et al., 2001). In adults, ipsilateral MEP in hand muscles is elicited only in a fraction of subjects and only if strong voluntary contraction of the target muscle and high-stimulus intensity are used (Wassermann et al., 1991; Ziemann et al., 1999). For testing of the ipsilateral MEP, it is important to use a focal stimulating coil in order to exclude current spread to the other motor cortex. 17.1.5.2. Physiology Compared with contralateral MEPs, ipsilateral MEPs are much smaller, the onset latency is delayed by 5 –10 ms, and the optimal stimulation site is slightly more lateral and anterior (Wassermann et al., 1991; Ziemann et al., 1999). The ipsilateral MEP is mediated by either a weak residual uncrossed corticospinal tract (Eyre et al., 2001) or by an oligosynaptic cortico-reticulospinal projection (Ziemann et al., 1999). 17.1.5.3. Pathophysiology In the context of neurodegenerative disorders, the occurrence of an ipsilateral MEP in a resting hand muscle most likely indicates an enhanced response of a hyperexcitable or disinhibited motor cortex to an excitatory callosal input from the other (stimulated) motor cortex. This was suggested in patients with corticobasal ganglionic degeneration with an alien hand sign in whom an ipsilateral MEP was elicited specifically when the healthy or less affected motor cortex ipsilateral to the alien hand sign was stimulated (Valls-Sole et al., 2001). 17.2. Paired pulse measures 17.2.1. Long-interval intracortical facilitation and long-interval intracortical inhibition 17.2.1.1. Methodology Paired-pulse excitability at long inter-stimulus intervals (20 – 200 ms) refers to the modulating effects of a supra-threshold conditioning pulse on

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the amplitude of the test MEP elicited by the subsequent supra-threshold test pulse. Both pulses are given through the same stimulating coil, usually at the same stimulus intensity of 110 –150% of MT. A specialized set-up is necessary for testing these and all other paired-pulse measures (see below) because a standard single pulse magnetic stimulator requires several seconds for recharge and repetitive stimulators do not allow independent variation of the intensities of the conditioning and test pulse (Ziemann, 2002). Paired-pulse excitability at long inter-stimulus intervals can be performed either with the target muscle at rest or during tonic voluntary contraction. Typically, the effect of the conditioning pulse is facilitatory at inter-stimulus intervals of 20 – 40 ms (long-interval intracortical facilitation (LICF)), but inhibitory at intervals . 50 ms (longinterval intracortical inhibition (LICI)) (Claus et al., 1992; Valls-Sole et al., 1992). 17.2.1.2. Physiology Epidural recordings of the descending corticomotoneuronal volley from the spinal cord showed that LICF was associated with an increase in the number and amplitude of late I-waves while LICI was associated with a decrease (Kaneko et al., 1996; Nakamura et al., 1997; Chen et al., 1999). This indicates that LICF and LICI occur mainly through mechanisms at the level of the motor cortex. The inhibitory mechanisms responsible for the LICI are not the same as those underlying the CSP. This can be concluded from data in patients with idiopathic Parkinson’s disease who showed a dissociation of pathological findings with a decreased CSP duration but an increased LICI (Berardelli et al., 1996). LICI may be conceived as a measure of motor cortical responsiveness to a synchronized excitatory input by TMS during cortical inhibition produced by the conditioning pulse while the CSP reflects the interaction of this inhibition with tonic voluntary motor drive to the motor cortex. On the other hand, CSP duration and LICI are similarly modulated by pharmacological manipulation. The GABA reuptake inhibitor tiagabine increases CSP duration and LICI, which led to the conclusion that both CSP and LICI are influenced by neurotransmission through the GABAB receptor (Werhahn et al., 1999). This idea was substantiated by showing that shortinterval intracortical inhibition (SICI), a form of

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cortical inhibition, which is mediated through the GABAA receptor (see Section 17.2.2) is significantly reduced in the presence of LICI (Sanger et al., 2001, 2002). This supports pre-synaptic GABAB receptor-mediated auto inhibition, a classical concept of connectivity in cortical neuronal circuits (Deisz, 1999). 17.2.1.3. Pathophysiology LICF may offer the interesting possibility to detect exaggerated oscillatory activity in motor cortex. This was demonstrated for certain types of epilepsy (Brodtmann et al., 1999; Valzania et al., 1999). The frequency of these oscillatory rhythms differs between epilepsy syndromes and this may be utilized for diagnostic purposes (Brodtmann et al., 1999; Valzania et al., 1999). A pathological decrease in SICI most likely indicates an alteration of longlasting inhibitory mechanisms mediated through the GABAB receptor. Furthermore, detection of a differential involvement of GABAA and GABAB receptors may be possible, if SICI and LICI are studied in conjunction (see Sections 17.2.1.2 and 17.2.2) (Sanger et al., 2001; Sailer et al., 2002). A role of excitatory neurotransmitters in LICF and LICI has as yet not been demonstrated. 17.2.2. Short-interval intracortical inhibition and intracortical facilitation 17.2.2.1. Methodology SICI and intracortical facilitation (ICF) are tested at short inter-stimulus intervals (1 –30 ms) and refer to the modulating effects of a sub-threshold conditioning pulse on the amplitude of the test MEP elicited through the same stimulating coil by the subsequent suprathreshold test pulse (Kujirai et al., 1993; Ziemann et al., 1996d; Fig. 3). SICI occurs at inter-stimulus intervals of 1 –5 ms, ICF at intervals of 7– 20 ms (Kujirai et al., 1993; Ziemann et al., 1996d; Ziemann, 1999; Fig. 3). The intensity of the conditioning pulse is usually set to 80% of resting MT or 90% of active MT, and the intensity of the test pulse to produce a test MEP of about 1 mV in peak-to-peak amplitude (Kujirai et al., 1993; Ziemann et al., 1996d). This produces optimal SICI (Kujirai et al., 1993; Ziemann et al., 1996d). As a consequence, this protocol may result in a saturation of SICI so that it becomes insensitive to any increase in SICI evoked by experimental manipulation (“floor effect”). One solution to this problem is to measure

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Fig. 3. SICI and ICF: MEPs by a supra-threshold magnetic cortical test stimulus in relaxed first dorsal interosseous muscle are inhibited by a prior sub-threshold conditioning stimulus at short inter-stimulus intervals of 1 – 5 ms (SICI) and facilitated at longer intervals of 10– 15 ms (ICF). The left panel shows examples of EMG data from one healthy subject. The first trace shows absence of any MEP to the conditioning stimulus alone. The lower two records have two superimposed traces, the MEP to the test stimulus given alone, and the MEP to the test stimulus when given 3 ms (middle traces) or 2 ms (lower traces) after the conditioning stimulus. The larger MEP (dotted line) is the response to the test stimulus alone. It is dramatically suppressed at these two inter-stimulus intervals. Each trace is the average of 10 trials. The right panel shows the averaged group data of six subjects (means ^ SD). The conditioned MEP is given as a percentage of the test MEP ( y-axis) and expressed as a function of the inter-stimulus interval (x-axis) (with permission, from Kujirai et al., 1993).

a SICI intensity curve at a fixed inter-stimulus interval by varying the intensity of the conditioning stimulus (Ilic et al., 2002b). SICI and ICF are significantly reduced by even slight voluntary contraction (Ridding et al., 1995). Therefore, many studies of SICI and ICF were performed in the resting target muscle. However, this may be difficult to accomplish in patients who are unable to fully relax, like patients with movement disorders. In this case, it is preferable to study SICI and ICF during slight voluntary contraction (Berardelli et al., 1996; Rona et al., 1998). SICI and ICF are obtained most often in hand muscles, but can be measured similarly in many other muscles (Stokic et al., 1997; Chen et al., 1998; Hanajima et al., 1998b; Abbruzzese et al., 1999; Shimizu et al., 1999; Kobayashi et al., 2001). SICI decreases with age while ICF does not (Peinemann et al., 2001). SICI may be affected by personal trait such as the level of neuroticism (Wassermann et al., 2001). SICI and ICF measurements are time consuming and therefore not suitable for quick testing in the clinical-neurophysiological routing setting.

17.2.2.2. Physiology Epidural recordings of the descending corticomotoneuronal volley provided strong evidence that SICI and ICF originate through mechanisms at the level of the motor cortex (Nakamura et al., 1997; Di Lazzaro et al., 1998b). SICI was associated with a decrease in the number and amplitude of late I-waves while ICF was associated with an increase. SICI is independent of the direction of current flow in the cortex induced by the conditioning stimulus, whereas ICF is clearly expressed with a posterior – anterior current but absent with a lateromedial current (Ziemann et al., 1996d). In addition, SICI has a lower threshold than ICF (Ziemann et al., 1996d). These findings suggest that ICF is not simply a rebound facilitation but physiologically distinct from SICI (Ziemann et al., 1996d; Strafella and Paus, 2001). SICI is reduced in the presence of LICI (see Section 17.2.1), which points out that SICI and LICI are physiologically distinct forms of cortical inhibition (Sanger et al., 2001). Recent experiments suggest that the SICI consists of at least two physiologically distinct phases of inhibition, one at very short interstimulus intervals of around 1 ms, and another at

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intervals of around 2.5 ms (Fisher et al., 2002). The first phase has a lower threshold and is reduced by voluntary contraction of the target muscle to a lesser extent compared with the second phase (Fisher et al., 2002). In addition, SICI at 1 ms is associated with a reduction of the amplitude of magnetic D-, I1- and I3-waves whereas SICI at 3 –5 ms is associated with a reduction of I3-waves only (Hanajima et al., 2003). At 1 ms, resynchronization of the corticomotoneuronal volley due to relative refractoriness of motor cortico-cortical and corticomotoneuronal axons most likely causes the reduction in MEP amplitude while, at 3 ms, the selective inhibition of the I3-wave points to a true synaptic inhibition (Hanajima et al., 2003). The range of inter-stimulus intervals effective for I3wave suppression increases with the intensity of the conditioning stimulus and may reach up to 20 ms (Hanajima et al., 1998a). This range is the same as the typical duration of an IPSP mediated through the GABAA receptor in slice preparations (Connors et al., 1988; Avoli et al., 1997). This supports the early notion (Kujirai et al., 1993) that SICI at intervals $2.5 ms measures motor cortical inhibition mediated through the GABAA receptor. Neuropharmacological experiments provided further and more direct evidence in favor of this hypothesis by showing that a single loading dose of GABAA receptor agonists such as benzodiazepines leads to an increase in SICI (Ziemann et al., 1995, 1996b,c; Di Lazzaro et al., 2000a; Ilic et al., 2002b). GABAA receptor agonists also decrease ICF. This may be a consequence either due to a superimposition with the concomitantly increased SICI or may indicate that the neural circuits responsible for the ICF are by themselves under the control of GABAergic inhibition. In contrast, the GABA reuptake inhibitor tiagabine decreases SICI (Werhahn et al., 1999). This may be explained by activation of pre-synpatic GABAB autoreceptors located on GABAergic nerve terminals, which results in auto-inhibition. SICI is increased and ICF decreased by NMDA receptor blockers (Ziemann et al., 1998a; Schwenkreis et al., 1999). In addition, the glutamate antagonist riluzole leads to an increase in SICI and a decrease in ICF (Liepert et al., 1997; Schwenkreis et al., 2000). Finally, SICI and ICF are influenced by various neuromodulators, which indicates further that both measures reflect synaptic excitability. DA receptor agonists (Ziemann et al., 1996a, 1997) and the NE antagonist guanfacine (Korchounov et al., 2003) increase SICI. Conversely,

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the DA antagonist haloperidol (Ziemann et al., 1997) and NE agonists (Herwig et al., 2002; Ilic et al., 2003) decrease SICI. Guanfacine (Korchounov et al., 2003) and the selective 5-HT reuptake inhibitor sertraline (Ilic et al., 2002a) decrease ICF whereas haloperidol (Ziemann et al., 1997) and NE agonists (Boroojerdi et al., 2001; Plewnia et al., 2001, 2002; Herwig et al., 2002) increase ICF. In summary, the currently leading hypothesis is that SICI and ICF test the integrity and excitability of inhibitory and excitatory neuronal circuits in the motor cortex, which are under the control of various neurotransmitter and neuromodulator systems and in turn control the excitability of the population of corticomotoneuronal cells. 17.2.2.3. Pathophysiology Measurements of SICI and ICF are of interest whenever a disorder of GABA or glutamatedependent neuronal circuits in motor cortex is suspected. As a matter of fact, various pathogenetically even very different neurological disorders may show a deficient SICI, such as various forms of epilepsy, movement disorders like Parkinson’s disease or taskspecific dystonia, limb amputation, or cerebral ischemic stroke (for review, see Ziemann, 1999). Therefore, SICI and ICF appear as rather sensitive measures to indicate a process which has altered the balance between GABA and glutamate-dependent excitability in motor cortex, but the specificity towards a certain pathological mechanism is low. It is also evident from the list of diseases, which show a reduced SICI, that this may occur through altered afferent signaling to the motor cortex while the pathological process does not necessarily need to affect directly the motor cortex itself. 17.2.3. Short-interval intracortical facilitation 17.2.3.1. Methodology Short-interval intracortical facilitation (SICF) refers to the facilitatory effects of a sub-threshold second pulse on the amplitude of a test MEP elicited by a supra-threshold first stimulus given through the same stimulation coil 0.5 –6.0 ms earlier (Ziemann et al., 1998b). Alternatively, two pulses close to MT can be used (Tokimura et al., 1996). SICF occurs at discrete inter-stimulus intervals of 1.1– 1.5, 2.3– 2.9, and 4.1 –4.5 ms (Tokimura et al., 1996; Ziemann et al., 1998b; Chen and Garg, 2000). The intervals

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between successive facilitatory MEP peaks are approximately 1.5 ms, which is comparable to the intervals between successive I-waves (see Section 17.1.2.2). This led to the alternative term I-wave facilitation (Ziemann et al., 1998b). 17.2.3.2. Physiology Epidural recordings of the descending corticomotoneuronal volley at the spinal cord showed that SICF is associated with an increase in the number and amplitude of late I-waves, indicating that SICF originates through mechanisms at the level of the motor cortex (Di Lazzaro et al., 1999b). Drugs that increase neurotransmission through the GABAA receptor decrease SICF (Ziemann et al., 1998c; Ilic et al., 2002b) while voltage-gated sodium channel blocking drugs had no effect (Ziemann et al., 1998c). In addition, NE antagonists also decrease SICF (Korchounov et al., 2003) whereas NE agonists increase SICF (Ilic et al., 2003). Despite these pharmacological effects, complex single motor unit experiments led to the conclusion that SICF originates mainly through a non-synaptic interaction of the first and second magnetic stimulus along the excitatory late I-wave pathway by direct excitation of the axon initial segment of those interneurons by the subthreshold second stimulus, which were made hyperexcitable through EPSP by the supra-threshold first stimulus but did not generate an action potential (Hanajima et al., 2002; Ilic et al., 2002b). It is not entirely clear why SICF occurs at discrete interstimulus intervals but not at the intermediate intervals. One possibility is that the duration of the EPSP at the initial axon segment of the interneurons is very short. In sum, the currently leading hypothesis proposes that SICF reflects non-synaptic facilitatory paired-pulse interaction at the initial axon segments of those neural elements responsible for the generation of the late I-waves. 17.2.3.3. Pathophysiology SICF is a relatively novel measure that has as yet not been tested except in a few pathological conditions (Ho et al., 1999; Fitzgerald et al., 2003). Conceptually, SICF most likely tests the excitability of the “subliminal fringe” of interneurons and corticospinal neurons, which received EPSP by the first magnetic pulse but did not fire.

17.2.4. Inter-hemispheric inhibition 17.2.4.1. Methodology The hand areas of the two motor cortexes are connected, although sparsely, by callosal fibers (Gould et al., 1986; Rouiller et al., 1994). This pathway is a point-to-point excitatory projection between homologous motor cortical representations (Asanuma and Okuda, 1962) and can be demonstrated by single (Amassian and Cracco, 1987; Cracco et al., 1989) and paired-pulse protocols (Ugawa et al., 1993; Hanajima et al., 2001a) in humans. However, the inter-hemispheric facilitatory effects are weak and in the paired-pulse protocols inter-hemispheric inhibition (IHI) is usually the predominant effect. IHI is elicited by a supra-threshold conditioning magnetic stimulus applied to one motor cortex (conditioning cortex) and refers to an inhibition of the test MEP produced by the test magnetic stimulus over the other motor cortex (test cortex) (Ferbert et al., 1992; Netz et al., 1995; Hanajima et al., 2001a). The conditioning and test stimulus are delivered through two different focal stimulating coils, which are placed over the hand area of either motor cortex. Typically, IHI starts at inter-stimulus intervals of around 6 –8 ms and peaks at around 10 ms. Magnitude and duration of IHI increase with the intensity of the conditioning stimulus and may reach up to 50% and 30 ms, respectively (Ferbert et al., 1992; Hanajima et al., 2001a). 17.2.4.2. Physiology It is very likely that the IHI occurs at the level of the test motor cortex because epidural recordings of the descending corticospinal volley from the cervical spinal cord showed a reduction of the amplitude of late I-waves, in particular the I3-wave, by the conditioning stimulus when given at least 6 ms prior to the test stimulus (Di Lazzaro et al., 1999a). The minimum conduction time from one motor cortex to the opposite one through the corpus callosum is estimated in humans to be 9– 12 ms (Cracco et al., 1989). The shortest effective interstimulus interval of 6– 7 ms is compatible with a mediation of IHI through the corpus callosum because one has to take into account that the major inhibitory effect is on the I3-wave of the test stimulus (Di Lazzaro et al., 1999a; Hanajima et al., 2001a), which allows to add the delay between the I1- and I3-wave of approximately 3 ms to the

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shortest effective inter-stimulus interval in order to calculate callosal conduction time. Another strong piece of evidence in favor of an involvement of the corpus callosum is the finding that the IHI was absent in a patient with callosal agenesis (Rothwell et al., 1991). The predominantly inhibitory interhemispheric interaction despite a primarily excitatory callosal pathway is most likely explained by strong surround inhibition in the test motor cortex (Hanajima et al., 2001a). Experimental evidence in favor of this idea comes from the findings that the shortest effective intervals for IHI are longer by 2– 3 ms compared with those for inter-hemispheric facilitation, and that IHI can be produced without a preceding facilitation if the conditioned motor cortex is stimulated a little bit off from the point that would be homologous to the stimulation site in the test motor cortex (Hanajima et al., 2001a). In summary, it is currently thought that IHI tests surround inhibition in the test motor cortex, which is elicited by conditioning stimulation in the other motor cortex and mediated through the corpus callosum. 17.2.4.3. Pathophysiology In patients with intact callosal nerve conduction, IHI may serve as an elegant means of testing inhibitory interactions between adjacent motor representations in the test cortex as elicited by excitatory input from the conditioning motor cortex through the corpus callosum. This is of interest in neurological disorders where a deficiency of long-range corticocortical inhibitory mechanisms is suspected, such as in certain forms of epilepsy (Brown et al., 1996; Hanajima et al., 2001b). 17.2.5. Short-latency afferent inhibition 17.2.5.1. Methodology Cutaneous and proprioceptive afferent information from the body can influence motor cortex excitability at short latencies. Short-latency afferent inhibition (SLAI) is defined as MEP inhibition in a hand muscle produced by conditioning afferent stimulation at short inter-stimulus intervals of around 20 ms (Tokimura et al., 2000). The conditioning pulse consists of a weak electrical stimulus, which is given contralateral to the test motor cortex either to the median nerve (intensity: at M-wave threshold) or to the digital nerves of one finger (intensity: 2– 3 times perceptual threshold)

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(Tokimura et al., 2000). The magnitude of SLAI is approximately 50%, and effective inter-stimulus intervals range between 20 and 30 ( – 40) ms (Tokimura et al., 2000). It is useful to relate the tested inter-stimulus intervals to the individual N20 latency of the median nerve somatosensory-evoked cortical potential to account for body length-related differences in afferent conduction time. 17.2.5.2. Physiology SLAI occurs through mechanisms at the level of the motor cortex because epidural recordings of the descending corticospinal volley from the cervical spinal cord showed that the number and amplitude of late I-waves decreased by afferent stimulation (Tokimura et al., 2000). SLAI evoked by digital nerve input is somatotopically organized provided that low-stimulus intensity is used for the conditioning afferent pulse. In this case, SLAI is elicited only by stimulation of fingers contiguous to the EMG target muscle but not by stimulation of noncontiguous fingers (Tamburin et al., 2001). Muscarinic receptor blocking drugs lead to a reduction of SLAI (Di Lazzaro et al., 2000b). The effects of GABA or glutamate on SLAI have as yet not been tested. 17.2.5.3. Pathophysiology Measurement of SLAI may be useful in neurological disorders with degeneration of the central cholinergic system, such as patients with Alzheimer’s disease who show a pathological reduction of SLAI (Di Lazzaro et al., 2002). Another issue is the possibility of a disordered somatotopy of SLAI, as was demonstrated in patients with focal dystonias who showed SLAI irrespective of whether a contiguous or non-contiguous finger was stimulated (Tamburin et al., 2002). 17.3. Summary Excitability measures that have been found particularly useful in the TMS assessment of patients with suspected ALS are MT, duration of the CSP tested at various stimulus intensities (CSP intensity curve), and SICI (see the clinical chapters in Section IV of this volume for a detailed account). All of these measures may be reduced early in the course of the disease. A reduced MT points to glutamatedriven motor cortical hyperexcitability while

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reduced CSP duration and SICI most likely indicate downregulation of GABA-dependent cortical inhibition.

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