Central Motor Conduction Measurements

With TMS, it is possible to measure conduction in central motor pathways (central conduction time; CCT). CCT can be estimated by subtracting the conduction time in the peripheral nerves and neuromuscular junction from the total latency of MEPs measured at the onset of the initial deflection. Peripheral motor conduction time is currently measured through two methods: (1) F-wave recordings for the measurement of spine-to-muscle conduction time and (2) direct stimulation of the efferent roots and nerves over the spine. Magnetic stimulation on the posterior neck or the dorsal spine activates spinal roots at the level of the intervertebral foramen. Since the cervical roots are excited about 3 cm away from the anterior horn cell, magnetic stimulation of the roots is not an accurate measurement of CCT and may miss a proximal partial or complete block of impulse propagation. F-waves are usually elicited in the relaxed state by delivering supramaximal stimulation to the peripheral motor nerve at a site near the muscle under examination. The stimulus evokes an orthodromic volley in the motor nerves that produces a short latency response in the muscle (M wave). In addition, an antidromic volley travels back to the spinal cord, exciting the spinal motoneurons, and an efferent volley travels down to the motor nerve, causing a late excitation of the muscle known as the F-wave. Total peripheral motor conduction time can be estimated as: (F + M − 1)/2 (1 is the time due to the central delay at the level of α-motoneuron). Consequently, the CCT can be obtained as follows: MEP latency − (F + M − 1)/2. Using this method, the average CCT is about 6.4 ms for the thenar muscles and 13.2 ms for the tibialis anterior.

Motor Thresholds

Motor threshold (MT) represents the minimal stimulation intensity producing MEPs in the target muscle. This can be measured in resting (resting motor threshold, RMT) or contracting (active motor threshold, AMT) muscles. RMT is determined to the nearest 1% of the maximum stimulator output and is commonly defined as the minimal stimulus intensity required to produce MEPs of greater than 50 µV in at least 5 out of 10 consecutive trials. Here the MEP amplitudes are usually measured peak to peak. AMT is determined in the moderately active muscle (usually between 5% and 10% of the maximal voluntary contraction) and is defined as the minimum intensity that produces either MEPs of greater than 100 µV or silent period or MEPs of greater than 200 µV in at least 5 out of 10 consecutive trials. MT in resting muscle reflects the excitability of a central core of neurons, depending on the excitability of individual neurons and their local density. Since MT can be influenced by drugs that affect voltage-gated sodium and calcium channels, it may represent membrane excitability.

MEP Recruitment Curve

The recruitment curve, also known as the stimulus response curve or the input-output curve, is the growth of MEP size as a function of stimulus intensity. This underlying physiology is poorly understood but appears to involve neurons in addition to the core region activated at threshold. The slope of the recruitment curve is related to the number of corticospinal neurons that can be activated at a given stimulus intensity, mainly indirectly through corticocortical connections. The neurons that can be activated at a lower threshold are highly excitable neurons located in core regions of corresponding motor cortex, while neurons recruited at a higher intensity may have a higher threshold for activation, either because they are intrinsically less excitable or because they are spatially further from the center of activation by the magnetic stimulus. These neurons would be part of the “subliminal fringe.” The changes in recruitment curve are usually more prominent with higher-intensity stimulations. This finding suggests that the recruitment curve may represent the excitability of less excitable or peripherally located neurons rather than highly excitable core neurons or the connections between them. The slope of the recruitment curve is increased by drugs that enhance adrenergic transmission (e.g., dextroamphetamine) and is decreased by sodium and calcium channel blockers and by γ-aminobutyric acid (GABA) agonists.

Silent Period and Long-Interval Intracortical Inhibition

The silent period (SP) is a pause in ongoing voluntary electromyography (EMG) activity produced by TMS (Fig. 32C.1, A). The SP is usually measured with a suprathreshold stimulus in moderately active (usually 5%−10% of maximal voluntary contraction) muscle. SP duration is usually defined as the interval between the magnetic stimulus and the first recurrence of rectified voluntary EMG activity (Chen et al., 1999; Curra et al., 2002). While the first part of the SP is due in part to spinal cord refractoriness, the latter part is entirely due to cortical inhibition (cortical silent period, CSP). If a second suprathreshold test stimulation (TS) is given during the SP following suprathreshold conditioning stimulus (CS) (usually 50−200 ms after the first stimulus), its MEP is significantly suppressed (long intracortical inhibition; LICI) (see Fig. 32C.1, B) (Chen et al., 1999; Curra et al., 2002). SP and LICI appear to assess GABA_B function, although other drugs affecting membrane excitability or dopaminergic transmission also influence SP. Although LICI and SP share similar mechanisms, they may not be identical, because they are affected differently in various diseases (Berardelli et al., 1996).

Fig. 32C.1 A, Rectified electromyography (EMG) recording of the first dorsal interosseus after single transcranial magnetic stimulation (TMS) under isometric contraction at 10% of maximal voluntary contraction. The silent period (SP) can be measured from TMS trigger (a) to reoccurrence of EMG activity (b). B, Paired-pulse TMS with suprathreshold conditioning stimulation. Test stimulation (b) with same stimulation intensity is applied at 80 ms after conditioning stimulation (a). MEP of test stimulation is significantly suppressed compared to conditioning stimulation. LICI, Long intracortical inhibition.

Short-Interval Intracortical Inhibition and Intracortical Facilitation

Various inhibitory and excitatory connections in the motor cortex can be evaluated by TMS using a paired-pulse technique. A subthreshold CS preferentially excites interneurons, by which MEPs from a following TS are suppressed at interstimulus intervals (ISIs) of 1 to 5 ms (short intracortical inhibition; SICI for such inhibition at short intervals) or facilitated at ISIs of 8-20 ms (intracortical facilitation; ICF) (Fig. 32C.2) (Ziemann, 1999; Ilic et al., 2002). SICI and ICF reflect interneuronal activity in the cortex. SICI is likely largely a GABAergic effect, especially related to GABA_A receptors, whereas ICF is largely a glutamatergic effect. SICI can be divided into two phases, with maximum inhibition at ISI of 1 ms and 2.5 ms. SICI at 1 ms ISI is presumably caused either by neuronal refractoriness resulting in desynchronization of the corticospinal volley or by different inhibitory circuits; SICI at ISI of 2 ms or longer is most likely a synaptic inhibition.

Fig. 32C.2 Paired-pulse transcranial magnetic stimulation with subthreshold conditioning stimulation. At 2 ms interstimulation interval (ISI) (B), motor evoked potential (MEP) amplitude is significantly suppressed compared to test stimulation alone (A) (i.e., short intracortical inhibition, SICI). At 10 ms ISI, MEP amplitude is significantly increased (C) (i.e., intracortical facilitation, ICF).

The magnitude of SICI depends on the intensity of CS and TS. With a given CS, TS intensity variation results in a U-shaped variation of SICI magnitude, with a maximum inhibition at TS producing MEPs with peak-to-peak amplitude of around 1 mV. Variation of CS intensity at a given TS intensity also leads to a U-shaped change in SICI magnitude, with maximum SICI occurring at CS intensity around 90% AMT or 70% RMT. The low end of CS intensity producing SICI represents SICI threshold. Increased magnitude of SICI with CS above SICI threshold may indicate increasing recruitment of inhibitory interneurons that contribute to SICI, and decreased magnitude of SICI with increased CS intensities above those producing maximum SICI may represent recruitment of facilitatory processes (presumably those mediating short-interval intracortical facilitation; see next section) that superimpose with SICI. Therefore, reduced SICI observed in various disease conditions may represent either a true reduction in SICI or enhanced facilitation or both. Measuring the low and high ends of CS producing SICI is now considered a more sensitive and informative method to assess neurophysiological changes occurring in various conditions than simply measuring the magnitude of SICI.

Short-Interval Intracortical Facilitation

Short-interval intracortical facilitation (SICF) is also known as facilitatory I-wave interactions and is measured in a paired-pulse TMS protocol. In contrast to SICI and ICF, however, SICF is elicited by a suprathreshold first stimulus and a subthreshold second stimulus, or two near-threshold stimuli. SICF is usually observed at discrete ISIs of 1.1 to 1.5 ms, 2.3 to 2.9 ms, and 4.1 to 4.4 ms. ISIs producing facilitatory response in SICF are about 1.5 ms apart, similar to the intervals of different I-waves, which suggests that SICF originates in those neural structures responsible for the generation of I-waves (Ziemann and Rothwell, 2000). The second pulse is thought to excite the initial axon segments of excitatory interneurons, which are depolarized by excitatory postsynaptic potentials from the first pulse without firing an action potential. GABA_A agonists reduce SICF.

Short-Latency and Long-Latency Afferent Inhibition

Afferent inhibition can be measured by applying a conditioning sensory stimulus such as median nerve stimulation followed by a test stimulus over the contralateral motor cortex. MEP inhibition usually occurs at ISIs of approximately 20 ms (short-latency afferent inhibition, SAI) and 200 ms (long-latency afferent inhibition, LAI) (Chen, 2004). SAI is thought to be of cortical origin because the recordings of corticospinal volleys demonstrate a strong suppression of later I-waves, with unaffected earlier descending waves. SAI is reduced by the acetylcholine antagonist, scopolamine, suggesting that SAI can be used to test the integrity of cholinergic neural circuits. Accordingly, SAI is reduced in patients with Alzheimer disease and is improved with a single dose of rivastigmine, an acetylcholinesterase inhibitor. The mechanism mediating LAI is still unclear but is thought to be different from that of SAI.

Surround Inhibition

Surround inhibition (SI), suppression of excitability in an area surrounding an activated neural network, has been proposed to be an essential mechanism in the motor system, where it could aid the selective execution of desired movements. Using a self-triggered TMS technique in which TMS is set to be triggered by EMG activity from the activated muscle (agonist), MEPs of the surrounding muscles (i.e., muscles near the agonist but unrelated to its movement) are suppressed during the movement (up to 80 ms after EMG onset) despite enhanced spinal excitability (Sohn and Hallett, 2004c). SI is reduced in patients with focal hand dystonia and may be altered in other disorders of human motor control such as Parkinson disease (PD).

Other Inhibitory Phenomena of the Motor Cortex

Interhemispheric inhibition (IHI) can also be assessed by TMS by applying a conditioning stimulus to the motor cortex, which suppresses MEPs produced by a test stimulus over the contralateral motor cortex at ISIs of between 6 and 50 ms (Di Lazzaro et al., 1999). IHI is thought to occur at the cortical level, although subcortical structures may also be involved. Long-latency IHI at ISIs between 20 and 50 ms is likely mediated by GABA_B receptors.

Magnetic stimulation of the cerebellum, which can be performed using a double-cone coil, inhibits the MEPs produced by stimulation of the contralateral motor cortex 5 to 7 ms later (cerebellar inhibition, CBI) (Iwata and Ugawa, 2005). Cerebellar stimulation is thought to activate Purkinje cells in the cerebellar cortex, leading to inhibition of the deep cerebellar nuclei, such as dentate nucleus, which have a disynaptic excitatory pathway to the motor cortex via the ventral thalamus. CBI is reduced or absent in patients with cerebellar degeneration or lesions in the cerebellothalamocortical pathway.

Table 32C.1 summarizes the characteristics of different motor excitability measures using TMS.

Parkinson Disease and Parkinson-Plus Syndromes

CCT is normal in Parkinson disease (PD) but can be prolonged in patients with multisystem atrophy (MSA) and progressive supranuclear palsy (PSP), which suggest a possible role of CCT measurements in patients with Parkinson-plus syndromes involving the pyramidal tracts. A reduction in SICI has been observed in various movement disorders regardless of the nature of the disturbances (Berardelli, 1999). In PD, reduced SICI is only observed at high CS intensities, suggesting increased facilitation rather than reduced inhibition (MacKinnon et al., 2005). In patients with corticobasal degeneration, SICI is often markedly reduced or turned into facilitation along with reduced IHI (Pal et al., 2008). SP is shortened in PD. Increased LICI has been noted in patients with PD and dystonia, but a recent study demonstrated a reduced LICI and reduced presynaptic inhibition in the motor cortex in PD (Chu et al., 2009). SAI is normal in patients with PD but is reduced in patients with MSA. LAI is reduced in PD, which is not affected by dopaminergic medications. SI is reduced or absent on the asymptomatic side of patients with unilateral PD (Shin et al., 2007). Dopaminergic drugs enhance SICI and prolong SP, whereas dopamine-blocking agents reduce SICI and increase ICF. These observations suggest that motor cortex excitability depends on the balance between different inhibitory mechanisms, some of which are under basal ganglia control. Several studies measured changes in TMS parameters after subthalamic nucleus deep brain stimulation (DBS). The SP is lengthened and ICF is enhanced after DBS, but no SP change was observed in another study. Reduced SAI, presumably associated with dopaminergic medications, and reduced LAI were restored by DBS.

Dystonia

In patients with focal dystonia, reduced SICI is not site specific and was also observed on unaffected sides in patients with upper-limb dystonia and in hand muscles of patients with cervical and facial dystonia. In patients with dystonia, shortening of SP is observed but only in dystonic muscles. In writer’s cramp, decrease in LICI was observed in the symptomatic hand during muscle activation. Both SICI and LICI were found to be abnormal in psychogenic dystonia, which limits the value of these measures in differentiating organic from psychogenic disorders (Espay et al., 2006; Quartarone et al., 2009). SICI is normal in dopa-responsive dystonia (DYT5) (Hanajima et al., 2007). Recruitment curve, SP, SICI, LICI, ICF, and SICF were all normal in patients with myoclonus-dystonia (DYT15) (Li et al., 2008; van der Salm et al., 2009). In patients with focal dystonia, LAI is diminished or absent, but SAI is normal. SI is reduced or absent in patients with focal hand dystonia (Sohn and Hallett, 2004a) but may be extended in patients with paroxysmal kinesigenic dyskinesia (Shin et al., 2010).

Huntington Disease

Patients with Huntington disease (HD) have shown prolonged SP that correlates with the severity of chorea. However, preclinical and early-stage patients with HD showed normal SP, normal or increased MT, normal SICI with slightly higher SICI threshold, enhanced ICF, and reduced SAI (Nardone et al., 2007; Schippling et al., 2009).