PhD Thesis. The role of transcranial magnetic stimulation in the investigation of the human motor system. Zsuzsanna Arányi, MD - PDF

PhD Thesis The role of transcranial magnetic stimulation in the investigation of the human motor system Zsuzsanna Arányi, MD 2002 Semmelweis University, Budapest Faculty of Medicine Department of Neurology

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PhD Thesis The role of transcranial magnetic stimulation in the investigation of the human motor system Zsuzsanna Arányi, MD 2002 Semmelweis University, Budapest Faculty of Medicine Department of Neurology Consultant: Anita Kamondi, MD, PhD Semmelweis University, School of PhD Studies in Neuroscience Committee for PhD examination: Professor Péter Rajna, MD, DSc Professor Ferenc Mechler, MD, DSc Sámuel Komoly, MD, DSc Referees: Péter Diószeghy, MD, PhD Ferenc Nagy, MD, PhD Doktori (PhD) Értekezés A transzkraniális mágneses ingerlés szerepe a humán motoros rendszer vizsgálatában Dr. Arányi Zsuzsanna 2002 Semmelweis Egyetem, Budapest Általános Orvostudományi Kar Neurológiai Klinika Témavezető: Dr. Kamondi Anita, PhD Semmelweis Egyetem, Idegtudományok Doktori Iskolája Szigorlati bizottság: Prof. Rajna Péter, MTA Doktora Prof. Mechler Ferenc, MTA Doktora Dr. Komoly Sámuel, MTA Doktora Hivatalos bírálók: Dr. Diószeghy Péter, PhD Dr. Nagy Ferenc, PhD 2 TABLE OF CONTENTS INTRODUCTION AND BACKGROUND... 4 AIMS TRANSCRANIAL MAGNETIC STIMULATION IN RESEARCH: VOLITIONAL CONTROL OF PROXIMAL AND DISTAL ARM MUSCLES Facilitation of motor evoked potentials in proximal and distal arm muscles Ipsilateral / transcallosal responses in proximal and distal arm muscles Transcallosal inhibition during effort induced mirror movements Conclusions: motor control of proximal and distal arm muscles TRANSCRANIAL MAGNETIC STIMULATION IN CLINICAL DIAGNOSIS Assessment of the corticospinal tract Assessment of the facial nerve CONCLUSION AND FUTURE DIRECTIONS SUMMARY ÖSSZEFOGLALÁS ABBREVIATIONS ACKNOWLEDGMENTS PUBLICATIONS REFERENCES INTRODUCTION AND BACKGROUND INTRODUCTION AND BACKGROUND Non-invasive transcranial electric stimulation of the human brain was first reliably achieved in 1980 by Merton and Morton. 1 They were able to elicit contralateral electromyographic responses with a very short latency, thereafter named motor evoked potentials (MEP), compatible with the activation of the paucisynaptic, fast-propagating corticospinal tract. Electric stimulation involves however the use of current with very high intensity, which is painful and poorly tolerated by subjects. As a major advent in the field, Barker et al. 2 introduced transcranial magnetic stimulation (TMS) in This revolutionary new technique allows painless, non-invasive excitation of neural structures located deep in the body or covered by bone, such as the cortex, spinal nerve roots and the intracranial portion of the facial nerve. It has received wide attention and has been applied since in many different areas, including the research of nervous system physiology in humans and the diagnosis, monitoring and therapy of nervous system dysfunction. After an overview of the technical and neurophysiological aspects of TMS, and of its various applications, we present our experimental work with transcranial magnetic stimulation concerning the volitional motor control of arm muscles and an analysis of our experience with TMS in the clinical setting. We thereby aim to illustrate the versatility and value of TMS both in the realm of research and clinical work. Biophysical principles of magnetic stimulation The technique of transcranial magnetic stimulation is based on the phenomenon of electromagnetic induction, first described by Michael Faraday in Accordingly, if a very brief, but strong electric current is passed through a coil of wire it generates a changing (time-varying) magnetic field (Fig. 1), which in turn induces a current in an adjacent wire circuit or volume conductor (Faraday's law). 4 INTRODUCTION AND BACKGROUND Figure 1. Generation of magnetic field. (Reproduced from R. Jalinous, Guide to Magnetic Stimulation, The Magstim Company Limited, Spring Gardens, UK, 1995.) Upon this principle, Barker et al. in Sheffield, UK constructed in 1985 a magnetic stimulator for the purpose of non-invasive stimulation of the human brain. 2 The stimulator essentially consists of a bank of capacitors that is charged and discharged during the stimulation process, and of a stimulating coil, attached to the stimulator via about a meter long cable (Fig. 2). The storage capacitor system can be charged to a set level, determined by the examiner using controls on the front panel, up to a maximum of 2,800 volts. The levels are expressed in percentage of maximum and can be increased in increments as small as 1%. If the charged stimulator receives a trigger input signal, the energy stored in the capacitor is discharged into the stimulating coil. The stored energy is transferred Figure 2. Main unit of a magnetic stimulator Magstim 200 of to the coil in approximately the Magstim Company Ltd., Spring Gardens, Whitland, UK. (Reproduced from R. Jalinous, Guide to Magnetic Stimulation, 0.1 ms and then returned to The Magstim Company Limited, Spring Gardens, UK, 1995.) the instrument to reduce coil heating. Most commercially available magnetic stimulators utilise an electronic discharge switch, which conducts current only in one direction and prevents current reversal, thereby producing a monophasic discharge current pulse (hence a monophasic 5 INTRODUCTION AND BACKGROUND magnetic pulse). Biphasic or polyphasic pulses are less accurate and produce more click noise and heat. The brief and strong discharge current of up to 5,000-8,000 amps flowing through the stimulating coil generates a magnetic pulse with a fast rise time (0.1 ms) and slower decay (up to 1 ms) (Fig. 3), and a peak magnetic field power of Tesla. Magnetic field crosses high resistance tissues unattenuated, as the scalp or the skull, without activating pain receptors, rendering TMS a well tolerable method. The rapidly changing magnetic field (the rising part of the magnetic pulse) induces a brief electric current in Figure 3. Monophasic magnetic field pulse. (Reproduced the neural tissue, which acts as a from R. Jalinous, Guide to Magnetic Stimulation, The Magstim Company Limited, Spring Gardens, UK, 1995.) volume conductor. The intensity of the induced current is proportional to the power of the magnetic field; it is in the range of 1-20 ma/cm 2, similar to that used in conventional electric stimulation. Field strength falls off rapidly with distance (as the inverse square of distance), therefore stimulation strength is at its highest close to the coil surface. If the induced electric current is strong enough, it depolarises and discharges neural membrane. The stimulating coil, housed in moulded plastic covers, consists of one or more tightly wound and well insulated copper windings, together with safety switches and temperature sensors. There are a number of different stimulating coils available, designed for different purposes. The shape and size determines the output (peak magnetic field) of the coil and its stimulating characteristics (strength, depth of penetration, size of stimulated tissue). 4 The peak magnetic field power is related to coil size: smaller coils have a stronger field power (stimulation strength), but strength falls off more rapidly, therefore depth of penetration is smaller. 6 INTRODUCTION AND BACKGROUND The coil most frequently employed for stimulation with the Magstim 200 stimulator is the large 90 mm round coil, with a peak magnetic field power of 2.0 Tesla (Fig. 5). The current induced by the round coil follows more or less the trajectory of the coil windings, i.e. a current loop parallel to the coil is generated in the brain (Fig. 4). The magnitude of the induced current is equal at any point along the loop (around the coil winding), but it is zero in the central axis of the coil; by contrast the power of magnetic field is maximum at the centre of the coil. The direction of the current flow in the Figure 4. Current loops induced by tangential (1), tissue is opposite to that in the coil saggital (2) and coronal (3) orientation of the round coil. (Reproduced from K.H. Chiappa, Evoked windings. It follows from the above Potentials in Clinical Medicine, Raven Press, New York 1990.) that if a large round coil is placed on the vertex in a tangential orientation for the purpose of motor cortex stimulation, it will activate both hemispheres underlying the coil windings, the motor cortices on either side. However, the hemispheres are preferentially activated by a current flowing in the posterior-anterior direction, therefore depending on the direction of current flow within the coil one hemisphere will be stimulated stronger than the other. In case of the most widely used Magstim 200 stimulator, that produces a monophasic magnetic pulse, if side A of the coil is facing upward, the current is flowing counter-clockwise within the coil and clock-wise in the brain, which leads to a preferential, but not exclusive stimulation of the left hemisphere; and vice versa with side B. Polyphasic magnetic pulses are not direction sensitive, because either the first or the opposite polarity second phase may be effective. The 90 mm round coil is also used to excite the spinal nerve roots and the intracranial portion of the facial nerve. For root stimulation it is placed tangentially on the appropriate part of the spine, with side A facing upward for the stimulation of the roots on the right side, and vice versa. It has been shown that excitation of the roots occurs at 7 INTRODUCTION AND BACKGROUND the level of the intervertebral foramina, bypassing the intraspinal segments. 5,6,7 To date stimulation of the spinal cord itself has not yet proved possible. Excitation of the intracranial portion of the facial nerve is achieved by placing the coil behind the ear, in the parieto-occipital region. 8 Large round coils are unsuited for focal, more circumscribed stimulation of the brain. The so-called double coil (figure-of-eight, butterfly coil), containing two adjacent windings with opposing current directions, has been devised for this purpose (Fig. 5). The standard 70 mm double-coil has a peak magnetic field power of 2.2 Tesla. Such a coil induces two current loops that are superimposed at the junction of the two loops, where a maximum in the magnitude of the induced electric field is formed. This results in a small preferential site of stimulation under the intercept (centre) of the coil. Nonetheless, it is important to see that weaker stimulation can still take place under either side of the windings. The natural curvature of the head, however, helps keep the outer edges away from other areas of the cortex, further improving accuracy of stimulation. The double coil allows the isolated stimulation of one hemisphere; furthermore, by moving the coil along the central gyrus it is even possible to activate muscle groups separately within a limb. For example, if the centre of the double coil is located about 4 cm lateral to the vertex, the proximal arm muscles, whereas at 6 cm the small hand muscles will be activated. It has been found that using a double-coil the lowest threshold responses are elicited when the centre of the coil is rotated around 45 degrees from the midline (the handle of the coil forms a 45 angle with the midline), thereby inducing a current perpendicular to the central sulcus. If the handle is pointing posterior, the direction of the induced current is posterior-anterior (preferential for the excitation of the cortex), and vice versa. 9 8 INTRODUCTION AND BACKGROUND Figure 5. 3D representation of the magnetic field produced by a 90 mm round coil (left) and a 70 mm double coil (right). (Reproduced from R. Jalinous, Guide to Magnetic Stimulation, The Magstim Company Limited, Spring Gardens, UK, 1995.) The double cone coil is a less commonly used coil, where two large cup shaped windings are positioned side by side in an angle with a flat central section. The angled sides closely fit the patient's head, allowing a more efficient magnetic field coupling to the head. In particular this coil is suited for stimulation within the central fissure and the brain stem. In spite of a relatively focal stimulation achieved by the double-coil, as opposed to the round coil, none of the coils provide a truly focal stimulation and indeed the precise site of stimulation (depolarisation) is always an approximation. For that reason, magnetic stimulation is less suited for the investigation of peripheral nerves, where the calculation of conduction velocity requires a positional accuracy to a few millimetres. Nonetheless, small round coils (40-50 mm) that have a stronger peak magnetic field power ( Tesla), concentrated on a smaller area (i.e. stimulation is more focal than with large round coils), have been used for peripheral nerve stimulation, for example at Erb's point. 9 INTRODUCTION AND BACKGROUND Physiology of magnetic stimulation Magnetic stimulation of the cortex activates the rapidly conducting corticospinal tract, resulting in a contralateral muscle twitch. It has been shown that a single stimulus (magnetic pulse) triggers repetitive discharges of the pyramidal neurons, leading to multiple, up to 8 descending volleys in the corticospinal tract, separated by ms intervals. 10 The first wave is directly triggered in the pyramidal axon ('D' for direct wave); the following ones are transsynaptically elicited in the same neuron via one or more cortical interneurons ('I' for indirect wave). Temporal and spatial summation of these descending corticospinal waves of excitation takes place in the spinal alphamotoneuron pool, leading to a progressive depolarisation of alpha-motoneurons until their threshold is reached and their action potential discharges. Thus, the degree of summation (number of descending waves) needed for discharge (i.e. muscle twitch) depends on the excitability status of the alpha-motoneurons. A major difference in the mechanism of magnetic and electric brain stimulation concerns the site of stimulation. Magnetic stimulation, as explained above, activates the pyramidal neurons not only directly at its axon, but also transsynaptically via interneurons. Electric stimulation on the other hand excites only the pyramidal axon deeper in the white matter, thereby producing only D-waves and resulting in the shortening of the central motor conduction time by about 2 ms, as compared with magnetic stimulation. 11 It also follows that the overall excitability level of the cortex and its spontaneous fluctuation influences responses to magnetic stimuli to a greater degree than to electric stimuli. This spontaneous fluctuation of excitability is partly reflected in the observed trial-to-trial variability in the latency and amplitude of MEPs elicited by a magnetic cortical stimulus of the same intensity. 12 The difference in the effects of electric and magnetic cortical stimulation has been exploited in numerous instances to investigate cortical, as opposed to subcortical or spinal contribution in various phenomena. The muscle compound action potential elicited by cortical stimulation is recorded by surface electrodes on the target muscle as the motor evoked potential. The parameters of MEPs measured include the onset (cortico-muscular) latency, the amplitude (baseline to 10 INTRODUCTION AND BACKGROUND peak or peak to peak) and stimulation threshold. Since the pioneering studies of Merton and Morton, it has been observed that MEPs elicited during the voluntary contraction of the target muscle have a lower stimulus threshold, are shorter in latency and larger in amplitude, in comparison to MEPs obtained during full muscular relaxation. 13,14 This is termed facilitation, it reflects an increased excitability of the motor pathway during voluntary contraction (Fig. 6). The most conspicuous aspect and best measure of facilitation is the increase in amplitude, which can Figure 6. Note the substantial increase in amplitude and be up to several fold in magnitude. reduction in latency of the MEP during contraction of the target muscle as opposed to muscle at rest. Latency shortening can reach 3-4 ms. Maximal facilitation occurs with the contraction of the target muscle, however there are numerous other facilitatory manoeuvres. As the amount of facilitation is an indication of the excitability and its changes in the motor pathway, it is a tool to explore the physiology of motor control. The phenomenon of facilitation has been, accordingly, investigated in different muscles under different conditions; a detailed discussion will follow later. The cortico-muscular latency of the MEP comprises the conduction time of both the corticospinal tract and the alpha-motoneuron. The conduction time in the corticospinal tract (central motor conduction time- CMCT) can be calculated by subtracting the conduction time of the alpha-motoneuron, which is obtained by magnetic or highvoltage electric stimulation of spinal roots, or using F-waves. It is generally 4-8 ms for the upper limb recorded from hand muscles, and ms for the lower limbs recorded from the tibialis anterior muscle. CMCT is a reliable, if not the best parameter providing information on the integrity of the corticospinal tract; it is thus mainly used in the clinical setting, to assess corticospinal tract function. It is important to stress that the 11 INTRODUCTION AND BACKGROUND interpretation of CMCT differs from that of the conduction time (conduction velocity) of peripheral nerves. Slowed peripheral conduction usually reflects demyelination in the peripheral nerve, whereas prolonged CMCT can be both a sign of demyelination and axon loss in the corticospinal tract. As explained above, the MEP is ultimately the result of the discharge of the alpha motoneuron pool, which requires the temporal and spatial summation of descending corticospinal volleys. Central demyelination and axon loss can both result in impaired summation. Demyelination leads to slowed conduction and thus summation takes longer; axon loss leads to a smaller number of descending volleys and therefore more consecutive volleys are needed for summation. The same principle applies to the interpretation of MEP amplitudes. Slowed central conduction, or conduction failure caused by demyelinative conduction block or axon loss can all lead to insufficient summation, thus lowered amplitudes or absent responses. Nonetheless, an MEP of normal amplitude but prolonged CMCT speaks more for central demyelination without substantial conduction failure, whereas an MEP of very low amplitude with near normal CMCT speaks more for conduction failure due to central axon loss. The interpretation of the MEP amplitude is further hampered by two factors. The amplitude of the MEP is usually smaller than the amplitude of the response evoked by peripheral nerve stimulation. Even with facilitation, the amplitude ratio between the response to peripheral and cortical stimulation can be as little as 18% in healthy individuals. 15 Furthermore, the amplitude of the MEP varies considerably from one stimulus to another. 12,16 It has been shown that the smaller amplitude of the MEP is the result of phase cancellation of the action potentials caused by desynchronisation of conduction occurring within the corticospinal tract or at spinal level. 17 Variability of this desynchronisation also plays a role in the variability of MEP amplitudes. 17 All these circumstances impede detection of central conduction failure in disease states. To circumvent this problem, recently the so-called triple stimulation technique (TST) has been developed. 17 This technique involves the application of three stimuli with delays, leading to two collisions. The first is the magnetic cortical stimulus, followed by an electric stimulus at the wrist (recording is done from the abductor digiti minimi muscle). The action potentials descending from the cortex collide with and cancel the antidromic potentials evoked at the wrist somewhere along the arm. After another delay a third 12 INTRODUCTION AND BACKGROUND (electric) stimulus is applied at Erb's point, and it is this response that is final
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