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Magnetic stimulation of motor cortex in children: maturity of corticospinal pathway and problem of clinical application
ELSEVIER
Brain & Development 19 (1997) 176-180
Original article
Magnetic stimulation of motor cortex in children: maturity of corticospinal pathway and problem of clinical application A t s u o N e z u a'*, Seiji K i m u r a a, S a o r i U e h a r a a, T a k u y a K o b a y a s h i a, M i y a b i T a n a k a a, K a o r u S a i t o b aDepartment of Pediatrics, Urafune Hospital of Yokohama City University, 3-46 Urafune-cho, Minami-ku, Yokohama 232, Japan bDepartment of Rehabilitation, Urafune Hospital of Yokohama City University, 3-46 Urafune-cho, Minami-ku, Yokohama 232, Japan
Received 8 March 1996; accepted 12 September 1996
Abstract
The developmental profile of the electromyographic responses to transcranial magnetic stimulation (TMS) was studied in 46 neurologically normal children aged from one to 14 years, compared with data in 10 normal control adults. To obtain motor evoked potentials (MEPs) from the first dorsal interosseous muscle in the resting state, the motor cortex was stimulated through a circular coil with the stimulus intensity set at 10% above the threshold intensity for eliciting MEPs. Reproducible MEPs were obtained in all but the children aged below 2 years, and the threshold intensity and central motor conduction time (CMCT) showed a linear decrease with maturation. The MEP amplitude changed little until 9 years of age, but it tended to increase between 10 years and adulthood. The MEP duration, which was not influenced by age, was less than 16 ms over the ages studied. The present data suggest that maturity of the corticospinal motor pathway that controls the intrinsic hand muscles is electrophysiologically complete at 13 years of age. Among the parameters of MEPs, CMCT and MEP duration may be useful for evaluating impairment of the corticospinal tracts in children aged 2 years and older. © 1997 Elsevier Science B.V. Keywords: Transcranial magnetic stimulation; Motor cortical excitability; Central motor conduction time
I. Introduction
For the sensory afferent pathways, evoked potentials have been fully studied with respect to their changes with maturation of the central nervous system (CNS), but for the corticospinal motor pathways, electrophysiological examinations in childhood have been limited methodologically. Transcranial magnetic stimulation (TMS) of the motor cortex, which Barker et al. introduced in 1985, can produce motor evoked potentials (MEPs) of the extremity muscles, more safely and painlessly than high voltage electrical stimulation of the brain [1,2]. As shown in several reports, TMS has the potential not only to evaluate the maturity of the corticospinal motor pathways in normal children, but also to become a routine diagnostic procedure in children with motor developmental delay or other disorders of motor control [3-6]. Although controversy remains regarding the procedure * Corresponding author. Tel.: +81 45 2615656; fax: +81 45 2433886.
0387-7604/97/$17.00 © 1997 Elsevier Science B.V. All rights reserved Pll S0387-7604(96)00552-9
of TMS in children, its safety has been confirmed in every respect, and it has been widely used to study motor control in adults for more than 10 years. The electrical energy generated by TMS has been estimated as 0.05-0.005% of that applied in a burst of electroconvulsive therapy [2]: the peak magnetic field of 2.0 T induced by TMS yields a maximum charge density of approximately 0.94 /~C/cm2/phase in a tissue, which is markedly below the minimum level of 40/~C/cm2/phase at which evidence of neural damage has been found when stimulating at 50 Hz [7]. No microscopic damage of the brain was recognized either in 31 rats given 10000 stimuli of 3.4 T or in 16 infant rabbits given 1000 stimuli of 2.0 T [8,9]. Two patients with intractable seizures who received 10001200 stimuli prior to temporal lobectomy also showed no organic damage of the target temporal cortex [10]. TMS scarcely impairs electroencephalographic (EEG) activity, cortical function, cerebral blood flow or prolactin secretion [ 11-14]: monkeys trained in a task that required short-term memory showed no change of EEG activity or
177
A. Nezu et al. / Brain & Development 19 (1997) 176-180
task achievements after TMS of more than 7000 stimuli. Regarding the risk of triggering epileptic activity and kindling, previous reports described no side-effect of activating epileptic activity in patients with idiopathic epilepsy [1517]. Some papers reported that TMS may activate an epileptic focus in patients with intractable symptomatic seizures [18], but this possibility is considered less than that with the routine provocation test with hyperventilation [19]. No risk of kindling should exist using commercial stimulators with a stimulus rate of less than 1 Hz. It is crucial in recording MEPs to define the suitable stimulus intensity and fix the condition of the target muscle, since MEPs elicited by TMS are greatly influenced by stimulus intensity and voluntary contraction of the target muscle [20]. Therefore, in contrast to the previous papers focusing on developmental influence [3-5], the present study reports the developmental changes in each component of MEPs obtained with a standard TMS procedure according to the reports of the Committee of International Federation of Clinical Neurophysiology (IFCN) and of the Japan Society of Electroencephalography and Electromyography in 1994 [21,22]. In addition, this paper discusses whether or not TMS is useful for clinical application in children.
Cx 3yr CTs
Cx
Ill
8yr CTs
f
Cx
Adult CTs
I 3001~V 20 ms
Fig. 2. Motor evoked potentials recorded from the first dorsal interosseous muscle in children at 3 and 8 years of age and in an adult, elicited by magnetic stimulation applied to the opposite motorcortex (Cx, upper traces) and to the cervical spinal roots (C7s, lower traces).
2. Methods
controls gave verbal informed consent to participate in this study.
2.1. Subjects
The MEPs elicited by magnetic stimulation in 46 neurologically normal children aged between one and 14 years (Fig. 1) were evaluated, compared with those in 10 neurologically normal control adults, who were members of our medical staff, with a mean age of 25.2 years (range, 20-30 years). The parents of all childhood subjects and the adult
Number (n) 6. 5. 4 3 2 10 1
3
5
7 9 Age (years)
11
13
Fig. I. Age distribution of the control children.
2.2. Transcranial m a g n e t i c stimulation
Magnetic stimulation was delivered by a Magstim 200 magnetic stimulator (Magstim Co., UK) through a circular coil with a mean diameter of 90 mm (peak magnetic field strength, 2.0 T, here designated as 100% intensity). To stimulate the left motor cortex, the edge of the coil was positioned tangentially over C3 of the international 10-20 system, and the current in the coil flowed anti-clockwise. When C3 was not the optimal scalp position with the lowest threshold intensity, the edge of the coil was replaced over neighboring positions 1.0 cm apart along the coronal line connecting T3-C3-C z. To stimulate the spinal roots, the edge of the coil was positioned over the seventh cervical spine (C7s). MEPs were recorded from surface electrodes placed over the right first dorsal interosseous muscle (FDI) with a filter setting of 20-3000 Hz. During stimulation, the subjects rested the FDI. Stimulus intensity for TMS was increased by 5% increments from 40%, and threshold intensity was defined as the lowest stimulator intensity needed to produce MEPs of more than 100 #V amplitude in at least three of five trials. Magnetic stimulation in this study was performed with an intensity 10% above the threshold. Stimulus intensity on stimulating the spinal roots was determined as 35-40%. Among at least three
178
A. Nezu et al. / Brain & Development 19 (1997) 176-180
Am ~litude (mV)
Threshold intensity (%) 110.
2.5-
1001
2.
9oi
1.5.
sol l.
7oi .5
6oi 5oi
0
40
,
,
1
,
,
,
3
,
,
,
,
,
5 7 9 Age (years)
,
,
11
,
,
13
,
,
Adult
Fig. 3. Age-dependent change in threshold intensity for transcranial magnetic stimulation shown as mean and standard deviation.
MEPs elicited by TMS, MEP latency was determined as the shortest onset latency, and MEP duration was measured as the longest interval between the onset and terminal latencies. MEP amplitude was defined as that between the two largest peaks of opposite polarity. Central motor conduction time (CMCT) was calculated by subtracting the MEP latency obtained by stimulation on C7s from the latency obtained by stimulation over the cortex.
3. Results MEPs were elicited by TMS in all children, except three of four children aged 1 year even with 100% stimulus intensity. Fig. 2 demonstrates typical examples of MEPs in childhood at 3 and 8 years of age, and the relationship between age and each component of the responses to magnetic stimulation is shown in Figs. 3-5. Threshold intensity for TMS, which was determined as more than 100% intensity for children aged 1 year, decreased almost linearly with age and reached an adult level (mean + standard deviation (SD) of control adults, 56.5 + 11.8%) at 13 years CMCT (ms) 22~ 2018.
14 12 10 8 6
.
1
,
,
3
,
.
5
,
,
,
,
7 9 Age (years)
,
,
11
.
,
13
,
,
Adult
Fig. 4. Age-dependent change in central motor conduction time shown as mean and standard deviation.
-.5
.........................................................................................................
,
1
,
,
3
,
,
5
,
,
,
,
7 9 Age (years)
,
,
11
,
,
13
.
.
Adult
Fig. 5. Relationship of amplitude of motor evoked potentials elicited by transcranial magnetic stimulation to age, shown as mean and standard deviation.
(Fig. 3). The latency of MEPs elicited by TMS (mean + SD of all subjects, 20.2 + 1.4 ms) was not influenced by age, while the latency of MEPs elicited by stimulation of the spinal roots increased linearly with age. As a result, CMCT was inversely correlated with age and fell below the adult mean (mean + SD of control adults, 8.90 + 0.85 ms) at 12 years of age (Fig. 4). The duration of MEPs elicited by TMS changed little with age (mean + SD of all subjects, 10.6 + 3.2 ms), and its maximum value was 15.9 ms in all the ages studied. The mean amplitude of MEPs elicited by TMS was less than 500 #V in almost all children aged between 1 and 9 years, while it tended to increase from 10 years, although the values varied widely even in adult individuals (mean + SD of control adults, 958 + 878/~V) (Fig. 5).
4. Discussion TMS activates the cortical motor neurons transsynaptically and produces multiple descending volleys via the corticospinal tracts [23-25]. Consequently, the anterior horn cells are depolarized by temporal summation of the multiple descending volleys. The previous studies in children were performed utilizing uncertain voluntary contraction of the target muscle [3,4] or with excessive stimulus intensity fixed as 100% intensity [5]; however, the reproducibility of MEPs elicited by TMS is markedly dependent on the degree by which stimulus intensity exceeds threshold intensity and the condition of the target muscle responsible for the excitability of the spinal neurons, in addition to whether or not the coil is positioned at the optimal site [23]. Therefore, to obtain comparable MEPs, we adjusted the stimulus intensity to an intensity 10% above each threshold intensity for TMS, and MEPs were recorded from a resting target muscle, since children cannot maintain a stable voluntary contraction of the studied muscle.
A. Nezu et al. / Brain & Development 19 (1997) 176-180
The present study demonstrates the developmental changes in threshold intensity for TMS, CMCT, and the amplitude of MEPs elicited by TMS, while their onset latency and duration were not influenced by age. Although Koh and Eyre, and Eyre et al. reported that MEPs failed to be evoked below the age of 6 years [3,4], we obtained reproducible MEPs from all children except those aged below 2 years, which almost coincided with the results reported by MOiler et al. [5]. Morphologically as shown in Fig. 2, MEPs are generally polyphasic in early childhood and gradually become triphasic. The present study suggests that electrophysiological maturation of the corticospinal motor pathways, which is defined as the condition of all parameters of MEPs reaching adult levels, is complete at the age of 13 years, and this maturational age was similar to that found in the previous papers [3-5]. Since developmental myelination of the pyramidal tracts is complete morphologically and on MR imaging by early childhood [26,27], these age-related changes occurring over 10 years appeared to be based more on the development of cortical synaptic efficacy (synaptogenesis) which continues to adolescence. The maturational age of the present motor responses to TMS was almost the same as that of early cortical responses of somatosensory evoked potentials and of movement-related cortical potentials [28-30], and these neurophysiological findings were considered to correspond with the age of acquisition of fine motor skills [31] and of reaching adult values of cortical metabolism shown by positron emission tomography study [32]. When the corticospinal pathways in adults are impaired, TMS parameters are reported to be altered as follows [33]: (i) prolonged CMCT, (ii) prolonged duration of MEPs due to temporal dispersion of the multiple descending volleys, (iii) elevated threshold intensity for TMS, and (iv) decreased MEP amplitude. The present study suggests that the clinical application of TMS in children aged 2 years and older is likewise useful for diagnosis of impairment of the corticospinal tracts. However, the procedure employed in this study was invalid for children below 2 years, since reliable MEPs could not be obtained. In children of 2 years and upward, prolonged CMCT is likely to be a helpful diagnostic clue, for example when CMCT increases to a mean value of each age added to more than 3.8 ms, since the largest SD value was 1.9 ms. The duration of MEPs, which was always less than 16 ms, also may be a useful parameter, if it is prolonged. For example, our earlier report showed that the MEP duration was significantly prolonged in a boy with subclinical involvement of the pyramidal tracts caused by adrenoleukodystrophy [34]. In contrast, threshold intensity for TMS may be less useful in children younger than 10 years, because of its higher mean value and variability between individuals, and the amplitude of MEPs is unlikely to be diagnostic because of its large intra- and inter-individual variability. In conclusion, we suggest that electrophysiological maturation of the corticospinal motor pathways is corn-
179
plete at the age of 13 years. TMS may be a useful and convenient method for quantitative evaluation of electrophysiological development and impairment of the corticospinal motor pathways in children aged 2 years and older, while further detailed study is necessary to investigate the facilitating condition to elicit reliable MEPs for the clinical application of TMS in children below 2 years.
References [ 1] Barker AT, Jalinous R, Freeston IL. Non-invasive magnetic stimulation of human motor cortex. Lancet 1985; 11:1106-1107. [2] Barker AT, Freeston IL, Jarrett JA, Jalinous R. Magnetic stimulation of the human nervous system: an introduction and basic principles. In: Chokroverty S, editor. Magnetic Stimulation in Clinical Neurophysiology. Boston: Butterworths, 1989: 52-72. [3] Koh THHG, Eyre JA. Maturation of corticospinal tracts assessed by electromagnetic stimulation of the motor cortex. Arch. Dis. Child. 1988; 63: 1347-1352. [4] Eyre JA, Miller S, Ramesh V. Constancy of central conduction delays during development in man: investigation of motor and somatosensory pathways. J. Physiol. 1991; 434: 441-452. [5] MUller K, Homberg V, Lenard HG. Magnetic stimulation of motor cortex and nerve roots in children. Maturation of cortico-motoneuronal projections. Electroenceph. Clin. Neurophysiol. 1991; 81: 6 3 70. [6] Mtiller K, Homberg V, Aulich A, Lenard HG. Magnetoelectrical stimulation of motor cortex in children with motor disturbances. Electroenceph. Clin. Neurophysiol. 1992; 85: 86-94. [7] Agnew WF, McCreery DB. Considerations for safety in the use of extracranial stimulation for motor evoked potentials. Neurosurgery 1987; 20: 143-147. [8] Sgro JA, Ghatak NR, Stanton PC, Emerson RG, Blair R. Repetitive high magnetic field stimulation: the effect upon rat brain. Electroenceph. Clin. Neurophysiol. Suppl. 1991 ; 43:180-185. [9] Counter SA. Neurobiological effects of extensive transcranial electromagnetic stimulation in an animal model. Electroenceph. Clin. Neurophysiol. 1993; 89: 341-348. [10] Gates JR, Dhuna A, Pascual LA. Lack of pathologic changes in human temporal lobes after transcranial magnetic stimulation. Epilepsia 1992; 33: 504-508. [11] Yamada H, Tamaki T, Wakano K, Mikami A, Transfeldt EE. Effect of transcranial magnetic stimulation on cerebral function in a monkey model. Electroenceph. Clin. Neurophysiol. 1995; 97: 140144. [12] Eyre JA, Flecknell PA, Kenyon BR, Kor THHG, Miller S. Acute effects of electromagnetic stimulation of the brain on cortical activity, cortical blood flow, blood pressure and heart rate in the cat: an evaluation of safety. J. Neurol. Neurosurg. Psychiat. 1990; 53: 507-513. [13] Bridgers SL, Delaney RC. Transcranial magnetic stimulation: assessment of cognitive and other cerebral effects. Neurology 1989; 39: 417-419. [14] Cohen LG, Hallet M. Cortical stimulation does not cause shortterm changes in the electroencephalogram. Ann. Neurol. 1987; 21: 512-513. [15] Tassinari CA, Michelucci R, Forti A et al. Transcranial magnetic stimulation in epileptic patients: usefulness and safety. Neurology 1990; 40: 1132-1133. [16] Reutens DC, Berkovic SF, Macdonell RA, Bladin PF. Magnetic stimulation of the brain in generalized epilepsy: reversal of cortical hyperexcitability by anticonvulsants. Ann. Neurol. 1993; 3 4 : 3 5 1 355. [17] Reutens DC, Berkovic SF. Increased cortical excitability in gener-
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alized epilepsy demonstrated with transcranial magnetic stimulation. Lancet 1992; 339: 362-363. Hufnagel A, Elger CE, Durwen HF, Btker DK, Entzian W. Activation of the epileptic focus by transcranial magnetic stimulation of the human brain. Ann. Neurol. 1990; 27: 49-60. Schiiler P, Claus D, Stefan H. Hyperventilation and transcranial magnetic stimulation: two methods of activation of epileptiform EEG activity in comparison. J. Clin. Neurophysiol. 1993; 10: 111-115. Kiers L, Cros D, Chippa KH, Fang J. Variability of motor potentials evoked by transcranial magnetic stimulation. Electroenceph. Clin. Neurophysiol. 1993; 89: 415-423. Rossini PM, Barker AT, Berardelli A et al. Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application. Report of an IFCN committee. Electroenceph. Clin. Neurophysiol. 1994; 91: 79-92. Kimura J, Mano Y, Ugawa Y e t al. The standard procedures of magnetic stimulation. Report of an committee of Japan Society of EEG and EMG. Jpn. J. Electroenceph. Electromyogr. 1994; 22: 218-219. Day BL, Dressier D, de Maertens NA et al. Electric and magnetic stimulation of human motor cortex: surface EMG and single motor unit responses. J. Physiol. 1989; 412: 449-473. Inghilleri M, Berardelli A, Cruccu G, Priori A, Manfredi M. Cortico-spinal potentials after transcranial stimulation in humans. J. Neurol. Neurosurg. Psychiat. 1989; 52: 970-974. Day, BL, Thompson PD, Dick JP, Nakashima K, Marsden CD. Different sites of action of electrical and magnetic stimulation of the human brain. Neurosci. Lett. 1987; 75: 101-106.
[26] Yakovlev PI, Lecours R. The myelinogenic cycles of regional maturation of the brain. In: Minkowski A, editor. Regional Development Of The Brain In Early Life. Oxford: Blackwell, 1966: 3 70. [27] Holland BA, Haas DK, Norman D, Brant-Zawadzki M, Newton TH. MRI of normal brain maturation. Am. J. Neuroradiol. 1986; 7: 201-208. [28] Desmedt JE, Brunko E, Debecker J. Maturation of the somatosensory evoked potentials in normal infants and children, with special reference to the early NI component. Electroenceph. Clin. Neurophysiol. 1976; 40: 43-58. [29] Zhu Y, Georgesco M, Cadihac J. Normal latency values of early cortical somatosensory evoked potentials in children. Electroenceph. Clin. Neurophysiol. 1987; 68: 471-474. [30] Ogawa K. Developmental changes in movement-related cortical potentials. Jpn. J. Electroenceph. Electromyogr. 1996; 24: 260267. [31] Denckla MB. Development of motor co-ordination in normal children. Dev. Med. Child Neurol. 1974; 16: 729-741. [32] Chugani HT, Phelps ME, Mazziotta JC. Positron emission tomography study of human brain functional development. Ann. Neurol. 1987; 22: 487-497. [33] Macdonell RAL, Donnan GA, Bladin PF. A comparison of somatosensory evoked and motor evoked potentials in stroke. Ann. Neurol. 1989; 25: 68-73. [34] Nezu A, Kimura S, Kobayashi T et al. Transcranial magnetic stimulation in adrenoleukodystrophy patient. Brain Dev. 1996; 18: 327-329.
Brain & Development 19 (1997) 176-180
Original article
Magnetic stimulation of motor cortex in children: maturity of corticospinal pathway and problem of clinical application A t s u o N e z u a'*, Seiji K i m u r a a, S a o r i U e h a r a a, T a k u y a K o b a y a s h i a, M i y a b i T a n a k a a, K a o r u S a i t o b aDepartment of Pediatrics, Urafune Hospital of Yokohama City University, 3-46 Urafune-cho, Minami-ku, Yokohama 232, Japan bDepartment of Rehabilitation, Urafune Hospital of Yokohama City University, 3-46 Urafune-cho, Minami-ku, Yokohama 232, Japan
Received 8 March 1996; accepted 12 September 1996
Abstract
The developmental profile of the electromyographic responses to transcranial magnetic stimulation (TMS) was studied in 46 neurologically normal children aged from one to 14 years, compared with data in 10 normal control adults. To obtain motor evoked potentials (MEPs) from the first dorsal interosseous muscle in the resting state, the motor cortex was stimulated through a circular coil with the stimulus intensity set at 10% above the threshold intensity for eliciting MEPs. Reproducible MEPs were obtained in all but the children aged below 2 years, and the threshold intensity and central motor conduction time (CMCT) showed a linear decrease with maturation. The MEP amplitude changed little until 9 years of age, but it tended to increase between 10 years and adulthood. The MEP duration, which was not influenced by age, was less than 16 ms over the ages studied. The present data suggest that maturity of the corticospinal motor pathway that controls the intrinsic hand muscles is electrophysiologically complete at 13 years of age. Among the parameters of MEPs, CMCT and MEP duration may be useful for evaluating impairment of the corticospinal tracts in children aged 2 years and older. © 1997 Elsevier Science B.V. Keywords: Transcranial magnetic stimulation; Motor cortical excitability; Central motor conduction time
I. Introduction
For the sensory afferent pathways, evoked potentials have been fully studied with respect to their changes with maturation of the central nervous system (CNS), but for the corticospinal motor pathways, electrophysiological examinations in childhood have been limited methodologically. Transcranial magnetic stimulation (TMS) of the motor cortex, which Barker et al. introduced in 1985, can produce motor evoked potentials (MEPs) of the extremity muscles, more safely and painlessly than high voltage electrical stimulation of the brain [1,2]. As shown in several reports, TMS has the potential not only to evaluate the maturity of the corticospinal motor pathways in normal children, but also to become a routine diagnostic procedure in children with motor developmental delay or other disorders of motor control [3-6]. Although controversy remains regarding the procedure * Corresponding author. Tel.: +81 45 2615656; fax: +81 45 2433886.
0387-7604/97/$17.00 © 1997 Elsevier Science B.V. All rights reserved Pll S0387-7604(96)00552-9
of TMS in children, its safety has been confirmed in every respect, and it has been widely used to study motor control in adults for more than 10 years. The electrical energy generated by TMS has been estimated as 0.05-0.005% of that applied in a burst of electroconvulsive therapy [2]: the peak magnetic field of 2.0 T induced by TMS yields a maximum charge density of approximately 0.94 /~C/cm2/phase in a tissue, which is markedly below the minimum level of 40/~C/cm2/phase at which evidence of neural damage has been found when stimulating at 50 Hz [7]. No microscopic damage of the brain was recognized either in 31 rats given 10000 stimuli of 3.4 T or in 16 infant rabbits given 1000 stimuli of 2.0 T [8,9]. Two patients with intractable seizures who received 10001200 stimuli prior to temporal lobectomy also showed no organic damage of the target temporal cortex [10]. TMS scarcely impairs electroencephalographic (EEG) activity, cortical function, cerebral blood flow or prolactin secretion [ 11-14]: monkeys trained in a task that required short-term memory showed no change of EEG activity or
177
A. Nezu et al. / Brain & Development 19 (1997) 176-180
task achievements after TMS of more than 7000 stimuli. Regarding the risk of triggering epileptic activity and kindling, previous reports described no side-effect of activating epileptic activity in patients with idiopathic epilepsy [1517]. Some papers reported that TMS may activate an epileptic focus in patients with intractable symptomatic seizures [18], but this possibility is considered less than that with the routine provocation test with hyperventilation [19]. No risk of kindling should exist using commercial stimulators with a stimulus rate of less than 1 Hz. It is crucial in recording MEPs to define the suitable stimulus intensity and fix the condition of the target muscle, since MEPs elicited by TMS are greatly influenced by stimulus intensity and voluntary contraction of the target muscle [20]. Therefore, in contrast to the previous papers focusing on developmental influence [3-5], the present study reports the developmental changes in each component of MEPs obtained with a standard TMS procedure according to the reports of the Committee of International Federation of Clinical Neurophysiology (IFCN) and of the Japan Society of Electroencephalography and Electromyography in 1994 [21,22]. In addition, this paper discusses whether or not TMS is useful for clinical application in children.
Cx 3yr CTs
Cx
Ill
8yr CTs
f
Cx
Adult CTs
I 3001~V 20 ms
Fig. 2. Motor evoked potentials recorded from the first dorsal interosseous muscle in children at 3 and 8 years of age and in an adult, elicited by magnetic stimulation applied to the opposite motorcortex (Cx, upper traces) and to the cervical spinal roots (C7s, lower traces).
2. Methods
controls gave verbal informed consent to participate in this study.
2.1. Subjects
The MEPs elicited by magnetic stimulation in 46 neurologically normal children aged between one and 14 years (Fig. 1) were evaluated, compared with those in 10 neurologically normal control adults, who were members of our medical staff, with a mean age of 25.2 years (range, 20-30 years). The parents of all childhood subjects and the adult
Number (n) 6. 5. 4 3 2 10 1
3
5
7 9 Age (years)
11
13
Fig. I. Age distribution of the control children.
2.2. Transcranial m a g n e t i c stimulation
Magnetic stimulation was delivered by a Magstim 200 magnetic stimulator (Magstim Co., UK) through a circular coil with a mean diameter of 90 mm (peak magnetic field strength, 2.0 T, here designated as 100% intensity). To stimulate the left motor cortex, the edge of the coil was positioned tangentially over C3 of the international 10-20 system, and the current in the coil flowed anti-clockwise. When C3 was not the optimal scalp position with the lowest threshold intensity, the edge of the coil was replaced over neighboring positions 1.0 cm apart along the coronal line connecting T3-C3-C z. To stimulate the spinal roots, the edge of the coil was positioned over the seventh cervical spine (C7s). MEPs were recorded from surface electrodes placed over the right first dorsal interosseous muscle (FDI) with a filter setting of 20-3000 Hz. During stimulation, the subjects rested the FDI. Stimulus intensity for TMS was increased by 5% increments from 40%, and threshold intensity was defined as the lowest stimulator intensity needed to produce MEPs of more than 100 #V amplitude in at least three of five trials. Magnetic stimulation in this study was performed with an intensity 10% above the threshold. Stimulus intensity on stimulating the spinal roots was determined as 35-40%. Among at least three
178
A. Nezu et al. / Brain & Development 19 (1997) 176-180
Am ~litude (mV)
Threshold intensity (%) 110.
2.5-
1001
2.
9oi
1.5.
sol l.
7oi .5
6oi 5oi
0
40
,
,
1
,
,
,
3
,
,
,
,
,
5 7 9 Age (years)
,
,
11
,
,
13
,
,
Adult
Fig. 3. Age-dependent change in threshold intensity for transcranial magnetic stimulation shown as mean and standard deviation.
MEPs elicited by TMS, MEP latency was determined as the shortest onset latency, and MEP duration was measured as the longest interval between the onset and terminal latencies. MEP amplitude was defined as that between the two largest peaks of opposite polarity. Central motor conduction time (CMCT) was calculated by subtracting the MEP latency obtained by stimulation on C7s from the latency obtained by stimulation over the cortex.
3. Results MEPs were elicited by TMS in all children, except three of four children aged 1 year even with 100% stimulus intensity. Fig. 2 demonstrates typical examples of MEPs in childhood at 3 and 8 years of age, and the relationship between age and each component of the responses to magnetic stimulation is shown in Figs. 3-5. Threshold intensity for TMS, which was determined as more than 100% intensity for children aged 1 year, decreased almost linearly with age and reached an adult level (mean + standard deviation (SD) of control adults, 56.5 + 11.8%) at 13 years CMCT (ms) 22~ 2018.
14 12 10 8 6
.
1
,
,
3
,
.
5
,
,
,
,
7 9 Age (years)
,
,
11
.
,
13
,
,
Adult
Fig. 4. Age-dependent change in central motor conduction time shown as mean and standard deviation.
-.5
.........................................................................................................
,
1
,
,
3
,
,
5
,
,
,
,
7 9 Age (years)
,
,
11
,
,
13
.
.
Adult
Fig. 5. Relationship of amplitude of motor evoked potentials elicited by transcranial magnetic stimulation to age, shown as mean and standard deviation.
(Fig. 3). The latency of MEPs elicited by TMS (mean + SD of all subjects, 20.2 + 1.4 ms) was not influenced by age, while the latency of MEPs elicited by stimulation of the spinal roots increased linearly with age. As a result, CMCT was inversely correlated with age and fell below the adult mean (mean + SD of control adults, 8.90 + 0.85 ms) at 12 years of age (Fig. 4). The duration of MEPs elicited by TMS changed little with age (mean + SD of all subjects, 10.6 + 3.2 ms), and its maximum value was 15.9 ms in all the ages studied. The mean amplitude of MEPs elicited by TMS was less than 500 #V in almost all children aged between 1 and 9 years, while it tended to increase from 10 years, although the values varied widely even in adult individuals (mean + SD of control adults, 958 + 878/~V) (Fig. 5).
4. Discussion TMS activates the cortical motor neurons transsynaptically and produces multiple descending volleys via the corticospinal tracts [23-25]. Consequently, the anterior horn cells are depolarized by temporal summation of the multiple descending volleys. The previous studies in children were performed utilizing uncertain voluntary contraction of the target muscle [3,4] or with excessive stimulus intensity fixed as 100% intensity [5]; however, the reproducibility of MEPs elicited by TMS is markedly dependent on the degree by which stimulus intensity exceeds threshold intensity and the condition of the target muscle responsible for the excitability of the spinal neurons, in addition to whether or not the coil is positioned at the optimal site [23]. Therefore, to obtain comparable MEPs, we adjusted the stimulus intensity to an intensity 10% above each threshold intensity for TMS, and MEPs were recorded from a resting target muscle, since children cannot maintain a stable voluntary contraction of the studied muscle.
A. Nezu et al. / Brain & Development 19 (1997) 176-180
The present study demonstrates the developmental changes in threshold intensity for TMS, CMCT, and the amplitude of MEPs elicited by TMS, while their onset latency and duration were not influenced by age. Although Koh and Eyre, and Eyre et al. reported that MEPs failed to be evoked below the age of 6 years [3,4], we obtained reproducible MEPs from all children except those aged below 2 years, which almost coincided with the results reported by MOiler et al. [5]. Morphologically as shown in Fig. 2, MEPs are generally polyphasic in early childhood and gradually become triphasic. The present study suggests that electrophysiological maturation of the corticospinal motor pathways, which is defined as the condition of all parameters of MEPs reaching adult levels, is complete at the age of 13 years, and this maturational age was similar to that found in the previous papers [3-5]. Since developmental myelination of the pyramidal tracts is complete morphologically and on MR imaging by early childhood [26,27], these age-related changes occurring over 10 years appeared to be based more on the development of cortical synaptic efficacy (synaptogenesis) which continues to adolescence. The maturational age of the present motor responses to TMS was almost the same as that of early cortical responses of somatosensory evoked potentials and of movement-related cortical potentials [28-30], and these neurophysiological findings were considered to correspond with the age of acquisition of fine motor skills [31] and of reaching adult values of cortical metabolism shown by positron emission tomography study [32]. When the corticospinal pathways in adults are impaired, TMS parameters are reported to be altered as follows [33]: (i) prolonged CMCT, (ii) prolonged duration of MEPs due to temporal dispersion of the multiple descending volleys, (iii) elevated threshold intensity for TMS, and (iv) decreased MEP amplitude. The present study suggests that the clinical application of TMS in children aged 2 years and older is likewise useful for diagnosis of impairment of the corticospinal tracts. However, the procedure employed in this study was invalid for children below 2 years, since reliable MEPs could not be obtained. In children of 2 years and upward, prolonged CMCT is likely to be a helpful diagnostic clue, for example when CMCT increases to a mean value of each age added to more than 3.8 ms, since the largest SD value was 1.9 ms. The duration of MEPs, which was always less than 16 ms, also may be a useful parameter, if it is prolonged. For example, our earlier report showed that the MEP duration was significantly prolonged in a boy with subclinical involvement of the pyramidal tracts caused by adrenoleukodystrophy [34]. In contrast, threshold intensity for TMS may be less useful in children younger than 10 years, because of its higher mean value and variability between individuals, and the amplitude of MEPs is unlikely to be diagnostic because of its large intra- and inter-individual variability. In conclusion, we suggest that electrophysiological maturation of the corticospinal motor pathways is corn-
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plete at the age of 13 years. TMS may be a useful and convenient method for quantitative evaluation of electrophysiological development and impairment of the corticospinal motor pathways in children aged 2 years and older, while further detailed study is necessary to investigate the facilitating condition to elicit reliable MEPs for the clinical application of TMS in children below 2 years.
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