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Changes of cortical motor area size during immobilization
ELSEVIER
Elecfroencephalography
and clinical Neurophysiology
97 (1995) 382-386
Changes of cortical motor area size during immobilization J. Liepert
*,
M. Tegenthoff,
J.-P. Malin
Deparrment of Neurology, Ruhr Unioersity. Bochum, Germany Accepted for publication:
17 August 1995
Abstract Changes of motor cortex organization after lesions in the nervous system can be demonstrated by mapping the motor cortex with transcranial magnetic stimulation. We studied cortical plasticity in 22 patients who had a unilateral immobilization of the ankle joint without peripheral nerve lesion. The motor cortex area of the inactivated tibia1 anterior muscle diminished compared to the unaffected leg without changes in spinal excitability or motor threshold. The area reduction was correlated to the duration of immobilization. It could be quickly reversed by voluntary muscle contraction. This indicates a functional (and not morphological) origin of the phenomenon. Keywords:
Transcranial
magnetic
stimulation;
Motor area size; Immobilization
1. Introduction Reorganization in the motor system following lesions in the central or peripheral nervous system has gained wide interest within the last decade. Sanes et al. (1988) described changes in motor cortex areas within hours after facial nerve transection in rats. Since the development of transcranial magnetic stimulation (TMS; Barker et al., 198.5) the painless examination of human motor cortex has become possible. With help of the double coil (figure-ofeight coil) a rather focussed stimulation of the motor cortex can be performed. This mapping technique was shown to be reliable and reproducible (Wilson et al., 1993b; Mortifee et al., 1994). This method allowed to demonstrate changes in motor cortex organization after limb amputations (Cohen et al., 1991a; Fuhr et al., 1991, 1992) and transient regional anaesthesia of the forearm (Brasil-Neto et al., 1992b). The changes consisted mainly of increased motor areas of muscles proximal to the amputation, decreased motor thresholds and larger amplitudes. Similar reorganization was seen in patients with complete spinal cord injuries (Topka et al., 1991). These changes in
Corresponding author. Universidtsklinik la-Camp Platz 1, 44789 Bochum, Germany. ??
Bergmannsheil, Blirkle-deFax: 0234/3026810.
0924-980X/95/$09.50 0 1995 Elsevier Science Ireland Ltd. All rights reserved SSDIOOl3-4694(95)00194-8
motor cortex were preceded by lesions to neural structures - our main interest focussed on the question whether restriction of volitional movement can induce alterations in the size of cortical motor areas.
2. Patients The patient group consisted of 22 persons (17 males, 5 females) with a mean age of 39.2 years (range: 19-71 years). They all gave their informed consent for participation in the study which was approved by the local ethics committee. All patients were wearing a splint which stabilized one ankle joint, in most cases because of complicated fractures in distal parts of the tibia or due to talus fractures. The mean duration of immobilization was 16 weeks (range: O-60 weeks). Two of the patients were studied within 24 h after the splint implantation. None of them had a neurological illness; especially a peroneal nerve lesion was excluded by clinical, electroneurographical and - if necessary - electromyographical examination. Long-term immobilization induces a disuse atrophy. Nevertheless, the tibia1 anterior muscle could be identified easily in all patients. None of the patients was allowed to use or to put a strain to the injured leg. Our control group consisted of 10 healthy persons (7 males, 3 females) with a mean age of 32.3 years (range: 19-60 years).
EEM 94758
J. Liepert et al./Electroencephalography
and clinical Neurophysiology 97 (1995) 382-386
383
3. Methods Transcranial magnetic stimulation (TMS) was performed with a Magstim 200 HP device (The Magstim Co.) and a figure-of-eight coil (outside diameter 8.7 cm, peak magnetic field strength: 2.2 Tesla, peak electric field strength: 660 V/m; The Magstim Co.) which predominantly stimulates neural structures under its centre. Motor evoked potentials (MEPs) were recorded with surface electrodes from the tibia1 anterior muscle on both sides and stored on an EMG machine (Neuropack 8, Nihon Kohden). The bandpass was 20 Hz-3 kHz, gain: 0.1-l mV/div. The magnetic stimuli were delivered while the patients were lying comfortably on a couch. The muscle relaxation was monitored with a loudspeaker connected to the recording unit. Stimulus intensity was 1.3 above the individual motor threshold. Threshold stimulus intensity was reached when 3 MEPs could be evoked out of 6 trials (amplification: 0.1 mV/div). Two to 5 stimuli were applied to each position. In each patient and control person both hemispheres were examined. Starting at the vertex, the motor cortex was examined in anterior, posterior and lateral directions in steps of 1 cm until no further MEP could be elicited. The direction of the coil was kept steady with the grip pointing backwards. The positions were identified with help of a tight fitting cap with a co-ordinate system on it. The areas from which potentials could be evoked were calculated and were presented as a ratio (motor cortex area of the tibia1 anterior muscle of the injured leg/motor cortex area of the tibia1 anterior muscle of the unaffected leg) in order to simplify the comparison with the control group. In a subgroup of 3 patients and of 3 healthy controls potentials were recorded at rest and during slight pre-innervation. Both peroneal nerves were also stimulated with supramaximal electrical shocks. F waves and M responses were
4
18 cm’
T
5
+
6
’
area of both tibia1 anterior
registrated and the ratio of the F wave amplitude/M response amplitude was calculated in order to assess the excitability of the spinal motor neurone, as already described by other authors (e.g. Eisen, 1987; Fisher et al., 1994). Statistical analysis was performed with the Wilcoxon test and the Spearman rank correlation coefficient.
4. Results The intraindividual comparison of left and right motor area size of the tibia1 anterior muscle showed that the areas were almost identical in the healthy control group. Ratio (motor cortex area of right tibia1 anterior muscle/left tibia1 ant. muscle): 1.01 + / - 0.08. The mean area amounts to 20.9 + / - 4.5 cm*, the range was 13.5-28 cm* (for example: Figs. 1 and 2). During pre-innervation ratios had a range from 0.96 to 1.05. In patients with a lower leg immobilization for at least 4 weeks the mean motor cortex area of the unaffected tibia1 anterior muscle was similar to that of the control group (22.6 + / - 4.8 cm*) whereas the area size of the immobi-
cm
18,s cm’
Table 1 Ratios of motor cortex area
vertex : point of ulterseetion Fig. 1. Motor cortex control.
Fig. 2. Original recordings of motor evoked potentials in a healthy control. Left side: recordings from the right tibia1 anterior muscle after magnetic stimulation of the left hemisphere. Right side: recordings from the left tibia1 anterior muscle. Midline: the demonstrated potentials belong to the right tibia1 anterior muscle; left-sided recordings arc not shown because of limitation in space.
muscles
in a healthy
Left-sided immobilized patients (n = 14) Right-sided immobilized patients (n = 8) Left- and right-sided immobilized patients (n = 22)
0.66+/-0.17 0.55 + / - 0.11 0.61 + / - 0.21
J. Liepert et al./ Eiectroencephalography
384
and clinical Neurophysiology Ratio
97 (1995)
(immob./unaffecled
382-386 leg)
1.2
0 -I
~~~-
i
1 100
1 vvLs r . 0.86
(p ( 0.01)
Fig. 4. Motor cortex area of tibia1 anterior immobilized ankle joint (n = 22).
izE%
motor
w:
motor
cortex cortex
area
of the
immobilized
area
of the
unaffected
muscle muscle
Fig. 3. Motor cortex areas of both tibia1 anterior muscles in a patient with unilateral immobilization of the ankle joint since 8 weeks.
lized muscle was significantly reduced (13.5 + / - 9.2 cm*, P < 0.01). The ratio (area of the injured leg/area of the unaffected leg) was 0.61 + / - 0.21 which means a significant decrease compared to the ratios of the control group (P < 0.01). In 14 patients the left leg was immobilized, the other 8 patients had an immobilization for the right ankle joint. Quotients did not differ significantly (Table 1). Thus right- and left-sided immobilized patients were considered as one group. Taking the duration of immobilization into consideration, there was a significant tendency (P < 0.01) towards further decrease of motor cortex area size with a long-term immobilization (r = 0.66), whereas the ratios were normal within the first 9 days after the operation (Fig. 4). The projection of both motor cortex areas on top of each other (Fig. 3) showed that motor area reductions of the immobilized muscle were most prominent in lateral parts of the skull but not near to the midline. Those 3 patients who were also studied during pre-innervation (dorsiflexion of both feet) showed a normalization in area size or even an enlargement on the affected side (Table 2).
Table 2 Three patients studied at rest and during pre-innervation
Patient 1 Patient 2 Patient 3
Ratio of mot. cortex area at rest
Ratio of mot. cortex area during pre-innerv.
0.78 0.60 0.66
0.91 1.15
1.23
muscle
in patients
with
This might be explained by the patient’s difficulty to maintain a steady pre-innervation. They tended to overactivate the immobilized muscle. Concerning the motor thresholds no clear difference was found in intraindividual comparisons: 43% of the patients had an identical motor threshold on both sides, in 28.5% the motor threshold for the immobilized muscle was increased, in 28.5% the threshold of the unaffected leg was increased compared to the other side. The amplitudes of the M response were slightly decreased on the affected side (8 1% of the unaffected leg) which is probably due to an immobilization-induced discrete loss of muscle volume. Most certainly this side-to-side difference has no important influence on the cortical area size as 4 patients with discrete enlargements of the M response amplitudes on the affected side also had a reduced ratio in cortical motor area size (mean: 0.64). The ratio of F wave amplitude/M response amplitude was not significantly different between the immobilized and unaffected leg (0.068 + / - 0.04 versus 0.047 + / - 0.02; P > 0.05).
5. Discussion Our results indicate that healthy individuals have an almost identical motor cortex area size of the tibia1 anterior muscle on both hemispheres. A similar finding was reported previously by Cohen et al. (1991b) and Wilson et al. (1993b) for the abductor pollicis brevis muscle. As there is some interindividual variability in area size, it is reasonable not to compare absolute values but to choose a ratio when looking for unilateral changes. Patients with an immobilized lower leg (and without any evidence of a nerve lesion) showed no significant difference in area size within the first days of immobilization but there was a significant decrease of motor cortex area size for the inactivated muscle after 4-6 weeks of immobilization. These changes became even more distinct with a longer duration of immobilization. The effect was not correlated with a change in spinal excitability as determined by the F
J. Liepert et al. /Electroencephalography
wave/M response ratio. A similar result was seen by Fuhr et al. (1992) who did not find changes in H/M ratio in patients with lower limb amputation. Pre-innervation was able to reduce side-to-side differences, thus showing a “re-occupation” of the cortical motor area by the now activated muscle. These results are consistent with a rapid change in synaptic thresholds and underline that these findings are functional. Our patients did not exhibit consistent increases in motor thresholds. In contrast to this, other investigators have described a decreased motor threshold in enlarged motor cortex areas following lesions of the central or peripheral nervous system. From experiments with rats it is known that motor cortex areas show rapid reorganization within hours after facial nerve transection (Sanes et al., 1988). Stimulation thresholds were found to be at or below normal levels (Sanes et al., 1990). One possible reason for the similar motor thresholds in our patients is that the threshold was determined at the optimal site of excitation where threshold-increasing influences might be smallest. At the borders of the area inhibitory influences might be more prominent, thus preventing a MEP to be evoked. Wilson et al. (1993a) demonstrated that inhibitory influences (area of silent period) surround the excitatory area; Wassermann et al. (1993) found a tight neighbourhood between inhibitory and excitatory responses to TMS in a hand muscle. Similar results were found by intracortical microstimulation in monkeys (Schmidt and McIntosh, 1990). Jacobs and Donoghue (1991) blocked cortical inhibition pharmacologically and found an expanded cortical area from which movements could be evoked by stimulation. They concluded that intracortical inhibition forms a substrate for reorganization of cortical maps. Summarising, topographically connected regions of inhibition and excitation could be in close exchange and therefore be able to modulate the area of motor outputs. What might induce an enhanced inhibition? Brasil-Neto et al. (1992b), who found higher amplitudes and lower thresholds in proximal muscles during regional anaesthesia of the forearm, suggested that deafferentation caused these changes. In chronically immobilized patients similar mechanisms might work: the afferent impulse rate from joint and skin receptors and spindle fibres is reduced as the activity of the tibia1 anterior muscle is markedly reduced, the ankle joint is not stretched and the foot does not touch the ground. We did not take amplitudes into consideration because an accurate and reproducible result can only be achieved with a higher number of stimuli as the variability of MEP amplitudes increases with suboptimal positions (BrasilNeto et al., 1992~) and the patient’s state of well-being did not always allow testing for longer periods of time. Besides, especially amplitudes can be influenced easily by other factors, e.g. the coil position. Different research groups have studied the importance of coil orientation for TMS by examining hand muscles (Mills et al., 1992;
and clinical Neurophysiology
97 (1995) 382-386
385
Pascual-Leone et al., 1994; Brasil-Neto et al., 1992a; Werhahn et al., 1994) finding that the best orientation for the induced current is approximately perpendicular to the line of the central sulcus. Instead there are only rare observations concerning the optimal orientation for mapping areas responsible for lower extremities. Amassian et al. (1992) reported a model where equal results with a transversely orientated figure-of-eight coil and a tangentially orientated round coil were found. In order to reduce variability we chose a stimulus intensity clearly above the motor threshold and kept the coil in the same tangential position (grip pointing backwards) for both hemispheres. In 1993, Pascual-Leone et al. reported results of a study with blind Braille readers; they found an enlarged motor cortex area of the first dorsal interosseous muscle in the reading finger compared to the other hand and to a control group (Pascual-Leone et al., 1993). Motor thresholds did not differ significantly. This result suggests that training and learning may enlarge the cortical representation. Our own results are in correspondence with these findings by pointing into the opposite direction: the lack of training and activation leads to a reduction of cortical representation. Possibly a decreased afferent impulse rate and an increase of inhibition, especially in the borders of the area, are responsible for these changes. They are quickly reversible by voluntary muscle contraction which indicates that these changes are functional (and not morphological). Our results show that motor cortex reorganization occurs during immobilization without lesions of nerve structures and is independent of age, thus giving another insight into the plasticity of the brain.
References Amassian, V.E., Eberle, L., Maccabee,
P.J. and Cracco, R.Q. (1992) Modelling magnetic coil excitation of human cerebral cortex with a peripheral nerve immersed in a brain-shaped volume conductor: the significance of fiber bending in excitation. Electroenceph. clin. Neurophysiol., 85: 291-301. Barker, A.T., Freeston, I.L., Jalinous, R., Merton, P.A. and Morton, H.B. (1985) Magnetic stimulation of the human brain. J. Physiol. (Land.), 369: 3P. Bras&Neto, J.P., Cohen, L.C., Panizza, M., Nilsson, J., Roth, B.J. and Hallett, M. (1992a) Optimal focal transcranial magnetic activation of the human motor cortex: effects of coil orientation, shape of the induced current pulse and stimulus intensity. J. Clin. Neurophysiol., 9: 132-136. Brasil-Neto, J.P., Cohen, L.G., Pascual-Leone, A., Jabir, F.K., Wall, R.T. and Hallett, M. (1992bJ Rapid reversible modulation of human motor outputs after transient deafferentation of the forearm: a study with transcranial magnetic stimulation. Neurology, 42: 1302-1306. Bras&Neto, J.P., McShane, L.M., Fuhr, P., Hallett, M. and Cohen, L.G. (1992~) Topographic mapping of the human motor cortex with magnetic stimulation: factors affecting accuracy and reproducibility. Electroenceph. clin. Neurophysiol., 85: 9-16. Cohen, L.G., Bandinelle, S., Findley, T.W. and Hallett, M. (1991aJ Motor reorganization after upper limb amputation in man. Brain, 114: 615627.
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J. Liepert et al./ Electroencephalography and clinical Neurophysiology 97 (1995) 382-386
Cohen, L.G.. Roth, B.J., Wassermann, E.M., Topka, H., Fuhr, P., Schultz, J.and Hallett, M. (1991b) Magnetic stimulation of the human cerebral cortex, an indicator of reorganization in motor pathways in certain pathological conditions. J. Clin. Neurophysiol., 8: 56-65. Eisen, A. (1987) Electromyography in disorders of muscle tone. Can. J. Neurol. Sci., 14 (Suppl. 3): 501-505. Fisher, M.A., Hoffen, B. and Hultman, C. (1994) Normative F wave values and the number of recorded F waves. Muscle Nerve, 17: 1185-1189. Fuhr, P., Cohen, L.G., Roth, B.J. and Hallett, M. (1991) Latency of motor evoked potentials to focal transcranial stimulation varies as a function of scalp positions stimulated. Electroenceph. clin. Neurophysiol., 81: 81-89. Fuhr, P., Cohen, L.G., Dang, N., Findley, T.W., Haghighi, S., Oro, J. and Hallett, M. (1992) Physiological analysis of motor reorganization following lower limb amputation. Electroenceph. clin. Neurophysiol., 85: 53-60. Jacobs, K.M. and Donoghue, J.P. (1991) Reshaping the cortical motor map by unmasking latent intracortical connections. Science, 251: 944947. Mills, K.R., Boniface, S.J. and Schubert, M. (1992) Magnetic brain stimulation with a double coil: the importance of coil orientation. Electroenceph. clin. Neurophysiol., 85: 17-21. Mortifee, P., Stewart, H., Schuler, M. and Eisen, A. (1994) Reliability of transcranial magnetic stimulation for mapping the human motor cortex. Electroenceph. clin. Neurophysiol., 93: 131-137. Pascual-Leone, A., Cammarota, A., Wassermann, E.M., Brasil-Neto, J.P., Cohen, L.G. and Hallett, M. (1993) Modulation of motor cortical outputs to the reading hand of Braille readers. Ann. Neurol., 34: 33-37. Pascual-Leone, A., Cohen, L.G., Brasil-Neto, J.P. and Hallett, M. (1994) Non-invasive differentiation of motor cortical representation of hand
muscles by mapping of optimal current directions. Electroenceph. clin. Neurophysiol., 93: 42-48. Sanes, J.N., Suner, S., Lando, J.F. and Donoghue, J.P. (1988) Rapid reorganization of adult rat motor cortex somatic representation patterns after motor nerve injury. Proc. Nat. Acad. Sci. (USA), 85: 2003-2007. Sanes, J.N., Suner, S. and Donoghue, J.P. (1990) Dynamic organization of primary motor cortex output to target muscles in adult rats. Long-term patterns of reorganization following motor or mixed peripheral nerve lesions. Exp. Brain Res., 79: 479-491. Schmidt, E.M. and McIntosh, J.S. (1990) Microstimulation mapping of precentral cortex during trained movements. J. Neurophysiol., 64: 1668-1682. Topka, H., Cohen, L.G., Cole, R.A. and Hallett, M. (1991) Reorganization of corticospinal pathways following spinal cord injury. Neurology, 41: 1276-1283. Wassermann, E.M., Pascual-Leone, A., Valls-Sole, J., Toro, C., Cohen, L.G. and Hallett, M. (1993) Topography of the inhibitory and excita tory responses to transcranial magnetic stimulation in a hand muscle. Electroenceph. clin. Neurophysiol., 89: 424-433. Werhahn, K.J., Fong, J.K.Y., Meyer, B.U., Priori, A., Rothwell, J.C., Day, B.L. and Thompson, P.D. (1994) The effect of magnetic coil orientation on the latency of surface EMG and single motor unit responses in the first dorsal interosseous muscle. Electroenceph. clin. Neurophysiol., 93: 138-146. Wilson, S.A., Thickbroom, G.W. and Mastaglia, F.L. (1993aJ Topography of excitatory and inhibitory muscle responses evoked by transcranial magnetic stimulation in the human motor cortex. Neurosci. Lett.. 154: 52-56. Wilson, S.A.. Thickbroom, G.W. and Mastaglia, F.L. (1993bJ Transcranial magnetic stimulation mapping of the motor cortex in normal subjects. J. Neurol. Sci., 118: 134-144.
Elecfroencephalography
and clinical Neurophysiology
97 (1995) 382-386
Changes of cortical motor area size during immobilization J. Liepert
*,
M. Tegenthoff,
J.-P. Malin
Deparrment of Neurology, Ruhr Unioersity. Bochum, Germany Accepted for publication:
17 August 1995
Abstract Changes of motor cortex organization after lesions in the nervous system can be demonstrated by mapping the motor cortex with transcranial magnetic stimulation. We studied cortical plasticity in 22 patients who had a unilateral immobilization of the ankle joint without peripheral nerve lesion. The motor cortex area of the inactivated tibia1 anterior muscle diminished compared to the unaffected leg without changes in spinal excitability or motor threshold. The area reduction was correlated to the duration of immobilization. It could be quickly reversed by voluntary muscle contraction. This indicates a functional (and not morphological) origin of the phenomenon. Keywords:
Transcranial
magnetic
stimulation;
Motor area size; Immobilization
1. Introduction Reorganization in the motor system following lesions in the central or peripheral nervous system has gained wide interest within the last decade. Sanes et al. (1988) described changes in motor cortex areas within hours after facial nerve transection in rats. Since the development of transcranial magnetic stimulation (TMS; Barker et al., 198.5) the painless examination of human motor cortex has become possible. With help of the double coil (figure-ofeight coil) a rather focussed stimulation of the motor cortex can be performed. This mapping technique was shown to be reliable and reproducible (Wilson et al., 1993b; Mortifee et al., 1994). This method allowed to demonstrate changes in motor cortex organization after limb amputations (Cohen et al., 1991a; Fuhr et al., 1991, 1992) and transient regional anaesthesia of the forearm (Brasil-Neto et al., 1992b). The changes consisted mainly of increased motor areas of muscles proximal to the amputation, decreased motor thresholds and larger amplitudes. Similar reorganization was seen in patients with complete spinal cord injuries (Topka et al., 1991). These changes in
Corresponding author. Universidtsklinik la-Camp Platz 1, 44789 Bochum, Germany. ??
Bergmannsheil, Blirkle-deFax: 0234/3026810.
0924-980X/95/$09.50 0 1995 Elsevier Science Ireland Ltd. All rights reserved SSDIOOl3-4694(95)00194-8
motor cortex were preceded by lesions to neural structures - our main interest focussed on the question whether restriction of volitional movement can induce alterations in the size of cortical motor areas.
2. Patients The patient group consisted of 22 persons (17 males, 5 females) with a mean age of 39.2 years (range: 19-71 years). They all gave their informed consent for participation in the study which was approved by the local ethics committee. All patients were wearing a splint which stabilized one ankle joint, in most cases because of complicated fractures in distal parts of the tibia or due to talus fractures. The mean duration of immobilization was 16 weeks (range: O-60 weeks). Two of the patients were studied within 24 h after the splint implantation. None of them had a neurological illness; especially a peroneal nerve lesion was excluded by clinical, electroneurographical and - if necessary - electromyographical examination. Long-term immobilization induces a disuse atrophy. Nevertheless, the tibia1 anterior muscle could be identified easily in all patients. None of the patients was allowed to use or to put a strain to the injured leg. Our control group consisted of 10 healthy persons (7 males, 3 females) with a mean age of 32.3 years (range: 19-60 years).
EEM 94758
J. Liepert et al./Electroencephalography
and clinical Neurophysiology 97 (1995) 382-386
383
3. Methods Transcranial magnetic stimulation (TMS) was performed with a Magstim 200 HP device (The Magstim Co.) and a figure-of-eight coil (outside diameter 8.7 cm, peak magnetic field strength: 2.2 Tesla, peak electric field strength: 660 V/m; The Magstim Co.) which predominantly stimulates neural structures under its centre. Motor evoked potentials (MEPs) were recorded with surface electrodes from the tibia1 anterior muscle on both sides and stored on an EMG machine (Neuropack 8, Nihon Kohden). The bandpass was 20 Hz-3 kHz, gain: 0.1-l mV/div. The magnetic stimuli were delivered while the patients were lying comfortably on a couch. The muscle relaxation was monitored with a loudspeaker connected to the recording unit. Stimulus intensity was 1.3 above the individual motor threshold. Threshold stimulus intensity was reached when 3 MEPs could be evoked out of 6 trials (amplification: 0.1 mV/div). Two to 5 stimuli were applied to each position. In each patient and control person both hemispheres were examined. Starting at the vertex, the motor cortex was examined in anterior, posterior and lateral directions in steps of 1 cm until no further MEP could be elicited. The direction of the coil was kept steady with the grip pointing backwards. The positions were identified with help of a tight fitting cap with a co-ordinate system on it. The areas from which potentials could be evoked were calculated and were presented as a ratio (motor cortex area of the tibia1 anterior muscle of the injured leg/motor cortex area of the tibia1 anterior muscle of the unaffected leg) in order to simplify the comparison with the control group. In a subgroup of 3 patients and of 3 healthy controls potentials were recorded at rest and during slight pre-innervation. Both peroneal nerves were also stimulated with supramaximal electrical shocks. F waves and M responses were
4
18 cm’
T
5
+
6
’
area of both tibia1 anterior
registrated and the ratio of the F wave amplitude/M response amplitude was calculated in order to assess the excitability of the spinal motor neurone, as already described by other authors (e.g. Eisen, 1987; Fisher et al., 1994). Statistical analysis was performed with the Wilcoxon test and the Spearman rank correlation coefficient.
4. Results The intraindividual comparison of left and right motor area size of the tibia1 anterior muscle showed that the areas were almost identical in the healthy control group. Ratio (motor cortex area of right tibia1 anterior muscle/left tibia1 ant. muscle): 1.01 + / - 0.08. The mean area amounts to 20.9 + / - 4.5 cm*, the range was 13.5-28 cm* (for example: Figs. 1 and 2). During pre-innervation ratios had a range from 0.96 to 1.05. In patients with a lower leg immobilization for at least 4 weeks the mean motor cortex area of the unaffected tibia1 anterior muscle was similar to that of the control group (22.6 + / - 4.8 cm*) whereas the area size of the immobi-
cm
18,s cm’
Table 1 Ratios of motor cortex area
vertex : point of ulterseetion Fig. 1. Motor cortex control.
Fig. 2. Original recordings of motor evoked potentials in a healthy control. Left side: recordings from the right tibia1 anterior muscle after magnetic stimulation of the left hemisphere. Right side: recordings from the left tibia1 anterior muscle. Midline: the demonstrated potentials belong to the right tibia1 anterior muscle; left-sided recordings arc not shown because of limitation in space.
muscles
in a healthy
Left-sided immobilized patients (n = 14) Right-sided immobilized patients (n = 8) Left- and right-sided immobilized patients (n = 22)
0.66+/-0.17 0.55 + / - 0.11 0.61 + / - 0.21
J. Liepert et al./ Eiectroencephalography
384
and clinical Neurophysiology Ratio
97 (1995)
(immob./unaffecled
382-386 leg)
1.2
0 -I
~~~-
i
1 100
1 vvLs r . 0.86
(p ( 0.01)
Fig. 4. Motor cortex area of tibia1 anterior immobilized ankle joint (n = 22).
izE%
motor
w:
motor
cortex cortex
area
of the
immobilized
area
of the
unaffected
muscle muscle
Fig. 3. Motor cortex areas of both tibia1 anterior muscles in a patient with unilateral immobilization of the ankle joint since 8 weeks.
lized muscle was significantly reduced (13.5 + / - 9.2 cm*, P < 0.01). The ratio (area of the injured leg/area of the unaffected leg) was 0.61 + / - 0.21 which means a significant decrease compared to the ratios of the control group (P < 0.01). In 14 patients the left leg was immobilized, the other 8 patients had an immobilization for the right ankle joint. Quotients did not differ significantly (Table 1). Thus right- and left-sided immobilized patients were considered as one group. Taking the duration of immobilization into consideration, there was a significant tendency (P < 0.01) towards further decrease of motor cortex area size with a long-term immobilization (r = 0.66), whereas the ratios were normal within the first 9 days after the operation (Fig. 4). The projection of both motor cortex areas on top of each other (Fig. 3) showed that motor area reductions of the immobilized muscle were most prominent in lateral parts of the skull but not near to the midline. Those 3 patients who were also studied during pre-innervation (dorsiflexion of both feet) showed a normalization in area size or even an enlargement on the affected side (Table 2).
Table 2 Three patients studied at rest and during pre-innervation
Patient 1 Patient 2 Patient 3
Ratio of mot. cortex area at rest
Ratio of mot. cortex area during pre-innerv.
0.78 0.60 0.66
0.91 1.15
1.23
muscle
in patients
with
This might be explained by the patient’s difficulty to maintain a steady pre-innervation. They tended to overactivate the immobilized muscle. Concerning the motor thresholds no clear difference was found in intraindividual comparisons: 43% of the patients had an identical motor threshold on both sides, in 28.5% the motor threshold for the immobilized muscle was increased, in 28.5% the threshold of the unaffected leg was increased compared to the other side. The amplitudes of the M response were slightly decreased on the affected side (8 1% of the unaffected leg) which is probably due to an immobilization-induced discrete loss of muscle volume. Most certainly this side-to-side difference has no important influence on the cortical area size as 4 patients with discrete enlargements of the M response amplitudes on the affected side also had a reduced ratio in cortical motor area size (mean: 0.64). The ratio of F wave amplitude/M response amplitude was not significantly different between the immobilized and unaffected leg (0.068 + / - 0.04 versus 0.047 + / - 0.02; P > 0.05).
5. Discussion Our results indicate that healthy individuals have an almost identical motor cortex area size of the tibia1 anterior muscle on both hemispheres. A similar finding was reported previously by Cohen et al. (1991b) and Wilson et al. (1993b) for the abductor pollicis brevis muscle. As there is some interindividual variability in area size, it is reasonable not to compare absolute values but to choose a ratio when looking for unilateral changes. Patients with an immobilized lower leg (and without any evidence of a nerve lesion) showed no significant difference in area size within the first days of immobilization but there was a significant decrease of motor cortex area size for the inactivated muscle after 4-6 weeks of immobilization. These changes became even more distinct with a longer duration of immobilization. The effect was not correlated with a change in spinal excitability as determined by the F
J. Liepert et al. /Electroencephalography
wave/M response ratio. A similar result was seen by Fuhr et al. (1992) who did not find changes in H/M ratio in patients with lower limb amputation. Pre-innervation was able to reduce side-to-side differences, thus showing a “re-occupation” of the cortical motor area by the now activated muscle. These results are consistent with a rapid change in synaptic thresholds and underline that these findings are functional. Our patients did not exhibit consistent increases in motor thresholds. In contrast to this, other investigators have described a decreased motor threshold in enlarged motor cortex areas following lesions of the central or peripheral nervous system. From experiments with rats it is known that motor cortex areas show rapid reorganization within hours after facial nerve transection (Sanes et al., 1988). Stimulation thresholds were found to be at or below normal levels (Sanes et al., 1990). One possible reason for the similar motor thresholds in our patients is that the threshold was determined at the optimal site of excitation where threshold-increasing influences might be smallest. At the borders of the area inhibitory influences might be more prominent, thus preventing a MEP to be evoked. Wilson et al. (1993a) demonstrated that inhibitory influences (area of silent period) surround the excitatory area; Wassermann et al. (1993) found a tight neighbourhood between inhibitory and excitatory responses to TMS in a hand muscle. Similar results were found by intracortical microstimulation in monkeys (Schmidt and McIntosh, 1990). Jacobs and Donoghue (1991) blocked cortical inhibition pharmacologically and found an expanded cortical area from which movements could be evoked by stimulation. They concluded that intracortical inhibition forms a substrate for reorganization of cortical maps. Summarising, topographically connected regions of inhibition and excitation could be in close exchange and therefore be able to modulate the area of motor outputs. What might induce an enhanced inhibition? Brasil-Neto et al. (1992b), who found higher amplitudes and lower thresholds in proximal muscles during regional anaesthesia of the forearm, suggested that deafferentation caused these changes. In chronically immobilized patients similar mechanisms might work: the afferent impulse rate from joint and skin receptors and spindle fibres is reduced as the activity of the tibia1 anterior muscle is markedly reduced, the ankle joint is not stretched and the foot does not touch the ground. We did not take amplitudes into consideration because an accurate and reproducible result can only be achieved with a higher number of stimuli as the variability of MEP amplitudes increases with suboptimal positions (BrasilNeto et al., 1992~) and the patient’s state of well-being did not always allow testing for longer periods of time. Besides, especially amplitudes can be influenced easily by other factors, e.g. the coil position. Different research groups have studied the importance of coil orientation for TMS by examining hand muscles (Mills et al., 1992;
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Pascual-Leone et al., 1994; Brasil-Neto et al., 1992a; Werhahn et al., 1994) finding that the best orientation for the induced current is approximately perpendicular to the line of the central sulcus. Instead there are only rare observations concerning the optimal orientation for mapping areas responsible for lower extremities. Amassian et al. (1992) reported a model where equal results with a transversely orientated figure-of-eight coil and a tangentially orientated round coil were found. In order to reduce variability we chose a stimulus intensity clearly above the motor threshold and kept the coil in the same tangential position (grip pointing backwards) for both hemispheres. In 1993, Pascual-Leone et al. reported results of a study with blind Braille readers; they found an enlarged motor cortex area of the first dorsal interosseous muscle in the reading finger compared to the other hand and to a control group (Pascual-Leone et al., 1993). Motor thresholds did not differ significantly. This result suggests that training and learning may enlarge the cortical representation. Our own results are in correspondence with these findings by pointing into the opposite direction: the lack of training and activation leads to a reduction of cortical representation. Possibly a decreased afferent impulse rate and an increase of inhibition, especially in the borders of the area, are responsible for these changes. They are quickly reversible by voluntary muscle contraction which indicates that these changes are functional (and not morphological). Our results show that motor cortex reorganization occurs during immobilization without lesions of nerve structures and is independent of age, thus giving another insight into the plasticity of the brain.
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