Cortical reorganization in patients with facial palsy

Cortical Reorganization in Patients with Facial Palsv Michel Rijntjes,* Martin Tegenthoff, MD,? Joachim Liepert, MD,? Georg Leonhardt, MD,$ Sylvia Kotterba, MD,? Stephan Muller, MD,$ Stephan Kiebel,* Jean-Pierre Malin, MD,? Hans-Christoph Diener, MD,+ and Cornelius Weiller, MD* zyxw zyxwvutsr zyx zyxw zy Possible changes in the organization of the cortex in patients with facial palsy, serving as a model of peripheral motor deefferentation, were investigated by using transcranial magnetic stimulation (TMS) and positron emission tomography (PET). With TMS, the size of the area producing muscle-evoked potentials (MEPs) of the abductor pollicis brevis muscle, the sum of MEP amplitudes within this area, and the volume over the mapping area were compared between both hemispheres in 8 patients. With PET, increases in regional cerebral blood flow, measured with the standard H,’50, bolus injection technique, were compared between 6 patients and 6 healthy volunteers during sequential finger opposition. Patients moved the hand ipsilateral to the facial palsy, the control subjects the right hand. Of 9 patients in total, 5 participated in both experiments. With both methods, an enlargement of the hand field contralateral to the facial palsy was found, extending in a lateral direction, into the site of the presumed face area. The PET data showed that the enlargement of the hand field in the somatosensory cortex (SMC) is part of a widespread cortical reorganization, including the ipsilateral SMC and bilateral secondary motor and sensory areas. We report for the first time, using two different noninvasive methods, that peripheral, mere motor deefferentation is a sufficient stimulus for reorganizational changes in the healthy adult human cortex. zyx Rijntjes M, Tegenthoff M, Liepert J, Leonhardt G, Kotterba S, Miiller S, Kiebel S, Malin J-P, Diener H-C, Weiller C. Cortical reorganization in patients with facial palsy. Ann Neurol 1997;41:621-630 The ability of the cortex to adapt to changing circumstances is called “cortical plasticity” or “cortical reorganization.” Recent studies on animals and humans have shown changes in cortical organization that are more extensive and rapid than previously thought based on static representations, as was suggested by the homunculus of Penfield and Jaspers [I]. Under normal conditions, noninvasive techniques like transcranial magnetic stimulation (TMS), positron emission tomography (PET), and functional magnetic resonance imaging (fMRI) seem to confirm the idea of stable cortical representations. In healthy humans, motor cortex areas of face, arm, and leg can be clearly distinguished by focal stimuli with TMS [2]. In PET studies in healthy volunteers, the hand area is consistently found between 44 and 64 mm above the intercommissural line (AC-PC line) [3]. However, Penfield’s findings have been challenged by the recent interpretation that the motor cortex acts as a complex network. Studies on the primary sensorimotor cortex (SMC), where a considerable overlap in finger representation has been found [4, 51, have been most revealing, since body representations in this re- gion were believed to be especially stable because of fixed anatomical connections [6, 71.Experiments to induce changes in cortical organization are essentially based on rwo principles. The first is to challenge the cortex to adapt to a different environment. Learning [8] and training [9] increases, immobilization [lo] decreases, the size of the hand field. Although the change of size in these experiments was larger than thought possible, somatotopic boundaries remained intact. The other principle of reorganization is found after peripheral or central nervous system lesions. Inside the hand area of monkeys, reorganization of representations has been shown after finger amputation [I 11 and artificial syndactyly [ 121. In humans, some studies have shown even more profound reorganization of the adult cortex, with representations crossing somatotopic boundaries. The clinical observation that some patients with arm amputation experience sensation of the missing hand after cutaneous stimulation of the face [13] was visualized by studies using PET, TMS [14], and magnetic encephalography [ 151. Face representation in such patients had come to include the fallow hand area, results that correspond to those obtained after up- From the Departments of Neurology at “University of Jena, tUniversiry of Bochum, and tUniversiry of Essen, and §Department of Nuclear Medicine, University of Essen, Germany. Address correspondence to Dr Rijntjes, Neurologische Klinik und Poliklinik der FSU Jena, Philosophenweg 3, 07740 Jena, Germany. zyxw zyxwvutsrqpo Received Feb 22, 1996, and in revised form JuI 22 and Oct 7. Accepted for publication Oct 7, 1996. zy zyxwv Copyright 0 1997 by the American Neurological Association 621 zyxwvut zyxwvutsrqp per limb amputation in primates [IG]. In these studies, cortical reorganization took place after combined sensory and motor deprivation. In rats, it has been demonstrated, after peripheral motor nerve lesion, that deefferentation alone can induce similar changes. O n e week to 4 months after facial nerve transection in adult rats, the forelimb area occupied t h e former vibrissae area on the motor cortex [17, 181. Complex reorganization occurs in patients recovered from stroke (for review, see Reference 19). In two of these studies [20, 211, a large lateral extension of the area activated during finger opposition was found in some patients, reaching well into the area supposedly representing the face. This lateral extension has been found as well in patients with amyotrophic lateral sclerosis when moving the paretic h a n d [22]. To further substantiate the finding of a lateral extension of the hand representation in the h u m a n brain, we designed the present study in patients with peripheral facial palsy. It was hypothesized that the motor representation of the hand would enlarge into the deefferented face representation, as indicated by changes of regional cerebral blood flow (rCBF) during finger movement, o r determined as the area from which motor response could be elicited with TMS. turbance of trigeminal function was found on clinical examination, confirmed by a normal contralateral orbicularis oculi reflex in each parient. In all patients, the facial palsy developed acutely; in the patients with parotic tumor or acoustic neurinoma, no facial weakness was apparent before surgery, but the facial nerve could not be spared intraoperatively. The patients did not suffer from other diseases of the nervous system. No patient received central acting drugs during the investigations. An MRI scan showed an intact brain in each patient. Transcranial Magnetic Stimulation TMS was performed with a Magstim 200 H P device (Magstim, Dyfed, UK) and a figure-eight coil (outside diameter, 8.7 cm; peak magnetic field strength, 2.2 T; peak electric field strength, 660 V/m), which stimulates predominately neural structures under its center. Motor-evoked potentials (MEPs) were recorded with surface electrodes from the contralateral abductor pollicis brevis muscle (APB) on both sides and stored on an electromyographic (EMG) machine (Neuropack 8, Nihon Kohden, Japan). The band pass was 20 Hz to 3 kHz, the gain 0.1 to 1 mVID. The magnetic stimuli were delivered while the patients were seated comfortably in a chair. During the whole examination, muscle relaxation was monitored with surface electrodes by EMG (gain, 0.1 mV/D). The lowest intensity producing a motor response in at least three of six trials (gain, 0.1 mV/D) was defined as threshold. Threshold was determined over that scalp position where TMS previously elicited the highest amplitude. Stimulus intensity was 1.2 times the intensity of the motor threshold. Up to five stimuli were applied to each position. The largest peak-to-peak amplitude was considered for statistical analysis. Amplitudes smaller than 10 IJ.V were considered as zero value. In each patient, both hemispheres were examined in random order. Starting at the vertex, the motor cortex was examined in rostral, dorsal, and lateral directions in steps of 1 cm until no fiirther MEP could be elicited. During the whole mapping procedure the coil was held steadily with the grip pointing backwards. The positions were identified with the help of a tight-fitting cap with a coordinate system that was positioned with the Cz-mark over the vertex using nasion, inion, and the preauricular areas as zyxwvutsr Patients and Methods Patients We studied 9 right-handed patients (5 males and 4 females; age, 25-73 years; mean age, 47 years) with a peripheral facial nerve palsy (Table 1). In 8 patients, TMS mapping studies were performed. Six patients were investigated by using PET. Five patients participated in the TMS mapping as well as in the PET studies. For comparison, an additional 6 healthy right-handed male subjects (age, 24-5 1 years) were studied as controls for the PET study, another 6 healthy righthanded male subjects (19-34 years) for the TMS study. Severity of facial palsy was graded according to the scoring system of House and Brackmann [23]. Duration and pathogenesis of the facial palsy are listed in Table 1 . N o dis- zyxwvuts zyxwvuts zyxwvu zyxwvu zyxwvu Table 1. Clinical Data of the Patients with Facial Palsy Patient Age (yr) Sex Side of Palsy Duration Cause" 40 41 F M F M F Left Left Right Left Right Left Right Right Left 3 yr 19 mo 12 yr 3 mo 4 mo 12 yr 36 yr 29 days 7 days Acoustic neurinoma Acoustic neurinoma Cholesteatoma Parotid tumor Acoustic neurinoma Herpes zoster Perinatal Idiopathic Idiopathic 55 67 39 73 36 44 25 M M F M Gradeb TMS PET X X X X X X X X X X X X X X "In the patients with facial palsy due to acoustic neurinoma or parotid tumor, no facial palsy was apparent before the operation. 'The extent of the facial palsy was graded after House and Brackmann [23], in which 0 = no palsy; 1 = mild palsy, no facial asymmetry at rest; 2 = moderate palsy, eye closure possible, obvious facial asymmetry at rest; 3 = severe palsy, incomplete eye closure, barely visible movement or tonus; 4 = total paralysis, no movement or ronus. .+ 1MS = transcranial tnagneric srimularion; PET = positron emission tomography. 622 Annals of Neurology Vol 41 No 5 May 1997 zyxwvutsrqp zyxwvutsrqpo zyxwvutsrqpon zy landmarks. The number of positions from which MEP could be elicited was calculated and expressed as an area where each position equals 1 cm2. In addition, the ratio (area of the hemisphere contralateral to the facial palsy divided by the area over the ipsilateral hemisphere), the centers of gravity (COGS),and the sum of MEP amplitudes (FV) were calculated for each hemisphere separately. The volume over the mapping area (cm2 * FV) was determined using an inverse distance interpolation and an integration formula. For comparison, the cortical representation areas of the APB muscle were mapped over both hemispheres in 6 healthy righthanded male subjects (19-34 years); the ratio (area of the left hemisphere divided by the area of the right hemisphere) was calculated. For statistical analysis, the Wilcoxon signed rank test, the Mann-Whitney U test, and Spearman’s rank correlation were used. The level of significance used for all tests was set at p < 0.05. Positron Emission Tomography rCBF was measured with an ECAT 953/15 PET scanner (CTI Inc, Knoxville, TN) after a slow bolus injection of maximal 700 MBq H2I5Oper application. After attenuation correction (using a transmission scan) the data were reconstructed into 15 transaxial planes by filtered back projection with a Hanning filter with cutoff frequency of 0.5 cycles/ pixel (1.96 mm pixel size), resulting in a full width half maximum (FWHM) resolution of 8 mm in the reconstructed image. The integrated counts accumulated were used as an index of rCBF [24]. Each subject underwent 12 consecutive measurements of rCBF. Six scans were performed at rest and six scans during the performance of finger movements of the hand ipsilateral to the facial palsy in the patients and with the right hand in the control subjects. The movements consisted of sequential opposition of the individual fingers to the thumb at a frequency of three oppositions every 2 seconds, paced by a metronome. Prior to scanning, all subjects practiced the task until movements were smooth and effortless. The rest scans and activation scans were performed alternately. T o compensate for auditory input, the metronome Table 2. Results of Transcranial Magnetic Stimulation Quotient (CH/IH) Patient CH IH 1 2 3 4 26 27 24 35 20 15 31 25 25.4 2 6.2 15 1.73 23 23 14 14 12 23 20 18.0 t 4.7 1.17 1.04 8 Average of all patients zyxwvutsrq zyxwv Sum of Amplitudes (w v ) Area (cm’) 5 6 7 was also on during the rest scans. This task leads to a robust increase in rCBF in normal subjects [25]. Due to the small axial field of view of the camera (5.4 cm), the gentry was oriented to include the upper part of the brain including the supposed hand area in its upper part. In effect, data were available for all subjects from 16 to 52 mm in the standard space. The scans of each individual were realigned to each other to correct for interscan movement artifacts. A threedimensional (3D) MRI of the brain was obtained for all subjects. An averaged image of the 12 PET runs was reoriented to the individual 3D MRI scan using statistical parametric mapping (MRC Cyclotron Unit, Hammersmith Hospital, London, UK). The parameters thus obtained were used to transform all 12 PET scans to the MRI space. PET and MRI data of those patients with left-sided palsy were flipped in the sagittal plane to enable comparison with the control subjects. The 3D MRI scans of each individual, after being stripped of noncerebral structures and aligned to the intercommissural line by using interactive image display software (ANALYZE, Biodynamic Research Unit, Mayo Clinic, Rochester, MN), were brought into the standard anatomical space of Talairach and Tournoux [26], so that comparison between individuals was possible using SPM software [27]. Using parameters for this transformation as a guide, the individual PET scans were brought into this normalized space as well [28]. The PET images were smoothed with a Gaussian filter of 10 X 10 X 6 m m for individual and at 20 X 20 X 12 mm for group comparisons. The blood flow in each voxel thus corresponded to a weighted mean rCBF centered on a spherical domain 10 mm (20 mm, respectively) in diameter. Global flow differences between the scans were normalized to a mean of 50 ml/dl/min by analysis of covariance with measured global flow as covariate [29]. Statistical significant differences between conditions were assessed using the general linear model and SPM 95 software ( p < 0.05, corrected for multiple comparisons) [28]. The study was approved by the ethics committee. All subjects gave written informed consent to the study. 2.5 1.43 1.25 1.35 1.25 1.47 CH IH Threshold Intensity Volume (cm’ x p,V) IH CH 3,934 2,002 2,009 39,018 6,212 37,638 1,666 2,040 2,045 33,997 2,267 33,985 832 1,420 1,413 8,562 2,225 8,565 27,990 5,692 27,993 12,404 21,805 12,400 2 0.44 15,929 2 15,440 5,579 ? 6,829 15,755 3,930 6,210 1,656 2,254 826 2,220 5,704 21,800 15,150 5,575 (YO) CH 60 37 31 41 45 44 43 65 ? 6,830 45.8 -t 11.3 IH 62 42 33 51 48 43 39 66 48.0 2 11.3 zyxwvutsrqp ( p < 0.05) ( p = 0.16) * ( p = 0.16) ( p = 0.17) zyx Individual values and average results of area, quotient, sum of amplitude, volume, and threshold intensity after transcranial magnetic stimulation mapping of patients with facial palsy. Values are given for contralateral (CH) and ipsilateral hemisphere (IH) with respect to the facial palsy. Patients 4-8 also participated in the positron emission tomography study. Rijntjes et al: Reorganization in Facial Palsy 623 zy zyx A 11 1111 1111111 zyxwvutsrq zyxwvutsrqpo 111 11111 111111 1I 1111I 1 11111111 -”11111 ”””1111 1111 palsy (grades 3 and 4 ) showed a significant lateralization of the COG contralateral to the facial palsy ( p = 0.037), whereas this was not found in patients with discrete symptoms (Table 3 ) . Therefore, the whole patient group only showed a nonsignificant trend of COG lateralization. A trend, but no significant increase, was observed for the sum of amplitudes and volume, mainly because of the large standard deviation. Threshold intensity showed a trend but no significant decrease over the contralateral hemisphere. The subgroup of 5 patients that also took part in the PET investigation showed identical statistical results concerning area size, ratios, COGS,sum of amplitudes, volume, and threshold intensities. 1111111 111111 11111 Positron Emission Tomogvdphy In the normal subjects as a group, rCBF increased in the contralateral hand field of the SMC during fractionated finger movements, as was expected, with the center of activation at 52 mm above the AC-PC line, ranging from 40 to 60 mm (Table 4). The supplementary motor area (SMA) in the medial premotor cortex was activated from 44 to 52 mm, which is in line with previous PET studies [ 3 , 251 (Fig 2). The patients as a group activated the contralateral SMC to a much larger extent compared with the control subjects when the hand ipsilateral to the facial palsy was moved, including both the hand representation and part of the presumed face representation (range, 20-52 mm) (Fig 3). Two peaks of rCBF increases were found, at 44 and at 32 mm, respectively. The size of activation in the SMC in patients, calculated as the number of voxels, was 1.5 times the size of activation in the control group. Direct comparison between the two groups showed the larger part of this difference benveen 20 and 48 mm above the intercommissural line, centered around the maximum at 36 GROUP RESULTS. zyxwvutsrqp Fig 1. Areas on the scalp in the group of patients with facial palsy fiom whom motor-evoked potentials could be recorded fiom the contralateral hand. CH = contralateral hemisphere; IH = ipsilateral hemisphere. One black square represents I cm2, measured f ; o m the vertex (cross). Results Ttznscruniul Magnetic Stimulation In the healthy subjects, the mean area ratio (left hemisphere/right hemisphere) was 1.01 ? 0.08. Considering 2.5 SD as a range of normal values, 6 of 8 patients showed a ratio beyond this limit, thus indicating an enlargement of the area contralateral to the facial palsy. This result was statistically significant for the group of patients (Table 2). The enlargement extended in a lateral direction (Fig 1). When comparing the COGSover both hemispheres, patients with a more severe facial Table 3. Results of Transcranial Magnetic Stimulation (Center COG: Contralateral Hemisphere .. ~ _ _ zyxwvuts Gravity (COG]) of ~ ~ COG:Ipsilateral Hemisphere _ _ _ ~ Patient x Coordinate y Coordinate x Coordinate y Coordinate 5 7 1.76 -2.42 1.54 I .04 0.32 2.04 -2.15 -0.92 -0.29 1.64 5.24 7.55 5.26 7.69 5.54 6.1 6.06 4.85 6.04 1.00 -1.8 -0.12 1.05 0.1 -0.3 1.32 -1.04 -0.68 -0.18 0.97 6.14 5.76 2.93 5.43 3.9 6.74 6.3 5.87 5.38 1.22 2 4 6 1 3 8 Mean SD - Grade“ zyxwvutsrqp zyxwvutsrqp Center of gravity (COG)is given in x a n d y coordinates for the contralateral and ipsilateral hemisphere with respect to the facial palsy. “Grade: Grade of the facial palsy according to House and Brackman [23] (see Table 1). For explanation see text. 624 Annals of Neurology Vol 41 No 5 May 1997 zyxwvutsr zyxwv zyxwv zyxwvutsrqpo Table 4. Results of the PET Study (Group Study) ~ zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA Normals Patients X Contralateral SMC -40 -46 -24 -56 -8 Range: 20-52 Size: 1,397 36 -20 Range: 20-52 44 32 9.40 6.65 48 6.13 -40 -38 48 10.06 -8 -6 48 -60 -2 28 6.49 6.41 -32 -68 -2 32 48 36 4.88 5.03 5.53 z Score x -22 52 9.74 Ipsilateral -2 z Score z Range: 40-60 Size: 984 SMC Contralateral BA 40 BA 7 SMA BA 6 z Y -4 48 5.20 Y Patients vs Normals Y z z Score -10 36 6.42 Range: 20-48 Size: 572 34 -24 Range: 20-48 48 5.43 -44 -22 40 48 7.0 1 4.75 24 4.33 44 44 32 3.38 4.46 4.36 x - - 52 -40 -68 62 2 Ipsilateral BA 40 BA 7 BA 6 58 22 54 32 22 56 -52 -68 -4 Brain regions with changes in regional blood flow in the comparison of fractionated finger movement against rest in the control group, in patients with facial palsy and in patients as compared with the control group are reported as coordinates ( y z ) in the standard stereotactic space [26] with corresponding z scores. Range is in millimeters above the intercommissural line. Size is number of significant voxels in the contralateral sensorimotor cortex accivared by the task. PET = positron emission tomography; SMC = sensorimotor cortex; BA 40 = parietal association cortex; BA 7 cortex; SMA = supplementary motor area; BA 6 = lateral premotor cortex. mm. Ipsilateral SMC showed significant increases as well, with an enlargement (20-52 mm) similar to that in the contralateral SMC, but with the maximum more rostrally (48 mm). There were strong increases in bilateral parietal association areas (Brodmann area [BA] 40), SMA, lateral premotor cortex (BA 6 ) , and in ipsilateral posterior parietal cortex (BA 7). The increases in both the contralateral SMC ( 2 0 4 4 mm) and the = posterior parietal association ipsilateral SMC (20-48 mm), in the contralateral lateral premotor cortex (BA 6) and in the bilateral parietal association area (BA 40), were significantly stronger in patients than in the controls in a direct group-to-group comparison in amplitude as well as extent. T o exclude the possibility that the variances in the rest states in the normal subjects was greater than those of the patients, making it easier to reach a significant Fig 2. Projection of statistically sign;ficant areas measured with positron emission tomography during righthanded finger opposition j o m the group of normal volunteers on transparent sagittal, coronal, and transverse views of the normalized brain. Rijntjes et al: Reorganization in Facial Palsy 625 zy zyx zyxw Fig 3. Projection of statistically signijcant areas measured with positron emission tomography during righthandedjnger opposition fiom the group of patients with right-sided facial pahy on transparent sagittal, coronal, and trunsverse views of the normalized brain, showing h e r d extension of the activation in the sensorimotor cortex and additional activation of secondary sensorimotor areas. activation in the patients, a post hoc comparison of rest states between the group of patients and healthy subjects for significant voxels was performed. The result showed that the variances were not greater in the rest states of the normal subjects than in the patients. INDIVIDUAI. PATIENTS. In Patient 9, who was examined 7 days after the onset of facial palsy, activation in the contralateral SMC was found in the normal hand field (Table 5). However, in each of the other patients, studied as single subjects, the activation consistently ex- tended laterally, down to 24 to 36 mm above the AC-PC line (Fig 4). No relation was found between the duration of the facial palsy (from 29 days to 36 years) in these patients and the size of the lateral extension. Patients 4 to 8 showed strong ipsilateral SMC activation, with a wider variation in size and local maximum than the activation on the contralateral side. Secondary motor and sensory areas showed significant increases in activation in all but the last patient. The strongest activation was found in contralateral BA 40. zyxwvu zyx zyxwvutsr Table 5. Results o f the PET Study (Individual Patients) Patient ~ Contralateral SMC Ipsilateral SMC Contralateral BA 40 BA 7 SMA BA 6 lpsilateral BA 40 BA 7 BA 6 Y z z Score x -48 -20 Range: 32-56 30 -34 Range: 32-56 48 3.60 52 4.40 -46 -20 Range: 28-64 30 -18 Range: 48-68 -34 48 5.22 Y X -38 38 -66 40 3.96 44 -12 44 4.11 -34 -30 -6 -34 24 26 ~~ No. 6 No. 5 No. 4 z z Score x 56 5.36 56 3.76 -32 -56 -4 -6 44 56 64 60 5.12 4.23 5.27 5.66 -72 -12 52 48 4.67 4.57 Y Score z z -48 -18 Range: 32-48 52 -6 Range: 20-44 36 5.30 28 4.14 -38 -32 44 3.64 -50 -10 40 4.18 -6 32 4.27 56 Brain regions with changes in regional blood flow in the comparison of fractionated finger movement against rest in the individual patients are millimeters above the intercommissural line. PET 626 = positron emission tomography; SMC = sensorimocor cortex; BA 40 Annals of Neurology Vol 41 No 5 May 1997 = parietal association cortex; BA 7 = posterior parietal association zy zyxwvutsr Other secondary areas included lateral premotor cortex and BA 7 bilaterally, and SMA contralaterally. All these differences were significant when compared with the group of control subjects. Discussion Patients with facial palsy activate a larger part of the cortex than normal volunteers when making fractionated finger movements, as measured with PET, and potentials of the abductor pollicis brevis muscle can be elicited from a larger part of the contralateral than from the ipsilateral cortex after TMS. The most striking finding was a lateral extension of the hand area within the contralateral SMC. However, reorganizational changes were found in other areas, eg, bilateral secondary somatosensory areas and ipsilateral SMC. This reorganization occurred even if the motor deefferentation was not complete, ie, in those patients with incomplete facial palsy. With TMS mapping, the amplitude parameters revealed a trend to enhanced amplitudes over the hemisphere contralaterally to the facial palsy. The lack of statistical significance is due to the common large interindividual variability of TMS amplitudes 1301. Nevertheless, the combination of increased amplitudes and decreased stimulus intensities over the hemisphere contralateral to the facial palsy indicates an enhanced excitability of this small hand muscle motor area. Consistent with TMS, fractionated finger movements in patients led to a larger activation in the contralateral SMC, as measured with PET. Local maxima were found in the hand area (44 mm above the intercommissural line) and in the supposed face area (32 mm) [ l , 311. Direct comparison between patients and normal subjects showed this additional activation to be in the face area (36 mm). The lateral extension in this study comprised the same area found in previous studies in recovered stroke patients with a posterior lesion of the internal capsula, sparing the corticobulbar fibers destined for facial movement [2O, 211, or in patients with amyotrophic lateral sclerosis without bulbar involvement when moving the paretic hand [22]. Whereas in these latter studies the lateral extension may reflect compensatory mechanisms to move the paretic hand, in our study the cortical representation of the healthy limb extended into a neighboring deefferented area in an intact brain. Also, our finding is complementary to previous studies [14, 321, in which an expansion of the face representation into the hand area was found. However, in the latter studies a combined sensory and motor lesion was present. Apparently, reorganizational processes in the motor cortex can occur after central or peripheral deefferentation and deafferentation and with different underlying mechanisms. In the heterogeneous group, neither TMS nor PET showed a statistically significant correlation between the duration or intensity of the facial palsies and the extent of cortical area involved, but the lateral extension was present as early as 1 month after onset of the facial palsy. Animal studies provide little anatomical evidence to support the notion that the newly recruited neurons in the lateral extension in the SMC are somehow related to finger movements under normal conditions, since virtually no overlap between hand and face representations are reported. Horseradish peroxidase injections placed in the forelimb representation of monkeys, close to the physiologically defined face representation, re- zyxwvutsrq zyx zyxwvutsrq zyxwv Table 5. Continued Patient No. 7 X Y z z Score -36 -30 44 5.05 Range: 24-60 28 -14 44 -36 z z Score -18 48 3.97 Y z z Score -46 -20 48 3.47 - 52 4.00 Range: 40-52 None 48 4.89 4.45 28 -30 x 40 Range: 40-56 52 4.52 - 36 -42 zyxwvutsrqp zyxwvu zyxw 36 -36 48 4.30 reported as coordinates (xy.)in the standard stereotactic space of Talairach and Tournoux SMA Y x Range: 36-56 Range: 40-54 -42 No. 9 No. 8 = supplementary motor area; [42]with corresponding z scores. Range is in cortex; BA 6 = lateral premotor cortex. Rijntjes et al: Reorganization in Facial Palsy 627 zyxwvutsrqpo zyxwvutsrqpo zyxwvutsrqp zyxwv Fig 4. Statistically signi$cant areas measured with positron emission tomography during right-handed finger opposition )om a normal volunteer (/&) and a patient (right, No. 7) with right-sided @cia/ palsy during right-handed finger opposition, projected on individual three-dimensional magnetic re.tonance imaging scans, showing lateral extension of the activation in the sensorimotor cortex in the patient. sulted in virtually no retrograde labeled cells or terminal fiber labeling that crossed into the face representation [33]. In another study on primates, digit movemenrs could be elicited only at the medial boundary of the orofacial representation [34]. However, there is increasing evidence that these seemingly stable representations are kept in place by powerful y-aminobutyric acid-mediated lateral inhibitory connections that are found to interconnect cortical areas over considerable distances [35]. Loss of these lateral inhibitory connections could well provide a stimulus for intracortical reorganization. Although axonal sprouting has been observed in macaque monkeys after long-term deafferentation [ 161, it does not explain the rapid changes observed in animal experiments [ 171 and in our study, in which lateral extension of the hand area was already observed after 29 days. Studies on lower levels of the system, where a somatopy similar to the one in the cortex can be found, show that injuryinduced reorganization can be as complete as in the cortex [36]. Thus, there is the possibility that cortical reorganizations simply reflect changes already manifest at lower levels. All patients reported normal feeling in the paretic face area, and the contralateral orbicularis oculi reflexes were normal, demonstrating intact trigeminal sensory pathways. However, since normal everyday proprioceptive information is absent due to lack of movement, or diminished in those patients with incomplete facial palsy, a certain amount of deafferentation must be assumed as well. A recent PET study in normal subjects showed that proprioception constitutes the larger part 628 Annals of Neurology Vol 41 No 5 May 1997 of [he activation seen in the SMC during a motor task [37].Thus, deafferentation may have played a role in our findings in patients with Bell’s palsy. In all comparisons made in the PET study, the ipsilateral SMC showed significant activation during performance of the task. The activation was mainly in the normal hand area, but extended downwards to 20 mm above the AC-PC line, which is in the supposed face area [I, 311. ‘This finding is difficult to interpret. The peripheral facial nerve lesion should have some impact on the ipsilateral face area, since the upper part of the face is innervated bilaterally. In monkeys, neurons for the ipsilateral and contralateral face in the face motor cortex are intermingled with each other, and ipsilateral facial movements can be elicited from 20% of the positive sites in the face motor cortex of either hemisphere with microelectrodes [34]. Therefore, deefferentation of one-half of the face will also deefferent partly the ipsilateral cortex, possibly initiating the same reorganizational mechanisms that are responsible for the contralateral hand area. Additional stimuli for ipsilateral activation could be provided by transcallosal connections. Calford and Tweedale [38] reported on interhemispheric transfer of plasticity in the somatosensory cortex after local anesthesia of one thumb of flying foxes, in which the extent and time course of the plasticity were mirrored in both hemispheres. There is some evidence for an ipsilateral hand representation in some normal subjects and this may be positioned lateroposterior to the normal hand area [21, 391. Hypothetically, lateral extension caused by deefferentation of the face may include or overlap with this area. There zy zyxwvutsrqpo zyxwvu zyxwvutsrq are conflicting reports in the literature whether movements with the nondominant hand are related to more ipsilateral activation than movements with the dominant hand [40, 411. However, we cannot dismiss the possibility that due to the mixture of dominant and nondominant hand movements in the patient group the results are biased toward ipsilateral activation in the patients. The additional activation of secondary motor and sensory areas seems to be a common finding in studies on cortical reorganization. A shift to modality-specific secondary or higher order processing areas (eg, prefrontal cortex and parietal cortex) has been consistently found in a variety of conditions with central [22,211 or peripheral [14] nervous lesions. From animal and human studies, there is ample evidence for strong anatomical connections between the different secondary areas, each of which contains a somatotopic representation of body parts [42]. In conclusion, our study shows for the first time with two entirely different and noninvasive methods a functional plasticity in the intact adult human brain in response to mere peripheral deefferentation. This study was supported in part by an EU grant (CT 94/1261) and by the Kuratorium ZNS, Bonn, Germany. 10. Liepert J, Tegenthoff M, Malin JP. Changes of cortical motor area size during immobilization. Electroencephalogr Clin Neurophysiol 1995;97:382-386 11. Merzenich MM, Randaall JN, Stryker MP, et al. Somatosensory cortical map changes following digit amputation in adult monkeys. J Comp Neurol 1984;224:591-605 12. Allard T , Clark SA, Jenkins WM, Merzenich MM. Reorganization of somatosensory area 3b representations in adult owl monkeys after digital syndactyly. 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