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Abnormality of N30 somatosensory evoked potentials in Parkinson’s disease: a multidisciplinary approach
Neurophysiol Clin 2000 ; 30 : 368-76 © 2000 Éditions scientifiques et médicales Elsevier SAS. All rights reserved S0987705300002355/FLA www.elsevier.fr/direct/nc-cn
ORIGINAL ARTICLE
Abnormality of N30 somatosensory evoked potentials in Parkinson’s disease: a multidisciplinary approach S. Bostantjopoulou1*, Z. Katsarou1, D. Zafiriou1, G. Gerasimou2, A. Alevriadou3, G. Georgiadis1, G. Kiosseoglou3, A. Kazis1 1 3rd Department of Neurology, University of Thessaloniki, Thessaloniki, Greece ; 2 Department of Nuclear Medicine, University of Thessaloniki, Thessaloniki, Greece ; 3 Department of Psychology, University of Thessaloniki, Thessaloniki, Greece
(Received 24 February 1999; accepted in revised form 2 March 2000)
Summary – Purpose of the study – Assess the N30 component of median nerve somatosensory evoked potentials (SEPs) in patients with Parkinson’s disease (PD) and correlate its parameters with the severity of the disease, general cognitive ability and regional cerebral blood flow (rCBF). Patients and methods – Twenty-three non-demented, non-depressed PD patients (at stage II and III of the disease) and 23 age- and education-matched normal controls were enrolled in the study. SEPs were elicited by median nerve stimulation. PD patients’ cognitive ability was assessed by means of: 1) Raven’s Colored Progressive Matrices (RCPM); 2) the Test of Non-Verbal Intelligence (TONI-2); and 3) the Wisconsin Card Sorting Test (WCST). The patients’ rCBF was evaluated by HMPAO SPECT. Results – There was no difference between SEP N30 latency in PD patients and controls (P > 0.05). The P20-N30 peak-to-peak amplitude was lower in PD patients bilaterally (P < 0.05), and the amplitude of N30-P40 was lower on the right side only (P < 0.05). A significant increase in the amplitude ratio P14-N20/P20-N30 was observed in PD patients (P < 0.05). The correlation of these findings with the clinical parameters of the disease, and notably motor signs, was not significant. Of the three neuropsychological tests only the RCPM showed a positive relation to right P20-N30 amplitude. Regression analysis between SEP parameters and rCBF showed a correlation of N30 amplitude with blood flow in parietal cortical areas, but not in frontal regions. © 2000 Éditions scientifiques et médicales Elsevier SAS cognitive function / Parkinson’s disease / somatosensory evoked potential / SPECT
Résumé – Anomalies de l’onde frontale N30 dans la maladie de Parkinson : une approche multidisciplinaire. Objectif – Nous avons étudié la composante N30 du potentiel évoqué somesthésique (PES) du nerf médian dans une population de malades parkinsoniens, et l’ avons comparée avec la sévérité de la maladie, l’ altération des fonctions cognitives et le débit sanguin cérébral régional. Patients et méthodes – Vingt-trois malades parkinsoniens (stade II ou III de la maladie) ne présentant pas de démence ni de dépression majeure ont été inclus dans l’ étude, et comparés à un groupe de 23 sujets normaux du même âge et du même niveau d’ études. Les PES ont été enregistrés après stimulation du nerf médian. Les capacités cognitives des malades parkinsoniens ont été mesurées par les tests suivants : Raven’s Colored Progressive Matrices (RCPM) ; Test
*Correspondence and reprints: S. Bostantjopoulou, 9 Navarinou Square, GR-546 22 Thessaloniki, Greece.
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of Non-Verbal Intelligence (TONI-2) ; et Wisconsin Card Sorting Test (WCST). Le débit sanguin cérébral régional a été mesuré par HMPAO-SPECT. Résultats – L’ amplitude du potentiel P20-N30 présentait une réduction bilatérale chez les malades parkinsoniens (p < 0,05), mais l’ amplitude du potentiel N30-P40 présentait une réduction unilatérale du côté droit (p < 0,05). Il existait aussi une augmentation significative du rapport d’ amplitude P14-N20/P20-N30 du même côté chez les malades (p < 0,05). Les autres paramètres du PES qui ont été mesurés ne présentaient aucune anomalie dans les deux groupes. Le test de RCPM a montré une corrélation positive avec l’ amplitude P20-N30 droit. L’amplitude de l’ onde N30 présentait une corrélation significative avec les valeurs du débit sanguin régional dans les régions pariétales, mais pas dans les régions frontales. © 2000 Éditions scientifiques et médicales Elsevier SAS fonction cognitive / maladie de Parkinson / potentiel évoqué somesthésique / SPECT
The assessment of conventional short-latency somatosensory evoked potentials (SEPs) is an objective procedure for the study of somatosensory pathways in clinical practice and research [8]. The N30 component of the median nerve SEPs has been found to be abnormal in different diseases characterized by deficits in motor function and programming such as Parkinson’s disease (PD), dystonia and chorea [7, 14, 23, 24, 27,31]. Rossini et al. reported a significant reduction of the frontal N30 wave but normal parietal SEPs in PD patients [24, 25, 27, 28]. This finding led to the hypothesis that N30 SEPs may be a useful tool for the diagnosis and even therapeutic monitoring of PD patients. However, other investigators failed to demonstrate a significant change in N30 SEPs in parkinsonian patients [9, 13, 19]. Controversy regarding this issue has increased, and there is considerable debate concerning the precise origin of N30. It has been speculated that although N30 is elicited by a sensory stimulus, it may partly reflect the activity of motor and premotor frontal areas,
Table I. Clinical characteristics of PD patients. Mean ± SD Age (year) Duration of disease (year) Main symptoms of disease: Tremor Rigidity Bradykinesia UPDRS motor score Stage (Hoehn and Yahr)
61.6 ± 6.3 10.7 ± 4.6 1.0 ± 0.6 1.87 ± 0.6 2.00 ± 0.6 17.35 ± 4.7 2.67 ± 0.4
particularly in those affected by Parkinson’s disease [7, 23, 26]. On the contrary, other authors have postulated that N30 may be connected with the parietal areas [1, 2]. The purpose of our study was to assess the N30 component of SEPs in PD patients, and correlate N30 parameters with motor and cognitive aspects of the disease as well as with cerebral blood flow findings in the frontal and parietal cortex obtained by 99mTcHMPAO SPECT. PATIENTS AND METHODS Subject characteristics Twenty-three patients (16 male and seven female) with idiopathic PD, who were non-demented (Mini-Mental State Examination [12]; DSM-IV [3]) and nondepressed (Beck Depression Inventory) [5] were enrolled in the study. All patients were at stage II and III of the disease, under optimal dosage of L-dopa (mean dose ± SD: 648 ± 75 mg/d); they were assessed via the Unified Parkinson’s Disease Rating Scale motor score (UPDRS) [10]. The patients’ clinical characteristics are shown in table I. Twenty-three (nine male and 14 female) healthy subjects served as controls for the neurophysiological study. They were matched according to age to the PD patients (mean control age ± SD: 59.8 ± 7.8, P > 0.05). Informed consent was obtained from all patients and controls. Neurophysiological, neuropsychological and SPECT studies were performed in PD patients during their ‘on’ phase.
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Neurophysiological assessment SEPs were recorded using a Nihon Kohden Neuropack Four Model MEM 4104K apparatus. During the examination, patients and controls were instructed to relax as much as possible, sitting comfortably in a semi-reclining chair in a darkened room. Each median nerve was stimulated at the wrist with square wave electrical pulses of 0.2 ms duration and 1 Hz frequency, which was sufficiently intense to produce a painless thumb twitch. Limb skin temperature was maintained at 34-36 °C. Somatosensory evoked potentials were recorded with Ag/AgCl disc scalp electrodes placed on four derivations corresponding to the following: two frontal (5 cm frontal to Cz and 5 cm lateral to the midline), and two parietal (7 cm lateral to Cz and 2 cm behind the Cz ear line) positions, according to the procedure of Rossini et al. [28]. A common reference was placed on the ear lobe contralateral to the stimulus, while the ground reference was placed on Fpz. Five hundred artefact-free responses were averaged at 5 kHz sampling frequency (1-1 000 Hz filters, -6 db/Oct) and using a 50 ms post-stimulus analysis time. Recordings were repeated at least twice in order to determine their reproducibility. The following SEP parameters were evaluated: – peak latencies of parietal N20 and frontal N30 waves; – peak to peak amplitudes of parietal P14-N20, and frontal P20-N30 and N30-P40 waves; – the P14-N20/P20-N30 amplitude ratio. Values were designated as right or left when they were produced after stimulation of the right or left median nerve respectively. SPECT scanning Regional cerebral blood flow (rCBF) in PD patients was measured by HMPAO SPECT. Parkinsonian patients were intravenously injected with 15 mCi (555 MBq) of 99mTcHMPAO (Ceretec-Amersham International). Scans were performed 10–30 min later with an ADAC-camera SPECT system. Horizontal, sagittal and coronal slices of 1 cm thickness were obtained. Analysis was performed semi-quantitatevely. 99mTcHMPAO uptake in individual brain areas was quantified by placing square 4 × 4 pixel regions of interest on positions standardized with reference to a stereotactic brain atlas. HMPAO uptake was expressed for each region as the ratio of uptake in that region to that in the
cerebellum. HMPAO uptake calculated in the frontal, parietal and temporal (medial and lateral) cortex bilaterally was used in the statistical analysis. SPECT scanning was performed five hours after the neurophysiological assessment. Neuropsychological assessment General cognitive ability of PD patients as well as executive functions were assessed by means of: a) Raven’s Colored Progressive Matrices (RCPM) [22]; b) the Test of Non-Verbal Intelligence (TONI-2) [6]; and c) the Wisconsin Card Sorting Test (WCST) [15]. Statistical methods The t-test was used to assess differences between the two groups (PD patients versus controls) with regard to SEP parameters. The significance of the interactions between the two groups and the different waves was tested by means of four two-way analyses of variance (ANOVAs), in which one factor was the ‘between subjects’ factor for groups (PD patients versus controls), and the other was the ‘within subjects’ factor for waves (P20-N30 versus P14-N20) and (N30-P40 versus P14-N20) for both hemispheres separately. Correlations between SEP N30 parameters and clinical characteristics were performed using the Pearson correlation coefficient. Finally, in order to explore predictive values of SEPs from rCBF measurements, stepwise multiple regression analysis was applied considering as dependent variables the P20-N30, N30-P40 waves and the ratio of P14-N20/P20-N30 separately and as independent variables the rCBF measurements. This procedure was used taking into consideration the values of the dependent variables on the contralateral hemisphere to that of the independent variables. The same statistical method was also used with the above dependent variables, while the independent variables this time were RCPM, TONI-2 and WCST score. RESULTS SEP parameters in PD patients and normal controls Wave N20 latency and P14-N20 amplitude were within normal limits in both patients and controls according to our laboratory standards. These
N30 abnormality in Parkinson’s disease
Figure 1. Mean N30 SEP amplitude in PD patients and normal controls *(P < 0.05).
parameters are believed to be an index of the arrival of a sensory input at the primary sensory cortex. There was no difference between SEP N30 latency in PD patients and controls (t[44]: 0.29, P > 0.05, right side; t[44]:
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1.39, P > 0.05 left side). The mean amplitude of P20N30 in PD patients was 2.1 ± 1.3 µV after right side stimulation, and 2.3 ± 1.4 µV after left side stimulation, while in controls it was 3.3 ± 1.6 µV and 3.4 ± 1.7 µV respectively. The difference between the two groups was significant (t [44]: 2.71, P < 0.05, right side; t[44]: 2.12, P < 0.05, left side). The mean amplitude of N30-P40 in PD patients was 2.0 ± 1.3 µV after right side stimulation, and 2.3 ± 1.5 µV after left side stimulation. In controls, these values were 2.9 ± 1.6 µV and 3.1 ± 1.4 µV respectively. A significant difference in N30-P40 amplitude on the right side was found (t[44]: 2.06, P < 0.05). The mean amplitude ratio of P14-N20 to P20-N30 of PD patients was calculated as 1.1 ± 0.6 on the right side and 1.1 ± 0.7 on the left side. In controls, these values were 0.7 ± 0.3 on both sides. There was a significant difference on the right side P14-N20 to P20-N30 ratio (t[44]: 2.35, P < 0.05) (figure 1, figure 2a, b). The fact that the parameter of interest, i.e., P20-N30 amplitude, was statistically different in PD patients led us to perform four two-way ANOVAs to determine whether there were significant interactions between the within subjects factor ‘waves’ (P20-N30 versus P14N20 and N30-P40 versus P14-N20 for both sides separately) and the between subjects factor ‘groups’
Figure 2a. Frontal and parietal SEP components to right median nerve stimulation recorded in a healthy subject. b. Frontal and parietal SEP components to right median nerve stimulation recorded in a parkinsonian patient.
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(PD patients versus controls). It was found that the only significant interaction was between the factor ‘groups’ and the factor P20-N30 versus P14-N20 on the right side (F[1,44] = 5.7, P < 0.05). Estimation of the simple main effect showed that there was no significant difference between the two groups in P14-N20 wave amplitude (PD patient mean: 1.95 µV, control mean: 2.24 µV). On the contrary, there was a significant difference in P20-N30 amplitude between PD patients and controls (PD patient mean: 2.1 µV, control mean: 3.3 µV). Correlation between SEP N30parameters and clinical characteristics The correlation between SEP N30 parameters and motor score was not statistically significant (r: –0.227, P > 0.05 for both sides). The same applied to the other clinical characteristics such as tremor, bradykinesia, rigidity and disease duration. Regression analysis of SEP values and rCBF values Mean rCBF values ± SD in PD patients in different cortical regions were as follows: a) frontal lobe, right: 0.75 ± 0.04, left: 0.74 ± 0.04 (normal values, right: 0.77 ± 0.06, left: 0.77 ± 0.06); b) lateral temporal lobe, right: 0.72 ± 0.04, left: 0.69 ± 0.05 (normal values, right: 0.77 ± 0.06, left: 0.76 ± 0.04); c) medial temporal lobe, right: 0.71 ± 0.05, left: 0.69 ± 0.04 (normal values, right: 0.74 ± 0.05, left: 0.74 ± 0.04); and d) parietal lobe, right: 0.75 ± 0.04, left: 0.72 ± 0.04 (normal values, right: 0.78 ± 0.04, left: 0.77 ± 0.03) (figure 3a, b). Table II presents the statistically significant results of the multiple regression analysis. Frontal lobe rCBF values showed no dependency on SEP values, and were omitted from this table. P20-N30 and N30-P40 amplitudes depended positively on rCBF values in the parietal lobe specifically (figure 4a, b), while no correlation was found with frontal CBF (figure 4a) Regression analysis of SEPs values and neuropsychological test scores Mean scores ± SD of PD patients in the neuropsychological tests employed in this study were as follows: a) RCPM: 24.9 ± 5.1; b) TONI-2: 91 ± 8 and the most important WCST variables: i) number of trials involved 92.1 ± 18.3; ii) number of categories completed
5.9 ± 0.5; iii) perseverative responses 19.5 ± 14.4; and v) perseverative errors 12.8 ± 10.7. Finally, it was found that values of P20-N30 amplitude (right) depended positively and significantly on RCPM scores (R square = 0.19, F [1,21]: 4.90, P < 0.05) only. TONI-2 scores and WCST variables showed no dependency. DISCUSSION In the present study, an evaluation was made of the N30 components of the median nerve SEPs in parkinsonian patients and age-matched healthy controls. Patients were either at stage II or III of the disease, all under optimal L-dopa treatment and they were assessed during their ‘on’ phase, thus forming a quite homogenous group. All the SEP components were similar in patients and controls regarding latency, amplitude and topography, except for the amplitudes of the P20-N30 and N30P40 waves, which were significantly decreased in parkinsonian patients. Since the parietal N20 response was normal, this decrease in N30 components led to a significantly enhanced parietal/frontal amplitude ratio in PD patients. Reports in the literature on the same subject are rather conflicting, probably because of methodological differences, the small number of patients or the great heterogeneity of PD patients studied in regard to treatment, stage and severity of the disease. Some studies have found depressed frontal N30 waves in PD patients [7, 24, 27, 30], while others report no change in amplitude during the on and off phase [19] or a change in a small percentage of patients only [20]. There are also studies with a predominantly unilateral PD, where there were no differences in N30 amplitude between patients and controls [9, 13, 16]. There is also controversy concerning the relation of motor impairment to N30 amplitude. Onofrj et al. [20] and Stanzione et al. [30] addressed this issue, but did not find a relation between N30 amplitude and clinical parameters of the disease, while Rossini et al. [24, 25, 27] reported a correlation with rigidity. Our results are in agreement with those of Onofrj et al. [20] and Stanzione et al. [30], since in our patients there was no correlation of N30 with either UPDRS motor score or scores of each cardinal PD symptom separately. Moreover, Stanzione et al. [30] found no correlation between N30 amplitude and disease duration. This lack of correlation was also evident in our study. The
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Figure 3a, b. Abnormal SPECT of a PD patient whose neurophysiological data are presented in figure 2; rCBF is reduced in both parietal lobes.
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Table II. Regression analysis of SEP values and rCBF measurements. Dependent variable
Independant variable
P20-N30 (right side stimulus) N30-P40 (right side stimulus) P20-N30 (left side stimulus)
Parietal lobe (left side) Parietal lobe (left side) Temporal lobe lateral- (right side)
effect of dopaminergic treatment on N30 amplitude is still obscure. Cheron et al. [7], Rossini et al. [24, 25, 28], and Stanzione et al. [30] reported N30 amplitude potentiation after apomorphine infusion, while Mauguiere et al. [19] found no change. Furthermore, Drory et al. [9] and Onofrj et al. [20] reported an absence of N30 amplitude modification during acute or chronic administration of L-dopa. Our results support a decrease of the N30 response in PD, but no relation between this finding and dopaminergic state as assessed by motor scores. There are some indications in the literature regarding the effect of cognitive impairment on N30 SEP parameters. Ferri et al. [11] reported an increase of N30 amplitude in patients with vascular dementia, while in those with Alzheimer’s disease there was a prolongation of its latency. Our patients were not clinically demented. Correlation of N30 amplitude with various
R-square
Beta
F
P
0.513 0.369 0.615
0.147 0.103 0.099
4.36 3.25 3.37
0.0004 0.0045 0.004
neuropsychological tests was very poor, and only showed a positive correlation between RCPM scores and SEP amplitude, elicited after right median nerve stimulation. This finding cannot yet be explained, and needs further investigation. The precise site of origin of the N30 component distributed over the frontal scalp has not yet been found. Its topography places it anatomically over the supplementary motor area (SMA); therefore, it has been supposed to arise from this area [23, 24, 26]. Another possible site may be from a dipole in the posterior bank of the central sulcus [1, 2, 14]. The SMA receives a major input from the basal ganglia relayed by the thalamic nuclei; therefore, if SMA contributes to N30 generation, it is logical to hypothesize that the abnormality in SEP N30 amplitude in parkinsonian patients may be related to the pathophysiology of the disease. It is well known that in PD, SMA excitation is
Figure 4a, b. Scatter plots presenting individual values of P20-N30 amplitude and parietal (a) as well as frontal (b) rCBF values in PD patients.
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deficient [21]. Could N30 amplitude decrease reflect this abnormality? Support for this hypothesis is provided by studies of N30 component in dystonia, which have found an increase in N30 amplitude [14, 23]. This condition has been considered the opposite of parkinsonism concerning SMA activation [23, 25]. This hypothesis was further explored by means of rCBF measurements in different brain cortical areas. Regression analysis of rCBF and SEP parameters showed that the reduced P20-N30 and N30-P40 amplitudes were related to rCBF values in postrolandic areas exclusively. Therefore, this finding could not provide support for the SMA hypothesis of N30 generation. Whether this result may reflect a strong postrolandic generator of N30 in PD patients, as inferred by studies of N30 in exposed cortex [4] is presently unknown. As far as we know, this is the first study in the literature that has compared N30 parameters to SPECT measurements, so no definite conclusions can be drawn based on similar findings by other investigators. Nevertheless, some insight can be obtained by extrapolating SPECT findings, and anatomical and physiological data from the literature. In various studies, rCBF values in PD patients were found to be reduced in parietal areas [17, 18]. Anatomical studies in primates postulated that although the parietal lobe receives no direct input from the basal ganglia, it has a strong reciprocal connection to frontal motor areas which are particularly compromised in PD [32]. Parietal-prefrontal circuits are regarded as important regulatory loops in motor control functions [29], and they are probably disturbed in PD. However, whether these pathophysiological aspects are relevant to N30 disturbances is remains an intriguing question, and further studies are required involving a larger number of patients and more sophisticated techniques for the evaluation of cortical function.
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ORIGINAL ARTICLE
Abnormality of N30 somatosensory evoked potentials in Parkinson’s disease: a multidisciplinary approach S. Bostantjopoulou1*, Z. Katsarou1, D. Zafiriou1, G. Gerasimou2, A. Alevriadou3, G. Georgiadis1, G. Kiosseoglou3, A. Kazis1 1 3rd Department of Neurology, University of Thessaloniki, Thessaloniki, Greece ; 2 Department of Nuclear Medicine, University of Thessaloniki, Thessaloniki, Greece ; 3 Department of Psychology, University of Thessaloniki, Thessaloniki, Greece
(Received 24 February 1999; accepted in revised form 2 March 2000)
Summary – Purpose of the study – Assess the N30 component of median nerve somatosensory evoked potentials (SEPs) in patients with Parkinson’s disease (PD) and correlate its parameters with the severity of the disease, general cognitive ability and regional cerebral blood flow (rCBF). Patients and methods – Twenty-three non-demented, non-depressed PD patients (at stage II and III of the disease) and 23 age- and education-matched normal controls were enrolled in the study. SEPs were elicited by median nerve stimulation. PD patients’ cognitive ability was assessed by means of: 1) Raven’s Colored Progressive Matrices (RCPM); 2) the Test of Non-Verbal Intelligence (TONI-2); and 3) the Wisconsin Card Sorting Test (WCST). The patients’ rCBF was evaluated by HMPAO SPECT. Results – There was no difference between SEP N30 latency in PD patients and controls (P > 0.05). The P20-N30 peak-to-peak amplitude was lower in PD patients bilaterally (P < 0.05), and the amplitude of N30-P40 was lower on the right side only (P < 0.05). A significant increase in the amplitude ratio P14-N20/P20-N30 was observed in PD patients (P < 0.05). The correlation of these findings with the clinical parameters of the disease, and notably motor signs, was not significant. Of the three neuropsychological tests only the RCPM showed a positive relation to right P20-N30 amplitude. Regression analysis between SEP parameters and rCBF showed a correlation of N30 amplitude with blood flow in parietal cortical areas, but not in frontal regions. © 2000 Éditions scientifiques et médicales Elsevier SAS cognitive function / Parkinson’s disease / somatosensory evoked potential / SPECT
Résumé – Anomalies de l’onde frontale N30 dans la maladie de Parkinson : une approche multidisciplinaire. Objectif – Nous avons étudié la composante N30 du potentiel évoqué somesthésique (PES) du nerf médian dans une population de malades parkinsoniens, et l’ avons comparée avec la sévérité de la maladie, l’ altération des fonctions cognitives et le débit sanguin cérébral régional. Patients et méthodes – Vingt-trois malades parkinsoniens (stade II ou III de la maladie) ne présentant pas de démence ni de dépression majeure ont été inclus dans l’ étude, et comparés à un groupe de 23 sujets normaux du même âge et du même niveau d’ études. Les PES ont été enregistrés après stimulation du nerf médian. Les capacités cognitives des malades parkinsoniens ont été mesurées par les tests suivants : Raven’s Colored Progressive Matrices (RCPM) ; Test
*Correspondence and reprints: S. Bostantjopoulou, 9 Navarinou Square, GR-546 22 Thessaloniki, Greece.
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of Non-Verbal Intelligence (TONI-2) ; et Wisconsin Card Sorting Test (WCST). Le débit sanguin cérébral régional a été mesuré par HMPAO-SPECT. Résultats – L’ amplitude du potentiel P20-N30 présentait une réduction bilatérale chez les malades parkinsoniens (p < 0,05), mais l’ amplitude du potentiel N30-P40 présentait une réduction unilatérale du côté droit (p < 0,05). Il existait aussi une augmentation significative du rapport d’ amplitude P14-N20/P20-N30 du même côté chez les malades (p < 0,05). Les autres paramètres du PES qui ont été mesurés ne présentaient aucune anomalie dans les deux groupes. Le test de RCPM a montré une corrélation positive avec l’ amplitude P20-N30 droit. L’amplitude de l’ onde N30 présentait une corrélation significative avec les valeurs du débit sanguin régional dans les régions pariétales, mais pas dans les régions frontales. © 2000 Éditions scientifiques et médicales Elsevier SAS fonction cognitive / maladie de Parkinson / potentiel évoqué somesthésique / SPECT
The assessment of conventional short-latency somatosensory evoked potentials (SEPs) is an objective procedure for the study of somatosensory pathways in clinical practice and research [8]. The N30 component of the median nerve SEPs has been found to be abnormal in different diseases characterized by deficits in motor function and programming such as Parkinson’s disease (PD), dystonia and chorea [7, 14, 23, 24, 27,31]. Rossini et al. reported a significant reduction of the frontal N30 wave but normal parietal SEPs in PD patients [24, 25, 27, 28]. This finding led to the hypothesis that N30 SEPs may be a useful tool for the diagnosis and even therapeutic monitoring of PD patients. However, other investigators failed to demonstrate a significant change in N30 SEPs in parkinsonian patients [9, 13, 19]. Controversy regarding this issue has increased, and there is considerable debate concerning the precise origin of N30. It has been speculated that although N30 is elicited by a sensory stimulus, it may partly reflect the activity of motor and premotor frontal areas,
Table I. Clinical characteristics of PD patients. Mean ± SD Age (year) Duration of disease (year) Main symptoms of disease: Tremor Rigidity Bradykinesia UPDRS motor score Stage (Hoehn and Yahr)
61.6 ± 6.3 10.7 ± 4.6 1.0 ± 0.6 1.87 ± 0.6 2.00 ± 0.6 17.35 ± 4.7 2.67 ± 0.4
particularly in those affected by Parkinson’s disease [7, 23, 26]. On the contrary, other authors have postulated that N30 may be connected with the parietal areas [1, 2]. The purpose of our study was to assess the N30 component of SEPs in PD patients, and correlate N30 parameters with motor and cognitive aspects of the disease as well as with cerebral blood flow findings in the frontal and parietal cortex obtained by 99mTcHMPAO SPECT. PATIENTS AND METHODS Subject characteristics Twenty-three patients (16 male and seven female) with idiopathic PD, who were non-demented (Mini-Mental State Examination [12]; DSM-IV [3]) and nondepressed (Beck Depression Inventory) [5] were enrolled in the study. All patients were at stage II and III of the disease, under optimal dosage of L-dopa (mean dose ± SD: 648 ± 75 mg/d); they were assessed via the Unified Parkinson’s Disease Rating Scale motor score (UPDRS) [10]. The patients’ clinical characteristics are shown in table I. Twenty-three (nine male and 14 female) healthy subjects served as controls for the neurophysiological study. They were matched according to age to the PD patients (mean control age ± SD: 59.8 ± 7.8, P > 0.05). Informed consent was obtained from all patients and controls. Neurophysiological, neuropsychological and SPECT studies were performed in PD patients during their ‘on’ phase.
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Neurophysiological assessment SEPs were recorded using a Nihon Kohden Neuropack Four Model MEM 4104K apparatus. During the examination, patients and controls were instructed to relax as much as possible, sitting comfortably in a semi-reclining chair in a darkened room. Each median nerve was stimulated at the wrist with square wave electrical pulses of 0.2 ms duration and 1 Hz frequency, which was sufficiently intense to produce a painless thumb twitch. Limb skin temperature was maintained at 34-36 °C. Somatosensory evoked potentials were recorded with Ag/AgCl disc scalp electrodes placed on four derivations corresponding to the following: two frontal (5 cm frontal to Cz and 5 cm lateral to the midline), and two parietal (7 cm lateral to Cz and 2 cm behind the Cz ear line) positions, according to the procedure of Rossini et al. [28]. A common reference was placed on the ear lobe contralateral to the stimulus, while the ground reference was placed on Fpz. Five hundred artefact-free responses were averaged at 5 kHz sampling frequency (1-1 000 Hz filters, -6 db/Oct) and using a 50 ms post-stimulus analysis time. Recordings were repeated at least twice in order to determine their reproducibility. The following SEP parameters were evaluated: – peak latencies of parietal N20 and frontal N30 waves; – peak to peak amplitudes of parietal P14-N20, and frontal P20-N30 and N30-P40 waves; – the P14-N20/P20-N30 amplitude ratio. Values were designated as right or left when they were produced after stimulation of the right or left median nerve respectively. SPECT scanning Regional cerebral blood flow (rCBF) in PD patients was measured by HMPAO SPECT. Parkinsonian patients were intravenously injected with 15 mCi (555 MBq) of 99mTcHMPAO (Ceretec-Amersham International). Scans were performed 10–30 min later with an ADAC-camera SPECT system. Horizontal, sagittal and coronal slices of 1 cm thickness were obtained. Analysis was performed semi-quantitatevely. 99mTcHMPAO uptake in individual brain areas was quantified by placing square 4 × 4 pixel regions of interest on positions standardized with reference to a stereotactic brain atlas. HMPAO uptake was expressed for each region as the ratio of uptake in that region to that in the
cerebellum. HMPAO uptake calculated in the frontal, parietal and temporal (medial and lateral) cortex bilaterally was used in the statistical analysis. SPECT scanning was performed five hours after the neurophysiological assessment. Neuropsychological assessment General cognitive ability of PD patients as well as executive functions were assessed by means of: a) Raven’s Colored Progressive Matrices (RCPM) [22]; b) the Test of Non-Verbal Intelligence (TONI-2) [6]; and c) the Wisconsin Card Sorting Test (WCST) [15]. Statistical methods The t-test was used to assess differences between the two groups (PD patients versus controls) with regard to SEP parameters. The significance of the interactions between the two groups and the different waves was tested by means of four two-way analyses of variance (ANOVAs), in which one factor was the ‘between subjects’ factor for groups (PD patients versus controls), and the other was the ‘within subjects’ factor for waves (P20-N30 versus P14-N20) and (N30-P40 versus P14-N20) for both hemispheres separately. Correlations between SEP N30 parameters and clinical characteristics were performed using the Pearson correlation coefficient. Finally, in order to explore predictive values of SEPs from rCBF measurements, stepwise multiple regression analysis was applied considering as dependent variables the P20-N30, N30-P40 waves and the ratio of P14-N20/P20-N30 separately and as independent variables the rCBF measurements. This procedure was used taking into consideration the values of the dependent variables on the contralateral hemisphere to that of the independent variables. The same statistical method was also used with the above dependent variables, while the independent variables this time were RCPM, TONI-2 and WCST score. RESULTS SEP parameters in PD patients and normal controls Wave N20 latency and P14-N20 amplitude were within normal limits in both patients and controls according to our laboratory standards. These
N30 abnormality in Parkinson’s disease
Figure 1. Mean N30 SEP amplitude in PD patients and normal controls *(P < 0.05).
parameters are believed to be an index of the arrival of a sensory input at the primary sensory cortex. There was no difference between SEP N30 latency in PD patients and controls (t[44]: 0.29, P > 0.05, right side; t[44]:
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1.39, P > 0.05 left side). The mean amplitude of P20N30 in PD patients was 2.1 ± 1.3 µV after right side stimulation, and 2.3 ± 1.4 µV after left side stimulation, while in controls it was 3.3 ± 1.6 µV and 3.4 ± 1.7 µV respectively. The difference between the two groups was significant (t [44]: 2.71, P < 0.05, right side; t[44]: 2.12, P < 0.05, left side). The mean amplitude of N30-P40 in PD patients was 2.0 ± 1.3 µV after right side stimulation, and 2.3 ± 1.5 µV after left side stimulation. In controls, these values were 2.9 ± 1.6 µV and 3.1 ± 1.4 µV respectively. A significant difference in N30-P40 amplitude on the right side was found (t[44]: 2.06, P < 0.05). The mean amplitude ratio of P14-N20 to P20-N30 of PD patients was calculated as 1.1 ± 0.6 on the right side and 1.1 ± 0.7 on the left side. In controls, these values were 0.7 ± 0.3 on both sides. There was a significant difference on the right side P14-N20 to P20-N30 ratio (t[44]: 2.35, P < 0.05) (figure 1, figure 2a, b). The fact that the parameter of interest, i.e., P20-N30 amplitude, was statistically different in PD patients led us to perform four two-way ANOVAs to determine whether there were significant interactions between the within subjects factor ‘waves’ (P20-N30 versus P14N20 and N30-P40 versus P14-N20 for both sides separately) and the between subjects factor ‘groups’
Figure 2a. Frontal and parietal SEP components to right median nerve stimulation recorded in a healthy subject. b. Frontal and parietal SEP components to right median nerve stimulation recorded in a parkinsonian patient.
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(PD patients versus controls). It was found that the only significant interaction was between the factor ‘groups’ and the factor P20-N30 versus P14-N20 on the right side (F[1,44] = 5.7, P < 0.05). Estimation of the simple main effect showed that there was no significant difference between the two groups in P14-N20 wave amplitude (PD patient mean: 1.95 µV, control mean: 2.24 µV). On the contrary, there was a significant difference in P20-N30 amplitude between PD patients and controls (PD patient mean: 2.1 µV, control mean: 3.3 µV). Correlation between SEP N30parameters and clinical characteristics The correlation between SEP N30 parameters and motor score was not statistically significant (r: –0.227, P > 0.05 for both sides). The same applied to the other clinical characteristics such as tremor, bradykinesia, rigidity and disease duration. Regression analysis of SEP values and rCBF values Mean rCBF values ± SD in PD patients in different cortical regions were as follows: a) frontal lobe, right: 0.75 ± 0.04, left: 0.74 ± 0.04 (normal values, right: 0.77 ± 0.06, left: 0.77 ± 0.06); b) lateral temporal lobe, right: 0.72 ± 0.04, left: 0.69 ± 0.05 (normal values, right: 0.77 ± 0.06, left: 0.76 ± 0.04); c) medial temporal lobe, right: 0.71 ± 0.05, left: 0.69 ± 0.04 (normal values, right: 0.74 ± 0.05, left: 0.74 ± 0.04); and d) parietal lobe, right: 0.75 ± 0.04, left: 0.72 ± 0.04 (normal values, right: 0.78 ± 0.04, left: 0.77 ± 0.03) (figure 3a, b). Table II presents the statistically significant results of the multiple regression analysis. Frontal lobe rCBF values showed no dependency on SEP values, and were omitted from this table. P20-N30 and N30-P40 amplitudes depended positively on rCBF values in the parietal lobe specifically (figure 4a, b), while no correlation was found with frontal CBF (figure 4a) Regression analysis of SEPs values and neuropsychological test scores Mean scores ± SD of PD patients in the neuropsychological tests employed in this study were as follows: a) RCPM: 24.9 ± 5.1; b) TONI-2: 91 ± 8 and the most important WCST variables: i) number of trials involved 92.1 ± 18.3; ii) number of categories completed
5.9 ± 0.5; iii) perseverative responses 19.5 ± 14.4; and v) perseverative errors 12.8 ± 10.7. Finally, it was found that values of P20-N30 amplitude (right) depended positively and significantly on RCPM scores (R square = 0.19, F [1,21]: 4.90, P < 0.05) only. TONI-2 scores and WCST variables showed no dependency. DISCUSSION In the present study, an evaluation was made of the N30 components of the median nerve SEPs in parkinsonian patients and age-matched healthy controls. Patients were either at stage II or III of the disease, all under optimal L-dopa treatment and they were assessed during their ‘on’ phase, thus forming a quite homogenous group. All the SEP components were similar in patients and controls regarding latency, amplitude and topography, except for the amplitudes of the P20-N30 and N30P40 waves, which were significantly decreased in parkinsonian patients. Since the parietal N20 response was normal, this decrease in N30 components led to a significantly enhanced parietal/frontal amplitude ratio in PD patients. Reports in the literature on the same subject are rather conflicting, probably because of methodological differences, the small number of patients or the great heterogeneity of PD patients studied in regard to treatment, stage and severity of the disease. Some studies have found depressed frontal N30 waves in PD patients [7, 24, 27, 30], while others report no change in amplitude during the on and off phase [19] or a change in a small percentage of patients only [20]. There are also studies with a predominantly unilateral PD, where there were no differences in N30 amplitude between patients and controls [9, 13, 16]. There is also controversy concerning the relation of motor impairment to N30 amplitude. Onofrj et al. [20] and Stanzione et al. [30] addressed this issue, but did not find a relation between N30 amplitude and clinical parameters of the disease, while Rossini et al. [24, 25, 27] reported a correlation with rigidity. Our results are in agreement with those of Onofrj et al. [20] and Stanzione et al. [30], since in our patients there was no correlation of N30 with either UPDRS motor score or scores of each cardinal PD symptom separately. Moreover, Stanzione et al. [30] found no correlation between N30 amplitude and disease duration. This lack of correlation was also evident in our study. The
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Figure 3a, b. Abnormal SPECT of a PD patient whose neurophysiological data are presented in figure 2; rCBF is reduced in both parietal lobes.
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Table II. Regression analysis of SEP values and rCBF measurements. Dependent variable
Independant variable
P20-N30 (right side stimulus) N30-P40 (right side stimulus) P20-N30 (left side stimulus)
Parietal lobe (left side) Parietal lobe (left side) Temporal lobe lateral- (right side)
effect of dopaminergic treatment on N30 amplitude is still obscure. Cheron et al. [7], Rossini et al. [24, 25, 28], and Stanzione et al. [30] reported N30 amplitude potentiation after apomorphine infusion, while Mauguiere et al. [19] found no change. Furthermore, Drory et al. [9] and Onofrj et al. [20] reported an absence of N30 amplitude modification during acute or chronic administration of L-dopa. Our results support a decrease of the N30 response in PD, but no relation between this finding and dopaminergic state as assessed by motor scores. There are some indications in the literature regarding the effect of cognitive impairment on N30 SEP parameters. Ferri et al. [11] reported an increase of N30 amplitude in patients with vascular dementia, while in those with Alzheimer’s disease there was a prolongation of its latency. Our patients were not clinically demented. Correlation of N30 amplitude with various
R-square
Beta
F
P
0.513 0.369 0.615
0.147 0.103 0.099
4.36 3.25 3.37
0.0004 0.0045 0.004
neuropsychological tests was very poor, and only showed a positive correlation between RCPM scores and SEP amplitude, elicited after right median nerve stimulation. This finding cannot yet be explained, and needs further investigation. The precise site of origin of the N30 component distributed over the frontal scalp has not yet been found. Its topography places it anatomically over the supplementary motor area (SMA); therefore, it has been supposed to arise from this area [23, 24, 26]. Another possible site may be from a dipole in the posterior bank of the central sulcus [1, 2, 14]. The SMA receives a major input from the basal ganglia relayed by the thalamic nuclei; therefore, if SMA contributes to N30 generation, it is logical to hypothesize that the abnormality in SEP N30 amplitude in parkinsonian patients may be related to the pathophysiology of the disease. It is well known that in PD, SMA excitation is
Figure 4a, b. Scatter plots presenting individual values of P20-N30 amplitude and parietal (a) as well as frontal (b) rCBF values in PD patients.
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deficient [21]. Could N30 amplitude decrease reflect this abnormality? Support for this hypothesis is provided by studies of N30 component in dystonia, which have found an increase in N30 amplitude [14, 23]. This condition has been considered the opposite of parkinsonism concerning SMA activation [23, 25]. This hypothesis was further explored by means of rCBF measurements in different brain cortical areas. Regression analysis of rCBF and SEP parameters showed that the reduced P20-N30 and N30-P40 amplitudes were related to rCBF values in postrolandic areas exclusively. Therefore, this finding could not provide support for the SMA hypothesis of N30 generation. Whether this result may reflect a strong postrolandic generator of N30 in PD patients, as inferred by studies of N30 in exposed cortex [4] is presently unknown. As far as we know, this is the first study in the literature that has compared N30 parameters to SPECT measurements, so no definite conclusions can be drawn based on similar findings by other investigators. Nevertheless, some insight can be obtained by extrapolating SPECT findings, and anatomical and physiological data from the literature. In various studies, rCBF values in PD patients were found to be reduced in parietal areas [17, 18]. Anatomical studies in primates postulated that although the parietal lobe receives no direct input from the basal ganglia, it has a strong reciprocal connection to frontal motor areas which are particularly compromised in PD [32]. Parietal-prefrontal circuits are regarded as important regulatory loops in motor control functions [29], and they are probably disturbed in PD. However, whether these pathophysiological aspects are relevant to N30 disturbances is remains an intriguing question, and further studies are required involving a larger number of patients and more sophisticated techniques for the evaluation of cortical function.
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