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Parkinson disease: Electrophysiological (CNV) analysis related to pharmacological treatment
Electroencephalography and clinical Neurophysiology, 1986, 64:521-524
521
Elsevier Scientific Publishers Ireland, Ltd.
Short communication P A R K I N S O N DISEASE: ELECTROPHYSIOLOGICAL (CNV) A N A L Y S I S PHARMACOLOGICAL T R E A T M E N T
RELATED
TO
GIUSEPPE AMABILE, FRANCESCO FATTAPPOSTA, GIUSEPPE POZZESSERE, GIORGIO ALBANI, LUCIA SANARELLI, PAOLO A N D R E A RIZZO and CRISTOFORO MOROCUTTI lstituto di Clinica delle Malattie Nervose e Mentali, Unit~ersith degli Studi di Roma "La Sapienza,' 00185 Rome (ha(v)
(Accepted for publication: August 12, 1986)
Summary The contingent negative variation (CNV) was studied in a group of patients with Parkinson's disease. Testing was carried out 3 times: after a pharmacological wash-out period and at 15 and 30 days after the start of treatment with L-DOPA and bromocryptine. Peak and area CNV increased significantly after each treatment. The post-imperative negative variation (PINV) was observed in 6 out of 10 patients. The correlation found between electrophysiological functioning (CNV) measures and pharmacological treatment supports the view that dopaminergic brain activity mediates the generation of the slow negative event-related brain potentials.
Keywords: contingent negative variation - Parkinson's disease - dopaminergic sensitivi O,
The contingent negative variation (CNV) is a bioelectrical phenomenon of the human brain that mediates higher mental functions involved in specific choice behaviour (Walter et al. 1964). Although the CNV has been studied in various clinical populations, such as subjects affected by neurosis, schizophrenia, affective disorders, dementia and other neuropsychological disturbances (Small and Small 1971; Tecce and Hamilton 1973; Timsit-Berthier et al. 1973; Abraham et al. 1974; Timsit-Berthier 1976; Rizzo et al. 1979, 1980, 1984), the complex mechanisms underlying its generation are not yet precisely known. Aside from psychophysiological mechanisms (Howard 1982), there has been an emphasis in CNV research on various neuroanatomical structures (Rebert 1977; Skinner and Yingling 1977) and, most recently, on biochemical mechanisms (dopaminergic and cholinergic systems) (Libet 1978; Marczynski 1978). One approach to testing a dopamine hypothesis would be to evaluate patients with Parkinson's disease, since this disorder has a putative subcortical dopaminergic deficit (Scatton et al. 1983). Such a conceptualization of parkinsonism constitutes a tentative model of neuroanatomical and biochemical systems involved in the genesis of the CNV. As one test of the heuristic value of this model, the present study investigated the possible relationship between the CNV and Parkinson's disease in order to assess the putative role of dopaminergic mechanisms as generators of event-related negative brain potentials.
Materials and Methods Subjects
Forty-seven parkinsonian patients were examined over a 3 year period. They showed tremors, bradykinesia and rigidity. In order to obtain a sample of patients who would yield artifact-free data, patients were excluded from testing if they showed the following characteristics: tremorogenetic manifestations; primary psychiatric disturbances; use of tranquillizers, including antidepressive and neuroleptic drugs; clinically evident cardiovascular disturbances in their clinical history. Sixteen patients were selected for testing; ten of them completed the study. They were females between the ages of 54 and 60 years (mean = 56.5). The duration of the disease was 60-84 months (mean = 75.1). Patients had received treatment irregularly with L-DOPA a n d / o r anticholinergic drugs. Medications
The first phase of the study was a pharmacological wash-out period which lasted 7 days. In the second phase, L-DOPA and bromocryptine were administered in increasing doses up to 375-500 mg and 5-10 mg, respectively. An optimal dosage was determined for each patient based on clinical improvement. The second phase lasted at least 30 days in all cases. Procedures
Correspondence to: Dr. G. Amabile, Istituto di Clinica delle Malattie Nervose e Mentali, Universith degli Studi di Roma 'La Sapienza,' V. le dell'Universith 30, 00185 Rome, Italy.
Each patient was tested for CNV 3 times: at the end of the pharmacological wash-out and at 15 and 30 days from the start of therapy. The clinical status was assessed on the Hoehn-Yahr scale (stages 1-4 from minimum to maximum invalidity; Hoehn and Yahr 1967) before the wash-out and again 15-30 days
0013-4649/86/$03.50 © 1986 Elsevier Scientific Publishers Ireland, Ltd.
G. AMABILE ET AL.
522 Results
TABLE I Evolution of Hoehn-Yahr scale in patients with Parkinson's disease. Patient no.
A
B
C
1 2 3 4 5 6 7 8 9 10
3 2 3 3 3 3 2 3 2 2
1 I 2 2 2 2 1 2 1 1
1 1 1 1 2 1 1 1 1 1
A = before therapy; B = after 15 days of therapy; C = after 30 days of therapy.
after the start of pharmacological treatment (see Table I). For each CNV recording a technique similar to that initially described by Walter et al. in 1964 was used. The subject was invited to sit in an anatomical chair in a partially soundproof and semi-dark room. The EEG was recorded through 5 silver-silver chloride electrodes; 2 electrodes were placed along the midline at Fpz and Cz, of the 10-20 system. The 2 reference electrodes were placed on the mastoid processes and directly connected to Fpz. The Cz electrode was referred to the central terminal of a 25 k$2 potentiometer connected to Fpz and the mastoid electrodes by a method similar to that used by McCallum and Walter (1968) to attenuate contamination of the CNV by ocular potentials. A further ground electrode was placed on the ear lobe. Vertical eye movements (EOG) were recorded with electrodes above and below the left eye. The time constant was 8 sec. The first stimulus ($1) was a light flash of 100 /tsec duration. A second stimulus ($2) followed $1 by 1500 msec and consisted in a tone of 200 or 4000 Hz which lasted 600 msec. A push button was placed in the preferred hand of the subject and he was invited to push it as rapidly as he could on hearing the 4000 Hz sound (execution of the task caused the sound signal to stop). The evoked bioelectrical potential was averaged by a signal processor (Model 7170A, Sunei Instruments). Further technical information has been described elsewhere (Rizzo et al. 1979). The following parameters were referred to a 500 msec baseline pre-Sl: maximum negativity of peak CNV; CNV area expressed in /tV z from the end of the visual evoked potential (S1) to the onset of $2; and the post-imperative negative variation (PINV), defined as a delay of 2 sec or more in the return of the EEG tracing to the baseline after $2 (Chouinard et al. 1975). All mean differences were evaluated for statistical significance by a t test for paired data.
All patients displayed measureable slow brain potentials under basal conditions as well as during pharmacological treatment. Table II presents CNV area (/~V2) and maximum peak (/tV). As can be seen in Fig. 1, the peak CNV and CNV area were increased at post-treatment compared to the basal condition. The peak CNV was significantly higher ( P < 0.001) following 15 days (mean = 38.0_+/~V) and 30 days of drug treatment (mean = 38.7_+ 2.6 ~V) compared to the basal condition (mean = 24.0_+ 2.3 ktV) (t = - 12.7,- 10.8 respectively). The CNV area was also significantly greater ( P < 0.001) following 15 days ( m e a n = 2 5 8 . 7 + l l . 9 ~tV2) and 30 days of drug treatment (mean = 260.3_+10.9 /~V2) compared to the basal condition (mean = 150.0 _+8.8/~V 2) ( t = - 48.6, - 60.2 respectively). There were no significant differences between means for peak CNV or area measured at 15 and 30 days post-treatment.
A
a
-V
v,~
A Sl
" ~
V
A S2
,s.v I 0.5 Sec
Fig. 1. Representative CNV tracings for one parkinsonian patient obtained before (A) and both 15 days (B) and 30 days (C) after drug treatment. The PINV observed after 30 days of pharmacotherapy was characteristic of 6 patients.
CNV IN PARKINSONIAN PATIENTS
523
TABLE II CNV data in patients with Parkinson's disease. P a t i e n t no.
Maximum peak (~V)
A r e a (~V 2 )
A
B
C
A
B
C
I 2 3 4 5 6 7 8 9 10
138 140 142 158 154 160 160 144 158 146
240 250 248 270 264 260 280 250 260 266
238 252 250 272 264 262 274 262 268 262
28 22 23 22 27 24 22 22 26 24
37 33 39 38 35 40 39 40 41 38
33 37 41 39 37 39 41 38 40 42
Mean ± S.D.
150± 8.8
258.7 ± 11.9
260.3 ± 10.9
24±2.3
38_+2.4
38.7±2.6
A = before therapy; B = after 15 days of therapy; C = after 30 days of therapy.
The PINV appeared in 1 patient after 15 days of drug therapy and in 6 patients after 30 days of treatment. N o patient showed a PINV during baseline testing.
Discussion
Previous studies based on non-patient subjects have suggested that the CNV is modulated by dopaminergic mechanisms in the brain (Marczynski 1978). This view is supported by two aspects of the present findings. First, a small magnitude of CNV was observed in the basal (non-drug) condition, a time at which dopaminergic activity in parkinsonian patients can be considered weakened. Secondly, an enhanced CNV was found during treatment with L-DOPA, at a time when dopaminergic activity was presumably increased compared to pre-treatment measurements. This increase in CNV following pharmacotherapy of parkinsonian patients may reflect a functional recovery, perhaps partial, in the dopaminergic pathways arising in the mesencephalon (Lindvall et al. 1978) and the brain-stem (Fuxe et al. 1974) and possibly projecting to the superficial frontal cortical layers. This hypothesis has been supported by the work of others (Timsit-Berthier et al. 1983). The present findings also agree with previous work showing decreased CNV magnitude following administration of dopamine antagonists (Thompson et al. 1978). A PINV appeared in the majority of subjects after 30 days of drug treatment. In our opinion, the PINV could reflect dopaminergic activity, rather than the general state of some psychopathological condition postulated by Timsit-Berthier et al. (1971, 1983). In our view, the PINV is more likely to indicate dopaminergic receptor hypersensitivity following a prolonged decrease in DA level in the nigro-striatal system (Hyttel and Christensen 1983). Thus, the alteration of this system by L-DOPA treatment apparently produces a selective (dopaminergic) facilitated sensitivity in the different types of
cortical and subcortical receptors (Hyttel and Christensen 1983). It is also possible that the PINV reflects the role of dopamine dominance in relation to other neurotransmitters and neuromodulators, e.g., GABA (Marczynski 1978). Whatever the specificity or non-specificity of mechanisms, the present study confirms the involvement of neurochemical functions in CNV genesis, one of which is likely to be dopaminergic. Furthermore, the CNV appears to be a potentially useful non-invasive technique for the assessment of neurophysiological activity, including neurochemical functions, that impinge on dopaminergic imbalance in parkinsonian patients.
R6sum6 Maladie de Parkinson: analyse ~lectrophysiologique (CNV) en liaison avec un traiternent pharmacologique
La variation n6gative contingente (VNC) a 6t6 6tudi6e chez un groupe de patients atteints de la maladie de Parkinson. Les tests ont 6t6 pratiqu6s 3 lois: apr6s une p6riode d'61imination de route trace de substances pharmacologiques, apr~s 15 jours et apr6s 30 jours du d6but d'un traitement h la L-DOPA et h la bromocryptine. Le pic et la surface de la VNC augmentaient significativement apr6s chaque traitement. La variation n6gative post-imp6rative 6tait observ6e chez 6 des 10 patients. La corr61ation trouv6e entre les 6valuations fonctionnelles 61ectrophysiologique (VNC) et le traitement pharmacologique conforte l'id6e que l'activit6 dopaminergique du cerveau est un interm6diaire dans la genbse des potentiels c6r6braux lents n6gatifs li6s h l'6v6nement. We are particularly grateful to M. Timsit-Berthier (Liege) and J.J. Tecce (Boston) for their encouragement and helpful criticisms.
524 The authors also thank Mr. Gattoni for technical assistance, and Mrs. F. Tomassoni for the excellent typewriting.
References
Abraham, P., McCallum, W.C., Docherty, T., Newton, P. and Fox, A. The CNV in schizophrenia. Electroenceph. clin. Neurophysiol., 1974, 36: 217-218. Chouinard, G., Annable, L., Dubrovsky, B. and DonNer, M. Post-imperative negative variation (PINV) in ambulatory schizophrenic patients. Comprehens. Psychiat., 1975, 16: 457-460. Fuxe, K., H~Skfelt, T., Johansson, D., Jonsson, G., Lidbrink, P. and Ljungdahl, .~. The origin of the dopamine nerve terminals in limbic and frontal cortex. Evidence for meso-cortico dopamine neurons. Brain Res., 1974, 82: 349-355. Hoehn, M.N. and Yahr, M.D. Parkinsonism: onset progression and mortality. Neurology (Minneap.), 1967, 17: 427-442. Howard, R.C. Event Related Brain Potentials in Personality and Psychopathology: a Pavlovian Approach. Wiley, Chichester, 1982. Hyttel, J. and Christensen, A.V. Biochemical and pharmacological differentiation of neuroleptic effect on dopamine D1 and D2 receptors. J. neural. Transm., 1983, 18 (Suppl.): 157-164. Libet, B. Slow postsynaptic responses of sympathetic ganglion cells as models for slow potential changes in the brain. In: D.A. Otto (Ed.), Multidisciplinary Perspectives in EventRelated Brain Potential Research. US Government Printing Office, Washington, DC, 1978: 12-19. Lindvall, O., Bj~Srklund, A. and Divac, I. Organization of catecholamine neurons projecting to the frontal cortex in the rat. Brain Res., 1978, 142: 1-24. Marczynski, T.J. Neurochemical mechanisms in the genesis of slow potentials: a review and some clinical implications. In: D.A. Otto (Ed.), Multidisciplinary Perspectives in EventRelated Brain Potential Research. US Government Printing Office, Washington, DC, 1978: 25-35. McCalhim, W.C. and Walter, W.G. The differential effects of distraction on the contingent negative variation in normal subjects and psychiatric patients. Electroenceph. clin. Neurophysiol., 1968, 24: 595. Rebert, C.S. Intracerebral slow potential changes in monkeys during the foreperiod of reaction time. In: J.E. Desmedt (Ed.), Attention, Voluntary Contraction and Event-Related Cerebral Potentials. Karger, Basel, 1977: 242-253. Rizzo, P.A., Amabile, G., Caporali, M., Pierelli, F., Spadaro,
G. AMABILE ET AL. M., Zanasi, M. and Morocutti, C. A longitudinal CNV study in a group of five bipolar cyclothymic patients. Biol. Psychiat., 1979, 14: 581-586. Rizzo, P.A., Albani, G., Cicardi, C., Spadaro, M. and Morocutti, C. Effects of distraction on the contingent negative variation in presenile dementia and normal subjects. Neuropsychobiology, 1980, 36: 217-218. Rizzo, P.A., Spadaro, M., Albani, G.F. and Morocutti, C. Contingent negative variation and schizophrenia: a longterm follow-up study. Biol. Psychiat., 1984, 19: 1719-1724. Scatton, B., Javoy-Agid, F., Rouquier, L., Dubois, B. and Agidy, Y. Reduction of cortical dopamine, noradrenaline, serotonin and their metabolites in Parkinson's disease. Brain Res., 1983, 275: 321-328. Skinner, J.E. and Yingling, C.D. Central gating mechanism that regulate event-related potentials and behavior. A neural model for attention. In: J.E. Desmedt (Ed.), Attention, Voluntary Contraction and Event-Related Cerebral Potentials. Karger, Basel, 1977: 30-69. Small, J.G. and Small, I.F. Contingent negative variation (CNV). Correlations with psychiatric diagnosis. Arch. gen. Psychiat., 1971, 25: 550-554. Tecce, J.J. and Hamilton, B.T. CNV reduction by sustained cognitive activity (distraction). Electroenceph. clin. Neurophysiol., 1973, 33: 229-237. Thompson, J.W., Newton, P., Pocock, P.V., Crow, H., McCallum, W.C. and Popakostopoulos, D. Preliminary study of pharmacology of CNV in man. In: D.A. Otto (Ed.), Multidisciplinary Perspectives in Event-Related Brain Potential Research. US Government Printing Office, Washington, DC, 1978: 51-55. Timsit-Berthier, M. La variation contingente nrgative et les maladies mentales. Acta neurol, psychiat, belg., 1976, 76: 521-550. Timsit-Berthier, M., Rousseau, J.C. et Dalaunoy, J. R~activit~ de l'onde d'attente et des ondes nggatives post-imperatives. Rev. E.E.G. Neurophysiol., 1971, 1: 245-248. Timsit-Berthier, M., Dalaunoy, J., Koninckx, N. and Rousseau, J.C. Slow potentials changes in psychiatry. I. Contingent negative variation. Electroenceph. clin. Neurophysiol., 1973, 35: 355-361. Timsit-Berthier, M., Mantanus, H., Ansseau, M., Doumon, A. and Legros, J.J. Methodological problems raised by contingent negative variation interpretation in psychopathological conditions. Adv. biol. Psychiat., 1983, 13: 80-92. Walter, W.G., Cooper, R., Aldrige, V.J., McCalhim, W.C. and Winter, A.L. Contingent negative variation: an electric sign of sensorimotor association and expectancy on the human brain. Nature (Lond.), 1964, 203: 380-384.
521
Elsevier Scientific Publishers Ireland, Ltd.
Short communication P A R K I N S O N DISEASE: ELECTROPHYSIOLOGICAL (CNV) A N A L Y S I S PHARMACOLOGICAL T R E A T M E N T
RELATED
TO
GIUSEPPE AMABILE, FRANCESCO FATTAPPOSTA, GIUSEPPE POZZESSERE, GIORGIO ALBANI, LUCIA SANARELLI, PAOLO A N D R E A RIZZO and CRISTOFORO MOROCUTTI lstituto di Clinica delle Malattie Nervose e Mentali, Unit~ersith degli Studi di Roma "La Sapienza,' 00185 Rome (ha(v)
(Accepted for publication: August 12, 1986)
Summary The contingent negative variation (CNV) was studied in a group of patients with Parkinson's disease. Testing was carried out 3 times: after a pharmacological wash-out period and at 15 and 30 days after the start of treatment with L-DOPA and bromocryptine. Peak and area CNV increased significantly after each treatment. The post-imperative negative variation (PINV) was observed in 6 out of 10 patients. The correlation found between electrophysiological functioning (CNV) measures and pharmacological treatment supports the view that dopaminergic brain activity mediates the generation of the slow negative event-related brain potentials.
Keywords: contingent negative variation - Parkinson's disease - dopaminergic sensitivi O,
The contingent negative variation (CNV) is a bioelectrical phenomenon of the human brain that mediates higher mental functions involved in specific choice behaviour (Walter et al. 1964). Although the CNV has been studied in various clinical populations, such as subjects affected by neurosis, schizophrenia, affective disorders, dementia and other neuropsychological disturbances (Small and Small 1971; Tecce and Hamilton 1973; Timsit-Berthier et al. 1973; Abraham et al. 1974; Timsit-Berthier 1976; Rizzo et al. 1979, 1980, 1984), the complex mechanisms underlying its generation are not yet precisely known. Aside from psychophysiological mechanisms (Howard 1982), there has been an emphasis in CNV research on various neuroanatomical structures (Rebert 1977; Skinner and Yingling 1977) and, most recently, on biochemical mechanisms (dopaminergic and cholinergic systems) (Libet 1978; Marczynski 1978). One approach to testing a dopamine hypothesis would be to evaluate patients with Parkinson's disease, since this disorder has a putative subcortical dopaminergic deficit (Scatton et al. 1983). Such a conceptualization of parkinsonism constitutes a tentative model of neuroanatomical and biochemical systems involved in the genesis of the CNV. As one test of the heuristic value of this model, the present study investigated the possible relationship between the CNV and Parkinson's disease in order to assess the putative role of dopaminergic mechanisms as generators of event-related negative brain potentials.
Materials and Methods Subjects
Forty-seven parkinsonian patients were examined over a 3 year period. They showed tremors, bradykinesia and rigidity. In order to obtain a sample of patients who would yield artifact-free data, patients were excluded from testing if they showed the following characteristics: tremorogenetic manifestations; primary psychiatric disturbances; use of tranquillizers, including antidepressive and neuroleptic drugs; clinically evident cardiovascular disturbances in their clinical history. Sixteen patients were selected for testing; ten of them completed the study. They were females between the ages of 54 and 60 years (mean = 56.5). The duration of the disease was 60-84 months (mean = 75.1). Patients had received treatment irregularly with L-DOPA a n d / o r anticholinergic drugs. Medications
The first phase of the study was a pharmacological wash-out period which lasted 7 days. In the second phase, L-DOPA and bromocryptine were administered in increasing doses up to 375-500 mg and 5-10 mg, respectively. An optimal dosage was determined for each patient based on clinical improvement. The second phase lasted at least 30 days in all cases. Procedures
Correspondence to: Dr. G. Amabile, Istituto di Clinica delle Malattie Nervose e Mentali, Universith degli Studi di Roma 'La Sapienza,' V. le dell'Universith 30, 00185 Rome, Italy.
Each patient was tested for CNV 3 times: at the end of the pharmacological wash-out and at 15 and 30 days from the start of therapy. The clinical status was assessed on the Hoehn-Yahr scale (stages 1-4 from minimum to maximum invalidity; Hoehn and Yahr 1967) before the wash-out and again 15-30 days
0013-4649/86/$03.50 © 1986 Elsevier Scientific Publishers Ireland, Ltd.
G. AMABILE ET AL.
522 Results
TABLE I Evolution of Hoehn-Yahr scale in patients with Parkinson's disease. Patient no.
A
B
C
1 2 3 4 5 6 7 8 9 10
3 2 3 3 3 3 2 3 2 2
1 I 2 2 2 2 1 2 1 1
1 1 1 1 2 1 1 1 1 1
A = before therapy; B = after 15 days of therapy; C = after 30 days of therapy.
after the start of pharmacological treatment (see Table I). For each CNV recording a technique similar to that initially described by Walter et al. in 1964 was used. The subject was invited to sit in an anatomical chair in a partially soundproof and semi-dark room. The EEG was recorded through 5 silver-silver chloride electrodes; 2 electrodes were placed along the midline at Fpz and Cz, of the 10-20 system. The 2 reference electrodes were placed on the mastoid processes and directly connected to Fpz. The Cz electrode was referred to the central terminal of a 25 k$2 potentiometer connected to Fpz and the mastoid electrodes by a method similar to that used by McCallum and Walter (1968) to attenuate contamination of the CNV by ocular potentials. A further ground electrode was placed on the ear lobe. Vertical eye movements (EOG) were recorded with electrodes above and below the left eye. The time constant was 8 sec. The first stimulus ($1) was a light flash of 100 /tsec duration. A second stimulus ($2) followed $1 by 1500 msec and consisted in a tone of 200 or 4000 Hz which lasted 600 msec. A push button was placed in the preferred hand of the subject and he was invited to push it as rapidly as he could on hearing the 4000 Hz sound (execution of the task caused the sound signal to stop). The evoked bioelectrical potential was averaged by a signal processor (Model 7170A, Sunei Instruments). Further technical information has been described elsewhere (Rizzo et al. 1979). The following parameters were referred to a 500 msec baseline pre-Sl: maximum negativity of peak CNV; CNV area expressed in /tV z from the end of the visual evoked potential (S1) to the onset of $2; and the post-imperative negative variation (PINV), defined as a delay of 2 sec or more in the return of the EEG tracing to the baseline after $2 (Chouinard et al. 1975). All mean differences were evaluated for statistical significance by a t test for paired data.
All patients displayed measureable slow brain potentials under basal conditions as well as during pharmacological treatment. Table II presents CNV area (/~V2) and maximum peak (/tV). As can be seen in Fig. 1, the peak CNV and CNV area were increased at post-treatment compared to the basal condition. The peak CNV was significantly higher ( P < 0.001) following 15 days (mean = 38.0_+/~V) and 30 days of drug treatment (mean = 38.7_+ 2.6 ~V) compared to the basal condition (mean = 24.0_+ 2.3 ktV) (t = - 12.7,- 10.8 respectively). The CNV area was also significantly greater ( P < 0.001) following 15 days ( m e a n = 2 5 8 . 7 + l l . 9 ~tV2) and 30 days of drug treatment (mean = 260.3_+10.9 /~V2) compared to the basal condition (mean = 150.0 _+8.8/~V 2) ( t = - 48.6, - 60.2 respectively). There were no significant differences between means for peak CNV or area measured at 15 and 30 days post-treatment.
A
a
-V
v,~
A Sl
" ~
V
A S2
,s.v I 0.5 Sec
Fig. 1. Representative CNV tracings for one parkinsonian patient obtained before (A) and both 15 days (B) and 30 days (C) after drug treatment. The PINV observed after 30 days of pharmacotherapy was characteristic of 6 patients.
CNV IN PARKINSONIAN PATIENTS
523
TABLE II CNV data in patients with Parkinson's disease. P a t i e n t no.
Maximum peak (~V)
A r e a (~V 2 )
A
B
C
A
B
C
I 2 3 4 5 6 7 8 9 10
138 140 142 158 154 160 160 144 158 146
240 250 248 270 264 260 280 250 260 266
238 252 250 272 264 262 274 262 268 262
28 22 23 22 27 24 22 22 26 24
37 33 39 38 35 40 39 40 41 38
33 37 41 39 37 39 41 38 40 42
Mean ± S.D.
150± 8.8
258.7 ± 11.9
260.3 ± 10.9
24±2.3
38_+2.4
38.7±2.6
A = before therapy; B = after 15 days of therapy; C = after 30 days of therapy.
The PINV appeared in 1 patient after 15 days of drug therapy and in 6 patients after 30 days of treatment. N o patient showed a PINV during baseline testing.
Discussion
Previous studies based on non-patient subjects have suggested that the CNV is modulated by dopaminergic mechanisms in the brain (Marczynski 1978). This view is supported by two aspects of the present findings. First, a small magnitude of CNV was observed in the basal (non-drug) condition, a time at which dopaminergic activity in parkinsonian patients can be considered weakened. Secondly, an enhanced CNV was found during treatment with L-DOPA, at a time when dopaminergic activity was presumably increased compared to pre-treatment measurements. This increase in CNV following pharmacotherapy of parkinsonian patients may reflect a functional recovery, perhaps partial, in the dopaminergic pathways arising in the mesencephalon (Lindvall et al. 1978) and the brain-stem (Fuxe et al. 1974) and possibly projecting to the superficial frontal cortical layers. This hypothesis has been supported by the work of others (Timsit-Berthier et al. 1983). The present findings also agree with previous work showing decreased CNV magnitude following administration of dopamine antagonists (Thompson et al. 1978). A PINV appeared in the majority of subjects after 30 days of drug treatment. In our opinion, the PINV could reflect dopaminergic activity, rather than the general state of some psychopathological condition postulated by Timsit-Berthier et al. (1971, 1983). In our view, the PINV is more likely to indicate dopaminergic receptor hypersensitivity following a prolonged decrease in DA level in the nigro-striatal system (Hyttel and Christensen 1983). Thus, the alteration of this system by L-DOPA treatment apparently produces a selective (dopaminergic) facilitated sensitivity in the different types of
cortical and subcortical receptors (Hyttel and Christensen 1983). It is also possible that the PINV reflects the role of dopamine dominance in relation to other neurotransmitters and neuromodulators, e.g., GABA (Marczynski 1978). Whatever the specificity or non-specificity of mechanisms, the present study confirms the involvement of neurochemical functions in CNV genesis, one of which is likely to be dopaminergic. Furthermore, the CNV appears to be a potentially useful non-invasive technique for the assessment of neurophysiological activity, including neurochemical functions, that impinge on dopaminergic imbalance in parkinsonian patients.
R6sum6 Maladie de Parkinson: analyse ~lectrophysiologique (CNV) en liaison avec un traiternent pharmacologique
La variation n6gative contingente (VNC) a 6t6 6tudi6e chez un groupe de patients atteints de la maladie de Parkinson. Les tests ont 6t6 pratiqu6s 3 lois: apr6s une p6riode d'61imination de route trace de substances pharmacologiques, apr~s 15 jours et apr6s 30 jours du d6but d'un traitement h la L-DOPA et h la bromocryptine. Le pic et la surface de la VNC augmentaient significativement apr6s chaque traitement. La variation n6gative post-imp6rative 6tait observ6e chez 6 des 10 patients. La corr61ation trouv6e entre les 6valuations fonctionnelles 61ectrophysiologique (VNC) et le traitement pharmacologique conforte l'id6e que l'activit6 dopaminergique du cerveau est un interm6diaire dans la genbse des potentiels c6r6braux lents n6gatifs li6s h l'6v6nement. We are particularly grateful to M. Timsit-Berthier (Liege) and J.J. Tecce (Boston) for their encouragement and helpful criticisms.
524 The authors also thank Mr. Gattoni for technical assistance, and Mrs. F. Tomassoni for the excellent typewriting.
References
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