A combined pharmacokinetic/pharmacodynamic model of levodopa motor response and dyskinesia in Parkinson's disease patients.

PURPOSE: Levodopa is the reference treatment for Parkinson's disease. However, after several years of treatment, dyskinesia may occur and strategies to overcome this side effect still need to be explored. We identified a unique population pharmacokinetic/pharmacodynamic model in Parkinson's disease to investigate the relationship and dissociability of motor response and dyskinesia. METHODS: Thirty parkinsonian patients (Hoehn and Yahr stages 3-4), treated with levodopa and suffering from peak-dose dyskinesia, were included in a prospective open-label study. They received a single dose of levodopa equal to 150 % of their usual daily dose. Blood samples, motor evaluations (UPDRS III scale) and peak-dose dyskinesia (Goetz scale) were examined after administration. A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed using NONMEM software. RESULTS: Pharmacokinetic analysis identified a one-compartment model with the following parameter values [bootstrap 95 % CI]: absorption rate constant (KA) 1.86 1/h [1.08-3.25], clearance 36.6 L/h [31.3-42.8], and volume of distribution 42.9 L [34.3-52.3]. Between-subject variability was 122 % [71-183] and 38 % [26-47] for KA and clearance, respectively. Residual variability was 1120 µg/L [886-1290]. UPDRS III and dyskinesia were best described with an effect compartment and similar KE0 values of 1.37 1/h [1.01-1.77]. For UPDRS III, the E0, EC50, Emax, and Hill coefficient were 31.4 [28.4-35.3], 1410 µg/L [1200-1700], 0.72 [0.71-0.75], and 4.26 [3.20-5.58], respectively. For dyskinesia, the EC50 and Emax were 6280 µg/L [3420-37,900] and 17.9 [12.3-80.8], respectively. Residual variability was 3.15 [2.75-3.53] for UPDRS III and 2.66 [1.94-3.51] for dyskinesia. No covariates influenced the parameters. CONCLUSIONS: In patients treated with levodopa and suffering from dyskinesia, the motor response and dyskinesia have close onsets and duration effects. Maximal motor response tends to be inevitably associated with dyskinesia.

[F0 characteristics in Parkinsonian speech: Contrast between the effect of hypodopaminergy due to Parkinson's disease and that of the therapeutic delivery of L-Dopa]. / Les anomalies de la fréquence fondamentale chez le locuteur Parkinsonien: contraste entre les effets respectifs de l'hypodopaminergie dûe à la maladie de Parkinson et de l'apport thérapeutique par L-Dopa.

Voice and speech impairments are frequent in Parkinson's disease, particularly when the disease is at an advanced stage. These impairments affect spoken communication and may become a serious disability for someone with Parkinson's disease. Many studies based on auditory-perceptual or acoustic methods have been carried out to characterize dysarthria. The heterogeneity of evaluation methods and experimental bias however make results difficult to understand. For instance, in terms of phonatory impairments and with regard to F0, results are contradictory: PD speech may be characterized by either higher F0 or lower F0 compared to control subjects, or there may be no difference at all between the two population. In this study, we aim to provide a conceptual and methodological framework which allows for interpreting the results obtained from 44 speakers (29 PD and 15 control subjects) in relation to physiological (gender, age, PD subjects' pharmacologic state) and linguistic (speech production tasks) constraints. For the present corpus, we did not observe any F0 mean difference between the two groups. Our results however reveal a significant increase in F0 mean in PD subjects under L-dopa. We assume a double and opposite effect on F0 mean during drug withdrawal: low sub-glottal pressure, due to PD, results in a decrease in F0, while laryngeal rigidity leads to an increase in F0. These two effects thus mutually annihilate. Under L-Dopa, however, the drug effect increases sub-glottal pressure, which combined with an increase in F0 due to rigidity, leads to a global increase in F0.

[Dysarthria across Parkinson's disease progression. Natural history of its components: dysphonia, dysprosody and dysarthria]. / La dysarthrie au cours de la maladie de Parkinson. Histoire naturelle de ses composantes: dysphonie, dysprosodie et dysarthrie.

Dysarthria refers to a collective name for a group of neurologic motor speech disorders, resulting from central and/or peripheral nervous system abnormalities. Speech alteration in Parkinson's disease, so-called hypokinetic dysarthria, presents with prosodic insufficiency, related to a monotony of pitch and intensity, a reduction of accentuation, variable speech rate and possible phoneme imprecision. In most cases, voice is harsh and breathy. This symptom can affect both voice and speech quality, as well as prosody and intelligibility. As a consequence, many patients complain about speech impairments, which affect their communication in daily living activities. Perceptual and instrumental assessments require different and numerous investigation methods, which use may help to further understand the specific dysarthria pathophysiology. This is of importance in order to adjust treatments for dysarthria; as a matter of fact, dopa-therapy, functional neurosurgery or even behavioural speech therapy have variable effects on voice and speech quality in Parkinson's disease.

[Measurement of intra-oral pressure as a contributor for the understanding of pneumophonic coordination impairment in Parkinsonian dysarthria]. / Contribution de la mesure de la pression intra-orale pour la compréhension des troubles de la coordination pneumophonique dans la dysarthrie parkinsonienne.

INTRODUCTION: Parkinsonian dysarthria can alter oral communication of the patients in the long-term. Subthalamic nucleus (STN) stimulation represents an interesting therapeutic option, although it does not seem to improve axial signs, of which dysarthric speech. The objective of our study was to contribute to the evaluation of STN stimulation effects on speech impairment and in particular on pneumophonic coordination: this latter parameter can be assessed indirectly by evaluating the temporal progression of the intraoral pressure (IOP) during the expiratory phase; thus, IOP represents the transient expression of subglottal pressure (SGP). PATIENTS AND METHOD: Using a dedicated system (EVA2), 20 parkinsonian patients were recorded in ON and OFF STN stimulation conditions in order to evaluate IOP on three measurement points (2nd, 4th and 6th consonants P) during realization of the sentence "Papa ne m'a pas parlé de beau-papa" ("Daddy did not speak to me about daddy-in-law") which corresponds to a breath group. Eleven control subjects were recorded in parallel in order to define reference measurements. RESULTS: STN stimulation improved significantly IOP at the level of the initial measurement points (2nd P and 4th P), with an effect of convergence at the level of the third point (6th P) where the difference between OFF and ON STIM conditions was not significant any more. In addition, the performance of the patients ON STIM remained much lower than that of the control subjects. CONCLUSION: Our results raise the significant concept that IOP measurement can be regarded as a relevant indicator for dysarthria in Parkinson's disease. They also show that the improvement of pneumophonic coordination by STN stimulation is restricted to the initial period of the expiratory phase, confirming again the mitigated and controversial effect of STN stimulation on axial signs.

Levodopa/DDCI and entacapone is the preferred treatment for Parkinson's disease patients with motor fluctuations in routine practice: a retrospective, observational analysis of a large French cohort.

Levodopa is the gold standard drug for the symptomatic control of Parkinson's disease (PD). However, long-term treatment with conventional formulations [levodopa and a dopa decarboxylase inhibitor (DDCI)], is associated with re-emergence of symptoms because of wearing-off and dyskinesia. Treatment with levodopa/DDCI and entacapone extends the half-life of levodopa, avoiding deep troughs in levodopa plasma levels and providing more continuous delivery of levodopa to the brain. In this open-label, retrospective, observational study we investigated the effects of levodopa/DDCI and entacapone therapy in 800 PD patients with motor fluctuations. Levodopa/DDCI and entacapone treatment was assessed as good/very good in improving motor fluctuations (64%) and activities of daily living (ADL; 62%). The therapeutic utility was considered to be good/very good in 70% of cases. Moreover, there was a reduction in levodopa dose in 20% of patients. Neurologists preferred levodopa/DDCI and entacapone compared with increasing levodopa dosage, dose-fractionation or addition of a dopamine agonist (63%, 29% and 23% of patients respectively). Reasons included achieving more continuous dopaminergic stimulation (40%), reducing motor fluctuations (54%) and improving ADL (41%). This analysis reveals the preference of neurologists for levodopa/DDCI and entacapone over conventional levodopa-modification strategies for the effective treatment of PD motor fluctuations in clinical practice.

Axial rotation in Parkinson's disease.

AIMS: To investigate the ability of patients with Parkinson's disease to perform a rotation around the longitudinal axis of the body. Three questions were raised. Is body rotation impaired in Parkinson's disease? Is there a level of the kinematic chain from the head to the foot at which the impairment is more severe? Is the deficit related to the general slowness of movement in Parkinson's disease? METHODS: Kinematic data were recorded. The temporal organisation of body rotation during gait initiation was analysed in 10 patients with Parkinson's disease, who were all at an advanced stage of the disease and had all experienced falls and freezing during their daily life, and in five controls. The latency of the onset of the rotation of each segment was measured by taking the onset of the postural phase of step initiation as reference value. Locomotor variables were also analysed. RESULTS: Body rotation was found to be impaired in patients with Parkinson's disease, as the delay in the onset of the rotation of each segment is greater than that in controls. Moreover, a specific uncoupling in the onset of shoulder and pelvis segment rotation was seen in patients. This impairment of rotation is not related only to the general slowness of movements. CONCLUSION: Patients with Parkinson's disease were found to have an impairment of posturo-kinetic coordination and impaired capacity to exert appropriate ground reaction forces to orient the pelvis in space.

Magnetic resonance imaging evidence of decreased putamenal iron content in idiopathic Parkinson's disease.

OBJECTIVE: To determine the changes in basal ganglia iron content associated with various stages of idiopathic Parkinson's disease. DESIGN: Prospective magnetic resonance imaging study using a 2-T magnet. SETTING: Ambulatory care referral center. PATIENTS AND PARTICIPANTS: Forty-five patients suffering from levodopa-responsive Parkinson's disease and 45 age-matched controls. MAIN OUTCOME MEASURES: The T2 relaxation time calculated in various regions of the basal ganglia, the duration of Parkinson's disease, and the age of subjects. RESULTS: Patients with Parkinson's disease exhibited significantly decreased T2 relaxation time in the pars compacta of the substantia nigra compared with controls (P < .01), regardless of disease duration. Patients with a duration of illness above 10 years (n = 12) exhibited significantly increased T2 relaxation time in the anterior and posterior putamen (P < .005 and P < .01, respectively) and in the pallidum (P < .05) compared with age-matched controls. Putamental T2 relaxation time positively correlated with disease duration (P < .05). CONCLUSION: These results suggest that more complex brain iron changes than those previously reported are associated with idiopathic Parkinson's disease, including increased nigral iron content and decreased putamenal and pallidal iron concentration in patients with a duration of illness above 10 years.

Bilateral and side-related reaction time impairments in patients with unilateral cerebral lesions of a medial frontal region involving the supplementary motor area.

Human subjects (nine patients with unilateral brain lesions of a medial frontal region involving the supplementary motor area, SMA, and 10 controls) performed two reaction time (RT) tasks in response to the presentation of a luminous signal: an aimed movement towards a spatially defined target involving hand lifting and pointing with the index finger, and a no-aimed movement consisting of the hand lifting phase completed by the stabilization of the limb posture without any pointing. When compared with controls, the patients exhibited a bilateral RT increase which was more pronounced in the hand contralateral to the lesion. Moreover, comparison between the two tasks showed that this contralateral RT impairment was more marked in the no-aiming than in the aiming task. These results suggest that unilateral lesions of a medial frontal region involving the SMA cause two types of RT impairment in these motor tasks. The first may concern a supramotor function which acts bilaterally and initiates the motor programme of the limb movement as the first step of preparatory processes. The second component of this RT impairment would concern a supplementary motor function which consists of the feed forward control of the coupling between the hand lifting and the appropriate posture, just before the triggering of the limb movement. This interpretation leads to the hypothesis that the SMA region, and the medial motor system in general, may have a dual motor function.

Multiple sclerosis: cell-mediated immunity to human brain gangliosides.

Cell-mediated immunity (CMI) to myelin components has been implicated in Multiple Sclerosis (MS) pathogenesis: two targets were suggested, Myelin Basic Protein with controversial results and, more recently, gangliosides. In order to investigate their possible involvement, we have performed Leukocyte Migration inhibition (LMI) tests in the presence of human brain gangliosides. Thirty nine MS patients (twenty four being "definite", according to McDonald and Halliday's classification), twenty nine patients with Other Neurological Diseases (OND), thirty six patients with Inflammatory diseases (ID) and forty healthy controls were tested. MS patients were divided into two groups, depending on the clinical stage of the disease. The mean migration inhibition percentage of the MS-attack group was found to be significantly different from the four others (p less than 0.01) (24.4 +/- 16.2 versus 10.9 +/- 8.5 in MS without attack, 4.4 +/- 12.9 in OND, 3.9 +/- 13.9 in ID and 11.1 +/- 12.1 in healthy subjects). LMI to gangliosides is therefore significantly increased during the attack stage in MS. These results support the notion of a Delayed Type Hypersensitivity to these glycolipids during the active stage of the disease.

Motor impairment after unilateral electrolytic lesions of the substantia nigra in baboons: behavioral data with quantitative and kinematic analysis of a pointing movement.

Unilateral electrolytic lesions of the substantia nigra (SN) were carried out stereotaxically on 4 baboons which had been previously trained to perform a visually guided pointing movement. For a few days after operation, all animals exhibited a behavioral impairment affecting the contralateral body half and consisting of dystonic flexed posture and akinesia. The animals were thus unable to perform the pointing task with the contralateral hand. After a delay which depended on the extent of the SN lesion, the animals began to make the pointing movement again. Postoperative changes were then observed only on the side opposite the SN lesion. These consisted of an increase in the latency and particularly the duration of the movement without any change in the accuracy. The kinematic analysis of the hand trajectory showed that the contralateral increase in the movement duration corresponded to a regular decrease in the velocities. Study of the recovery over 120 days after SN lesion showed a progressive improvement which was faster with regard to movement duration than to movement latency. These data clearly point to the functional role of the SN in the initiation and particularly in the execution of movement. Quantitative and kinematic analysis of this pointing movement makes it possible to detect and quantify very closely the changes in movement program and execution induced by a SN lesion. This experimental model will be useful for pharmacological in vivo studies allowing a more specific assessment of the functional role of the neurotransmitters involved in SN dysfunction.

Bradykinesia following unilateral lesions restricted to the substantia nigra in the baboon.

Unilateral lesions were made in the substantia nigra of baboons which had been previously trained to carry out a visually guided pointing movement. During the early post-operative period, the animals were unable to perform the task with the contralateral forelimb because of the severity of the akinesia affecting it. After one or two weeks, the animals began to make the movement; at this time, there was a purely contralateral increase in the latency and particularly the duration of the movement, while its accuracy remained unchanged.

Preparatory postural adjustments in parkinsonian patients with postural instability.

BACKGROUND: Postural instability is a common problem in patients with Parkinson's disease. This paper reports results of a study undertaken to investigate some of the possible mechanisms responsible for this instability. METHODS: Preparatory postural adjustments associated with a lateral leg raising task were studied in five parkinsonian patients and four age-matched controls. Recordings included ground reaction forces, kinematics, and surface EMG activity from multiple leg muscles. RESULTS: In normal subjects there was a well-defined sequence of events preceding the onset of leg elevation, beginning with a transfer of centre of foot pressure (CP), initially toward the moving leg and then back to the support side, followed by displacement of the trunk toward the support side. In the more severely affected parkinsonian patients, the amplitude of the initial displacement of CP was markedly reduced. The interval between the earliest force changes and the onset of leg elevation was prolonged and the relative timing of the kenematic adjustments during this interval was disrupted. In addition the alternating burst and periods of inhibition observed in the EMG recordings from the normal subjects were replaced by continuous tonic EMG activity. CONCLUSIONS: These observations suggest that abnormalities in programming preparatory postural adjustments may contribute to postural instability in some patients with advanced Parkinson's disease.

[Spatial orienting of attention: a study of reaction time during pointing movement]. / Orientation spatiale de l'attention: étude des temps de réaction lors du mouvement de pointage.

AIM: The aim of this study was to investigate how advance information both explicit and implicit provided prior to movement may affect the spatial orientation and the internal attention control processes in normal adult subjects. The originality of this work compared to the test of Posner, lies essentially in the methodology used to study the attentional systems. The use of three procedures of reaction time (RT) allowed us to study the setting concerned of the specific and non-specific components of the attention in the motor preparation. By associating of these three procedures of RT, we have evaluated the effects of the explicit and implicit components of advance information on motor preparation. The use of advance information to the movement requires the implication of the attentional systems. MATERIAL AND METHODS: Experiments were carried out using a simple reaction time (RT) procedure involving the use of an orientation cue and two choice reaction time situations: one with a neutral preparatory cue and one with a priming cue giving the likelihood of the preparatory stimulus (S1) being compatible with the imperative stimulus (S2). The mechanisms underlying the subjects' vigilance and the orientation of their attention were studied by assessing the effects on their reaction times of the preparatory signal and those of the cue giving the likelihood of S1 and S2 being compatible. The preparatory signal was designed to explicitly attract the subjects' attention towards the position of the forthcoming pointing target, whereas the cue giving the compatibility between S1 and S2 was intended to mobilize the subject's attention more implicitly. Prior to performing the pointing movement towards a visual target, the subjects' attention was therefore mobilized by the advance information containing two components: the explicit information about the position of S1 and the implicit information about the probability of S1 and S2 being compatible. RESULTS AND CONCLUSION: The results obtained here on 17 normal adult subjects show that the subjects significantly improved their RTs by using the explicit component of the information provided. The implicit information available was also used in the choice reaction situations: a priming effect was found to occur, which resulted in the shortening of the primed "compatible cue" reaction times in comparison with the "neutral cue" reaction times, and in the correlation which was found to exist between the reaction time performances and the degree of compatibility between the preparatory signal and the imperative signal. These results suggest that various components of the attentional system may participate in processing the advance information provided prior to the movement in reaction time tasks of the kind used here. The explicit information provided prior to the movement may mobilize the subject's vigilance and spatially orients his attention; whereas the implicit information available may rather subserve the internal control of the subject's attention.

[Diagnosis of narcolepsy-cataplexy: importance of continuous recording in ambulatory EEG. Report of 20 cases]. / Diagnostic de la narcolepsie-cataplexie: intérêt de l'enregistrement continu sous EEG ambulatoire. A propos de 20 observations.

Ambulatory EEG (A-EEG) allows longterm polygraphic recording over 24 hours or more and proves to be particularly useful in the diagnosis of narcolepsy-cataplexy (N/C). We performed A-EEG using the Medilog 9000-8 channel system over a total of 36 24-hour periods in 20 consecutive N/C patients and recorded an average of 3.5 daytime sleep episodes, of which 2.2 were with SOREMP, AND 21 evening SOREMP (58%). A MSLT was performed using A-EEG in 16 cases. Continuous A-EEG proved to be more informative than the MSLT, and may represent a valid alternative to the classic continuous polygraphic recordings performed in the sleep lab, that are more cumbersome and costly. Although a full-night polysomnographic recording is still necessary whenever other sleep disorders are suspected in association with N/C, A-EEG is a first-line, practical method for the confirmation of N/C, which remains a clinical diagnosis.

Coordination of axial rotation and step execution: deficits in Parkinson's disease.

To determine why parkinsonian patients (PP) present some difficulties to initiate locomotion, a diagonal step has been investigated in two tasks in five control subjects (CS) and in ten PP. In the first task, the subjects had to perform one diagonal step without change in their orientation (WR); in the second task, they had to perform one diagonal step with a body rotation in the step direction (RO). The defended hypothesis is that the gait initiation deficits in Parkinson disease are a consequence of their difficulties to coordinate al the component of a complex movement. The analysed parameters were the duration of the postural and movement phases, the step length and velocity, and the amplitude of the horizontal ground reaction forces during each phase. Compared to CS, the PP showed a lengthening of the postural phase, a decrease in the step length and velocity and a reduction of the horizontal forces. The comparisons between the performances obtained in the WR versus those obtained the RO show in CS that the performances remained unchanged, whereas in PP the performances were significantly more altered in the RO. It illustrates the specific deficit occurring in PP while performing complex tasks where coordination between several components has to be achieved simultaneously.

Devic's neuromyelitis optica: a clinicopathological review of the literature in connection with a case showing fatal dysautonomia.

A new clinicopathological case of Devic's neuromyelitis optica, including unusual predominant clinical features (fatal dysautonomia) is described herein: pathological examination showed extensive and severe demyelination mainly involving the optic nerves, the medulla, and spinal cord, which was particularly pronounced in the thoracic segments, and thus explained the unusual vegetative symptomatology. In a review of 45 clinicopathological cases described in the literature as Devic's disease (DD), it turned out that only 22 cases, including the patient described here, fulfilled the recently defined diagnostic criteria [Devic 1980]. Among the other 23 cases, 15 did not fulfill the criteria because of the occurrence of relapses, 3 others had 2 separate pathological locations within the spinal cord, and the remaining 5 showed evidence that a disease other than DD was involved. Among the 22 cases which were definitely taken to be DD, the mean age at clinical onset was 39 years (+/- 14); it was characterized by acute bilateral visual loss and transversal myelitis which gradually led either to death or to partial or complete recovery. The pathological lesions, which mostly were located along the optic tracts and the spinal cord, were characterized by demyelination with inflammation and necrosis; in some cases the pathological process diffused into the medulla (8/22 cases) or the whole brainstem (4/22 cases). The cavitation of the spinal cord was not a key feature of the diagnosis, since it was observed on only 9/22 cases. Devic's neuromyelitis optica may be a separate nosological entity which differs from multiple sclerosis.

[Capsulo-thalamic hemorrhage (author's transl)]. / Les hémorragies capsulo-thalamiques. Etude clinique et scanographique a propos de 26 observations.

The authors report clinical and scanographic findings in 26 cases of capsulo-thalamic hemorrhage. They stress the frequency of arterial hypertension as a pre-disposing factor. The clinical picture is represented by the association of disorders of consciousness (usually obnubilation), contralateral flaccid hemiplegia with hemianesthesia, oculomotor disorders (disturbance of vertical gaze, miosis) and disorders of linguistic and motor behaviour. The paraclinical examination of choice is scanography which enables the site, volume and extent of the hemorrhage to be estimated, together with the mass effect and intraventricular rupture. Clinical and scanographic follow-up indicates a favourable prognosis for capsulo-thalamic hemorrhage (77% survival). Follow-up findings point to several unfavourable prognostic factors: immediate coma, persistent and massive flaccid hemiplegia, hemorrhage size exceeding 3 cm, and severe intraventricular rupture. In the light of the data in the literature, the authors discuss the clinical and scanographic signs of capsulo-thalamic hemorrhage.

Specific functions of the motor cortex in reorganizing coordinations during motor training in animals and humans.

The involvement of the motor cortex in learning movements has recently attracted much attention. One aspect of motor learning is the inhibition of innate synergies which interfere with performance of the acquired movement. Various models of operant responses in dogs have demonstrated the critical role of the motor cortex in the reorganization and inhibition of interfering synergies during learning. The role of the motor cortex and corticospinal influences in the formation of new coordinations in humans was studied here in patients with organic lesions of the cerebral circulation involving the internal capsule, using postural coordination and movements in a bimanual unloading response as an example. Formation of the forearm stabilization response was deeply lesioned on the afflicted side. Some degree of impairment was also seen on the ipsilateral side, but it was no different from the level of learning impairment in patients with lesions not involving the internal capsule or in patients with parkinsonism. The existence of specific contralateral influences of the motor cortex and non-specific descending influences on the process of motor learning is proposed.

[Diagnostic criteria for idiopathic Parkinson's disease]. / Criteres de diagnostic de la maladie de Parkinson idiopathique.

Clinical diagnosis of parkinsonian syndrome is reasonably easy, but the distinction between idiopathic Parkinson's disease (IPD) and other parkinsonian syndromes (Secondary parkinsonisms and "Parkinsons plus") may be very difficult particularly in early cases. A correct diagnosis is not only important for counselling and management of patients but also in conducting pharmacological and epidemiological studies. A critical analysis of the diagnosis criteria of IPD, based on the pathological verification, is discussed from recent data of literature. Without any validated and available criteria from functional imaging or molecular biology, the most effective diagnostic criteria remain on the clinical range; the five most effective criteria are resting tremor, rigidity, bradykinesia, asymmetry at onset and marked levoDOPA responsiveness. The diagnosis of IPD should be periodically reassessed along the course of its natural history.

[Neuroplasticity and Parkinson's disease] / Neuroplasticité et maladie de Parkinson.

Emerging concept, to date, neuroplasticity becomes a concrete reality in the adult central nervous system (CNS), particularly in a so-called neurodegenerative disease as idiopathic Parkinson's disease (IPD). After a brief survey of some general aspects of plasticity in the CNS, the present tutorial review illustrates with recent data from the literature the modes of plastic changes during the course of IPD, either resulting from dopaminergic denervation (hyperactivity of remaining dopaminergic neurons with increase of their excitatory cholinergic innervation in the substantia nigra, enhancement of the corticostriatal glutamatergic synaptic activity at the striatal level) or due to dopaminergic treatment (change in phosphorylation state of the striatal glutamate receptors, internalization of D1 Dopamine receptors). Neuroplasticity in Parkinson's disease could represent a rational basis for forthcoming therapeutic issues