History of exposure to dopaminergic medication does not affect motor cortex plasticity and excitability in Parkinson's disease.

OBJECTIVE: Little is known whether and how chronic exposure to dopaminergic treatment alters physiological mechanisms in Parkinson's disease (PD). METHODS: Two clinically similar groups of PD patients, one consisting of drug-naïve patients and another of patients already on chronic dopaminergic medication (when off medication), were compared to each other and to a control group. Plasticity and excitability of the hand primary motor cortex of the more affected side were evaluated using transcranial magnetic stimulation (TMS) techniques. RESULTS: There was little difference between two patient groups, and both groups showed similar differences in comparison to controls: decreased facilitatory sensory-motor plasticity (as measured by paired associative stimulation [PAS] protocol), impaired short-interval intracortical inhibition (SICI), and diminished slope of input-output curves at higher TMS intensities. The exception was that 30 min after PAS, intracortical facilitation (ICF) was significantly reduced in drug-naïve patients, whereas it changed much less in other two groups. CONCLUSIONS: Chronic exposure to dopaminergic drugs does not affect substantially the features of motor cortex excitability and plasticity in PD. There is little interaction between plasticity and excitability features of motor cortex in PD. SIGNIFICANCE: Reduced response to facilitatory PAS protocol, reduced SICI, and reduced slope of the input-output curve at higher TMS pulse intensities, seem to be physiological markers for the presence of the pathological disease process in PD. Long term treatment does not seem to change the underlying physiology of the disease.

Paired-associative stimulation can modulate muscle fatigue induced motor cortex excitability changes.

The aim of this study was to examine whether the changes of the motor cortex excitability induced by muscle fatigue could be affected by prior or subsequent intervention protocol supposed to induce opposing excitability changes. For this purpose we used paired associative stimulation (PAS) method, where peripheral nerve stimuli were associated with transcranial magnetic stimulation (TMS) of the motor cortex at a fixed interstimulus interval of 25 ms. The PAS protocol used is known to produce a long lasting, long-term potentiation (LTP) like change of cortical plasticity manifested by significant increase in motor evoked potentials (MEPs) amplitude. In this study, we confirmed significant MEP size reduction following fatigue, which had been already reported in the literature. When PAS was applied either immediately before or after muscle fatigue protocol, the excitability changes were largely occluded and MEP sizes remained close to baseline levels. However, in spite of the effects on cortical excitability, conditioning with PAS did not cause any change in target fatigue measure, the endurance point, which remained the same as when fatiguing protocol was applied alone. The present results demonstrate that fatigue-related changes in cortical excitability can be modulated by either prior or subsequent excitability promoting activity. They also suggest that muscle fatigue associated changes in motor cortical excitability probably represent non-specific activity-related plasticity, rather than a direct expression of the so-called central fatigue.

Changes in corticospinal motor excitability induced by non-motor linguistic tasks.

The excitability of the corticospinal motor pathways to transcranial magnetic stimulation (TMS) can be differentially modulated by a variety of motor tasks. However, there is emerging evidence that linguistic tasks may alter excitability of the corticospinal motor pathways also. In this study we evaluated the effect of several movement-free, low-level linguistic processes involved in reading and writing on the excitability of the bilateral corticospinal motor pathways in a group of right-handed subjects. The study included two series of tasks, visual searching/matching and imaginal writing/drawing. The tasks were designed to roughly correspond with elemental aspects of the reading and writing, grapheme recognition and grapheme generation, respectively. Each task series included separate blocks with different task targets: letters, digits, semantically easy-to-code (i.e. geometric) shapes, and semantically hard-to-code shapes, as well as control blocks with no task. During task performance, TMS was delivered randomly over the hand area of either the left or right motor cortex and the modulation of the excitability of the corticospinal motor pathways was measured bilaterally through changes of the size of the motor-evoked potential (MEP) induced in the relaxed right and left first dorsal interosseous (FDI) muscles. We found that the size of the MEP in hand muscles increased during visual searching/matching tasks, particularly when targets were letters or geometric shapes, and the increase was significant for the dominant hand (left hemisphere) only. No such consistent effects were seen across subjects during imaginal tasks. This study provides evidence that even the performance of certain low-level linguistic tasks can modulate the excitability of the corticospinal motor pathways, particularly those originating from the left (dominant) hemisphere, despite the absence of overt motor activity. Moreover, in the light of the recently increased awareness of the role of "mirror neurons" in perception, the results suggest that activation of motor circuits used in generation of the written output may be an essential part of the perception of the written material as well. Understanding the patterns of task-dependent changes in excitability of the corticospinal motor pathways will provide insights into the organisation of central nervous system functional networks involved in linguistic processes, and may also be useful for future development of novel approaches to rehabilitation therapy of linguistic and motor functions.

Spontaneously changing muscular activation pattern in patients with cervical dystonia.

The objective of this study was to determine stability of the neck muscle activation pattern in a given dystonic head position in patients with cervical dystonia (CD). We assessed 26 patients with CD and botulinum toxin (BT) treatment failure before surgical denervation. None of them had received BT injections for at least 4 months. To relate dystonic head position to underlying neck muscle activity, we used synchronised video and poly-electromyographic (EMG) recording over a period of 10 minutes. The muscle activation pattern during constant ("stable") maximal dystonic excursions was analysed. EMG data of nine patients was excluded from the analysis, as these patients had a constantly changing head position or marked head tremor. In the remaining 17 patients, who had a fairly stable dystonic position, muscular activation patterns during the recording spontaneously changed in nine (Group A) while in eight it remained stable (Group B). There was no significant difference in demographic variables between the two groups other than a male predominance in Group A. However, the retrospectively determined initial response to BT treatment (before BT treatment failure had occurred) was significantly worse in Group A as compared with Group B. Neck muscle activation patterns can spontaneously change in CD patients despite constant dystonic head position, implying an inherent variability of the underlying central motor program in some patients. This should be considered when BT treatment response is unsatisfactory, and should also be taken into account when interpreting results of EMG recordings of neck muscles in these patients.

Motor cortex excitability following short trains of repetitive magnetic stimuli.

Trains of repetitive transcranial magnetic stimuli (rTMS) appear to have effects on corticospinal excitability that outlast the duration of the train. In order to investigate the mechanism of this effect in more detail we applied short periods of rTMS consisting of up to 20 stimuli at 5 Hz, 10 Hz or 20 Hz (rTMS) to the motor cortex at an intensity equal to resting threshold in 11 healthy, relaxed subjects. Spinal excitability, as judged by effects on the H-reflex or on transcranial anodal facilitation of the H-reflex, was not affected by the rTMS. However, cortical excitability, as judged by the effect on the size of EMG responses evoked by a suprathreshold TMS pulse, was decreased for up to 1 s after the end of rTMS. Post-train suppression was more powerful following longer trains or higher frequencies of rTMS. The predominant suppression contrasts with previous reports of facilitation, particularly after high-frequency rTMS. A second set of experiments, however, showed that this could be converted into facilitation if the intensity of rTMS was increased. We conclude that the after-effects of rTMS depend on its frequency, intensity and duration. The results are consistent with a model in which inhibition and facilitation build up gradually during the course of a conditioning train. Inhibition reaches its maximum effect after only a small number of stimuli, whereas facilitation takes longer. The threshold for evoking inhibition is lower than that for facilitation. Thus if moderate intensities of conditioning train are applied, inhibition is predominant after short trains, whereas facilitation dominates after long trains.

Uncoupling of contingent negative variation and alpha band event-related desynchronization in a go/no-go task.

OBJECTIVES: To examine how the differences in the sequences of brain activation during the go/no-go delayed response choice reaction time (RT) task are reflected into two concurrent methods of measuring brain electrical activity, the alpha band event-related desynchronization (alpha ERD) and the contingent negative variation (CNV). METHODS: alpha ERD and CNV were calculated using appropriate techniques from the same samples of electroencephalographic activity recorded during performance of a cued choice go/no-go delayed response RT task (i.e. S1 (go/no-go)--S2 paradigm) in 8 healthy subjects. RESULTS: All segments of the CNV traces were different in the go and the no-go conditions. The go CNV traces displayed a typical pattern of slow rising negativity reflecting the build-up of attentional resources necessary for adequate performance of the task. On the other hand, the no-go traces remained close to zero reflecting the 'withdrawal' of further preparation after evaluation of S1. During the same period, both go and no-go ERD traces showed a gradual decrease in alpha band power (desynchronization) that was evident until shortly before the presentation of S2. It was only in the 500 ms before S2 presentation that there was any indication that the go and no-go ERD traces were different, but this did not reach statistical significance. CONCLUSIONS: Our data show that the pattern of the go/no-go difference in alpha ERD traces does not correspond to the pattern that can be seen in the CNV traces. This suggests that there is no direct coupling of CNV and alpha ERD, most probably because they measure different aspects of cortical electrical activity. In addition, the extent of the no-go alpha ERD reveals that refraining from performance of a pre-programmed movement is by no means a passive/inactive process.

Bereitschaftspotential in depressed and non-depressed patients with Parkinson's disease.

Impaired initiation and slowed execution of movements are two of the principal characteristics of Parkinson's disease (PD). A similar pattern of movement impairments (psychomotor retardation) can be seen frequently in patients with idiopathic depression. In addition, affective disorders have been frequently reported in patients with different basal ganglia disorders. The aim of this study was to determine whether there are some particularities in the cerebral electrical activity during the preparation and execution of voluntary internally paced movements (i.e., Bereitschaftspotential, BP) in depressed PD patients, which can distinguish them from non-depressed PD patients, as well as from healthy controls. The BPs were recorded in 16 patients with idiopathic PD, eight of whom were depressed (PD-D), and eight of whom were not (PD-ND). Additional recordings were taken from a group of eight age- and sex-matched healthy subjects. Depression was classified using the Research Diagnostic Criteria and the two PD groups were matched for age, disease severity, and disease duration. The amplitudes and slopes of the BPs from PD patients were generally smaller than in controls, but there was no specific pattern of BP changes that distinguished depressed from non-depressed PD patients. In addition, there was no particular association between measures of depression severity and BP parameters. The data suggest that presence of depression in PD might not have any additional deteriorating influence on already impaired preparation for self-paced spontaneous movements.

Cortical potentials related to the nogo decision.

The go/nogo reaction time task has been frequently used to assess volitional inhibition. Psychophysiological studies of the correlates of the go/nogo decision have almost exclusively been concerned with N2 and P3 potentials of the event-related potentials (ERPs). However, in studies where the EMG onset latency was available, it was obvious that this latency was shorter than or at least equal to the latencies of the studied cerebral potentials. In this study, by concurrent recording of the EEG and EMG activity we aimed to better define the temporal relationship between cortical activity and motor response. Particularly, we wanted to identify the early (i.e. pre EMG-onset) electrophysiological correlates of the nogo decision. We used a modified S1-S2 paradigm that involved a two-stage go/nogo decision. In this task both S1 and S2 were informative and required the subject to make a decision, but the nature of the decision differed. The decision at S1 involved whether to prepare a movement, whereas the decision at S2 involved whether to initiate or inhibit an already prepared response. To better visualise the nogo decision related components of the ERPs, the go ERPs were subtracted from the corresponding nogo ERPs and difference ERPs were formed. Before EMG onset, a small negative component common to both go/nogo difference traces and corresponding roughly with the N1 wave was detected. It is suggested that this early negativity may be a more specific electrophysiological reflection of the nogo decision proper.

Cortical potentials related to decision-making: comparison of two types of go/no-go decision.

The S1-S2 go/no-go reaction time task has been frequently used to assess volitional inhibition. In this study our aim was to compare the ERPs elicited by S1 and S2 by using a modified S1-S2 paradigm which involved a two-stage go/no-go decision. The go and the no-go S1 ERPs did not differ substantially, and both displayed a prominent negativity with peaks at 260 ms (S1N260) and at 330 ms (S1N330) post-S1. The S1N260 was similar to the N2 from no-go S2 trials. Since after all three types of stimuli, movement is not required and is inappropriate, this negativity may represent the correlate of the voluntary decision to suppress movement. Later, the S1 ERPs were dominated by frontal negativity (S1N330), probably reflecting further processes related to response preparation, while the S2 ERPs displayed a large central and parietal positivity (P3), probably reflecting the processes of evaluation of response accuracy.

[Buspirone in the treatment of cerebellar ataxia]. / Buspiron u lecenju cerebelarne ataksije.

Ataxia is defined as a disturbance which, quite independent of any motor weakness, alters direction and extent of voluntary movement and impairs the sustained voluntary of reflex muscle contraction necessary for maintaining postiue and equilibrium [1]. Since pathophysiological basis of cerebeller ataxia is still not completely clear, the current therapeutic attempts are mainly symptom-oriented [3]. One possible approach could be a modification of potentially involved neurotransmitter systems of the cerebellum, where particularly interesting is the serotonergic system. However, attempts with levorotatory form of tryptophan (5-HT precursors) proved to be ineffective [4, 5]. Since receptors in the cerebellum are mainly of 5-HTIA subtype, the use of specific agonists might be a more reasonable therapy [6]. The study initially involved 11 patients, but only 9 completed the protocol due to unfavorable side effects. Our open label prospective study lasted for 15 weeks. The patients were tested before the beginning of the treatment (initial visit), at 7th (first visit) and 11th week (second visit) of continuous therapy, and eventually at 15th week (final visit). The daily dose was 40 mg at the first and 60 mg at the second visit. We used the evaluation scale gurposed for cerebellar functions testing (speech, gait, coordination and ocular movements). Significant improvement of cerebellar ataxia in patients under buspiron therapy has been noted. We analyzed the results obtained from our 9 patients (4 females and 5 males), of which 6 patients suffered from cerebellar degeneration, one from multiple sclerosis, one from Ramsey-Hunt syndrome, and one from pontine myelinolysis. At the initial visit the patient score was 18.9 (SD = 7.3), subsequently, at the iirst visit the score was 15.4 (SD = 8), while the second visit yielded the score of 12.9 (SD = 8.2), and finally, after a two-weeks lasting wash-out period, it was 17.7 (SD = 7.1) (Table 1). It was found that patients exhibiting mild ataxia showed a better improvement in comparison to the patients who had marked cerebellar symptoms at the beginning of the treatment (Table 2). In conclusion, our prospective study shows that buspiron treatment improves cerebellar symptoms.

Depression in Parkinson's disease: an EEG frequency analysis study.

Although depression is a common finding in Parkinson's disease (PD), its neurobiological mechanism is still unknown. The purpose of this study was to determine whether there are specific spectral electroencephalographic (EEG) characteristics that distinguish depressed from non-depressed PD patients. The study was performed in 24 patients with idiopathic PD whose antiparkinson medication was stopped 24h beforehand. They were divided into two groups of 12 patients each, one with depressive symptomatology, and one without. The groups did not differ with respect to age, sex distribution, and disease severity and duration. All recordings were conducted using a 16-channel electroencephalograph, and artifact-free EEG was processed using a Fast Fourier Transformation. The EEG of depressed PD patients showed significantly less absolute and relative power in spectral band 7.5-10Hz (alpha1), and slightly more relative power in spectral band 10.513Hz (alpha2), while there was no difference in other spectral bands. Topographic analysis of the alpha1 absolute power revealed that, while in non-depressed patients this activity has a clear occipital maximum (and thus corresponds to the standard background activity), in depressed patients its maximum was shifted anteriorally toward the parietal region. Topographic analysis of the significance of the difference between the groups in the relative power of alpha1 and alpha2 bands revealed opposite gradients, posterior to anterior and anterior to posterior directions, respectively. The spectral EEG characteristics of the depressed PD patients not only differed from the spectral EEG characteristics of non-depressed PD patients, but they were also different from the usually reported spectral EEG characteristics of depressed patients without neurological disease. We propose that our data are sufficient to raise the possibility for the existence of a distinctive neurobiological substrate of depression in PD. This is not just a simple addition of two neurobiological substrata, one of depression (as it is determined in non-neurological patients) and one of PD, but rather a complex product of their interaction.

[Clozapine in the treatment of adverse psychiatric manifestations of long-term therapy with levodopa]. / Clozapin u lecenju nezeljenih psihijatrijskih manifestacija dugotrajne terapije levodopom.

INTRODUCTION: Chronic administration of dopaminomimetic drugs, levodopa before all, to patients with Parkinson's disease (PD) is accompanied with numerous complications. Psychiatric complications are not only frequent, but also difficult to manage. Reduction of the daily dose or complete discontinuation of dopaminomimetic therapy and usage of conventional neuroleptic drugs may relieve the psychotic symptoms, but both these approaches are associated with unacceptable deterioration of motor symptoms. The aim of the study is to present our experience in the treatment of levodopa-induced psychoses by clozapine in patients with PD. Clozapine is a non-typical antipsychotic drug with low potential fr inducing extrapyramidal symptoms. METHODS: A two-year open study in which clozapine was used as the treatment of choice covered 16 patients with PD and psychosis (8.7% of all patients with PD treated at the Department of CNS Degenerative Diseases, Institute of Neurology, Clinical Centre of Serbia, Belgrade). All patients presented for examination with psychotic manifestations whose severity necessitated hospitalization so that the whole study was conducted on the in-patient basis. Patients with haematological disorders, history of epileptic seizures or major dysfunction of the heart, liver and kidneys were not included in the study. In none of the patients EEG records suggested epileptic focl or other major disorders. The stage of PD was determined according to Hoehn and Yahr scale. After the comprehensive evaluation, the treatment was initiated with a bedtime dose of 6.25-12.5 mg clozapine, with gradual increase in 6.25 mg increments in two or three day intervals until the dose which optimally relieved the psychotic symptoms. The levodopa doses were not reduced, except in cases when clozapine action was not satisfactory after the 50 mg dose had been reached. The patients were subjected to daily evaluation of therapeutic response and adverse effects (particularly in the first 19 days) while the blood count and leukocyte formula were determined twice a week. RESULTS: A group of 16 patients with PD consisted of 7 women and 9 men, average age 64.8 years (range 51-72), and average duration of PD 13.7 years (range 7-19). All patients received the combination of levodopa and benserazide, mean dose 875.5 mg (range 500-1250 mg), while eight patients received bromocriptine (15 mg), as well. Relief of psychotic symptoms was achieved in 12 (75%) patients in whom the improvement was manifest 5-7 days after the onset of clozapine therapy. The average daily dose of clozapine in this group of patients was 30 mg (range 12.5-100 mg) which was continued even after the discharge of the patients, in the follow-up period of 6-18 months, with unchanged effect. In two patients the therapy was discontinued due to marked orthostatic hypotension and somnolence. In another two patients (13%) the therapy failed to induce the desired effect in spite of the clozapine dose increase to 300 mg. DISCUSSION: The basic conclusion of our study is that clozapine effectively suppresses levodopa-induced psychoses in patients with PD. Low daily doses are required, while no reduction of levodopa and other dopaminomimetic drugs is needed. Thus, antipsychotic action of clozapine does not affect the treatment of the underlying disease, i.e. relief of parkinsonism.

Correlation between Bereitschaftspotential and reaction time measurements in patients with Parkinson's disease. Measuring the impaired supplementary motor area function?

For a long time, reaction time (RT) testing has been used for objective assessment of characteristics of the movement impairments in patients with Parkinson's disease (PD). On the other hand, it is supposed that Bereitschaftspotential (BP) reflects CNS preparatory activity for the execution of voluntary movements, and amplitudes of BP are generally smaller in PD. In order to analyze possible correlations between two methods, we studied 15 drug-naive patients with idiopathic PD (Hoehn and Yahr stage from 1 to 2.5). BP was recorded from three scalp locations: Cz, C3, and C4, and Lateralized Potential (LP) was additionally calculated as a C3-C4 difference waveform. We recorded amplitudes of the initial part of BP (at 650 ms before movement-NS1), the maximal amplitude immediately before movement onset (N1), and the N1-NS1 difference (NS2), from the Cz and LP recordings. Two RT testing paradigms were used: Simple Reaction Time (SRT) and Choice Reaction Time (ChRT). The only significant correlation between RT parameters and BP amplitudes from Cz was negative correlation between dT (difference time between Choice Reaction Time and Simple Reaction Time), on one hand, and NS1 (P = 0.006) and N1 (P = 0.026), on the other. However, Cz-NS2 did not correlate with any of the RT parameters. Our data suggest that PD patients with smaller difference between ChRT and SRT, that is presumably caused by the lesser capacity of the movement pre-programming, have smaller (i.e., less negative) BP amplitudes. This association is especially pronounced for the earlier, NS1 amplitude that is supposed to reflect the activity of the supplementary motor area (SMA). The diminished capacity of SMA activation may be the cause of the both, smaller early BP amplitudes, and smaller ChRT-SRT difference, in PD patients.

Impairment of cortical inhibition in writer's cramp as revealed by changes in electromyographic silent period after transcranial magnetic stimulation.

Changes in silent period (SP) duration following transcranial magnetic stimulation (TMS) set at 20% above the motor threshold were studied in six subjects suffering from writer's cramp, while performing dystonic movement and during voluntary isometric contraction of the muscles mostly involved in the dystonic movement. Dependency of SP duration on the intensity of preceding muscle contraction was compared on both affected and healthy side. In all subjects SP duration during dystonic contraction was shorter than during voluntary contraction of the similar strength performed with the same hand. Also, in five subjects, SP duration during dystonic contraction was shorter than during voluntary contraction of the similar strength performed with the healthy hand. In addition, the SP duration on the affected side was negatively associated with the intensity of the preceding contraction (i.e. the stronger contraction the shorter SP), while on the healthy side it was not the case. It is concluded that central inhibitory mechanisms are abnormal in writer's cramp.

The effects of high-dose intravenous methylprednisolone on event-related potentials in patients with multiple sclerosis.

The aim of this study was to assess the effects of high-dose (i.e. 1000 mg per day) intravenous methylprednisolone (HDMP) on event-related potentials (ERPs), elicited by a standard auditory 'oddball' paradigm, in patients with clinically active multiple sclerosis. In a double-blind study design, forty-four consecutive inpatients were randomly assigned in two clinically similar groups of 22 subjects each; one treated with HDMP for five days, and other with placebo. ERPs were recorded before and after the treatment. After HDMP therapy the P3 peak latency was significantly shortened (P=0.006), while peak latencies of other waves (i.e. N1, P2, and N2) remained unchanged. On the other hand, ERPs were uninfluenced by placebo treatment. Our results suggest the beneficial effect of intravenous HDMP therapy on, at least some aspects of, cognitive processing capabilities (as assessed by the auditory ERPs) in patients with multiple sclerosis.

Utility of auditory P300 in detection of presenile dementia.

The significance of P300 in investigation of the cognitive changes characteristic of aging and dementia is well established. But some controversies about sensitivity and specificity of P300 latency prolongation in detection of dementia still exist, and its predictive value and specificity in "real" clinical situations (i.e., in mixed population of neurological patients, both demented and nondemented but potentially cognitively impaired) were seldom estimated. In order to elucidate these questions, we recorded auditory event-related potentials ("oddball" paradigm) in 40 demented patients, 58 nondemented neurological patients, and 39 healthy subjects aged < or = 65 years. In addition, for the qualitative analysis of the data, we calculated three normality ranges of different width (i.e., control group's mean +/- 3 SD, 2.5 SD, and 2 SD, respectively). Our results showed that P300 latency was significantly longer in demented patients as compared to both controls and nondemented patients. Sensitivity of the P300 latency prolongation in detection of dementia depends on the width of the selected normality range, and is greatest for the narrowest range (70%), and diminishes with its widening. Specificity of this parameter, when only demented patients and controls were considered (approach used in the majority of the previous studies) was 100%, regardless of the range used. However, when the assessment was done in a mixed population of neurological patients, the P300 latency prolongation showed smaller but still very high specificity (from 86.2 to 100%) and the predictive value (from 77.8 to 100%). Depending on the width of the normality range selected, the rise of sensitivity was associated with fall of specificity and predictive value (and vice versa).

Effect of age at onset on frequency of depression in Parkinson's disease.

In a consecutive series of 169 outpatients with Parkinson's disease the frequency of depression was compared in two groups: those who developed Parkinson's disease before the age of 50, and those who developed the disease after 50. Major depression was found in 36% of patients with early onset and in 16% of patients with late onset Parkinson's disease. This significant difference disappeared when both groups were matched for duration of Parkinson's disease. A stepwise regression analysis in both the early onset and the late onset Parkinson's disease showed a significant correlation only between depression scores and the impairment scores of activities of daily living.