Impulse control disorder related behaviours during long-term rotigotine treatment: a post hoc analysis.

BACKGROUND AND PURPOSE: Dopamine agonists in Parkinson's disease (PD) are associated with impulse control disorders (ICDs) and other compulsive behaviours (together called ICD behaviours). The frequency of ICD behaviours reported as adverse events (AEs) in long-term studies of rotigotine transdermal patch in PD was evaluated. METHODS: This was a post hoc analysis of six open-label extension studies up to 6 years in duration. Analyses included patients treated with rotigotine for at least 6 months and administered the modified Minnesota Impulse Disorders Interview. ICD behaviours reported as AEs were identified and categorized. RESULTS: For 786 patients, the mean (±SD) exposure to rotigotine was 49.4 ± 17.6 months. 71 (9.0%) patients reported 106 ICD AEs cumulatively. Occurrence was similar across categories: 2.5% patients reported 'compulsive sexual behaviour', 2.3% 'buying disorder', 2.0% 'compulsive gambling', 1.7% 'compulsive eating' and 1.7% 'punding behaviour'. Examining at 6-month intervals, the incidence was relatively low during the first 30 months; it was higher over the next 30 months, peaking in the 54-60-month period. No ICD AEs were serious, and 97% were mild or moderate in intensity. Study discontinuation occurred in seven (9.9%) patients with ICD AEs; these then resolved in five patients. Dose reduction occurred for 23 AEs, with the majority (73.9%) resolving. CONCLUSIONS: In this analysis of >750 patients with PD treated with rotigotine, the frequency of ICD behaviour AEs was 9.0%, with a specific incidence timeline observed. Active surveillance as duration of treatment increases may help early identification and management; once ICD behaviours are present rotigotine dose reduction may be considered.

Rotigotine transdermal patch for the treatment of Parkinson's disease and restless legs syndrome.

The nonergoline dopamine agonist rotigotine, is delivered transdermally using a silicone-based patch (Neupro(R); UCB Pharma GmbH), which promotes unidirectional drug flow from the transdermal system to the skin. Pharmacokinetic data show stable steady-state plasma concentrations over 24 h, maintained with once-daily patch administration. Stable plasma concentrations are reflected by stable concentrations in the brain, as has been shown in animal studies. This suggests a continuous stimulation of dopaminergic receptors, which may result in a reduction in or prevention of abnormal involuntary movements in Parkinson's disease (PD) after prolonged treatment. Clinical trials have demonstrated that rotigotine is efficacious as monotherapy for PD and restless legs syndrome (RLS), and open-label extension studies have shown its long-term efficacy. Furthermore, rotigotine can be used effectively in coadministration with levodopa, enabling a reduction of the levodopa treatment doses in PD. Transdermal application also yields favorable pharmacokinetics for rotigotine: rapid metabolism and lack of skin accumulation allow for good control of chronic administration or withdrawal by patch removal, and the transdermal application approach circumvents problems of gastrointestinal absorption and enables administration prior to, during or following surgery. In addition, no dose adaptation is required regarding gender or ethnicity, or for patients with impaired liver or kidney function or on hemodialysis. The safety profile of rotigotine transdermal patch is favorable; common side effects attributed to transdermal delivery or dopaminergic stimulation are generally mild to moderate in intensity. Importantly, augmentation of RLS is uncommon under long-term rotigotine treatment and dyskinesia in PD patients mostly developed only after levodopa initiation. Overall, rotigotine transdermal patch has demonstrated favorable clinical efficacy and tolerability in the treatment of PD and RLS.

Randomized, blind, controlled trial of transdermal rotigotine in early Parkinson disease.

OBJECTIVE: This multicenter, randomized, double-blind study was performed to compare the safety and efficacy of the once-daily dopamine agonist rotigotine, in a continuous-dosing transdermal-patch formulation, vs placebo in patients with early-stage Parkinson disease (PD). METHODS: Patients were randomized to receive placebo (n = 96) or rotigotine (n = 181), starting at 2 mg/24 h (10-cm(2) patch size; 4.5-mg total drug content), titrated weekly up to 6 mg/24 h (30-cm(2) patch size; 13.5-mg total drug content), and then maintained for 6 months. The primary efficacy measures were 1) the change in the Unified Parkinson's Disease Rating Scale (UPDRS) scores (parts II and III) from baseline to end of treatment and 2) responder rates (patients with > or =20% improvement). RESULTS: Patients receiving rotigotine had a mean absolute difference of 5.28 (+/-1.18) points lower in UPDRS subtotal scores compared with those receiving placebo (p < 0.0001). The mean change in part III motor scores was -3.50 (+/-7.26) (n = 177) and was the greatest contributor to UPDRS improvement. The rotigotine group had more responders (48 vs 19%; p < 0.0001). The most commonly reported adverse events were application site reactions (44% rotigotine vs 12% placebo), nausea (41 vs17%), somnolence (33 vs 20%), and dizziness (19 vs 13%), and most were mild or moderate in intensity. CONCLUSIONS: Transdermal rotigotine, when titrated to a dosage of 6 mg/24 h, was effective for the treatment of early-stage Parkinson disease in this trial. Adverse events were similar to those found with other transdermal systems and dopamine agonists.

Task-dependent modulation of functional connectivity between hand motor cortices and neuronal networks underlying language and music: a transcranial magnetic stimulation study in humans.

Although language functions are, in general, attributed to the left hemisphere, it is still a matter of debate to what extent the cognitive functions underlying the processing of music are lateralized in the human brain. To investigate hemispheric specialization we evaluated the effect of different overt musical and linguistic tasks on the excitability of both left and right hand motor cortices using transcranial magnetic stimulation (TMS). Task-dependent changes of the size of the TMS-elicited motor evoked potentials were recorded in 12 right-handed, musically naive subjects during and after overt speech, singing and humming, i.e. the production of melody without word articulation. The articulation of meaningless syllables served as control condition. We found reciprocal lateralized effects of overt speech and musical tasks on motor cortex excitability. During overt speech, the corticospinal projection of the left (i.e. dominant) hemisphere to the right hand was facilitated. In contrast, excitability of the right motor cortex increased during both overt singing and humming, whereas no effect was observed on the left hemisphere. Although the traditional concept of hemispheric lateralization of music has been challenged by recent neuroimaging studies, our findings demonstrate that right-hemisphere preponderance of music is nevertheless present. We discuss our results in terms of the recent concepts on evolution of language and gesture, which hypothesize that cerebral networks mediating hand movement and those subserving language processing are functionally linked. TMS may constitute a useful tool to further investigate the relationship between cortical representations of motor functions, music and language using comparative approaches.

Rotigotine transdermal system for perioperative administration.

We present a series of patients participating in clinical trials with the rotigotine transdermal system. All patients were scheduled for surgery with general anaesthesia unrelated to the trial procedure or to rotigotine. Perioperative administration of rotigotine appeared to be feasible and efficacious. No safety issues emerged from these observations.

Hemiextinction induced by transcranial magnetic stimulation over the right temporo-parietal junction.

Whereas it is widely accepted that the parietal cortex is crucial for visual attention, the role of the temporal cortex and the temporo-parietal junction (TPJ) is less clear. There are clinical reports of patients with lesions in different posterior temporal areas which exhibit contralateral visual neglect but this syndrome seems to be less frequent than in patients with parietal lesions. In a previous study, we could show that single-pulse transcranial magnetic stimulation (TMS) over the right inferior parietal cortex is capable to induce both neglect-like and extinction-like impairments of performance in normal subjects. In the present study, we used this method to examine the functional role of the superior temporal gyrus (STG) and the TPJ of the right hemisphere for visuo-spatial attention. Healthy volunteers were asked to detect small dots appearing for 40 ms unilaterally on right or left side or bilaterally on a computer screen. TMS was applied over the TPJ or STG. TMS over the TPJ induced an extinction-like behavioral pattern to the contralateral hemifield. TMS over the STG had no effect. The results demonstrate a functional involvement of the TPJ in visuo-attentional processing of competing stimuli in both hemifields. This region is part of the cortical network mediating stimulus-driven attention which is relevant for processing of competing stimuli.

Functional connectivity between cortical hand motor and language areas during recovery from aphasia.

Previous data indicate that in healthy subjects, there is a connectivity between cortical areas for hand movement and language on the left hemisphere. This link is possibly mediated by the so-called mirror neuron system. The present study investigated the functional relationship between linguistic and hand movement processing in patients who were recovering from post-stroke aphasia. The excitability of the right- and left-hand motor cortex during language production in patients who were recovering from post-stroke aphasia and age-matched controls was investigated. As control, phonation was investigated. Hand motor cortex excitability was assessed with Motor Evoked Potentials which were elicited by Transcranial Magnetic Stimulation (TMS). In patients, reading aloud enhanced the excitability of the right hemispheric hand motor cortex, whereas phonation had no effect on hand motor cortex excitability. In the control group, an increased excitability of the left hemispheric hand motor system was found during reading aloud in accordance with previous data. The present data suggest a functional connectivity between regions mediating hand movements and reading. This may indicate that the right hemisphere participates in language processing as far as involved in single word reading in patients recovering from aphasia. The coactivation between cerebral representations of hand movements and language may be used therapeutically for aphasia rehabilitation.

Playing piano in the mind--an fMRI study on music imagery and performance in pianists.

Reading of musical notes and playing piano is a very complex motor task which requires years of practice. In addition to motor skills, rapid and effective visuomotor transformation as well as processing of the different components of music like pitch, rhythm and musical texture are involved. The aim of the present study was the investigation of the cortical network which mediates music performance compared to music imagery in 12 music academy students playing the right hand part of a Bartok piece using functional magnetic resonance imaging (fMRI). In both conditions, fMRI activations of a bilateral frontoparietal network comprising the premotor areas, the precuneus and the medial part of Brodmann Area 40 were found. During music performance but not during imagery the contralateral primary motor cortex and posterior parietal cortex (PPC) bilaterally was active. This reflects the role of primary motor cortex for motor execution but not imagery and the higher visuomotor integration requirements during music performance compared to simulation. The notion that the same areas are involved in visuomotor transformation/motor planning and music processing emphasizes the multimodal properties of cortical areas involved in music and motor imagery in musicians.

Transcranial magnetic stimulation for the treatment of seizures: a controlled study.

OBJECTIVE: To perform a controlled trial of transcranial magnetic stimulation (TMS). METHODS: Twenty-four patients with localization-related epilepsy were randomized to blinded active or placebo stimulation. Weekly seizure frequency was compared for 8 weeks before and after 1 week of 1-Hz TMS for 15 minutes twice daily. RESULTS: When the 8-week baseline and post-stimulation periods were compared, active patients had a mean seizure frequency reduction of 0.045 +/- 0.13 and sham-stimulated control subjects -0.004 +/- 0.20. Over 2 weeks, actively treated patients had a mean reduction in weekly seizure frequency of 0.16 +/- 0.18 and sham-stimulated control subjects 0.01 +/- 0.24. Neither difference was significant. CONCLUSION: The effect of TMS on seizure frequency was mild and short lived.

Focal enhancement of motor cortex excitability during motor imagery: a transcranial magnetic stimulation study.

OBJECTIVES: In order to learn more about the physiology of the motor cortex during motor imagery, we evaluated the changes in excitability of two different hand muscle representations in the primary motor cortex (M1) of both hemispheres during two imagery conditions. MATERIALS AND METHODS: We applied focal transcranial magnetic stimulation (TMS) over each M1, recording motor evoked potentials (MEPs) from the contralateral abductor pollicis brevis (APB) and first dorsal interosseus (FDI) muscles during rest, imagery of contralateral thumb abduction (C-APB), and imagery of ipsilateral thumb abduction (I-APB). We obtained measures of motor threshold (MT), MEP recruitment curve (MEP-rc) and F waves. RESULTS: Motor imagery compared with rest significantly decreased the MT and increased MEPs amplitude at stimulation intensities clearly above MT in condition C-APB, but not in condition I-APB. These effects were not significantly different between right and left hemisphere. MEPs simultaneously recorded from the FDI, which was not involved in the task, did not show facilitatory effects. There were no significant changes in F wave amplitude during motor imagery compared with rest. CONCLUSIONS: Imagery of unilateral simple movements is associated with increased excitability only of a highly specific representation in the contralateral M1 and does not differ between hemispheres.

Cholinergic influences on use-dependent plasticity.

Motor practice elicits use-dependent plasticity in humans as well as in animals. Given the influence of cholinergic neurotransmission on learning and memory processes, we evaluated the effects of scopolamine (a muscarinic receptor antagonist) on use-dependent plasticity and corticomotor excitability in a double-blind placebo-controlled randomized design study. Use-dependent plasticity was substantially attenuated by scopolamine in the absence of global changes in corticomotor excitability. These results identify a facilitatory role for cholinergic influences in use-dependent plasticity in the human motor system.

Mechanisms underlying rapid experience-dependent plasticity in the human visual cortex.

Visual deprivation induces a rapid increase in visual cortex excitability that may result in better consolidation of spatial memory in animals and in lower visual recognition thresholds in humans. gamma-Aminobutyric acid (GABA)ergic, N-methyl-d-aspartate (NMDA), and cholinergic receptors are thought to be involved in visual cortex plasticity in animal studies. Here, we used a pharmacological approach and found that lorazepam (which enhances GABA(A) receptor function by acting as a positive allosteric modulator), dextrometorphan (NMDA receptor antagonist), and scopolamine (muscarinic receptor antagonist) blocked rapid plastic changes associated with light deprivation. These findings suggest the involvement of GABA, NMDA, and cholinergic receptors in rapid experience-dependent plasticity in the human visual cortex.

Mechanisms influencing stimulus-response properties of the human corticospinal system.

BACKGROUND: Stimulus-response (S-R) properties of the corticospinal system in humans depend on the interactions that take place at different sites along the corticospinal pathway. The mechanisms influencing stimulus-response curves elicited by transcranial magnetic stimulation (TMS) and their operation site along the human neuraxis are poorly understood. In this study, we investigated the effects of CNS-active drugs with distinct mechanisms of action on S-R curves. Effects of each of these drugs on S-R curves would point to the involvement of specific mechanisms. Additionally, relative sensitivity of S-R curves compared with other measures of corticospinal excitability was studied. METHODS: We studied the effects of lorazepam, which is a positive allosteric modulator of GABA(A) receptors; lamotrigine, an inhibitor of voltage-gated Na(+) and Ca(2+) channels; and D-amphetamine, an indirect agonist of the dopaminergic-adrenergic system on S-R curves, motor thresholds (MT), and intracortical inhibition (ICI) and facilitation (ICF) with a double-pulse technique. Maximum peripheral M responses and F waves were investigated as measures of the total alpha-motoneuron pool and its excitability. RESULTS: F and M waves were unaffected by either the drugs or placebo. S-R curves were significantly depressed by lorazepam and lamotrigine without changes in ICI and ICF. Both S-R curves and ICF were enhanced by D-amphetamine. MT increased only with lamotrigine. CONCLUSIONS: S-R curves were influenced by changes in the GABAergic and monoaminergic system and Na(+) and Ca(2+) channel properties. Our results indicate that, out of different parameters of motor system excitability, S-R curves were the most sensitive.

Role of the human motor cortex in rapid motor learning.

Recent studies suggest that the human primary motor cortex (M1) is involved in motor learning, but the nature of that involvement is not clear. Here, learning-related changes in M1 excitability were studied with transcranial magnetic stimulation (TMS) while na subjects practiced either a ballistic or a ramp pinch task to the 0.5-Hz beat of a metronome. Subjects rapidly learned to optimize ballistic contractions as indicated by a significant increase in peak pinch acceleration and peak force after the 60-min practice epoch. The increase in force and acceleration was associated with an increase in motor evoked potential (MEP) amplitude in a muscle involved in the training (flexor policis brevis) but not in a muscle unrelated to the task (abductor digiti minimi). MEPs returned to their baseline amplitude after subjects had acquired the new skill, whereas no practice-induced changes in MEP amplitude were observed after subjects had overlearned the task, or after practicing slow ramp pinches. Since the changes in MEP amplitude were observed only after TMS of M1 but not after direct stimulation of the corticospinal tract, these findings indicate task- and effector-specific involvement of human M1 in rapid motor learning.

Mechanisms underlying human motor system plasticity.

There has been increased interest in the ability of the adult human nervous system to reorganize and adapt to environmental changes throughout life. This ability has been termed "plasticity." Plastic changes in the cerebral cortex have been studied: (a) as modifications of sensory or motor cortical representation of specific body parts (cortical maps, body representation level); and (b) as changes in the efficacy of existing synapses or generation of new synapses (neuronal or synaptic level). In this review, we describe paradigms used to study mechanisms of plasticity in the intact human motor system, the functional relevance of such plasticity, and possible ways to modulate it.

Enhancing analogic reasoning with rTMS over the left prefrontal cortex.

The authors utilized repetitive transcranial magnetic stimulation (rTMS) in 16 normal volunteers to investigate the role of the left dorsolateral prefrontal cortex (PFC) in analogic reasoning. rTMS over the left and right PFC, over the left motor cortex, and sham stimulation over the left PFC were administered during memory and analogic reasoning conditions. rTMS over the left PFC led to a significant reduction in response times only in the analogy condition without affecting accuracy. These results indicate that the left PFC is relevant for analogic reasoning and that rTMS applied to the PFC can speed up solution time.

Motor control in simple bimanual movements: a transcranial magnetic stimulation and reaction time study.

OBJECTIVE: Simple reaction time (RT) can be influenced by transcranial magnetic stimulation (TMS) to the motor cortex. Since TMS differentially affects RT of ipsilateral and contralateral muscles a combined RT and TMS investigation sheds light on cortical motor control of bimanual movements. METHODS: Ten normal subjects and one subject with congenital mirror movements (MM) were investigated with a RT paradigm in which they had to move one or both hands in response to a visual go-signal. Suprathreshold TMS was applied to the motor cortex ipsilateral or contralateral to the moving hand at various interstimulus intervals (ISIs) after presentation of the go-signal. EMG recordings from the thenar muscles of both hands were used to determine the RT. RESULTS: TMS applied to the ipsilateral motor cortex shortened RT when TMS was delivered simultaneously with the go-signal. With increasing ISI between TMS and go-signal the RT was progressively delayed. This delay was more pronounced if TMS was applied contralateral to the moving hand. When normal subjects performed bimanual movements the TMS-induced changes in RT were essentially the same as if they had used the hand in an unimanual task. In the subject with MM, TMS given at the time of the go-signal facilitated both the voluntary and the MM. With increasing ISI, however, RT for voluntary movements and MM increased in parallel. CONCLUSIONS: Ipsilateral TMS affects the timing of hand movements to the same extent regardless of whether the hand is engaged in an unimanual or a bimanual movement. It can be concluded, therefore, that in normal subjects simple bimanual movements are controlled by each motor cortex independently. The results obtained in the subject with MM are consistent with the hypothesis that mirror movements originate from uncrossed corticospinal fibres. The alternative hypothesis that a deficit in transcallosal inhibition leads to MM in the contralateral motor cortex is not compatible with the presented data, because TMS applied to the motor cortex ipsilateral to a voluntary moved hand affected voluntary movements and MM to the same extent.

Analogous corticocortical inhibition and facilitation in ipsilateral and contralateral human motor cortex representations of the tongue.

How the human brain controls activation of the ipsilateral part of midline muscles is unknown. We studied corticospinal and corticocortical network excitability of both ipsilateral and contralateral motor representations of the tongue to determine whether they are under analogous or disparate inhibitory and facilitatory corticocortical control. Motor evoked potentials (MEPs) to unilateral focal transcranial magnetic stimulation (TMS) of the tongue primary motor cortex were recorded simultaneously from the ipsilateral and contralateral lingual muscles. Single-pulse TMS was used to assess motor threshold (MT) and MEP recruitment. Paired-pulse TMS was used to study intracortical inhibition (ICI) and intracortical facilitation (ICF) at various interstimulus intervals (ISIs) between the conditioning stimulus (CS) and the test stimulus (TS), and at different CS and TS intensities, respectively. Focal TMS invariably produced MEPs in both ipsilateral and contralateral lingual muscles. MT was lower and MEP recruitment was steeper when recorded from the contralateral muscle group. ICI and ICF were identical in the ipsilateral and contralateral representations, with inhibition occurring at short ISIs (2 and 3 ms) and facilitation occurring at longer ISIs (10 and 15 ms). Moreover, changing one stimulus parameter regularly produced analogous changes in MEP size bilaterally, revealing strong linear correlations between ipsilateral and contralateral ICI and ICF (P < 0.0001). These findings indicate that the ipsilateral and contralateral representations of the tongue are under analogous inhibitory and facilitatory control, possibly by a common intracortical network.

Reproducibility of intracortical inhibition and facilitation using the paired-pulse paradigm.

We have evaluated the reproducibility of intracortical inhibition (ICI) and facilitation (ICF) studied with paired-pulse focal transcranial magnetic stimulation. Three investigators studied the same subjects (n = 4) in three different sessions. A high variability was shown across subjects [coefficient of variation, (cv) 67.3% for ICI and 21.2% for ICF]. Intersession variability was up to 37.1% for ICI and 22.7% for ICF. Interinvestigator variability was 17.3% for ICI and negligible for ICF. Our results may have implications for planning future studies.