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.

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.

Reduction of human visual cortex excitability using 1-Hz transcranial magnetic stimulation.

The effects of low-frequency (1-Hz) repetitive transcranial magnetic stimulation on visual cortex excitability were investigated by measuring phosphene thresholds (PTs) and stimulus-response curves. Stimulation over the visual cortex led to significantly decreased visual cortex excitability, expressed as an increase in PT. The motor threshold of the hand muscles did not change, indicating the topographic specificity of this effect. This intervention may be useful in situations associated with a hyperexcitable visual cortex.

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.

Facilitation of picture naming after repetitive transcranial magnetic stimulation.

OBJECTIVE: To investigate the effect of repetitive transcranial magnetic stimulation (rTMS) on picture naming. BACKGROUND: Previous studies have shown that rTMS disrupts ongoing speech processes when delivered over frontal or parietal areas of the dominant hemisphere. METHODS: In 15 healthy right-handed male individuals, rTMS trains of 20 Hz with a duration of 2 seconds and an intensity of 55% of maximum stimulator output were delivered either to Wernicke's area, to the right-hemisphere homologue of Wernicke's area, to Broca's area, or to the primary visual cortex. Twenty black-and-white line drawings, which the individuals had to name as quickly as possible, were shown immediately after the completion of rTMS and again 2 minutes later. RESULTS: Immediately after the end of a train over Wernicke's area a shortening of naming latency was observed compared with naming without rTMS (p < 0.001). No significant effects on picture naming were observed 2 minutes later or at any time after stimulation of the right-hemisphere homologues of Wernicke's area, Broca's area, or the visual cortex. CONCLUSION: Repetitive transcranial magnetic stimulation over Wernicke's area leads to a brief facilitation of picture naming by shortening linguistic processing time.

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.

RTMS induces brief events of muscle atonia in patients with narcolepsy.

STUDY OBJECTIVES: To investigate the effect of repetitive transcranial magnetic stimulation (rTMS) in patients with narcolepsy. DESIGN: Using rTMS, three patients with narcolepsy and cataplexy were investigated with and without their anticataplectic medication. rTMS of the motor cortex was performed at an intensity of 110% of resting motor threshold, a frequency of 20 Hz, and a duration of 2s. EMG activity was recorded for both the right and left first dorsal interosseous muscle (FDI). Eight healthy controls were also investigated under the same conditions. SETTING: The study was carried out in the sleep laboratory of the Neurology Department (University of Aachen). PATIENTS: One female and two male patients with narcolepsy/cataplexy. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: In three narcoleptic patients, after three days of not taking their usual anticataplectic medication, rTMS of the motorcortex induced an interruption of voluntary EMG activity in the FDI. EMG reduction lasted from 0.6 to 3.5s and was more pronounced in the hand contralateral to the stimulated hemisphere. This result was not observed in these patients when taking their regular medication nor in the normal controls. Stimulation of other cortical areas, as well as stimulation of the peripheral nervous system, did not induce muscle weakness episodes. CONCLUSIONS: We postulate that rTMS of the descending voluntary motor pathway triggers muscle atonia similar to cataplexy by indirectly activating the mechanisms responsible for the generation of muscle atonia during REM sleep and cataplexy. We conclude that rTMS, in the future, might prove to be a useful addition to the diagnostic repertoire for narcolepsy.

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.

The representation of the plegic hand in the motor cortex: a combined fMRI and TMS study.

TMS mapping and fMRI were used to investigate changes in the motor cortex representation of the hand in a patient with complete loss of right hand function following traumatic avulsion of the cervical roots C7 and C8. Both TMS and fMRI demonstrated an expansion of the motor representation of the forearm into the hand area contralateral to the injured side. fMRI of the hand area, however, revealed that this area could still be activated when the patient was instructed to imagine finger tapping with his plegic hand. These results indicate that the plegic hand is still represented in the motor cortex, despite the fact that the same cortical area is also now active during movements involving forearm muscles.

Changes in motor cortex excitability during ipsilateral hand muscle activation in humans.

OBJECTIVES: To test whether unilateral hand muscle activation involves changes in ipsilateral primary motor cortex (M1) excitability. METHODS: Single- and paired-pulse transcranial magnetic stimulation (TMS) of the right hemisphere was used to evoke motor evoked potentials (MEPs) from the resting left abductor pollicis brevis (APB) in 9 normal volunteers. We monitored changes in motor threshold (MT), MEP recruitment, intracortical inhibition (ICI) and intracortical facilitation (ICF) while the ipsilateral right APB was either at rest or voluntarily activated. Spinal motoneuron excitability was assessed using F-wave recording procedures. RESULTS: Voluntary muscle activation of the ipsilateral APB significantly facilitated the MEPs and F-waves recorded from the contralateral APB. Facilitation was observed with muscle activation >50% of the maximum voluntary force and with stimulus intensities >20% above the individual resting motor threshold. Intracortical inhibition significantly decreased in the ipsilateral M , while there was no significant change in intracortical facilitation during this maneuver. CONCLUSIONS: Unilateral hand muscle activation changes the excitability of homotopic hand muscle representations in both the ipsilateral M1 and the contralateral spinal cord. While the large proportion of MEP facilitation most likely occurred at a spinal level, involvement of the ipsilateral hemisphere may have contributed to the enlargement of magnetic responses.

Effects of low-frequency transcranial magnetic stimulation on motor excitability and basic motor behavior.

OBJECTIVE: To explore effects of low-frequency repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) on motor excitability and basic motor behavior in humans. DESIGN AND METHODS: Seven normal volunteers underwent 1 Hz rTMS of the hand representation of the right M1 for 15 min at an intensity of 115% of the individual resting motor threshold. The effects of rTMS on motor excitability were assessed by monitoring changes in individual resting motor threshold and input-output curves of motor evoked potentials (MEPs) in the flexor pollicis brevis, first dorsal interosseus, abductor digiti minimi and biceps brachii muscles. Changes in basic motor behavior were studied by measuring maximal and mean peak force and peak accelerations of thumb flexions and abductions of the fifth finger before and after rTMS. RESULTS: rTMS produced a significant increase in resting motor threshold and a significant suppression of MEP input-output curves that persisted for 30 min. The suppressing effect was restricted to the hand motor representation which was the prime target of the stimulation procedure, and there were no significant effects on the biceps representation. Peak force and peak acceleration were not affected while the motor representations of muscles involved in the behavioral measurements were significantly suppressed by rTMS. CONCLUSIONS: Low-frequency rTMS of M1 transiently depresses motor excitability but this does not affect basic motor behavior. This is relevant for the therapeutic use of low-frequency rTMS in disorders with abnormal cortical excitability.

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.

Voluntary teeth clenching facilitates human motor system excitability.

OBJECTIVE: Voluntary contraction of the teeth is a common maneuver used to facilitate peripheral monosynaptic reflexes. It was the aim of this study to determine the site along the neuraxis where this effect occurs. METHODS: Focal transcranial magnetic stimulation (TMS) was used to measure recruitment curves, motor thresholds and intracortical inhibition and facilitation from the right first dorsal interosseus (FDI) and tibialis anterior (TA) muscles in seven normal volunteers. Changes in excitability in subcortical structures during teeth clenching were studied using F waves, H reflexes, and brainstem magnetic stimulation. RESULTS: Recruitment curves of FDI and TA showed significant facilitation during voluntary teeth clenching indicating an overall enhancement in the motor system excitability. Teeth clenching additionally resulted in decreased intracortical inhibition in the FDI but not in TA, pointing to an intracortical site of enhancement for the hand. Motor evoked potentials (MEPs) following stimulation at the brainstem level and F waves in FDI and soleus H reflex amplitude were also facilitated by teeth clenching, indicating a subcortical site for this effect for the upper and lower extremity. M wave amplitudes did not change. CONCLUSIONS: The teeth clenching maneuver had a similar facilitatory effect on upper and lower extremities. Cortical and subcortical sites contribute to this effect in a hand muscle while only subcortical sites were identified in this facilitatory effect on the lower extremity.

Localization of the motor hand area using transcranial magnetic stimulation and functional magnetic resonance imaging.

OBJECTIVE: The anatomical location of the motor area of the hand may be revealed using functional magnetic resonance imaging (fMRI). The motor cortex representation of the intrinsic hand muscles consists of a knob-like structure. This is omega- or epsilon-shaped in the axial plane and hook-shaped in the sagittal plane. As this knob lies on the surface of the brain, it can be stimulated non-invasively by transcranial magnetic stimulation (TMS). It was the aim of our study to identify the hand knob using fMRI and to reveal if the anatomical hand knob corresponds to the hand area of the motor cortex, as identified by TMS, by means of a frameless MRI-based neuronavigation system. METHODS: Suprathreshold transcranial magnetic stimuli were applied over a grid on the left side of the scalp of 4 healthy volunteers. The motor evoked potentials (MEPs) were recorded from the contralateral small hand muscles, and the centers of gravity (CoG) of the MEPs were calculated. The exact anatomical localization of each point on the grid was determined using a frameless MRI-based neuronavigation system. In each subject, the hand area of the motor cortex was visualized using fMRI during sensorimotor activation achieved by clenching the right hand. RESULTS: In all 4 subjects, the activated precentral site in the fMRI and the CoG of the MEP of all investigated muscles lay within the predicted anatomical area, the so-called hand knob. This knob had the form of an omega in two subjects and an epsilon in the other two subjects. CONCLUSIONS: TMS is a reliable method for mapping the motor cortex. The CoG calculated from the motor output maps may be used as an accurate estimation of the location of the represented muscle in the motor cortex.

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.

Transcallosal inhibition in cortical and subcortical cerebral vascular lesions.

The excitability of the motor cortex after transcranial magnetic stimulation was investigated in 10 patients with purely subcortical, and in 22 patients with cortical-subcortical cerebrovascular lesions. In the first investigation we applied magnetic double stimuli over both motor cortices with different inter-stimulus intervals. The first (conditioning) stimulus was applied to the affected hemisphere and the second stimulus (test stimulus) to the unaffected side. The responses of the first dorsal interosseal (FDI) muscle, contralateral to the test stimulus, were recorded after applying the test stimulus alone and at inter-stimulus intervals of 5 ms, 7 ms, 15 ms, 30 ms and 60 ms. In a second investigation the patients were asked to activate their non-paretic first dorsal interosseus muscle and the magnetic stimulus was applied over the affected hemisphere. The EMG responses were rectified and averaged. Patients with subcortical cerebral lesions below the centrum semiovale (i.e., having no effect on the transcallosal fibres) displayed a pronounced inhibition of one motor cortex after the stimulation of the contralateral side, comparable with normal subjects. Patients with cortical-subcortical cerebral lesions displayed only partly less inhibition of their motor cortex but the results in this group were not uniform. Since inhibition was preserved in patients with subcortical lesions, which had destroyed the corticospinal tract, we conclude that this inhibition is not mediated through an ipsilateral projection but via a transcallosal route.

X-linked dominant Charcot-Marie-Tooth neuropathy: clinical, electrophysiological, and morphological phenotype in four families with different connexin32 mutations(1).

The sensorimotor neuropathy of the Charcot-Marie-Tooth type (CMT) is the most common hereditary disorder of the peripheral nervous system. The X-linked dominant form of CMT (CMTX) is associated with mutations in the gene for the gap junction protein connexin32. We examined four CMTX pedigrees two of which had potentially novel mutations in the only coding exon of connexin32. One previously unreported missense mutation, Ala39Val, was found in a family displaying a CMT phenotype with additional upper limb postural tremor reminiscent of a Roussy-Lévy syndrome. A novel single base insertion, 679insT, is among the first mutations found in the fourth transmembrane domain of connexin32. Frameshift and premature stop of translation are supposed to result in a non-functional carboxy-terminus. Two further families had the known missense mutations Arg15Trp and Arg22Gln. Several female carriers were found normal on clinical presentation, however, the genotype was paralleled by decreased nerve conduction velocities (NCV) and slowed central conduction of brain stem auditory evoked responses (BAER). Median motor NCVs showed mild (in women) to intermediate (in males) reduction, indicating a peripheral neuropathy with a predominating axonal component. Nerve biopsy findings were consistent with the electrophysiological data showing a marked loss of large myelinated fibres and clusters of regenerating axons. Electron microscopy revealed various alterations of the axoglial attachment zone. This suggests defective axon-Schwann cell interactions which may induce the axonopathy in CMTX.

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.