We have previously shown in normal subjects that motor adaptation to imposed visual rotation is significantly enhanced when tested few days later. This occurs through a process of sleep-dependent memory consolidation. Here we ascertained whether patients with Parkinson's disease (PD) learn, improve, and retain new motor skills in the same way as normal subjects. We tested 16 patients in early stages of PD and 21 control subjects over two days. All subjects performed reaching movements on a digitizing tablet. Vision of the limb was precluded with an opaque screen; hand paths were shown on the screen with the targets' position. Unbeknownst to the subjects, the hand path on the screen was rotated by 30 degrees . In experiment 1, patients taking dopaminergic treatment and controls adapted to rotation with targets appearing in an unpredictable order. In experiment 2, drug-naïve patients and controls adapted to rotation in a less challenging task where target's appearance was predictable. Patients and controls made similar movements and adapted to rotation in the same way. However, when tested again over the following days, controls' performance significantly improved compared to training, while patients' performance did not. This lack of consolidation, which is present in the early stages of the disease and is independent from therapy, may be due to abnormal homeostatic processes that occur during sleep.

Repetitive transcranial magnetic stimulation (rTMS) induces neuronal long-term potentiation or depression. Although brain-derived neurotrophic factor (BDNF) and its cognate tyrosine receptor kinase B (TrkB) contribute to the effects of rTMS, their precise role and underlying mechanism remain poorly understood. Here we show that daily 5 Hz-rTMS for 5 days improves BDNF-TrkB signaling in rats by increasing the affinity of BDNF for TrkB that results in higher tyrosine-phosphorylated TrkB, increased recruitment of PLC-γ1 and shc/N-shc to TrkB, and heightened downstream ERK2 and PI-3K activities in prefrontal cortex and in lymphocytes. The elevated BDNF-TrkB signaling is accompanied by an increased association between the activated TrkB and N-methyl-D-aspartate receptor (NMDAR). In normal human subjects, 5-day rTMS to motor cortex decreased resting motor threshold that correlates with heightened BDNF-TrkB signaling and intensified TrkB-NMDAR association in lymphocytes. These findings suggest that rTMS to cortex facilitates BDNF-TrkB-NMDAR functioning in both cortex and lymphocytes.

The excitability of inhibitory circuits in patients with writer's cramp is reduced at multiple levels within the sensorimotor system, including the primary motor hand area (M1). Although this may play a major role in the pathophysiology of writer's cramp, it is still unclear what factors may cause the imbalance between inhibition and excitation to arise. One possibility is that homeostatic mechanisms that keep cortical excitability within a normal physiological range are impaired. In eight patients with writer's cramp and eight healthy age-matched controls, we combined low-frequency repetitive transcranial magnetic stimulation (rTMS) with transcranial direct current stimulation (TDCS) to probe regional homeostatic plasticity of the left M1. Confirming our previous study (Siebner et al., J Neurosci 2004; 24: 3379-85), 'facilitatory' preconditioning of the M1 with anodal TDCS enhanced the inhibitory effect of subsequent 1 Hz rTMS on corticospinal excitability. Conversely, 'inhibitory' preconditioning with cathodal TDCS reversed the after effect of 1 Hz rTMS, producing an increase in corticospinal excitability. The results were quite different in patients with writer's cramp. Following preconditioning with TDCS, 1 Hz rTMS induced no consistent changes in corticospinal excitability, indicating a loss of the normal 'homeostatic' response pattern. In addition, the normal inhibitory effect of preconditioning with cathodal TDCS was absent. The present data suggest that homeostatic mechanisms that stabilize excitability levels within a useful dynamic range are impaired in patients with writer's cramp. We propose that a faulty homeostatic response to acute increases in corticospinal excitability favours maladaptive motor plasticity. The role of homeostatic-like plasticity in the pathophysiology of task-specific dystonias warrants further study.

Summary:Purpose: To assess the effectiveness of slow repetitive transcranial magnetic stimulation (rTMS) as an adjunctive treatment for drug-resistant epilepsy.Methods: Forty-three patients with drug-resistant epilepsy from eight Italian Centers underwent a randomized, doubleblind, sham-controlled, crossover study on the clinical and EEG effects of slow rTMS. The stimulus frequency was 0.3 Hz. One thousand stimuli per day were given at the resting motor threshold intensity for 5 consecutive days, with a round coil at the vertex.Results: "Active" rTMS was no better than placebo for seizure reduction. However, it decreased interictal EEG epileptiform abnormalities significantly (p < 0.05) in one-third of the patients, which supports a detectable biologic effect. No correlation linked the rTMS effects on seizure frequency to syndrome or anatomic classification, seizure type, EEG changes, or resting motor threshold (an index of motor cortex excitability).Conclusions: Although the antiepileptic action was not significant (p > 0.05), the individual EEG reactivity to "active" rTMS may be encouraging for the development of more-powerful, noninvasive neuromodulatory strategies.

With a series of novel arm-reaching tasks, we have shown that visuomotor sequence learning encompasses the acquisition of the order of sequence elements, and the ability to combine them in a single, skilled behavior. The first component, which is mostly declarative, is reflected by changes in movement onset time (OT); the second, which occurs without subject’s awareness, is measured by changes in kinematic variables, including movement time (MT). Key-press-based serial reaction time tasks (SRTT) have been used to investigate sequence learning and results interpreted as indicative of the implicit acquisition of the sequence order. One limitation to SRT studies, however, is that only one measure is used, the response time, the sum of OT and MT: this makes interpretation of which component is learnt difficult and disambiguation of implicit and explicit processes problematic. Here we used an arm-reaching version of SRTT to propose a novel interpretation of such results. The pattern of response time changes we obtained was similar to the key-press-based tasks. However, there were significant differences between OT and MT, suggesting that both partial learning of the sequence order and skill improvement took place. Further analyses indicated that the learning of the sequence order might not occur without subjects’ awareness.

We tested the hypothesis that fatigue in MS is related to a dysfunction in cortical areas involved in movement preparation. Thirty-three patients with clinically definite MS (16 with fatigue MS-F, 17 without fatigue MS-NF) and a relapsing-remitting course, matched for disease severity and duration, disability scores and level of depression were enrolled. They underwent a combined assessment with magnetic resonance imaging (MRI) and transcranial magnetic stimulation (TMS) and, for the electrophysiological study, were compared with 12 healthy controls. MRI was used to assess regional and total lesion-load volume (LL) on T1- and T2-weighted sequences and total brain volume on T1-weighted sequences. With TMS we tested central motor conduction time, short intracortical inhibition (SICI) and facilitation (ICF), pre-movement facilitation related to a simple reaction time paradigm and the effect of short trains of 5-Hz repetitive TMS (rTMS). No significant differences were found in total and regional LL between MS-F and MS-NF, except for a significant increase in frontal lobe LL in MS-F. Neurophysiological assessment did not disclose any difference of SICI and ICF among the three groups. The significant increase of MEP size produced by 5 Hz rTMS in controls was absent in both MS-NF and MS-F. MS-F lacked pre-movement facilitation compared with MS-NF and controls. The lack of pre-movement facilitation and the increased frontal lobe lesion load were significantly correlated to the FSS score, suggesting that central fatigue in MS is probably due to a dysfunction of cortical motor areas involved in movement preparation.

Learning deficits may be part of the early symptoms of Huntington's disease (HD). Here we characterized implicit and explicit aspects of sequence learning in eleven pre-symptomatic HD gene carriers (pHD) and eleven normal controls. Subjects moved a cursor on a digitizing tablet and performed the following tasks: SEQ: learning to anticipate the appearance of a target sequence in two blocks; VSEQ: learning a sequence by attending to the display without moving for one block, and by moving to the sequence in a successive block (VSEQtest). Explicit learning was measured with declarative scores and number of anticipatory movements. Implicit learning was measured as a strategy change reflected in movement time. By the end of SEQ, pHD had a significantly lower number of correct anticipatory movements and lower declarative scores than controls, while in VSEQ and VSEQtest these indices improved. During all three tasks, movement time changed in controls, but not in pHD. These results suggest that both explicit and implicit aspects of sequence learning may be impaired before the onset of motor symptoms. However, when attentional demands decrease, explicit, but not implicit, learning may improve.

Motor imagery (MI) is the mental rehearsal of a motor act without overt movement. Using transcranial magnetic stimulation (TMS), we tested the effect of MI on corticospinal excitability in patients with writer's cramp. In 10 patients with writer's cramp and 10 healthy controls, we applied focal TMS over each primary motor area and recorded motor evoked potentials (MEPs) from contralateral hand and arm muscles while participants imagined a tonic abduction of the index finger contralateral to the stimulated hemisphere. In healthy controls and patients, the MEP amplitude in the relaxed first dorsal interosseus muscle (FDI) showed a muscle-specific increase during MI; however, the increase was less pronounced in patients than in healthy controls. In addition, in patients but not in controls, the MEP amplitude also increased in hand and forearm muscles not involved in the imagined movement. This abnormal spread of facilitation was observed in the affected and unaffected upper limb. MI of simple hand movements is less efficient and less focussed in patients with writer's cramp than it is in normal subjects.