Faculty Bibliography

The authors' aim was to determine the cortical mechanisms that underlie the transition from effective performance to its disruption. They thus used transcranial magnetic stimulation (TMS) to study changes of corticospinal excitability after a motor exercise that did not produce overt or perceived neuromuscular fatigue. Forty-four subjects performed either 5 or 10 min of repetitive finger movements paced by tones at 2 Hz, a frequency below the spontaneous movement rate. Changes of corticospinal excitability were assessed with TMS at rest and during motor response preparation (premovement facilitation paradigm). Over time, variability of movement rate increased, while the average movement rate shifted toward self-paced rhythms, without significant changes in other kinematic parameters. Amplitudes of motor evoked potentials at rest decreased depending on task duration and TMS intensity. Moreover, 5-min exercise induced fully compensatory increases in premovement facilitation, while 10-min exercise produced partially compensatory increases with loss of temporal modulation. Our findings suggest that protracted exercise induces significant decrements in corticospinal excitability with initial impairment of the phasic motor neurons that are recruited at higher stimulus intensities. Changes in premovement facilitation likely represent compensation of premotor areas for decreased efficiency of the primary motor cortex induced by exercise.

OBJECTIVE: Adapting movements to a visual rotation involves the activation of right posterior parietal areas. Further performance improvement requires an increase of slow wave activity in subsequent sleep in the same areas. Here we ascertained whether a post-learning trace is present in wake EEG and whether such a trace is influenced by sleep slow waves. METHODS: In two separate sessions, we recorded high-density EEG in 17 healthy subjects before and after a visuomotor rotation task, which was performed both before and after sleep. High-density EEG was recorded also during sleep. One session aimed to suppress sleep slow waves, while the other session served as a control. RESULTS: After learning, we found a trace in the eyes-open wake EEG as a local, parietal decrease in alpha power. After the control night, this trace returned to baseline levels, but it failed to do so after slow wave deprivation. The overnight change of the trace correlated with the dissipation of low frequency (<8Hz) NREM sleep activity only in the control session. CONCLUSIONS: Visuomotor learning leaves a trace in the wake EEG alpha power that appears to be renormalized by sleep slow waves. SIGNIFICANCE: These findings link visuomotor learning to regional changes in wake EEG and sleep homeostasis

We investigated whether dopamine influences the rate of adaptation to a visuomotor distortion and the transfer of this learning from the right to the left limb in human subjects. We thus studied patients with Parkinson disease as a putative in vivo model of dopaminergic denervation. Despite normal adaptation rates, patients showed a reduced transfer compared with age-matched healthy controls. The magnitude of the transfer, but not of the adaptation rate, was positively predicted by the values of dopamine-transporter binding of the right caudate and putamen. We conclude that striatal dopaminergic activity plays an important role in the transfer of visuomotor skills

The formation of new motor memories, which is fundamental for efficient performance during adaptation to a visuo-motor rotation, occurs when accurate planning is achieved mostly with feedforward mechanisms. The dynamics of brain activity underlying the switch from feedback to feedforward control is still matter of debate. Based on the results of studies in declarative learning, it is likely that phase synchronization of low and high frequencies as well as their temporal modulation in power amplitude underlie the formation of new motor memories during visuo-motor adaptation. High-density EEG (256 electrodes) was recorded in 17 normal human subjects during adaptation to a visuo-motor rotation of 60 degrees in four incremental steps of 15 degrees . We found that initial learning is associated with enhancement of gamma power in a right parietal region during movement execution as well as gamma/theta phase coherence during movement planning. Late stages of learning are instead accompanied by an increase of theta power over that same right parietal region during movement planning, which is correlated with the degree of learning and retention. Altogether, these results suggest that the formation of new motor memories and, thus, the switch from feedback to feedforward control is associated with the modulation of gamma and theta spectral activities, with respect to their amplitude and phase, during movement planning and execution. Specifically, we propose that gamma/theta phase coupling plays a pivotal role in the integration of a new representation into motor memories

Movement kinematic variables related to force production can be modulated to respond appropriately to different contexts. We previously showed that in a choice-reaction time and a predictable timed-response task, normal subjects perform reaching movements to the same targets with two different kinematic patterns, a marker of flexibility. Here, we used the two tasks to determine whether basal ganglia are involved in the selection and modulation of movement kinematics and therefore in flexible force production. We tested seventeen patients in the early stages of Parkinson's disease, eleven pre-symptomatic Huntington's disease carriers and sixteen age-matched normal controls with the above-mentioned motor tasks. In both patient groups, the difference in kinematics (movement duration, peak velocity and acceleration) between the two tasks was significantly reduced compared to controls, indicating a limited range of choices or flexibility. However, this reduction was skewed in opposite directions in the two disorders, with force production being generally higher in Huntington's carriers and lower in Parkinson's patients compared to controls. We conclude that basal ganglia are involved in adapting movement to different contexts and selecting the appropriate movement force. The opposite trends in Parkinson's and Huntington's disease suggest that such regulation might depend on the balance between the outputs of direct and indirect pathways

Study Objectives: We used a sequence-learning task to assess whether: 1. The time interval between awakening and training equally affects the rate of acquisition of sequence order, a declarative component, and the kinematic optimization process, an implicit component; 2. Sleep enhances the retention of both these aspects of sequence learning. Design: For aim 1, we compare the acquisition rate of a new motor sequence in a group trained in the morning and another in the evening. For aim 2., we tested retention of the same motor sequence twelve hours later, either without sleep (normal day activity or a night of sleep deprivation) or with interposed sleep (afternoon napping or regular full night sleep). Setting: Training and Testing were performed in a controlled laboratory setting. Participants: Thirty-six right-handed normal subjects (age range 18-24 years; 16 women). Results: During the training, acquisition rate of the sequence order was significantly higher in the AM-trained than in the PM-trained group, without differences in the kinematic optimization processes. Both declarative and implicit learning indices were significantly higher in the subjects tested after sleep compared to those tested without interposed sleep. Conclusion: The best time for fast and efficient acquisition of new declarative material is the morning, while the kinematic aspects of skill acquisition are not sensitive to the time of day. However, better retention of both declarative material and motor skills requires two conditions: a period of post-training sleep and the achievement of performance saturation during training

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 d improves BDNF-TrkB signaling in rats by increasing the affinity of BDNF for TrkB, which results in higher tyrosine-phosphorylated TrkB, increased recruitment of PLC-gamma1 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 NMDA receptor (NMDAR). In normal human subjects, 5 d rTMS to motor cortex decreased resting motor threshold, which 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

When reaching movements are performed in an unusual area of work, normal subjects produce a rightward directional error. This has been considered to be caused by an impaired representation of limb configuration, which hampers the actual movement vector. Motor programming has been found to be impaired in dystonia. To understand how patients affected by idiopathic cervical dystonia (CD) perform reaching movements in an unusual area of work, we investigated 10 CD patients and 10 age-matched controls. Reaching movements on a digitized tablet were recorded both with the right arm aligned to the midline (central position) and shifted to the right (lateral position), but hidden from view. While differences in the main kinematic parameters were not affected by the position both in patients and controls, the directional error was significantly increased in dystonic patients for the lateral position. We hypothesise that an impaired integration of proprioceptive information with the motor output and egocentric spatial perception could be responsible for a greater error in spatial representation of hand location and consequently to an increased directional error in dystonic patients

Motor sequence learning is not a unitary phenomenon, but involves optimizing different components that include declarative and procedural aspects. In this work we designed an experimental approach that allows monitoring all the aspects of sequence learning using a finger opposition task and a movement-by-movement analysis. Subjects performed a visuomotor sequence learning paradigm with (Explicit) or without (Implicit) instructions and we measured response time (RT) and touch duration (TD) for each finger opposition movement of the sequence. Our results indicated that sequence learning induced a double-faced effect on motor performance: a decrease of RT and an increase of TD. However, the above changes manifested differently among subjects: all subjects that, by the end of session, had complete recall of the sequence order, reached an equal level of performance by the last sequence block while in those who had on average only a poor recall of the sequence order, learning was evident only as a slight decrease of RT across sequence blocks, while no kinematic changes (i.e., changes in TD) occurred. Our results indicate that, in the absence of specific instructions, learning evolves from an early stage in which only small decreases of RT are observed to a phase in which progressive knowledge of the sequential structure allows for dramatic changes of RT, together with a progressive change of motor performance (i.e., changes in TD)

Abnormalities in motor sequence learning have been observed in non-manifesting carriers of the DYT1 dystonia mutation. Indeed, motor sequence learning deficits in these subjects have been associated with increased cerebellar activation during task performance. In the current study, we determined whether similar changes are also present in clinically manifesting DYT1 carriers as well as in carriers of other primary dystonia mutations such as DYT6. Additionally, we determined whether sequence learning performance and associated brain activation in these subjects correlate with previously described genotype-related abnormalities of cerebellar pathway integrity and striatal D2 dopamine receptor binding. Nineteen DYT1 carriers (10 non-manifesting DYT1: 51.5+/-15.1 years; nine manifesting DYT1: 46.1+/-15.1 years) and 12 healthy control subjects (42.8+/-15.3 years) were scanned with H2(15)O positron emission tomography while performing controlled sequence learning and reference tasks. Eleven DYT6 carriers (four non-manifesting DYT6: 38.0+/-22.1; seven manifesting DYT6: 35.3+/-14.2 years) were evaluated during task performance without concurrent imaging. DYT1 and DYT6 carriers also underwent diffusion tensor magnetic resonance imaging for the assessment of tract integrity and 11C-raclopride positron emission tomography to measure caudate/putamen D2 receptor binding. These imaging measures were correlated with sequence learning performance and associated activation responses. Sequence learning deficits of similar magnitude were observed in manifesting and non-manifesting DYT1 carriers. In contrast, learning deficits were not detected in DYT6 carriers, irrespective of clinical penetrance. Affected DYT1 carriers exhibited significant increases in sequence learning-related activation in the left lateral cerebellar cortex and in the right premotor and inferior parietal regions. Increases in premotor cortical activation observed in the mutation carriers correlated with reductions in cerebellar pathway integrity measured using magnetic resonance diffusion tensor imaging and probabilistic tractography. Additionally, the cerebellar tract changes correlated with reductions in dentate nucleus activation recorded during task performance. Sequence learning performance and task-related activation responses did not correlate with striatal D2 receptor binding. In summary, we found that sequence learning deficits and concomitant increases in cerebellar activation are specific features of the DYT1 genotype. The close relationship between reduced cerebellar pathway integrity and increased learning-related activation of the premotor cortex is compatible with the view of DYT1 dystonia as a neurodevelopmental circuit disorder