Faculty Bibliography

Impairment of sequence learning is common in Parkinson's disease (PD), but the time course of this cognitive abnormality is not known. We assessed longitudinal changes in sequence learning performance and associated task-related cerebral blood flow in 13 early stage PD patients who underwent H(2)(15)O PET at baseline and again 2 years later. Ten healthy volunteer subjects served as controls. A trend toward decline in learning performance (p=0.08) was evident over the 2 years of follow-up. During this interval, significant declines in learning-related activation were detected in parietal and temporo-occipital association areas and in the right dorsolateral prefrontal cortex. Learning-related activation in these regions was normal at baseline, but declined to subnormal levels (p<0.01) at 2 years. Significant hippocampal activation (p<0.005) was present in the subjects with high learning performance over time. The findings are consistent with a decline in learning-related neural activity in cortical areas with prominent Lewy body formation

Patients with focal dystonia exhibit proprioception abnormalities that can lead to kinematic deficits. Proprioceptive abnormalities are present in both symptomatic and asymptomatic body parts of dystonic patients. To ascertain whether in patients with idiopathic cervical dystonia (CD) movements performed with nondystonic segments display kinematic abnormalities, we studied trajectory formation of out and back arm reaching movements in 10 patients with CD (before and 3 weeks after treatment with Botulinum toxin) and in 10 age-matched controls. Before treatment, patients with CD showed significant trajectory abnormalities when compared with normal controls. Patients' trajectories were more curved with asymmetrical temporal velocity profiles as well as increased hand path areas, and had longer reversal lags between the out and back segments. Treatment with botulinum toxin improved all the kinematic parameters. These results suggest that in patients with CD, movements performed with nondystonic segments are abnormal. The kinematic abnormalities are likely to derive from long-standing defective integration of the proprioceptive input, which, in turn, causes general changes in the internal models of limb dynamics. It is plausible that treatment with botulinum toxin partially restores proprioceptive processing and thus, such internal models

STUDY OBJECTIVES: Sleep after learning often benefits memory consolidation, but the underlying mechanisms remain unclear. In previous studies, we found that learning a visuomotor task is followed by an increase in sleep slow wave activity (SWA, the electroencephalographic [EEG] power density between 0.5 and 4.5 Hz during non-rapid eye movement sleep) over the right parietal cortex. The SWA increase correlates with the postsleep improvement in visuomotor performance, suggesting that SWA may be causally responsible for the consolidation of visuomotor learning. Here, we tested this hypothesis by studying the effects of slow wave deprivation (SWD). DESIGN: After learning the task, subjects went to sleep, and acoustic stimuli were timed either to suppress slow waves (SWD) or to interfere as little as possible with spontaneous slow waves (control acoustic stimulation, CAS). SETTING: Sound-attenuated research room. PARTICIPANTS: Healthy subjects (mean age 24.6 +/- 1.0 years; n = 9 for EEG analysis, n = 12 for behavior analysis; 3 women). MEASUREMENTS AND RESULTS: Sleep time and efficiency were not affected, whereas SWA and the number of slow waves decreased in SWD relative to CAS. Relative to the night before, visuomotor performance significantly improved in the CAS condition (+5.93% +/- 0.88%) but not in the SWD condition (-0.77% +/- 1.16%), and the direct CAS vs SWD comparison showed a significant difference (P = 0.0007, n = 12, paired t test). Changes in visuomotor performance after SWD were correlated with SWA changes over right parietal cortex but not with the number of arousals identified using clinically established criteria, nor with any sign of 'EEG lightening' identified using a novel automatic method based on event-related spectral perturbation analysis. CONCLUSION: These results support a causal role for sleep slow waves in sleep-dependent improvement of visuomotor performance

Observation of people performing movements facilitates motor planning, execution and memory formation. Tempo, a crucial aspect involved in the execution of rhythmic movements, is normally perceived and learned through auditory channels. In this work, we ascertained whether: first, the frequency of self-paced finger movements (SPMs), which in normal subjects is around 2 Hz, is modified by prior observation of movements performed at either 1 or 3 Hz; second, such changes are lasting; third, there is an effect of time interval between observation and performance. We finally determined the effect of providing explicit information about the upcoming motor task. Seventy-two normal subjects (12 groups) performed a simple finger sequence at different intervals after observation of videos of either landscapes or finger opposition movements. Both with and without information about the upcoming task, observation influenced the tempo of SPMs and led to memory formation. With knowledge of the upcoming task, such changes occurred at all observation-execution intervals, while without instructions, changes took place only when SPMs were performed immediately after observation. Compared to explicit instructions, the absence of instructions produced tempo's changes that more closely resembled the observed rhythms. We conclude that learning requires a prompt comparison between visual and sensorimotor representations of movements; moreover, learning with explicit instructions is more efficient, as activity in both the dorsal and ventral streams might be potentiated by the chatecholaminergic attentional systems that promote long-term potentiation. These results provide the bases for novel neurorehabilitation strategies in terms of temporal re-organization of movement

The ability to perform accurate sequential movements is essential to normal motor function. Learning a sequential motor behavior is comprised of two basic components: explicit identification of the order in which the sequence elements should be performed and implicit acquisition of spatial accuracy for each element. Here we investigated the time course of learning of these components for a first sequence (SEQA) and their susceptibility to interference from learning a second sequence (SEQB). We assessed explicit learning with a discrete index, the number of correct anticipatory movements, and implicit learning with a continuous variable, spatial error, which decreased during learning without subject awareness. Spatial accuracy to individual sequence elements reached asymptotic levels only when the whole sequence order was known. Interference with recall of the order of SEQA persisted even when SEQB was learned 24 h after SEQA. However, there was resistance to interference by SEQB with increased initial training with SEQA. For implicit learning of spatial accuracy, SEQB interfered at 5 min but not 24 h after SEQA. As in the case of sequence order, prolonged initial training with SEQA induced resistance to interference by SEQB. We conclude that explicit sequence learning is more susceptible to anterograde interference and implicit sequence learning is more susceptible to retrograde interference. However, both become resistant to interference with saturation training. We propose that an essential feature of motor skill learning is the process by which discrete explicit task elements are combined with continuous implicit features of movement to form flawless sequential actions

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 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-naive 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

Cognitive processing is associated with deactivation of the default mode network. The presence of dopaminoceptive neurons in proximity to the medial prefrontal node of this network suggests that this neurotransmitter may modulate deactivation in this region. We therefore used positron emission tomography to measure cerebral blood flow in 15 Parkinson's disease (PD) patients while they performed a motor sequence learning task and a simple movement task. Scanning was conducted before and during intravenous levodopa infusion; the pace and extent of movement was controlled across tasks and treatment conditions. In normal and unmedicated PD patients, learning-related deactivation was present in the ventromedial prefrontal cortex (p < 0.001). This response was absent in the treated condition. Treatment-mediated changes in deactivation correlated with baseline performance (p < 0.002) and with the val(158)met catechol-O-methyltransferase genotype. Our findings suggest that dopamine can influence prefrontal deactivation during learning, and that these changes are linked to baseline performance and genotype

Sleep after learning often enhances task performance, but the underlying mechanisms remain unclear. Using a well-characterized rotation learning paradigm implemented both behaviorally and in computer simulations, we compared two main hypotheses: the first, that off-line replay during sleep leads to further potentiation of synaptic circuits involved in learning; the second, that sleep enhances performance by uniformly downscaling synaptic strength. A simple computer model implemented synaptic changes associated with rotation adaptation (30 degrees ), yielding a reduction in mean directional error. Simulating further synaptic potentiation led to a further reduction of mean directional error, but not of directional variability. By contrast, simulating sleep-dependent synaptic renormalization by scaling down all synaptic weights by 15% decreased both mean directional error and variability. Two groups of subjects were tested after either two rotation adaptation training sessions or after a single training session followed by sleep. After two training sessions, mean direction error decreased, but directional variability remained high. However, subjects who slept after a single training session showed a reduction in both directional error and variability, consistent with a downscaling mechanism during sleep

We investigated synaptic plasticity in persons with Down' syndrome (DS) and control subjects used paired associative stimulation (PAS) protocol, a paradigm capable of producing long-term potentiation (LTP)-like changes in the sensorimotor system. After PAS, patients showed less LTP-like plasticity compared to control subjects. Abnormal motor cortex synaptic plasticity may play a role in the development of motor signs in DS