M. Felice Ghilardi

Local sleep and learning

Human sleep is a global state whose functions remain unclear. During much of sleep, cortical neurons undergo slow oscillations in membrane potential, which appear in electroencephalograms as slow wave activity (SWA) of <4 Hz. The amount of SWA is homeostatically regulated, increasing after wakefulness and returning to baseline during sleep. It has been suggested that SWA homeostasis may reflect synaptic changes underlying a cellular need for sleep. If this were so, inducing local synaptic changes should induce local SWA changes, and these should benefit neural function. Here we show that sleep homeostasis indeed has a local component, which can be triggered by a learning task involving specific brain regions. Furthermore, we show that the local increase in SWA after learning correlates with improved performance of the task after sleep. Thus, sleep homeostasis can be induced on a local level and can benefit performance.

Arm immobilization causes cortical plastic changes and locally decreases sleep slow wave activity

Sleep slow wave activity (SWA) is thought to reflect sleep need, increasing after wakefulness and decreasing after sleep. We showed recently that a learning task involving a circumscribed brain region produces a local increase in sleep SWA. We hypothesized that increases in cortical SWA reflect synaptic potentiation triggered by learning. To further investigate the link between synaptic plasticity and sleep, we asked whether a procedure leading to synaptic depression would cause instead a decrease in sleep SWA. We show here that if a subjects arm is immobilized during the day, motor performance deteriorates and both somatosensory and motor evoked potentials decrease over contralateral sensorimotor cortex, indicative of local synaptic depression. Notably, during subsequent sleep, SWA over the same cortical area is markedly reduced. Thus, cortical plasticity is linked to local sleep regulation without learning in the classical sense. Moreover, when synaptic strength is reduced, local sleep need is also reduced.

Adaptation to Visuomotor Transformations: Consolidation, Interference, and Forgetting

The paradigm task A→task B→task A, which varies the time interval between task A and task B, has been used extensively to investigate the consolidation of motor memory. Consolidation is defined as resistance to retrograde interference (interference by task B on initial learning of task A). Consolidation has been demonstrated for simple skills, motor sequencing, and learning of force fields. In contrast, evidence to date suggests that visuomotor learning does not consolidate. We have shown previously that adaptation to a 30° screen-cursor rotation is faster and more complete on relearning 24 hr later. This improvement is prevented if a 30° counter-rotation is learned 5 min after the original rotation. Here, we sought to identify conditions under which rotation learning becomes resistant to interference by a counter-rotation. In experiment 1, we found that interference persists even when the counter-rotation is learned 24 hr after the initial rotation. In experiment 2, we removed potential anterograde interference (interference by task B on relearning of task A) by introducing washout blocks before all of the learning blocks. In contrast to experiment 1, we found resistance to interference (i.e., consolidation) when the counter-rotation was learned after 24 hr but not after 5 min. In experiment 3, we doubled the amount of initial rotation learning and found resistance to interference even after 5 min. Our results suggest that persistent interference is attributable to anterograde effects on memory retrieval. When anterograde effects are removed, rotation learning consolidates both over time and with increased initial training.

Cortical plasticity in Alzheimer's disease in humans and rodents.

BACKGROUND The aim of this study was to determine whether neocortical long-term potentiation (LTP) is deficient in patients with Alzheimers disease (AD) and in amyloid precursor protein (APP)/presenilin-1 (PS1) mice, an AD animal model. We then ascertained whether this deficit might be paralleled by functional abnormalities of N-methyl-D-aspartate (NMDAR) glutamate receptors. METHODS We studied neocortical LTP-like plasticity in 10 patients with mild-to-moderate AD and 10 age-matched normal controls using paired associative stimulation (PAS). We assessed neocortical (medial prefrontal cortex and primary motor cortex) and hippocampal LTP in brain slices of symptomatic APP/PS1 mice. NMDAR composition and signaling as well as synaptic calcium influx were determined in motor, prefrontal and hippocampal cortices of APP/PS1 mice. RESULTS Both AD patients and transgenic animals showed a deficit in NMDAR-dependent forms of neocortical plasticity. Biochemical analysis showed impaired NMDAR function in symptomatic APP/PS1 mice. CONCLUSIONS Neocortical plasticity is impaired in both patients with AD and APP/PS1 mice. The results of our biochemical studies point to impaired NMDAR function as the most likely cause for the neocortical plasticity deficit in AD.

Repetitive Transcranial Magnetic Stimulation Enhances BDNF–TrkB Signaling in Both Brain and Lymphocyte

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-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 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.

Learning of a Sequential Motor Skill Comprises Explicit and Implicit Components That Consolidate Differently

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.

The serial reaction time task revisited: a study on motor sequence learning with an arm-reaching task

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.

The slow-wave components of the cyclic alternating pattern (CAP) have a role in sleep-related learning processes.

Slow waves, a key feature of the EEG of NREM sleep, may be causally involved in producing a sleep-dependent, progressive downscaling of synaptic strength, which would lead to several benefits in terms of both cellular function and network performance. Also the A1 subtypes of the so-called cyclic alternating pattern (CAP) are composed mostly of slow waves and map over the frontal and prefrontal regions of the scalp. The aim of this study was to evaluate the eventual changes of CAP induced by an implicit learning paradigm which has already been shown to be able to increase locally sleep slow-wave activity (SWA). Our hypothesis was that learning is accompanied by a change in the components of CAP characterized by SWA (0.5-2.5Hz), i.e. its A1 subtypes. For this reason, in the present study we evaluated sleep recordings obtained in 10 healthy young normal subjects (mean age 25.8+/-1.8 years) who were asked to perform a motor learning task just before going to sleep. Sleep EEG was recorded for 2h and subjects were also tested after the night following the rotation task. Sleep stages and CAP (classified into three subtypes: A1, A2, and A3) were identified in the first hour of each recording. We found a significant increase in the number of CAP A1 subtypes per hour of NREM sleep on the night following the rotation test; the correlation between the change in A1 index and the post-sleep performance improvement after the rotation task was positive. These results confirm our hypothesis that CAP slow components are modified by a learning task during the day preceding sleep and support the idea that these components may play a role in sleep-related cognitive processes.

Intensive Rehabilitation Treatment in Early Parkinson’s Disease A Randomized Pilot Study With a 2-Year Follow-up

Background. Although physical exercise improves motor aspects of Parkinson’s disease (PD), it is not clear whether it may also have a neuroprotective effect. Objective. In this 2-year follow-up study, we determined whether intensive exercise in the early stages of the disease slows down PD progression. Methods. Forty newly diagnosed patients with PD were treated with rasagiline and randomly assigned to 2 groups: MIRT Group (two 28-day multidisciplinary intensive rehabilitation treatments [MIRT], at 1-year interval) and Control Group (only drug). In both groups, Unified Parkinson’s Disease Rating Scale Section II (UPDRS II), UPDRS III, 6-minute walking test (6MWT), Timed Up-and-Go test (TUG); PD Disability Scale (PDDS), and l-dopa equivalents were assessed at baseline (T0), 6 months (T1), 1 year (T2), 18 months (T3), and 2 years (T4) later. Results. Over 2 years, UPDRS II, UPDRS III, TUG, and PDDS differentially progressed in the 2 groups: In the MIRT Group, all scores at T4 were better than at T0 (all Ps < .03). No changes were noted in the Control Group. l-dopa equivalent dosages increased significantly only in the Control Group (P = .0015), with a decrease in the percentages of patients in monotherapy (T1 40%; T2, T3, and T4 20%). In the MIRT Group, the percentages of such patients remained higher (T1 and T2 100%; T3 89%; T4 75%). Conclusions. These results suggest that MIRT might slow down the progression of motor decay, it might delay the need for increasing drug treatment, and thus, it might have a neuroprotective effect.

Temporal Evolution of Oscillatory Activity Predicts Performance in a Choice-Reaction Time Reaching Task

In this study, we characterized the patterns and timing of cortical activation of visually guided movements in a task with critical temporal demands. In particular, we investigated the neural correlates of motor planning and on-line adjustments of reaching movements in a choice-reaction time task. High-density electroencephalography (EEG, 256 electrodes) was recorded in 13 subjects performing reaching movements. The topography of the movement-related spectral perturbation was established across five 250-ms temporal windows (from prestimulus to postmovement) and five frequency bands (from theta to beta). Nine regions of interest were then identified on the scalp, and their activity was correlated with specific behavioral outcomes reflecting motor planning and on-line adjustments. Phase coherence analysis was performed between selected sites. We found that motor planning and on-line adjustments share similar topography in a fronto-parietal network, involving mostly low frequency bands. In addition, activities in the high and low frequency ranges have differential function in the modulation of attention with the former reflecting the prestimulus, top-down processes needed to promote timely responses, and the latter the planning and control of sensory-motor processes.