Faculty Bibliography

Recently we found that modulation depth of beta power during movement increases with practice over sensory-motor areas in normal subjects but not in patients with Parkinson's disease (PD). As such changes might reflect use-dependent modifications, we concluded that reduction of beta enhancement in PD represents saturation of cortical plasticity. A few questions remained open: What is the relation between these EEG changes and retention of motor skills? Would a second task exposure restore beta modulation enhancement in PD? Do practice-induced increases of beta modulation occur within each block? We thus recorded EEG in patients with PD and age-matched controls in two consecutive days during a 40-min reaching task divided in fifteen blocks of 56 movements each. The results confirmed that, with practice, beta modulation depth over the contralateral sensory-motor area significantly increased across blocks in controls but not in PD, while performance improved in both groups without significant correlations between behavioral and EEG data. The same changes were seen the following day in both groups. Also, beta modulation increased within each block with similar values in both groups and such increases were partially transferred to the successive block in controls, but not in PD. Retention of performance improvement was present in the controls but not in the patients and correlated with the increase in day 1 modulation depth. Therefore, the lack of practice-related increase beta modulation in PD is likely due to deficient potentiation mechanisms that permit between-block saving of beta power enhancement and trigger mechanisms of memory formation.

Neurocognitive decline, including deficits in motor learning, occurs in the presymptomatic phase of Huntington's disease (HD) and precedes the onset of motor symptoms. Findings from recent neuroimaging studies have linked these deficits to alterations in fronto-striatal and fronto-parietal brain networks. However, little is known about the temporal dynamics of these networks when subjects approach phenoconversion. Here, 10 subjects with presymptomatic HD were scanned with 15O-labeled water at baseline and again 1.5 years later while performing a motor sequence learning task and a kinematically matched control task. Spatial covariance analysis was utilized to characterize patterns of change in learning-related neural activation occurring over time in these individuals. Pattern expression was compared to corresponding values in 10 age-matched healthy control subjects. Spatial covariance analysis revealed significant longitudinal changes in the expression of a specific learning-related activation pattern characterized by increasing activity in the right orbitofrontal cortex, with concurrent reductions in the right medial prefrontal and posterior cingulate regions, the left insula, left precuneus, and left cerebellum. Changes in the expression of this pattern over time correlated with baseline measurements of disease burden and learning performance. The network changes were accompanied by modest improvement in learning performance that took place concurrently in the gene carriers. The presence of increased network activity in the setting of stable task performance is consistent with a discrete compensatory mechanism. The findings suggest that this effect is most pronounced in the late presymptomatic phase of HD, as subjects approach clinical onset.

Learning leads to rapid microstructural changes in gray (GM) and white (WM) matter. Do these changes continue to accumulate if task training continues, and can they be reverted by sleep? We addressed these questions by combining structural and diffusion weighted MRI and high-density EEG in 16 subjects studied during the physiological sleep/wake cycle, after 12 h and 24 h of intense practice in two different tasks, and after post-training sleep. Compared to baseline wake, 12 h of training led to a decline in cortical mean diffusivity. The decrease became even more significant after 24 h of task practice combined with sleep deprivation. Prolonged practice also resulted in decreased ventricular volume and increased GM and WM subcortical volumes. All changes reverted after recovery sleep. Moreover, these structural alterations predicted cognitive performance at the individual level, suggesting that sleep's ability to counteract performance deficits is linked to its effects on the brain microstructure. The cellular mechanisms that account for the structural effects of sleep are unknown, but they may be linked to its role in promoting the production of cerebrospinal fluid and the decrease in synapse size and strength, as well as to its recently discovered ability to enhance the extracellular space and the clearance of brain metabolites.

The neural correlates of memory formation in humans have long been investigated by exposing subjects to diverse material and comparing responses to items later remembered to those forgotten. Tasks requiring memorization of sensory sequences afford unique possibilities for linking neural memorization processes to behavior, because, rather than comparing across different items of varying content, each individual item can be examined across the successive learning states of being initially unknown, newly learned, and eventually, fully known. Sequence learning paradigms have not yet been exploited in this way, however. Here, we analyze the event-related potentials of subjects attempting to memorize sequences of visual locations over several blocks of repeated observation, with respect to pre- and post-block recall tests. Over centro-parietal regions, we observed a rapid P300 component superimposed on a broader positivity, which exhibited distinct modulations across learning states that were replicated in two separate experiments. Consistent with its well-known encoding of surprise, the P300 deflection monotonically decreased over blocks as locations became better learned and hence more expected. In contrast, the broader positivity was especially elevated at the point when a given item was newly learned, i.e., started being successfully recalled. These results implicate the Broad Positivity in endogenously-driven, intentional memory formation, whereas the P300, in processing the current stimulus to the degree that it was previously uncertain, indexes the cumulative knowledge thereby gained. The decreasing surprise/P300 effect significantly predicted learning success both across blocks and across subjects. This presents a new, neural-based means to evaluate learning capabilities independent of verbal reports, which could have considerable value in distinguishing genuine learning disabilities from difficulties to communicate the outcomes of learning, or perceptual impairments, in a range of clinical brain disorders.

BACKGROUND: The cognitive status is generally considered as a major determinant of rehabilitation outcome in Parkinson's disease (PD). No studies about the effect of cognitive impairment on motor rehabilitation outcomes in PD have been performed before. OBJECTIVE: This study is aimed to evaluate the impact of cognitive decline on rehabilitation outcomes in patients with PD. METHODS: We retrospectively identified 485 patients with PD hospitalized for a 4-week Multidisciplinary Intensive Rehabilitation Treatment (MIRT) between January 2014 and September 2015. According to Mini Mental State Examination (MMSE), patients were divided into: group 1-normal cognition (score 27-30), group 2-mild cognitive impairment (score 21-26), group 3-moderate or severe cognitive impairment (score /=13.8) and pathological (score <13.8) executive functions. The outcome measures were: Unified Parkinson's Disease Rating Scale (UPDRS), Parkinson's Disease Disability Scale (PDDS), Six Minutes Walking Test (6MWT), Timed Up and Go Test (TUG) and Berg Balance Scale (BBS). RESULTS: All scales had worse values with the increase of cognitive impairment and passing from normal to pathological executive functions. After rehabilitation, all the outcome measures improved in all groups (p < 0.0001). Between groups, the percentage of improvement was significantly different for total UPDRS (p = 0.0009, best improvement in normal MMSE group; p = 0.019, best improvement in normal FAB group), and BBS (p < 0.0001, all pairwise comparisons significant, best improvement in patients with worse MMSE score; p < 0.0001, best improvement in patients with pathological FAB). TUG (p = 0.006) and BBS (p < 0.0001) improved in patients with pathological FAB score, more than in those with normal FAB score. CONCLUSIONS: Patients gain benefit in the rehabilitative outcomes, regardless of cognition. Our data suggest that rehabilitation could be effective also in Parkinsonian subjects with cognitive impairment, as well as with dysexecutive syndrome.

BACKGROUND: In a combined animal and human study, we have previously found that a 5-day treatment that enhances cortical plasticity also facilitates brain-derived neurotrophic factor (BDNF)-tyrosine receptor kinase B (TrkB) signaling and increases activated TrkB and N-methyl-d-aspartate receptor (NMDAR) association in both the cortex and the peripheral lymphocytes. Patients with Parkinson's disease (PD), in general, show decreased cortical plasticity, as demonstrated by electrophysiological and behavioral studies. Here, we test the hypothesis that an exercise program that improves motor function and seems to slow down symptom progression can enhance BDNF-TrkB signaling in lymphocytes. METHODS: A total of 16 patients with PD underwent a 4-week multidisciplinary intensive rehabilitation treatment (MIRT), which included aerobic training and physical and occupational therapy. Blood was collected before and after 2 and 4 weeks of MIRT. Lymphocytes were isolated to examine BDNF-TrkB signaling induced by incubation with recombinant human BDNF. TrkB signaling complexes, extracellular-signal-regulated kinase-2 and protein-kinase-B were immunoprecipitated; the content of immunocomplexes was determined by Western blotting. RESULTS: After MIRT, all patients showed improvement in motor function. TrkB interaction with NMDAR and BDNF-TrkB signaling increased in peripheral lymphocytes at receptor, intracellular mediator, and downstream levels. The decrements in Unified Parkinson's Disease Rating Scale II (UPDRSII) and total scores were significantly correlated with the increases in TrkB signaling at receptor, intracellular mediator, and NMDAR interaction levels. CONCLUSIONS: The significant correlation between reduced UPDRS scores and the changes in lymphocyte activity suggest that enhanced BDNF-TrkB signaling in lymphocyte and reduced severity of PD symptoms may be related.

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.

BACKGROUND: Sleep disturbances are among the most common non-motor symptoms of Parkinson's disease (PD), greatly interfering with daily activities and diminishing life quality. Pharmacological treatments have not been satisfactory because of side effects and interactions with anti-parkinsonian drugs. While studies have shown that regular exercise improves sleep quality in normal aging, there is no definitive evidence in PD. METHODS: In a retrospective study, we determined whether an intense physical and multidisciplinary exercise program improves sleep quality in a large group of patients with PD. We analyzed the scores of PD Sleep Scale (PDSS), which was administered twice, 28 days apart, to two groups of patients with PD of comparable age, gender, disease duration and pharmacological treatment. The control group (49 patients) did not receive rehabilitation, The treated group (89 patients) underwent a 28-day multidisciplinary intensive rehabilitation program (three one-hour daily sessions comprising cardiovascular warm-up, relaxation, muscle-stretching, balance and gait training, occupational therapy to improve daily living activities). RESULTS: At enrolment, control and treated groups had similar UPDRS and PDSS scores. At re-test, 28 days later, UPDRS and total PDSS scores improved in the treated (p < 0.0001) but not in the control group. In particular, the treated group showed significant improvement in PDSS scores for sleep quality, motor symptoms and daytime somnolence. The control group did not show improvement for any item. CONCLUSIONS: These results suggest that multidisciplinary intensive rehabilitation treatment may have a positive impact on many aspects of sleep in PD.

Balance dysfunction (BD) in Parkinson's disease (PD) is a disabling symptom, difficult to treat and predisposing to falls. The dopaminergic drugs or deep brain stimulation does not always provide significant improvements of BD and rehabilitative approaches have also failed to restore this condition. In this study, we investigated the suitability of quantitative posturographic indicators to early identify patients that could develop disabling BD. Parkinsonian patients not complaining of a subjective BD and controls were tested using a posturographic platform (PP) with open eyes (OE) and performing a simple cognitive task [counting (OEC)]. We found that patients show higher values of total standard deviation (SD) of body sway and along the medio-lateral (ML) axis during OE condition. Furthermore, total and ML SD of body sway during OE condition and total SD of body sway with OEC were higher than controls also in a subgroup of patients with normal Berg Balance Scale. We conclude that BD in Parkinsonian patients can be discovered before its appearance using a PP and that these data may allow developing specific rehabilitative treatment to prevent or delay their onset.

BACKGROUND: PD (Parkinson's disease) is characterized by impairments in cortical plasticity, in beta frequency at rest and in beta power modulation during movement (i.e., event-related ERS [synchronization] and ERD [desynchronization]). Recent results with experimental protocols inducing long-term potentiation in healthy subjects suggest that cortical plasticity phenomena might be reflected by changes of beta power recorded with EEG during rest. Here, we determined whether motor practice produces changes in beta power at rest and during movements in both healthy subjects and patients with PD. We hypothesized that such changes would be reduced in PD. METHODS: We thus recorded EEG in patients with PD and age-matched controls before, during and after a 40-minute reaching task. We determined posttask changes of beta power at rest and assessed the progressive changes of beta ERD and ERS during the task over frontal and sensorimotor regions. RESULTS: We found that beta ERS and ERD changed significantly with practice in controls but not in PD. In PD compared to controls, beta power at rest was greater over frontal sensors but posttask changes, like those during movements, were far less evident. In both groups, kinematic characteristics improved with practice; however, there was no correlation between such improvements and the changes in beta power. CONCLUSIONS: We conclude that prolonged practice in a motor task produces use-dependent modifications that are reflected in changes of beta power at rest and during movement. In PD, such changes are significantly reduced; such a reduction might represent, at least partially, impairment of cortical plasticity.