Supplementing Best Care with Specialized Rehabilitation Treatment in Parkinson's Disease: A Retrospective Study by Different Expert Centers.

Background: This is a retrospective longitudinal study comparing 374 patients with Parkinson's disease (PD) who were treated in centers offering a specialized program of enhanced rehabilitation therapy in addition to expert outpatient care to 387 patients with PD, who only received expert outpatient care at movement disorders centers in Italy. Methods: The data are from subjects recruited in the Parkinson's Outcome Project (POP) at six Italian centers that are part of a multicenter collaboration for care quality improvement (the Fresco Network). The effects were measured with a baseline and a follow-up clinical evaluation of the Timed-Up-and-Go test (TUG), Parkinson's Disease Questionnaire (PDQ-39), and Multidimensional Caregiver Strain Index (MCSI), the number of falls and hospitalizations for any cause. We used a generalized linear mixed model with the dependent variables being the response variable, which included the covariates demographics, evaluation, and treatment variables. Results: We found that the subjects who underwent specialized enhanced rehabilitation had a better motor outcome over time than those who were managed by expert neurologists but had participated in community programs for exercise and other allied health interventions. The greatest effects were seen in patients in the early stages of the disease with a high amount of vigorous exercise per week in the last six months. Similar effects were seen for PDQ39, MCSI, the number of falls, and hospitalization. Conclusions: Long-term benefits to motor function and the quality of life in patients with PD and burden reduction in their caregivers can be achieved through a systematic program of specialized enhanced rehabilitation interventions.

Electromyographic Patterns of Paratonia in Normal Subjects and in Patients with Mild Cognitive Impairment or Alzheimer's Disease.

BACKGROUND: Information on prevalence, pathophysiology, and clinical assessment of paratonia are scarce. In a previous study, we suggested that surface electromyography (EMG) can be used to assess paratonia. OBJECTIVE: To assess clinical and EMG features of paratonia in both patients with cognitive impairment and healthy subjects. METHODS: We examined 18 patients with Alzheimer's disease (AD), 21 patients with mild cognitive impairment (MCI), 30 healthy seniors (seniors), and 30 healthy juniors (juniors). Paratonia was assessed using the "Paratonia Scale". EMG bursts were recorded from biceps and triceps during manually applied passive movements of elbow joint. Continuous (sinusoidal) and discontinuous (linear) movements were applied at 2 different velocities (fast and slow). RESULTS: In comparison to juniors, seniors had higher clinical scores. In comparison to seniors, AD had higher oppositional scores, while MCI had higher facilitatory scores. EMG activity during passive movements correlated with paratonia clinical scores, was velocity-dependent and increased with movement repetition, most effectively for sinusoidal movements. Similar EMG activity was detected in not paratonic muscles. CONCLUSION: Paratonia increases with normal aging and cognitive decline progression. While facilitatory paratonia is due to involuntary contraction of the shortening muscle, oppositional paratonia is due, at least partially, to involuntary contraction of the lengthening muscle. Most characteristic feature of this muscle contraction is the progressive increase with movement repetition, that helps distinguish oppositional paratonia from spasticity and rigidity. A similar EMG activity is detected in not paratonic muscles, showing that, during tone assessment, the descending motor system is incompletely inactivated also in normotonic muscles.

Modulation of Gamma Spectral Amplitude and Connectivity During Reaching Predicts Peak Velocity and Movement Duration.

Modulation of gamma oscillations recorded from the human motor cortex and basal ganglia appears to play a key role in movement execution. However, there are still major questions to be answered about the specific role of cortical gamma activity in both the planning and execution of movement features such as the scaling of peak velocity and movement time. In this study, we characterized movement-related gamma oscillatory dynamics and its relationship with kinematic parameters based on 256-channels EEG recordings in 64 healthy subjects while performing fast and uncorrected reaching movements to targets located at three distances. In keeping with previous studies, we found that movement-related gamma synchronization occurred during movement execution. As a new finding, we showed that gamma synchronization occurred also before movement onset, with planning and execution phases involving different gamma peak frequencies and topographies. Importantly, the amplitude of gamma synchronization in both planning and execution increased with target distance and predicted peak velocity and movement time. Additional analysis of phase coherence revealed a gamma-coordinated long-range network involving occipital, frontal and central regions during movement execution that was positively related to kinematic features. This is the first evidence in humans supporting the notion that gamma synchronization amplitude and phase coherence pattern can reliably predict peak velocity amplitude and movement time. Therefore, these findings suggest that cortical gamma oscillations have a crucial role for the selection, implementation and control of the appropriate kinematic parameters of goal-directed reaching movements.

Neuroplasticity in dystonia: Motor symptoms and beyond.

This chapter first focuses on the role of altered neuroplasticity mechanisms and their regulation in the genesis of motor symptoms in the various forms of dystonia. In particular, a review of the available literature about focal dystonia suggests that use-dependent plasticity may become detrimental and produce dystonia when practice and repetition are excessive and predisposing conditions are present. Interestingly, recent evidence also shows that functional or psychogenic dystonia, despite the normal plasticity in the sensorimotor system, is characterized by plasticity-related dysfunction within limbic regions. Finally, this chapter reviews the non-motor symptoms that often accompany the motor features of dystonia, including depression and anxiety as well as obsessive-compulsive disorders, pain, and cognitive dysfunctions. Based on the current understanding of these symptoms, we discuss the evidence of their possible relationship to maladaptive plasticity in non-motor basal ganglia circuits involved in their genesis.

Beta power and movement-related beta modulation as hallmarks of energy for plasticity induction: Implications for Parkinson's disease.

Extensive work on movement-related beta oscillations (~13-30 Hz) over the sensorimotor areas in both humans and animals has demonstrated that sensorimotor beta power decreases during movement and transiently increases after movement. This beta power modulation has been interpreted as reflecting interactions between sensory and motor cortical areas with attenuation of sensory afferents during movement and their subsequent re-activation for internal models updating. More recent studies in neurologically normal subjects have demonstrated that this movement-related modulation as well as mean beta power at rest increase with practice and that previous motor learning enhances such increases. Conversely, patients with Parkinson's disease (PD) do not show such practice-related increases. Interestingly, a 2-h inactivity period without sleep can restore beta power values to baseline in normal subjects. Based on these results and on those of biochemical and electrophysiological studies in animals, we expand the current interpretation of beta activity and propose that the practice-related increases of beta power over sensorimotor areas are local indices of energy used for engaging plasticity-related activity. This paper provides some preliminary evidence in this respect linking findings of biochemical and electrophysiological studies in both humans and animals. This novel interpretation may explain the high level of beta power at rest, the deficient modulation during movement as well as the decreased skill formation in PD as resulting from deficiency in energy consumption, availability and regulation that are altered in this disease.

Prior Practice Affects Movement-Related Beta Modulation and Quiet Wake Restores It to Baseline.

Beta oscillations (13.5-25 Hz) over the sensorimotor areas are characterized by a power decrease during movement execution (event-related desynchronization, ERD) and a sharp rebound after the movement end (event-related synchronization, ERS). In previous studies, we demonstrated that movement-related beta modulation depth (peak ERS-ERD) during reaching increases within 1-h practice. This increase may represent plasticity processes within the sensorimotor network. If so, beta modulation during a reaching test should be affected by previous learning activity that engages the sensorimotor system but not by learning involving other systems. We thus recorded high-density EEG activity in a group of healthy subjects performing three 45-min blocks of motor adaptation task to a visually rotated display (ROT) and in another performing three blocks of visual sequence-learning (VSEQ). Each block of either ROT or VSEQ was followed by a simple reaching test (mov) without rotation. We found that beta modulation depth increased with practice across mov tests. However, such an increase was greater in the group performing ROT over both the left and frontal areas previously involved in ROT. Importantly, beta modulation values returned to baseline values after a 90-min of either nap or quiet wake. These results show that previous practice leaves a trace in movement-related beta modulation and therefore such increases are cumulative. Furthermore, as sleep is not necessary to bring beta modulation values to baseline, they could reflect local increases of neuronal activity and decrease of energy and supplies.

New insights into cortico-basal-cerebellar connectome: clinical and physiological considerations.

The current model of the basal ganglia system based on the 'direct', 'indirect' and 'hyperdirect' pathways provides striking predictions about basal ganglia function that have been used to develop deep brain stimulation approaches for Parkinson's disease and dystonia. The aim of this review is to challenge this scheme in light of new tract tracing information that has recently become available from the human brain using MRI-based tractography, thus providing a novel perspective on the basal ganglia system. We also explore the implications of additional direct pathways running from cortex to basal ganglia and between basal ganglia and cerebellum in the pathophysiology of movement disorders.

Cognitive performance in mid-stage Parkinson's disease: functional connectivity under chronic antiparkinson treatment.

Cognitive impairment in Parkinson's disease (PD) is related to the reorganization of brain topology. Although drug challenge studies have proven how levodopa treatment can modulate functional connectivity in brain circuits, the role of chronic dopaminergic therapy on cognitive status and functional connectivity has never been investigated. We sought to characterize brain functional topology in mid-stage PD patients under chronic antiparkinson treatment and explore the presence of correlation between reorganization of brain architecture and specific cognitive deficits. We explored networks topology and functional connectivity in 16 patients with PD and 16 matched controls through a graph theoretical analysis of resting state-functional MRI data, and evaluated the relationships between network metrics and cognitive performance. PD patients showed a preserved small-world network topology but a lower clustering coefficient in comparison with healthy controls. Locally, PD patients showed lower degree of connectivity and local efficiency in many hubs corresponding to functionally relevant areas. Four disconnected subnetworks were also identified in regions responsible for executive control, sensory-motor control and planning, motor coordination and visual elaboration. Executive functions and information processing speed were directly correlated with degree of connectivity and local efficiency in frontal, parietal and occipital areas. While functional reorganization appears in both motor and cognitive areas, the clinical expression of network imbalance seems to be partially compensated by the chronic levodopa treatment with regards to the motor but not to the cognitive performance. In a context of reduced network segregation, the presence of higher local efficiency in hubs regions correlates with a better cognitive performance.

Efficacy of intensive multidisciplinary rehabilitation in Parkinson's disease: a randomised controlled study.

OBJECTIVE: To evaluate whether a 4-week multidisciplinary, aerobic, motor-cognitive and intensive rehabilitation treatment (MIRT) improves the quality of life (QoL) of patients with Parkinson's disease (PD), in the short-term and long-term period. METHODS: This is a prospective, parallel-group, single-centre, single-blind, randomised clinical trial (ClinicalTrials.gov NCT02756676). 186 patients with PD, assigned to experimental group, underwent MIRT; conversely, 48 patients, assigned to control group, did not receive rehabilitation. Parkinson's Disease Questionnaire-39 was assessed 2 (T0), 10 (T1) and 18 (T2, only experimental group) weeks after the enrolment. We compared T1 versus T0 scores within subjects and delta scores (T1-T0) between subjects. To investigate the long-term effects, we compared T2 and T0 scores in the experimental group. RESULTS: At T0, no between-group differences in the Global Index Score (GBI) were observed (experimental group: 43.6±21.4, controls: 41.6±22.9, P=0.50). At T1, we did not find significant changes in controls (delta score: 1.2±9.9, P=0.23), and we found an improvement in GBI in the experimental group (delta score: -8.3±18.0, P<0.0001), significant also between subjects (P<0.0001). Comparing T2 versus T0 in the experimental group, the GBI maintained a significant improvement (delta score: -4.8±17.5, P<0.0001). CONCLUSIONS: A rehabilitation treatment such as MIRT could improve QoL in patients with PD in the short-term and long-term period. Even though the single-blind design and the possible role of the placebo effect on the conclusive results must be considered as limitations of this study, the improvement in outcome measure, also maintained after a 3-month follow-up period, suggests the effectiveness of MIRT on the QoL. CLINICAL TRIAL REGISTRATION: NCT02756676: Pre-results.

Learning "How to Learn": Super Declarative Motor Learning Is Impaired in Parkinson's Disease.

Learning new information is crucial in daily activities and occurs continuously during a subject's lifetime. Retention of learned material is required for later recall and reuse, although learning capacity is limited and interference between consecutively learned information may occur. Learning processes are impaired in Parkinson's disease (PD); however, little is known about the processes related to retention and interference. The aim of this study is to investigate the retention and anterograde interference using a declarative sequence learning task in drug-naive patients in the disease's early stages. Eleven patients with PD and eleven age-matched controls learned a visuomotor sequence, SEQ1, during Day1; the following day, retention of SEQ1 was assessed and, immediately after, a new sequence of comparable complexity, SEQ2, was learned. The comparison of the learning rates of SEQ1 on Day1 and SEQ2 on Day2 assessed the anterograde interference of SEQ1 on SEQ2. We found that SEQ1 performance improved in both patients and controls on Day2. Surprisingly, controls learned SEQ2 better than SEQ1, suggesting the absence of anterograde interference and the occurrence of learning optimization, a process that we defined as "learning how to learn." Patients with PD lacked such improvement, suggesting defective performance optimization processes.

Visual System Involvement in Patients with Newly Diagnosed Parkinson Disease.

Purpose To assess intracranial visual system changes of newly diagnosed Parkinson disease in drug-naïve patients. Materials and Methods Twenty patients with newly diagnosed Parkinson disease and 20 age-matched control subjects were recruited. Magnetic resonance (MR) imaging (T1-weighted and diffusion-weighted imaging) was performed with a 3-T MR imager. White matter changes were assessed by exploring a white matter diffusion profile by means of diffusion-tensor imaging-based parameters and constrained spherical deconvolution-based connectivity analysis and by means of white matter voxel-based morphometry (VBM). Alterations in occipital gray matter were investigated by means of gray matter VBM. Morphologic analysis of the optic chiasm was based on manual measurement of regions of interest. Statistical testing included analysis of variance, t tests, and permutation tests. Results In the patients with Parkinson disease, significant alterations were found in optic radiation connectivity distribution, with decreased lateral geniculate nucleus V2 density (F, -8.28; P < .05), a significant increase in optic radiation mean diffusivity (F, 7.5; P = .014), and a significant reduction in white matter concentration. VBM analysis also showed a significant reduction in visual cortical volumes (P < .05). Moreover, the chiasmatic area and volume were significantly reduced (P < .05). Conclusion The findings show that visual system alterations can be detected in early stages of Parkinson disease and that the entire intracranial visual system can be involved. © RSNA, 2017 Online supplemental material is available for this article.

The many facets of motor learning and their relevance for Parkinson's disease.

The final goal of motor learning, a complex process that includes both implicit and explicit (or declarative) components, is the optimization and automatization of motor skills. Motor learning involves different neural networks and neurotransmitters systems depending on the type of task and on the stage of learning. After the first phase of acquisition, a motor skill goes through consolidation (i.e., becoming resistant to interference) and retention, processes in which sleep and long-term potentiation seem to play important roles. The studies of motor learning in Parkinson's disease have yielded controversial results that likely stem from the use of different experimental paradigms. When a task's characteristics, instructions, context, learning phase and type of measures are taken into consideration, it is apparent that, in general, only learning that relies on attentional resources and cognitive strategies is affected by PD, in agreement with the finding of a fronto-striatal deficit in this disease. Levodopa administration does not seem to reverse the learning deficits in PD, while deep brain stimulation of either globus pallidus or subthalamic nucleus appears to be beneficial. Finally and most importantly, patients with PD often show a decrease in retention of newly learned skill, a problem that is present even in the early stages of the disease. A thorough dissection and understanding of the processes involved in motor learning is warranted to provide solid bases for effective medical, surgical and rehabilitative approaches in PD.

Cortical plasticity and levodopa-induced dyskinesias in Parkinson's disease: Connecting the dots in a multicomponent network.

Levodopa-induced dyskinesias are motor complications following long term dopaminergic therapy in Parkinson's disease (PD). Impaired brain plasticity resulting in the creation of aberrant motor maps intended to encode normal voluntary movement is proposed to result in the development of dyskinesias. Traditionally, the various nodes in the motor network like the striato-cortical and the cerebello-thalamic loops were thought to function independent of each other with little communication among them. Anatomical evidence from primates revealed the existence of reciprocal loops between the basal ganglia and the cerebellum providing an anatomical basis for communication between the motor network loops. Dyskinetic PD patients reveal impaired brain plasticity within the motor cortex which may be modulated by cortico-cortical, cerebello-cortical or striato-cortical connections. In this article, we review the evidence for altered plasticity in the multicomponent motor network in the context of levodopa induced dyskinesias in PD. Current evidence suggests a pivotal role for the cerebellum in the larger motor network with the ability to integrate sensorimotor information and independently influence multiple nodes in this network. Targeting the cerebellum seems to be a justified approach for future interventions aimed at attenuating levodopa-induced dyskinesias.

Sleep Consolidates Motor Learning of Complex Movement Sequences in Mice.

Introduction: Sleep-dependent consolidation of motor learning has been extensively studied in humans, but it remains unclear why some, but not all, learned skills benefit from sleep. Aims and Methods: Here, we compared 2 different motor tasks, both requiring the mice to run on an accelerating device. In the rotarod task, mice learn to maintain balance while running on a small rod, while in the complex wheel task, mice run on an accelerating wheel with an irregular rung pattern. Results: In the rotarod task, performance improved to the same extent after sleep or after sleep deprivation (SD). Overall, using 7 different experimental protocols (41 sleep deprived mice, 26 sleeping controls), we found large interindividual differences in the learning and consolidation of the rotarod task, but sleep before/after training did not account for this variability. By contrast, using the complex wheel, we found that sleep after training, relative to SD, led to better performance from the beginning of the retest session, and longer sleep was correlated with greater subsequent performance. As in humans, the effects of sleep showed large interindividual variability and varied between fast and slow learners, with sleep favoring the preservation of learned skills in fast learners and leading to a net offline gain in the performance in slow learners. Using Fos expression as a proxy for neuronal activation, we also found that complex wheel training engaged motor cortex and hippocampus more than the rotarod training. Conclusions: Sleep specifically consolidates a motor skill that requires complex movement sequences and strongly engages both motor cortex and hippocampus.

Spatial and Temporal High Processing of Visual and Auditory Stimuli in Cervical Dystonia.

OBJECTIVE: Investigation of spatial and temporal cognitive processing in idiopathic cervical dystonia (CD) by means of specific tasks based on perception in time and space domains of visual and auditory stimuli. BACKGROUND: Previous psychophysiological studies have investigated temporal and spatial characteristics of neural processing of sensory stimuli (mainly somatosensorial and visual), whereas the definition of such processing at higher cognitive level has not been sufficiently addressed. The impairment of time and space processing is likely driven by basal ganglia dysfunction. However, other cortical and subcortical areas, including cerebellum, may also be involved. METHODS: We tested 21 subjects with CD and 22 age-matched healthy controls with 4 recognition tasks exploring visuo-spatial, audio-spatial, visuo-temporal, and audio-temporal processing. Dystonic subjects were subdivided in three groups according to the head movement pattern type (lateral: Laterocollis, rotation: Torticollis) as well as the presence of tremor (Tremor). RESULTS: We found significant alteration of spatial processing in Laterocollis subgroup compared to controls, whereas impairment of temporal processing was observed in Torticollis subgroup compared to controls. CONCLUSION: Our results suggest that dystonia is associated with a dysfunction of temporal and spatial processing for visual and auditory stimuli that could underlie the well-known abnormalities in sequence learning. Moreover, we suggest that different movement pattern type might lead to different dysfunctions at cognitive level within dystonic population.

Electromyographic assessment of paratonia.

Many years after its initial description, paratonia remains a poorly understood concept. It is described as the inability to relax muscles during muscle tone assessment with the subject involuntary facilitating or opposing the examiner. Although related to cognitive impairment and frontal lobe function, the underlying mechanisms have not been clarified. Moreover, criteria to distinguish oppositional paratonia from parkinsonian rigidity or spasticity are not yet available. Paratonia is very frequently encountered in clinical practice and only semi-quantitative rating scales are available. The purpose of this study is to assess the feasibility of a quantitative measure of paratonia using surface electromyography. Paratonia was elicited by performing consecutive metronome-synchronized continuous and discontinuous elbow movements in a group of paratonic patients with cognitive impairment. Goniometric and electromyographic recordings were performed on biceps and triceps brachii muscles. Facilitatory (mitgehen) and oppositional (gegenhalten) paratonia could be recorded on both muscles. After normalization with voluntary maximal contraction, biceps showed higher paratonia than triceps. Facilitatory paratonia was higher than oppositional on the biceps. Movement repetition induced increased paratonic burst amplitude only when flexion and extension movements were performed continuously. Both facilitatory and oppositional paratonia increased with movement repetition. Only oppositional paratonia increased following faster movements. This is the first study providing a quantitative and objective characterization of paratonia using electromyography. Unlike parkinsonian rigidity, oppositional paratonia increases with velocity and with consecutive movement repetition. Like spasticity, oppositional paratonia is velocity-dependent, but different from spasticity, it increases during movement repetition instead of decreasing. A quantitative measure of paratonia could help better understanding its pathophysiology and could be used for research purposes on cognitive impairment.

Does Cognitive Impairment Affect Rehabilitation Outcome in Parkinson's Disease?

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 ≤ 20). According to Frontal Assessment Battery (FAB), subjects were divided into patients with normal (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.