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.

A Multimodal Training Modulates Short Afferent Inhibition and Improves Complex Walking in a Cohort of Faller Older Adults With an Increased Prevalence of Parkinson's Disease.

BACKGROUND: Falls are frequent in Parkinson's disease and aging. Impairments in the cholinergic-mediated attentional supervision of gait may contribute to increased fall risk, especially when obstacles challenge gait. Interventions combining motor-cognitive approaches have been shown to improve motor performance, cognitive skills, and falls number. Here, we hypothesized that an intervention simulating an attention-demanding walking condition could affect not only complex gait performance and fall risk but also short-latency afferent inhibition (SAI), as a marker of cholinergic activity. METHODS: Thirty-nine participants at falls risk (24 Parkinson's disease participants and 15 older adults) were recruited in a randomized controlled trial. Participants were assigned to treadmill training or treadmill training with non-immersive virtual reality intervention and trained three times a week for 6 weeks. SAI, a transcranial magnetic stimulation paradigm, was used to assess cholinergic activity. Gait kinematics was measured during usual walking and while negotiating physical obstacles. Transcranial magnetic stimulation and gait assessments were performed pre, post, and 6 months post-intervention. RESULTS: Treadmill training combined with non-immersive virtual reality induced an increase in inhibition of the SAI protocol on cortical excitability, improved obstacle negotiation performance, and induced a reduction of the number of falls compared with treadmill training. Furthermore, the more SAI increased after training, the more the obstacle negotiation performance improved and fall rate decreased. CONCLUSIONS: We provide evidence that an innovative rehabilitation approach targeting cognitive components of complex motor actions can induce changes in cortical cholinergic activity, as indexed by SAI, thereby enabling functional gait improvements.

Mirror Visual Feedback to Improve Bradykinesia in Parkinson's Disease.

Mirror visual feedback (MVF) therapy has been applied to improve upper limb function in stroke. When combined with motor training, MVF improves the performance of the trained and untrained hand by enhancing the excitability of both primary motor cortices (M1s). Bradykinesia is a typical feature of Parkinson's disease (PD), characterized by slowness in the execution of movement. This condition is often asymmetrical and possibly supported by a volitional hypoactivation of M1. MVF therapy could tentatively treat bradykinesia since the untrained hand, which benefits from the exercise, is generally more severely impaired in undertaking sequential movements. Aim of the study was to evaluate whether MVF therapy may improve bradykinesia of the more affected hand in PD patients. Twelve PD patients and twelve healthy controls performed for 10 minutes a finger sequence, receiving MVF of the more affected/nondominant hand. Before and after MVF training, participants performed a finger sequence at their spontaneous pace with both hands. M1 excitability was assessed in the trained and untrained hemispheres by means of transcranial magnetic stimulation. Movement speed increased after MVF training in either hand of both groups. MVF therapy enhanced cortical excitability of M1s in both groups. Our preliminary data support the use of MVF therapy to improve bradykinesia in PD patients.

Attentional Control of Gait and Falls: Is Cholinergic Dysfunction a Common Substrate in the Elderly and Parkinson's Disease?

The aim of this study was to address whether deficits in the central cholinergic activity may contribute to the increased difficulty to allocate attention during gait in the elderly with heightened risk of falls. We recruited 50 participants with a history of two or more falls (33 patients with Parkinson's Disease and 17 older adults) and 14 non-fallers age-matched adults. Cholinergic activity was estimated by means of short latency afferent inhibition (SAI), a transcranial magnetic stimulation (TMS) technique that assesses an inhibitory circuit in the sensorimotor cortex and is regarded as a global marker of cholinergic function in the brain. Increased difficulty to allocate attention during gait was evaluated by measuring gait performance under single and dual-task conditions. Global cognition was also assessed. Results showed that SAI was reduced in patients with PD than in the older adults (fallers and non-fallers) and in older adults fallers with respect to non-fallers. Reduction in SAI indicates less inhibition i.e., less cholinergic activity. Gait speed was reduced in the dual task gait compared to normal gait only in our faller population and changes in gait speed under dual task significantly correlated with the mean value of SAI. This association remained significant after adjusting for cognitive status. These findings suggest that central cholinergic activity may be a predictor of change in gait characteristics under dual tasking in older adults and PD fallers independently of cognitive status.

The cerebellum predicts the temporal consequences of observed motor acts.

It is increasingly clear that we extract patterns of temporal regularity between events to optimize information processing. The ability to extract temporal patterns and regularity of events is referred as temporal expectation. Temporal expectation activates the same cerebral network usually engaged in action selection, comprising cerebellum. However, it is unclear whether the cerebellum is directly involved in temporal expectation, when timing information is processed to make predictions on the outcome of a motor act. Healthy volunteers received one session of either active (inhibitory, 1 Hz) or sham repetitive transcranial magnetic stimulation covering the right lateral cerebellum prior the execution of a temporal expectation task. Subjects were asked to predict the end of a visually perceived human body motion (right hand handwriting) and of an inanimate object motion (a moving circle reaching a target). Videos representing movements were shown in full; the actual tasks consisted of watching the same videos, but interrupted after a variable interval from its onset by a dark interval of variable duration. During the 'dark' interval, subjects were asked to indicate when the movement represented in the video reached its end by clicking on the spacebar of the keyboard. Performance on the timing task was analyzed measuring the absolute value of timing error, the coefficient of variability and the percentage of anticipation responses. The active group exhibited greater absolute timing error compared with the sham group only in the human body motion task. Our findings suggest that the cerebellum is engaged in cognitive and perceptual domains that are strictly connected to motor control.

Electroretinographic modifications induced by agomelatine: a novel avenue to the understanding of the claimed antidepressant effect of the drug?

BACKGROUND: Agomelatine, the first melatonergic antidepressant, has been postulated to enhance the dopaminergic activity at the central nervous system by 5-hydroxytryptamine receptor type 2C (5-HT2C) antagonism, yet the impact of melatonergic agonism on this pathway is unclear. Previous studies employing simplified, yet reliable, proxy (retinal) measures of the central nervous system dopaminergic activity, namely the standard electroretinogram (ERG) technique, suggested a reduction of the dopaminergic activity of the main ERG parameter, the b-wave, by pure melatonin, notably a hormone devoid of any antidepressant activity. Therefore, the antidepressant effects of the melatonergic antidepressant drug agomelatine should be reflected by a differential b-wave trend at ERG versus the effect exerted by pure melatonin, which was eventually found to be due to a contrasting effect on central dopaminergic transmission between the two drugs. OBJECTIVE AND METHODS: The aim of the present preliminary ERG study carried out on healthy volunteers (n=23) receiving agomelatine was to explore the impact of this antidepressant drug on b-wave amplitude and latency of cones in daylight conditions using standard ERG. RESULTS: As postulated, agomelatine induced an enhancement of retinal dopaminergic activity, in contrast to what has been previously documented for melatonin. CONCLUSION: Given the limits of this explorative study, especially the lack of a control group and that of a luminance response function to measure retinal sensitivity, further studies in clinical samples are recommended to allow more tenable conclusions about the potential role of ERG in discriminating between 5-HT antagonism and melatonergic (MT) agonism in relationship to the claimed antidepressant effect of agomelatine.

Training based on mirror visual feedback influences transcallosal communication.

Mirror visual feedback (MVF) therapy has been demonstrated to be successful in neurorehabilitation, probably inducing neuroplasticity changes in the primary motor cortex (M1). However, it is not known whether MVF training influences the hemispheric balance between the M1s. This topic is of extreme relevance when MVF training is applied to stroke rehabilitation, as the competitive interaction between the two hemispheres induces abnormal interhemispheric inhibition (IHI) that weakens motor function in stroke patients. In the present study, we evaluated, in a group of healthy subjects, the effect of motor training and MVF training on the excitability of the two M1s and the IHI between M1s. The IHI from the 'active' M1 to the opposite M1 (where 'active' means the M1 contralateral to the moving hand in the motor training and the M1 of the seen hand in the MVF training) increased, after training, in both the experimental conditions. Only after motor training did we observe an increase in the excitability of the active M1. Our findings show that training based on MVF may influence the excitability of the transcallosal pathway and support its use in disorders where abnormal IHI is a potential target, such as stroke, where an imbalance between the affected and unaffected M1s has been documented.

Electroretinographic assessment in major depressed patients receiving duloxetine: might differences between responders and non-responders indicate a differential biological background?

INTRODUCTION: Despite intense research efforts, still too little is known about the biological determinants of depression, thus soliciting diverse study approaches. Among others, the electroretinography (ERG) has been proposed even as a putative proxy (retinal) measurement of central dopaminergic activity for Major Depressive Disorder (MDD) both in drug-naïve patients and subjects receiving antidepressant treatments. Nonetheless, current evidences are merely preliminary, essentially considering just older classes of antidepressants, thus requiring confirmation studies even with newer agents as duloxetine. METHOD: Twenty MDD subjects and 20 matched controls received duloxetine 60 mg/day for 12 weeks, being monitored both by standard ERG recording and by administration of the Hamilton scales for Depression and Anxiety and the Young Mania Rating Scale at baseline and week 12 (end of the study). RESULTS: ERG mean rod b-wave amplitude significantly reduced from baseline to week 12 in those depressed subjects achieving final response (p=.024), decreasing from the highest rank values to the ones, substantially unmodified, seen among non-responders and controls. LIMITATIONS: Small sample size and lack of multiple assessments. CONCLUSIONS: At least some MDD patients responding to duloxetine might exhibit a peculiar ERG pattern, hypothetically indicating a specific biological background. If confirmed by larger-sampled studies, these results might shed further light in the understanding of the biological determinants of different subtypes of depression, ideally showing alternative patterns of response upon different treatment interventions.

Real-time artifact filtering in continuous VEPs/fMRI recording.

Continuous recording of Visual Evoked Potentials (VEPs) and functional Magnetic Resonance Imaging (fMRI) exploits the VEPs high temporal resolution and the fMRI high spatial resolution. In this work, we present a new method of continuous VEPs/fMRI recording to study visual function in seven normal subjects. Our real-time artifact filtering is characterized by a procedure based on an analytical study of echo-planar imaging (EPI) sequence parameters related electro-encephalogram (EEG)-artifact shapes. The magnetic field artifacts were minimized by using a dedicated amagnetic device and by a subtraction algorithm that takes into account the EPI sequence parameters. No significant decrease in signal-to-noise ratio was observed in case of EEG recording simultaneously with MR acquisition; similarly, transient and steady-state VEPs parameters were comparable during fMRI acquisition and in the off-phase of fMRI recording. We also applied this method to one patient with optic neuritis, and, compared with controls, found different results. We suggest that our technique can be reliably used to investigate the function of human visual cortex and properly correlate the electrophysiological and functional neuroimaging related changes.

Interaction between finger opposition movements and aftereffects of 1Hz-rTMS on ipsilateral motor cortex.

One-hertz repetitive transcranial magnetic stimulation (1Hz-rTMS) over ipsilateral motor cortex is able to modify up to 30 min the motor performance of repetitive finger opposition movements paced with a metronome at 2 Hz. We investigated whether the long-lasting rTMS effect on motor behavior can be modulated by subsequent engagement of the contralateral sensorimotor system. Motor task was performed in different experimental conditions: immediately after rTMS, 30 min after rTMS, or when real rTMS was substituted with sham rTMS. Subjects performing the motor task immediately after rTMS showed modifications in motor behavior < or =30 min after rTMS. On the other hand, when real rTMS was substituted with sham stimulation or when subjects performed the motor task 30 min after the rTMS session, the effect was no longer present. These findings suggest that the combination of ipsilateral 1Hz-rTMS and voluntary movement is crucial to endure the effect of rTMS on the movement itself, probably acting on synaptic plasticity-like mechanism. This finding might provide some useful hints for neurorehabilitation protocols.

1-Hz repetitive TMS over ipsilateral motor cortex influences the performance of sequential finger movements of different complexity.

To elucidate the role of ipsilateral motor cortex (M1) in the control of unilateral finger movements (UFMs) in humans we used a conditioning protocol of 1-Hz repetitive transcranial magnetic stimulation (1-Hz rTMS) over M1 in 11 right-handed healthy subjects. We analysed the effects of conditioning rTMS on UFMs of different complexity (simple vs sequential finger movements), and performed with a different modality (internally vs externally paced movements). UFMs were monitored with a sensor-engineered glove, and a quantitative evaluation of the following parameters was performed: touch duration (TD); inter-tapping interval (ITI); timing error (TE); and number of errors (NE). 1-Hz rTMS over ipsilateral M1 was able to affect the performance of a sequence of finger opposition movements in a metronome-paced condition, significantly increasing TD and reducing ITI without TE changes. The effects on motor behaviour had a different magnitude as a function of the sequence complexity. Further, we found a different effect of the ipsilateral 1-Hz rTMS on externally paced movements with respect to an internally paced condition. All these findings indicate that ipsilateral M1 plays an important role in the execution of sequential UFMs. Interestingly, NE did not change in any experimental condition, suggesting that ipsilateral M1 influences only the temporal and not the spatial accuracy of UFMs. Finally, the duration (up to 30 min) of 1-Hz rTMS effects on ipsilateral M1 can indicate its direct action on the mechanisms of cortical plasticity, suggesting that rTMS can be used to modulate the communication between the two hemispheres in rehabilitative protocols.