Faculty Bibliography

In Parkinson's disease (PD) degeneration of mesocortical dopaminergic projections may determine cognitive and behavioral symptoms. Choice reaction time task is related to attention, working memory, and goal-directed behavior. Such paradigm involves frontal cortical circuits receiving mesocortical dopamine which are affected early in PD. The aim of this study is to characterize the role of dopamine on the cognitive processes that precede movement in a reaction time paradigm in PD. We enrolled 16 newly diagnosed and untreated patients with PD without cognitive impairment or depression and 10 control subjects with essential tremor. They performed multiple-choice reaction time task with the right upper limb and brain (18)F-DOPA PET/CT scan. A significant inverse correlation was highlighted between average reaction time and (18)F-DOPA uptake in the left lateral orbitofrontal cortex. No correlations were found between reaction time and PD disease severity or between reaction time and (18)F-DOPA uptake in controls. Our study shows that in PD, but not in controls, reaction time is inversely related to the levels of dopamine in the left lateral orbitofrontal cortex. This novel finding underlines the role of dopamine in the lateral orbitofrontal cortex in the early stages of PD, supporting a relation between the compensatory cortical dopamine and movement preparation.

Recent work has demonstrated that behavioral manipulations targeting specific cortical areas during prolonged wakefulness lead to a region-specific homeostatic increase in theta activity (5-9 Hz), suggesting that theta waves could represent transient neuronal OFF periods (local sleep). In awake rats, the occurrence of an OFF period in a brain area relevant for behavior results in performance errors. Here we investigated the potential relationship between local sleep events and negative behavioral outcomes in humans. Volunteers participated in two prolonged wakefulness experiments (24 h), each including 12 h of practice with either a driving simulation (DS) game or a battery of tasks based on executive functions (EFs). Multiple high-density EEG recordings were obtained during each experiment, both in quiet rest conditions and during execution of two behavioral tests, a response inhibition test and a motor test, aimed at assessing changes in impulse control and visuomotor performance, respectively. In addition, fMRI examinations obtained at 12 h intervals were used to investigate changes in inter-regional connectivity. The EF experiment was associated with a reduced efficiency in impulse control, whereas DS led to a relative impairment in visuomotor control. A specific spatial and temporal correlation was observed between EEG theta waves occurring in task-related areas and deterioration of behavioral performance. The fMRI connectivity analysis indicated that performance impairment might partially depend on a breakdown in connectivity determined by a "network overload." Present results demonstrate the existence of an association between theta waves during wakefulness and performance errors and may contribute explaining behavioral impairments under conditions of sleep deprivation/restriction.

BACKGROUND: The neural mechanisms underlying fatigue in multiple sclerosis (MS) are still poorly understood. Cortico-cortical and cortico-subcortical circuitry abnormalities may play a central role in its pathogenesis. Our previous studies suggest that central fatigue may be related to an impairment of volition drive during movement preparation. OBJECTIVE: We further explored the central mechanisms of fatigue at the premovement level in MS patients during a sustained motor task. METHODS: In MS patients with (MS-F) and without (MS-NF) fatigue and age-matched healthy controls, we evaluated the motor cortex excitability and the premovement facilitation (PMF) through transcranial magnetic stimulation before and after 5min of sequenced finger-tapping movements at a fixed frequency of 2Hz. RESULTS: In MS-F patients, the number of correct sequences performed and the ability to keep a fixed movement rate during the 5-min motor task were significantly decreased in comparison to the normal controls and MS-NF patients. Also, in MS-F patients, post-exercise PMF was significantly decreased. The PMF abnormalities were highly correlated with the performance decay. CONCLUSIONS: PMF may be considered as a kind of servo-mechanism which could play a crucial role during sustained motor task in order to prevent motor performance disruption and to avoid motor exhaustion.

In previous studies of young subjects performing a reaction-time reaching task, we found that faster reaction times are associated with increased suppression of beta power over primary sensorimotor areas just before target presentation. Here we ascertain whether such beta decrease similarly occurs in normally aging subjects and also in patients with Parkinson's disease (PD), where deficits in movement execution and abnormalities of beta power are usually present. We found that in both groups, beta power decreased during the motor task in the electrodes over the two primary sensorimotor areas. However, before target presentation, beta decreases in PD were significantly smaller over the right than over the left areas, while they were symmetrical in controls. In both groups, functional connectivity between the two regions, measured with imaginary coherence, increased before the target appearance; however, in PD, it decreased immediately after, while in controls, it remained elevated throughout motor planning. As in previous studies with young subjects, the degree of beta power before target appearance correlated with reaction time. The values of coherence during motor planning, instead, correlated with movement time, peak velocity and acceleration. We conclude that planning of prompt and fast movements partially depends on coordinated beta activity of both sensorimotor areas, already at the time of target presentation. The delayed onset of beta decreases over the right region observed in PD is possibly related to a decreased functional connectivity between the two areas, and this might account for deficits in force programming, movement duration and velocity modulation.

BACKGROUND: In Parkinson's disease (PD), skill retention is poor, even when acquisition rate is generally preserved. Recent work in normal subjects suggests that 5 Hz-repetitive transcranial magnetic stimulation (5Hz-rTMS) may induce phenomena of long-term potentiation at the cortical level. OBJECTIVE/HYPOTHESIS: We thus verified whether, in PD, 5Hz-rTMS enhances retention of a visuo-motor skill that involves the activity of the right posterior parietal cortex. METHODS: A group of patients with PD was tested in two two-day sessions, separated by one week (treatment and placebo sessions). The first day of each session, they learned to adapt their movements to a step-wise 60 degrees visual rotation. Immediately after the task, either real 5Hz-rTMS (treatment) or sham (placebo) stimulation was applied over the right posterior parietal cortex (P6). Retention of this motor skill was tested the following day. RESULTS: In patients with PD, adaptation achieved at the end of training was comparable in the treatment and placebo sessions and was similar to that of a group of age-matched controls. However, retention indices tested on the following day were significantly lower in the placebo compared to the treatment session in which retention indices were restored to the level of the controls. Importantly, reaction and movement time as well as other kinematic measures were the same in the treatment and placebo sessions. CONCLUSION: These results suggest that rTMS applied after the acquisition of a motor skill over specific areas involved in this process might enhance skill retention in PD.

INTRODUCTION: Studies with diffusion tensor imaging (DTI) analysis have produced conflicting information about the involvement of the cerebellar hemispheres in Parkinson's disease (PD). We, thus, used a new approach for the analysis of DTI parameters in order to ascertain the involvement of the cerebellum in PD. METHODS: We performed a fiber tract-based analysis of cerebellar peduncles and cerebellar hemispheres in 16 healthy subjects and in 16 PD patients with more than 5 years duration of disease, using a 3T MRI scanner and a constrained spherical deconvolution (CSD) approach for tractographic reconstructions. In addition, we performed statistical analysis of DTI parameters and fractional anisotropy (FA) XYZ direction samplings. RESULTS: We found a statistically significant decrement of FA values in PD patients compared to controls (p < 0.05). In addition, extrapolating and analyzing FA XYZ direction samplings for each patient and each control, we found that this result was due to a stronger decrement of FA values along the Y axis (antero-posterior direction) (p < 0.01); FA changes along X and Z axes were not statistically significant (p > 0.05). We confirmed also no statistically significant differences of FA and apparent diffusion coefficient (ADC) for cerebellar peduncles in PD patients compared to healthy controls. CONCLUSIONS: The DTI-based cerebellar abnormalities in PD could constitute an advance in the knowledge of this disease. We demonstrated a statistically significant reduction of FA in cerebellar hemispheres of PD patients compared to healthy controls. Our work also demonstrated that the use of more sophisticated approaches in the DTI parameter analysis could potentially have a clinical relevance.

Several evidences in animal models have consistently an alteration of cortico-striatal plasticity, which is related to the degeneration of the substantia nigra. An alteration of plasticity have also been reported in humans by recording evoked field potentials in the substantia nigra pars reticulata of PD patients undergoing subthalamic nucleus (STN) stimulation where high-frequency (HF) in the OFF state did not induce a lasting change in field potential amplitude in the substantia nigra. In addition protocols of non-invasive brain stimulation, such as paired associative stimulation (PAS) and theta-burst stimulation (TBS), can be used to investigate cortical plasticity of the human primary motor cortex. Despite data reported in literature are apparently controversial with some studies showing a reduced or increased or even normal LTP and LTD like plasticity, recent evidences suggest the hypothesis that these different pat- terns of cortical plasticity likely depend on the stage of the disease and on the concomitant administration of L-DOPA. The current review will provide an up-to-date of these issues on cortical plasticity in PD discussing the clinical implications in rehabilitation. In addition in the last section we will review the state of art of non invasive neuro- modulation as adjuvant treatment in the advanced stage of the disease.

It has been proposed that synchronous and convergent afferent input arising from repetitive motor tasks may play an important role in driving the maladaptive cortical plasticity seen in focal hand dystonia (FHD). This hypothesis receives support from several sources. First, it has been reported that in subjects with FHD, paired associative stimulation produces an abnormal increase in corticospinal excitability, which was not confined to stimulated muscles. These findings provide support for the role of excessive plasticity in FHD. Second, the genetic contribution to the dystonias is increasingly recognized indicating that repetitive, stereotyped afferent inputs may lead to late-onset dystonia, such as FHD, more rapidly in genetically susceptible individuals. It can be postulated, according to the two factor hypothesis that dystonia is triggered and maintained by the concurrence of environmental factors such as repetitive training and subtle abnormal mechanisms of plasticity within somatosensory loop. In the present review, we examine the contribution of sensory-motor integration in the pathophysiology of primary dystonia. In addition, we will discuss the role of non-invasive brain stimulation as therapeutic approach in FHD.

BACKGROUND: Exercise may decrease the risk of Parkinson's disease (PD) in humans and reduce PD symptoms in animal models. The beneficial effects have been linked to increased levels of neurotrophic factors. OBJECTIVE: We examined whether intensive rehabilitation treatment reduces motor disability in patients in the early stages of PD and increases brain-derived neurotrophic factor (BDNF) serum levels. METHODS: Thirty participants in the early stages of PD treated with rasagiline were randomly assigned to 3 hours of rehabilitation treatment that included aerobic exercise for 28 days (Group 1) or to not therapy (control; Group 2). BDNF serum levels were assessed at time T0 (baseline, before treatment), T1 (10 days), T2 (20 days), and T3 (28 days). At T0 and T3, we assessed the Unified Parkinson's Disease Rating Scale (UPDRS) III in both groups, as well as the UPDRS II and total, Berg Balance Scale, and 6-minute walking test only in Group 1. RESULTS: BDNF levels significantly increased at T1 in Group 1, an increase that was maintained throughout the treatment period. At T3 compared to T0, UPDRS III scores significantly improved in Group 1 along with scores for UPDRS II, total, Berg Balance Scale, and 6-minute walking test. CONCLUSIONS: Intensive rehabilitation treatment increases the BDNF levels and improves PD signs in patients in the early stages of the disease. These results are in line with studies on animal models of PD and healthy subjects.