Luca Marsili

Excessive Daytime Sleepiness in Multiple System Atrophy (SLEEMSA Study)

BACKGROUND Sleep disorders are common in multiple system atrophy (MSA), but the prevalence of excessive daytime sleepiness (EDS) is not well known. OBJECTIVE To assess the frequency and associations of EDS in MSA. DESIGN Survey of EDS in consecutive patients with MSA and comparison with patients with Parkinson disease (PD) and individuals without known neurologic disease. SETTING Twelve tertiary referral centers. PARTICIPANTS Eighty-six consecutive patients with MSA; 86 patients with PD matched for age, sex, and Hoehn and Yahr stage; and 86 healthy subject individuals matched for age and sex. MAIN OUTCOME MEASURES Epworth Sleepiness Scale (ESS), modified ESS, Sudden Onset of Sleep Scale, Tandberg Sleepiness Scale, Pittsburgh Sleep Quality Index, disease severity, dopaminergic treatment amount, and presence of restless legs syndrome. RESULTS Mean (SD) ESS scores were comparable in MSA (7.72 [5.05]) and PD (8.23 [4.62]) but were higher than in healthy subjects (4.52 [2.98]) (P < .001). Excessive daytime sleepiness (ESS score >10) was present in 28% of patients with MSA, 29% of patients with PD, and 2% of healthy subjects (P < .001). In MSA, in contrast to PD, the amount of dopaminergic treatment was not correlated with EDS. Disease severity was weakly correlated with EDS in MSA and PD. Restless legs syndrome occurred in 28% of patients with MSA, 14% of patients with PD, and 7% of healthy subjects (P < .001). Multiple regression analysis (with 95% confidence intervals obtained using nonparametric bootstrapping) showed that sleep-disordered breathing and sleep efficiency predicted EDS in MSA and amount of dopaminergic treatment and presence of restless legs syndrome in PD. CONCLUSIONS More than one-quarter of patients with MSA experience EDS, a frequency similar to that encountered in PD. In these 2 conditions, EDS seems to be associated with different causes.

Dopamine Influences Primary Motor Cortex Plasticity and Dorsal Premotor-to-Motor Connectivity in Parkinson’s Disease

We investigated abnormal premotor to motor (PMd-to-M1) connectivity in Parkinsons disease (PD) with repetitive transcranial magnetic stimulation (rTMS). We studied 28 patients off and on dopaminergic therapy and 28 healthy subjects. We delivered 5 Hz rTMS over M1 before and after conditioning PMd with 5 Hz rTMS. In healthy subjects, motor-evoked potentials (MEPs) elicited by M1-rTMS were facilitated and PMd-rTMS left MEPs unchanged. In patients, before PMd-rTMS, M1-rTMS induced no MEP facilitation, whereas after PMd-rTMS, it significantly facilitated MEPs only when patients were on therapy. In the second experiment, we delivered M1-rTMS under 3 different attention-demanding tasks: eyes closed, attention directed to the stimulated hand, and attention directed to the nonstimulated hand. In healthy subjects, a more pronounced MEP facilitation was present when subjects directed attention to the stimulated hand. In patients, the MEP facilitation was present when attention was directed to the stimulated hand only when patients were on therapy. Finally, we delivered M1-rTMS in patients on therapy while they were looking at the stimulated hand, before and after 1 Hz PMd-rTMS. PMd-rTMS reduced the attention-induced MEP facilitation. We conclude that in addition to abnormal M1 plasticity, the reduced MEP facilitation in PD also reflects altered PMd-to-M1 connectivity.

Abnormal cortical and brain stem plasticity in Gilles de la Tourette syndrome

We investigated primary motor cortex and brain stem plasticity in patients with Gilles de la Tourette syndrome. The study group comprised 12 patients with Gilles de la Tourette syndrome and 24 healthy subjects. Patients were clinically evaluated using the Yale Global Tic Severity Scale. We tested cortical plasticity by conditioning left primary motor cortex with intermittent or continuous theta‐burst stimulation in 2 separate sessions. Test stimulation consisted of 20 motor‐evoked potentials recorded from right first interosseous muscle before and after theta‐burst stimulation. We also tested brain stem plasticity by conditioning the right supraorbital nerve with facilitatory electric high‐frequency stimulation delivered at the same time as the late response of the blink reflex or inhibitory high‐frequency stimulation delivered before the late response on 2 separate sessions. Test stimulation consisted of 10 blink reflexes from the right orbicularis oculi muscle before and after high‐frequency stimulation. After intermittent theta‐burst stimulation, motor‐evoked potential amplitudes in healthy subjects increased significantly but remained unchanged in patients. Similarly, after continuous theta‐burst stimulation, motor‐evoked potential amplitudes decreased significantly in healthy subjects but did not in patients. After facilitatory high‐frequency stimulation, the blink reflex late response area in healthy subjects increased, whereas after inhibitory high‐frequency stimulation, it decreased. Conversely, in patients, both interventions left the blink reflex late response area unchanged. The lack of the expected inhibitory and facilitatory changes in motor‐evoked potential amplitudes and blink reflex late response area suggests that abnormal plasticity in the primary motor cortex and brain stem play a role in the pathophysiology of Gilles de la Tourette syndrome.

Heat-Evoked Experimental Pain Induces Long-Term Potentiation-Like Plasticity in Human Primary Motor Cortex

We designed a new paired associative stimulation (PAS) protocol that combines experimental pain evoked by laser stimuli and transcranial magnetic stimulation (TMS) (Laser-PAS) to primary motor cortex (M1). We tested in healthy subjects whether Laser-PAS elicits cortical plasticity as reflected by long-term changes in motor-evoked potentials (MEPs) (after-effects). In separate experiments, we examined numerous variables including changes induced by varying the interstimulus intervals (ISIs) and Laser-PAS-induced changes in target and non-target muscle MEPs. We measured MEPs after repetitive laser or TMS (rTMS) pulses, and compared magnetic- and electric (TES)-induced MEPs. We tested MEPs after applying Laser-PAS with laser pulses ipsilaterally to M1. Finally, we studied subjects receiving an N-methyl-D-aspartate (NMDA) receptor antagonist (memantine) or placebo (α-lipoic acid). During Laser-PAS at the 50 ms ISI MEPs decreased, thereafter they increased for 60 min; other ISIs induced no after-effects. The after-effects remained restricted to the target muscle. Repetitive laser pulses and rTMS induced no after-effects. After Laser-PAS, TMS-induced MEPs increased, whereas TES-induced MEPs did not. Laser-PAS with laser pulses ipsilaterally to M1 left MEPs unchanged. Memantine, but not α-lipoic acid, abolished the after-effects. In conclusion, Laser-PAS elicits NMDA-dependent cortical plasticity and provides new insights into human pain-motor integration.

Cortical and brainstem plasticity in Tourette syndrome and obsessive-compulsive disorder.

Gilles de la Tourette syndrome is characterized by motor/vocal tics commonly associated with psychiatric disorders, including obsessive‐compulsive disorder. We investigated primary motor cortex and brainstem plasticity in Tourette patients, exposed and unexposed to chronic drug treatment, with and without psychiatric disturbances. We also investigated primary motor cortex and brainstem plasticity in obsessive‐compulsive disorder. We studied 20 Tourette patients with and without psychiatric disturbances, 15 with obsessive‐compulsive disorder, and 20 healthy subjects. All groups included drug‐naïve patients. We conditioned the left primary motor cortex with intermittent/continuous theta‐burst stimulation and recorded motor evoked potentials. We conditioned the supraorbital nerve with facilitatory/inhibitory high‐frequency stimulation and recorded the blink reflex late response area. In healthy subjects, intermittent theta‐burst increased and continuous theta‐burst stimulation decreased motor evoked potentials. Differently, intermittent theta‐burst failed to increase and continuous theta‐burst stimulation failed to decrease motor evoked potentials in Tourette patients, with and without psychiatric disturbances. In obsessive‐compulsive disorder, intermittent/continuous theta‐burst stimulation elicited normal responses. In healthy subjects and in subjects with obsessive‐compulsive disorder, the blink reflex late response area increased after facilitatory high‐frequency and decreased after inhibitory high‐frequency stimulation. Conversely, in Tourette patients, with and without psychiatric disturbances, facilitatory/inhibitory high‐frequency stimulation left the blink reflex late response area unchanged. Theta‐burst and high‐frequency stimulation elicited similar responses in drug‐naïve and chronically treated patients. Tourette patients have reduced plasticity regardless of psychiatric disturbances. These findings suggest that abnormal plasticity contributes to the pathophysiology of Gilles de la Tourette syndrome. However, obsessive‐compulsive disorder patients have normal cortical and brainstem plasticity.

Bradykinesia of posed smiling and voluntary movement of the lower face in Parkinson's disease

OBJECTIVE Impaired facial expression, including spontaneous and emotional movements such as smiling, has been often reported in Parkinsons disease (PD). There is a general consensus that spontaneous smiling is abnormal in PD. Investigations on posed smiling yield contrasting results. Moreover, no study has yet addressed the relationship between posed smiling and abnormalities of voluntary movements of the lower face, global motor impairment and the effects of dopaminergic medication. METHODS We investigated the kinematics of posed smiling (mimicking a smile shown in a picture) and those of voluntary movements of the lower face (showing the teeth as fast as possible - voluntary grinning) in 15 patients with PD (ON and OFF therapy) and in 16 healthy controls. Facial movements were recorded using a 3D optoelectronic system and analyzed using dedicated software. RESULTS Some kinematic parameters of both posed smiling and voluntary grinning were abnormally lower in PD patients in comparison to healthy subjects. The kinematics of posed smiling correlated with those of voluntary grinning in PD patients but not in healthy controls. Posed smiling and voluntary grinning abnormalities were related to global motor severity but did not significantly improve upon L-dopa administration. CONCLUSIONS These results suggest that posed smiling and voluntary grinning are both abnormal in PD patients and that they are likely mediated by a common pathophysiological mechanism.

Electrical activation of the orbicularis oculi muscle does not increase the effectiveness of botulinum toxin type A in patients with blepharospasm

Background:  Our primary aim in this study was to determine whether electrically induced activation of the injected muscle increases effectiveness of botulinum type A toxin (BonT‐A) in patients with blepharospasm (BPS). The second aim was to assess the safety of BonT‐A by investigating whether BonT‐A injection alters the excitability of blink reflex circuits in the brainstem.

Altered Kinematics of Facial Emotion Expression and Emotion Recognition Deficits Are Unrelated in Parkinson’s Disease

Background Altered emotional processing, including reduced emotion facial expression and defective emotion recognition, has been reported in patients with Parkinson’s disease (PD). However, few studies have objectively investigated facial expression abnormalities in PD using neurophysiological techniques. It is not known whether altered facial expression and recognition in PD are related. Objective To investigate possible deficits in facial emotion expression and emotion recognition and their relationship, if any, in patients with PD. Methods Eighteen patients with PD and 16 healthy controls were enrolled in this study. Facial expressions of emotion were recorded using a 3D optoelectronic system and analyzed using the facial action coding system. Possible deficits in emotion recognition were assessed using the Ekman test. Participants were assessed in one experimental session. Possible relationship between the kinematic variables of facial emotion expression, the Ekman test scores, and clinical and demographic data in patients were evaluated using the Spearman’s test and multiple regression analysis. Results The facial expression of all six basic emotions had slower velocity and lower amplitude in patients in comparison to healthy controls (all Ps < 0.05). Patients also yielded worse Ekman global score and disgust, sadness, and fear sub-scores than healthy controls (all Ps < 0.001). Altered facial expression kinematics and emotion recognition deficits were unrelated in patients (all Ps > 0.05). Finally, no relationship emerged between kinematic variables of facial emotion expression, the Ekman test scores, and clinical and demographic data in patients (all Ps > 0.05). Conclusion The results in this study provide further evidence of altered emotional processing in PD. The lack of any correlation between altered facial emotion expression kinematics and emotion recognition deficits in patients suggests that these abnormalities are mediated by separate pathophysiological mechanisms.

Blinking in patients with clinically probable multiple system atrophy

Clinical studies in patients with MSA document facial motor abnormalities, but no studies have objectively assessed blinking abnormalities in this condition.

Therapeutic interventions in parkinsonism: Corticobasal degeneration

Corticobasal degeneration (CBD) is a progressive neurodegenerative disorder resulting from pathological accumulation of tau protein and is included in the spectrum of Atypical Parkinsonism. The typical clinical phenotype of CBD is characterized by the Corticobasal syndrome (CBS). In recent years it has become clear that the clinical picture of CBS may be caused by different pathological conditions, resulting in frequent misdiagnosis. CBD has high morbidity and poor prognosis with no effective therapies. In this review, we will discuss the symptomatic treatment, the palliative care and the disease modifying strategies currently in use. Symptomatic treatment in patients with CBD may sometimes be useful for improving motor (parkinsonism, dystonia and myoclonus) and non-motor (cognitive-behavioral) symptoms, but the effects are often unsatisfactory. In addition, non-pharmacological strategies and palliative care are useful integrating components of the multidisciplinary therapeutic approach for patients with CBD. Despite many efforts, a disease-modifying treatment is still unavailable for CBD.