A 15-day course of donepezil modulates spectral EEG dynamics related to target auditory stimuli in young, healthy adult volunteers.

OBJECTIVE: To identify possible electroencephalographic (EEG) markers of donepezil's effect on cortical activity in young, healthy adult volunteers at the group level. METHODS: Thirty subjects were administered a daily dose of either 5mg donepezil or placebo for 15days in a double-blind, randomized, cross-over trial. The electroencephalogram during an auditory oddball paradigm was recorded from 58 scalp electrodes. Current source density (CSD) transformations were applied to EEG epochs. The event-related potential (ERP), inter-trial coherence (ITC: the phase consistency of the EEG spectrum) and event-related spectral perturbation (ERSP: the EEG power spectrum relative to the baseline) were calculated for the target (oddball) stimuli. RESULTS: The donepezil and placebo conditions differed in terms of the changes in delta/theta/alpha/beta ITC and ERSP in various regions of the scalp (especially the frontal electrodes) but not in terms of latency and amplitude of the P300-ERP component. CONCLUSION: Our results suggest that ITC and ERSP analyses can provide EEG markers of donepezil's effects in young, healthy, adult volunteers at a group level. SIGNIFICANCE: Novel EEG markers could be useful to assess the therapeutic potential of drug candidates in Alzheimer's disease in healthy volunteers prior to the initiation of Phase II/III clinical studies in patients.

A functional magnetic resonance imaging investigation of theory of mind impairments in patients with temporal lobe epilepsy.

Although patients with mesial temporal lobe epilepsy (mTLE) are known to have theory of mind (ToM) impairments, the latter's neural functional bases have yet to be explored. We used functional magnetic resonance imaging (fMRI) to gain insights into the neural dysfunction associated with ToM impairments in patients with mTLE. Twenty-five patients (12 and 13 with right and left mTLE, respectively) and 25 healthy controls performed the "animated shapes" task during fMRI. This complex ToM task requires both explicit reasoning about mental states and implicit processing of information on biological motion and action. The animated shapes evoke both ToM and non-ToM interaction perception, and the corresponding neural activation patterns were compared. Behavioral performance (i.e. categorization of the interactions) was also recorded. Relative to healthy controls, both patients with right and left mTLE were impaired in categorizing ToM interactions. The fMRI results showed that both patients with right and left mTLE had less intense neural activation (relative to controls) in regions involved in the implicit component of ToM processes (i.e. the fusiform gyrus in patients with right mTLE and the supplementary motor area in patients with left mTLE). In patients with right mTLE, we also observed more intense activation (relative to controls) in regions involved in the explicit component of ToM processes (i.e. the dorsal medial prefrontal cortex); age at onset of epilepsy also mediated activation in regions involved in the explicit component (i.e. the ventral medial prefrontal cortex and the temporoparietal junction). Patients with left mTLE displayed greater activation of the contralateral mesial regions (relative to controls); we speculate that this may correspond to the deployment of a compensatory mechanism. This study provides insights into the disturbances of the implicit/explicit ToM neural network in patients with mTLE. These impairments in the ToM neural network depend on clinical characteristics, such as the laterality (right or left mTLE) and the age at onset of epilepsy.

Hallucinations and conscious access to visual inputs in Parkinson's disease.

The pathophysiology of visual hallucinations in Parkinson's disease has yet to be characterized. Although stimulus-driven ("bottom-up") processes are known to be impaired, the role of "top-down" processes remains to be determined. Distinguishing between conscious and non-conscious detections (i.e. access to consciousness) may be a valuable way of monitoring top-down processes. Conscious access to visual inputs was investigated to identify the neural substrates underlying susceptibility to hallucinations in Parkinson's disease. Seventeen healthy controls, 18 Parkinson's disease patients with minor visual hallucinations and 16 without were enrolled in the study. During functional magnetic resonance imaging, the participants performed a visual detection task. The detection threshold was significantly higher in each patient group than in healthy controls while the two groups of patients did not differ significantly. Compared with hallucination-free patients, patients with minor hallucinations displayed hyperactivation of prefrontal and right occipital cortices, and hypoactivation of the left cingulate, temporal and occipital cortices. During conscious access to visual inputs, the functional network in patients with visual hallucinations differed from that seen in patients without visual hallucinations. This suggests that the supremacy of top-down processes in visual information processing may enhance susceptibility to hallucinations in Parkinson's disease.

Cognitive disorders in Parkinson's disease: Confirmation of a spectrum of severity.

INTRODUCTION: Clinical presentation and progression of cognitive disorders in Parkinson's disease (PD) is heterogeneous. Our objective was to confirm prospectively a previous exploratory cluster analysis based on retrospective data that identified five cognitive phenotypes in PD. METHODS: A model-based confirmatory cluster analysis was conducted on the results of neuropsychological tests administered in 156 PD patients from two European movement disorder centers (Lille, n = 81; Maastricht, n = 75). The number of clusters was determined on the basis of statistical criteria as well as clinical plausibility. A factorial discriminant analysis assessed the quality of the clusters' separation. RESULTS: A five-cluster model was statistically superior and clinically the most relevant. These clusters can be described as follows: 1) cognitively intact patients with high level of performance in all cognitive domains (25.64%), 2) cognitively intact patients slightly slower than those in cluster 1 (26.92%), 3) patients with deficits in executive functions (37.18%), 4) patients with severe deficits in all cognitive domains, particularly executive functions (3.20%), 5) patients with severe deficits in all cognitive domains, particularly working memory and recall in verbal episodic memory (7.05%). The groups differed in terms of age, apathy and frequency of hallucinations that were all higher in the clusters with cognitive deficits, and the duration of formal education was lower in those groups. CONCLUSION: We confirm our previous exploratory analysis. Cognitive disorders in PD patients are heterogeneous and can be separated in five clusters ranging from patients with performance in the normal range to patients with severe disorders in all cognitive domains.

Apathy in untreated early-stage Parkinson disease: relationship with other non-motor symptoms.

Apathy is a frequent and disabling behavioral disorder in patients with Parkinson's disease (PD). Its prevalence in treatment-naive patients with early-stage PD has not been extensively investigated. Moreover, whether apathy is related to other non-motor symptoms in early-stage PD is unknown. Our objective was to determine the prevalence and features of apathy and associated factors in a group of treatment-naive patients with early-stage PD. Ninety-five treatment-naive patients with early-stage PD participated in the study. Apathy, depression, motor symptoms, and overall cognitive efficiency were assessed. The presence of the main non-motor symptoms was checked during a detailed clinical interview. Group comparisons were carried out to investigate the association with apathy. Eighteen patients (18.95%) were diagnosed as apathetic, and five of the latter had concomitant depression. Apathetic patients had significantly more severe motor symptoms (P < 0.001) and a lower cognitive status (P = 0.032) than non-apathetic patients. When considering non-motor symptoms, apathy was significantly associated only with fatigue (P = 0.007) and anhedonia (P = 0.010), both of which were more prevalent in apathetic patients than in non-apathetic patients. In treatment-naive patients with early-stage PD, apathy was significantly associated with more severe motor symptoms and a lower cognitive status. After adjustment for these factors, apathy appeared to be a relatively isolated, independent symptom because the only other associated non-motor symptoms were fatigue and anhedonia.

Impaired visual perception in rapid eye movement sleep behavior disorder.

OBJECTIVE: Patients with idiopathic REM sleep behavior disorder (iRBD) often develop synucleinopathies (Parkinson's disease [PD], in particular). Cognitive disorders affecting different domains have been reported in patients with iRBD. Dysexecutive disorders seem to predominate, but there is no consensus on the nature of visuospatial disorders in iRBD. The objective is to identify and characterize visuospatial disorders in patients with REM sleep behavior disorder (RBD - either idiopathic or associated with PD). METHODS: Fifteen patients with iRBD, 30 patients with PD (15 of whom had RBD), and 20 healthy control subjects underwent an extensive assessment of visuospatial functions. Two computerized tasks were used: a Biederman task (to assess the 3 levels of visuoperceptive processing) and a Posner paradigm (to assess visual attention). RESULTS: The visual priming effects classically described for the Biederman task in healthy controls were not found in iRBD patients. Patients with iRBD were no quicker in naming objects with the same general structure as previously presented objects but did have a normal priming effect for strictly identical objects. Parkinson's disease patients with RBD had poorer visuoperceptive performance levels than PD patients without RBD. There were no significant differences between the 4 groups in the Posner attentional task. CONCLUSIONS: First, this study confirms the presence of visuoperceptive dysfunction in iRBD patients and revealed a selective defect in intermediate visuoperceptive processing (i.e., general object representation). Second, RBD in PD appeared to be associated with poorer visuoperceptive abilities. Third, this visuoperceptive dysfunction in RBD patients was not associated with impaired attention.

Rapid eye movement sleep behavior disorder in treatment-naïve Parkinson disease patients.

OBJECTIVE: Rapid eye movement (REM) sleep behavior disorder (RBD) is a risk factor for dementia in Parkinson disease (PD) patients. The objectives of our study were to prospectively evaluate the frequency of RBD in a sample of treatment-naïve, newly diagnosed PD patients and compare sleep characteristics and cognition in RBD and non-RBD groups. METHODS: Fifty-seven newly diagnosed PD patients were consecutively recruited in a university medical center. All patients underwent two overnight polysomnography (PSG) sessions and were diagnosed with RBD according to the International Classification of Sleep Disorders, Second Revision criteria. Daytime sleepiness was measured in a multiple sleep latency test (MSLT). Cognition was assessed in a standard neuropsychologic examination. RESULTS: Seventeen PD patients (30%) met the criteria for RBD. The RBD patients and non-RBD patients did not significantly differ in mean age, gender ratio, disease duration, motor symptom subtype and severity, total sleep time, percentage of REM sleep, apnea-hypopnea index, mean oxygen saturation, and importantly cognitive performance. However, non-RBD patients had a significantly shorter mean daytime sleep latency than RBD patients (15 vs. 18 min, respectively; P=.014). CONCLUSION: A high frequency of RBD was found in our sample of 57 newly diagnosed PD patients. At this stage in the disease, RBD was not found to be associated with other sleep disorders or cognitive decline. Follow-up is needed to assess the risk for developing dementia in early-stage PD patients with RBD.

Effect of intermittent theta-burst stimulation on akinesia and sensorimotor integration in patients with Parkinson's disease.

High-frequency (HF) repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex (M1) has been shown to reduce akinesia in Parkinson's disease (PD). Given that the processing of sensory afferents is deficient in PD and might be involved in akinesia, we sought to determine whether or not the application of very HF rTMS [intermittent theta-burst stimulation (iTBS) protocol] over the M1 affected sensorimotor integration (SMI) and akinesia. The experiments were carried out in: (i) 11 patients taking their usual dopaminergic treatment ('on-drug'); (ii) eight of the latter patients after withdrawal of dopaminergic treatment ('off-drug'); and (iii) 10 de novo (drug-naive) patients. Sham stimulation was applied in 11 other patients in the 'on-drug' condition. SMI was investigated by conditioning a supra-threshold transcranial magnetic stimulation pulse in the motor region controlling the abductor pollicis brevis with a nerve shock over the median nerve at time intervals corresponding to short- and long-latency afferent inhibition (SAI and LAI) and afferent-induced facilitation (AIF). Akinesia was assessed with a pointing test. In on-drug, off-drug and de novo patients, akinesia in the contralateral arm was lower after iTBS. Sham stimulation had no effect. In on-drug patients (but not other groups), SMI was also influenced by iTBS, with an increase in AIF. No changes in SAI and LAI were observed. Our data suggest that iTBS might improve both akinesia and sensory processing in patients with PD taking levodopa.