An Alzheimer Disease Challenge Model: 24-Hour Sleep Deprivation in Healthy Volunteers, Impact on Working Memory, and Reversal Effect of Pharmacological Intervention: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study.

PURPOSE/BACKGROUND: Alzheimer disease (AD) is a public health issue because of the low number of symptomatic drugs and the difficulty to diagnose it at the prodromal stage. The need to develop new treatments and to validate sensitive tests for early diagnosis could be met by developing a challenge model reproducing cognitive impairments of AD. Therefore, we implemented a 24-hour sleep deprivation (SD) design on healthy volunteers in a randomized, double-blind, placebo-controlled, crossover study on 36 healthy volunteers. METHODS/PROCEDURE: To validate the SD model, cognitive tests were chosen to assess a transient worsening of cognitive functions after SD and a restoration under modafinil as positive control (one dose of 200 mg). Then, the same evaluations were replicated after 15 days of donepezil (5 mg/d) or memantine (10 mg/d). The working memory (WM) function was assessed by the N-back task and the rapid visual processing (RVP) task. FINDINGS/RESULTS: The accuracy of the N-back task and the reaction time of the RVP revealed the alteration of the WM with SD and its restoration with modafinil (changes in score after SD compared with baseline before SD), respectively, in the placebo group and in the modafinil group (-0.2% and +1.0% of satisfactory answers, P = 0.022; +21.3 and +1.9 milliseconds of reaction time, P = 0.025). Alzheimer disease drugs also tended to reverse this deterioration: the accuracy of the N-back task was more stable through SD (compared with -3.0% in the placebo group, respectively, in the memantine group and in the donepezil group: -1.4% and -1.6%, P = 0.027 and P = 0.092) and RVP reaction time was less impacted (compared with +41.3 milliseconds in the placebo group, respectively, in the memantine group and in the donepezil group: +16.1 and +29.3 milliseconds, P = 0.034 and P = 0.459). IMPLICATIONS/CONCLUSIONS: Our SD challenge model actually led to a worsening of WM that was moderated by both modafinil and AD drugs. To use this approach, the cognitive battery, the vulnerability of the subjects to SD, and the expected drug effect should be carefully considered.

Core Competencies in Clinical Neuropsychology as a Training Model in Europe.

The multitude of training models and curricula for the specialty of clinical neuropsychology around the world has led to organized activities to develop a framework of core competencies to ensure sufficient expertise among entry-level professionals in the field. The Standing Committee on Clinical Neuropsychology of the European Federation of Psychologists' Associations is currently working toward developing a specialty certification in clinical neuropsychology to establish a cross-national standard against which to measure levels of equivalency and uniformity in competence and service provision among professionals in the field. Through structured interviews with experts from 28 European countries, we explored potential areas of core competency. Specifically, questions pertained to the perceived importance of a series of foundational, functional, and other competencies, as well as current training standards and practices, and optimal standards. Our findings revealed considerable agreement (about three quarters and above) on academic and clinical training, despite varied actual training requirements currently, with fewer respondents relegating importance to training in teaching, supervision, and research (a little over half), and even fewer to skills related to management, administration, and advocacy (fewer than half). European expert clinical neuropsychologists were in agreement with previous studies (including those conducted in the United States, Australia, and other countries) regarding the importance of sound theoretical and clinical training but management, administrative, and advocacy skills were not central to their perspective of a competent specialist in clinical neuropsychology. Establishing a specialty certificate in clinical neuropsychology based on core competencies may enable mobility of clinical neuropsychologists across Europe, and, perhaps, provide an impetus for countries with limited criteria to reconsider their training requirements and harmonize their standards with others.

Neuropsychology in France.

The purpose of this study was to investigate sociodemographic characteristics, clinical and academic training, and the types of activities engaged in by practicing psychologists specialized in neuropsychology in France. A total of 804 French psychologists specializing in neuropsychology participated in an online-based survey: 90.2% of the participants were women, with a mean age of 32 (range 22-60). In the total sample, 54.2% of the participants worked in the hospital system, 38.2% in the private sector, and 24.9% had a private practice job; and 97.3% engage in evaluation, 74% in rehabilitation, 22.1% in research, and 35.8% in teaching. Clinicians primarily work with individuals with stroke/vascular (56.7%), dementia (53.3%), depression (36.7%), and learning disabilities (34.5%). The top perceived barriers to the field include: lack of willingness to collaborate between professionals (43.7%), lack of professional leaders in the field (40.7%), and lack of clinical training opportunities (24.9%). A total of 68.9% of the clinicians indicate that normative data for their countries do not exist. It is essential for psychologists specialized in neuropsychology in France to establish better-defined guidelines for academic and clinical education, since there is no legal protection of the specialty and given that needs for neuropsychological services are increasing.

European Clinical Neuropsychology: Role in Healthcare and Access to Neuropsychological Services.

This study analyzed aspects of the work of clinical neuropsychologists across Europe. There are no published comparisons between European countries regarding the nature of clinical neuropsychologists' work. Forty-one national psychological and neuropsychological societies were approached, of which 31 (76%) responded. Data from seven countries with less than 10 neuropsychologists were excluded. A license is required to practice clinical neuropsychology in 50% of the countries. Clinical neuropsychologists work independently in 62.5%. Diagnostic/assessment work is the most frequently reported activity (54%). Most neuropsychologists work in public hospitals, followed by health centers. Adult neuropsychology was the most frequent area of activity. Services in public institutions are covered by public entities (45.8%), or by a combination of patient funds and public entities (29.2%) and only 4.2% by the patient; whereas services in private institutions are covered by the patient (26.1%) and the combination of patient, public entities (21.7%) or patient and private entities (17.4%). The data suggest that the number of neuropsychologists working across European countries is considerably low in comparison to other medical professionals. The results of the survey identified similar aspects of neuropsychologists' work, despite variations in terms of reimbursement and mechanisms, reflecting economic and healthcare differences. Estimates on the number of clinical neuropsychologists suggest insufficient access to neuropsychological services.

Clinical Neuropsychology as a Specialist Profession in European Health Care: Developing a Benchmark for Training Standards and Competencies Using the Europsy Model?

The prevalence and negative impact of brain disorders are increasing. Clinical Neuropsychology is a specialty dedicated to understanding brain-behavior relationships, applying such knowledge to the assessment of cognitive, affective, and behavioral functioning associated with brain disorders, and designing and implementing effective treatments. The need for services goes beyond neurological diseases and has increased in areas of neurodevelopmental and psychiatric conditions, among others. In Europe, a great deal of variability exists in the education and training of Clinical Neuropsychologists. Training models include master's programs, continuing education courses, doctoral programs, and/or post-doctoral specialization depending on the country, with no common framework of requirements, although patients' needs demand equal competencies across Europe. In the past 5 years, the Standing Committee on Clinical Neuropsychology of the European Federation of Psychologists' Association has conducted a series of surveys and interviews with experts in the field representing 30 European countries. The information, along with information from the existing literature, is used in presenting an overview of current and relevant topics related to policy and guidelines in the training and competencies in Clinical Neuropsychology. An option for the way forward is the EuroPsy Specialist Certificate, which is currently offered in Work and Organizational Psychology, and in psychotherapy. It builds upon the basic certificate and complements national standards without overriding them. General principles can be found that can set the basis for a common, solid, and comprehensive specialty education/training, sharpening the Neuropsychologists' competencies across Europe. The requirements in Clinical Neuropsychology should be comparable to those for the existing specialty areas in the EuroPsy model. Despite the perceived challenges, developing a specialist certificate appears a step forward for the development of Clinical Neuropsychology. Recommendations are proposed toward a shared framework of competencies by the means of a common level of education/training for the professionals in Europe. Benchmarking training standards and competencies across Europe has the potential of providing protection against unqualified and ethically questionable practice, creating transparency, raising the general European standard, and promoting mobility of both Clinical Neuropsychologists and patients in Europe, for the benefit of the professional field and the population.

Recovery from cortical blindness with mepivacaïne.

We report the case of a patient suffering from cortical blindness following bilateral occipital stroke, who recovered normal vision in his right visual field following injection of the local anesthetic mepivacaïne. The effect was transient but reproducible, allowing the patient to lead a normal life. Effect duration increased after adjunction of paroxetine. We provide anatomical and functional brain imaging correlates of this improvement, showing particularly how functional connectivity is restored between intact perilesional cortex and distant brain regions. This serendipitous finding may potentially benefit patients suffering from visual but also nonvisual handicap following brain lesions.

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.

Influence of Medication on Fatigue Six Months after Stroke.

Poststroke fatigue (PSF) is frequent and affects patients' quality of life. Medication use was hypothesized as being responsible for PSF. Our objective was to evaluate potential relationships between 6-month PSF and medication use at discharge and 6 months after an ischemic stroke. This study is part of STROKDEM, an ongoing longitudinal cohort study, whose main aim is to determine predictors of poststroke dementia. Patients were included within 72 hours after an ischemic stroke and followed up with standardized evaluations. Medication use 7 days and 6 months after stroke was rated, and polypharmacy was defined as the number of categories of treatments received by a patient. PSF was evaluated using the Chalder Fatigue Scale. Medical history, vascular risk factors, depression, anxiety, and sleep disturbances were evaluated. One hundred and fifty-three patients were included: 52.9% presented PSF. PSF at 6 months was not predicted by medication use at discharge nor associated with medication use at month 6. We found severity of PSF to be increased in patients with polypharmacy. Our results suggest that PSF is not a side effect of drugs use, which more reflects presence of disturbances frequently observed after stroke such as depression, anxiety, or sleep disturbances. Clinical study is registered on clinicaltrials.gov (NCT01330160).

Factors Associated with Poststroke Fatigue: A Systematic Review.

Background. Poststroke fatigue (PSF) is a frequent, disabling symptom that lacks a consensual definition and a standardized evaluation method. The (multiple) causes of PSF have not been formally characterized. Objective. To identify factors associated with PSF. Method. A systematic review of articles referenced in MEDLINE. Only original studies having measured PSF and potentially associated factors were included. Data was extracted from articles using predefined data fields. Results. Although PSF tends to be more frequent in female patients and older patients, sociodemographic factors do not appear to have a major impact. There are strong associations between PSF and emotional disturbances (such as depression and anxiety). PSF may also be linked to attentional disturbances (mainly slowing in processing speed). The literature data have failed to demonstrate a clear impact of the type and severity of stroke. It has been suggested that PSF results from alterations in the frontothalamostriatal system and/or inflammatory processes. Pain, sleep disorders, and prestroke fatigue also appeared to be associated with PSF. Implications. A better understanding of PSF may improve stroke patient care and facilitate the development of effective treatments.

Donepezil increases contrast sensitivity for the detection of objects in scenes.

We assessed the effects of donepezil, a drug that stimulates cholinergic transmission, and scopolamine, an antagonist of cholinergic transmission, on contrast sensitivity. 30 young male participants were tested under three treatment conditions: placebo, donepezil, and scopolamine in a random order. Pairs of photographs varying in contrast were displayed left and right of fixation for 50 ms. Participants were asked to locate the scene containing an animal. Accuracy was better under donepezil than under scopolamine, particularly for signals of high intensity (at higher levels of contrast). A control experiment showed that the lower performance under scopolamine did not result from the mydriasis induced by scopolamine. The results suggest that cholinergic stimulation, through donepezil, facilitates signal detection in agreement with studies on animals showing that the pharmacological activation of cholinergic receptors controls the gain in the relationship between the stimulus contrast (intensity of the visual input) and visual response. As Alzheimer disease is associated to depletion in acetylcholine, and there is evidence of deficits in contrast sensitivity in Alzheimer, it might be interesting to integrate such rapid and sensitive visual tasks in the biomarkers at early stage of drug development.

Cholinergic modulation of stimulus-driven attentional capture.

Distraction is one of the main problems encountered by people with degenerative diseases that are associated with reduced cortical cholinergic innervations. We examined the effects of donepezil, a cholinesterase inhibitor, on stimulus-driven attentional capture. Reflexive attention shifts to a distractor are usually elicited by abrupt peripheral changes. This bottom-up shift of attention to a salient item is thought to be the result of relatively inflexible hardwired mechanisms. Thirty young male participants were randomly allocated to one of two groups: placebo first/donepezil second session or the opposite. They were asked to locate a target appearing above and below fixation whilst a peripheral distractor moved abruptly (motion-jitter attentional capture condition) or not (baseline condition). A classical attentional capture effect was observed under placebo: moving distractors interfered with the task in slowing down response times as compared to the baseline condition with fixed distractors. Increased interference from moving distractors was found under donepezil. We suggest that attentional capture in our paradigm likely involved low level mechanisms such as automatic reflexive orienting. Peripheral motion-jitter elicited a rapid reflexive orienting response initiated by a cholinergic signal from the brainstem pedunculo-pontine nucleus that activates nicotinic receptors in the superior colliculus.