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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.

Objective It has been reported that sleep deprivation affects the neurophysiological mechanisms underpinning the vigilance. Here, we tested the following hypotheses in the PharmaCog project ( www.pharmacog.org ): (i) sleep deprivation may alter posterior cortical delta and alpha sources of resting state eyes-closed electroencephalographic (rsEEG) rhythms in healthy young adults; (ii) after the sleep deprivation, a vigilance enhancer may recover those rsEEG source markers. Methods rsEEG data were recorded in 36 healthy young adults before (Pre-sleep deprivation) and after (Post-sleep deprivation) one night of sleep deprivation. In the Post-sleep deprivation, these data were collected after a single dose of PLACEBO or MODAFINIL. rsEEG cortical sources were estimated by eLORETA freeware. Results In the PLACEBO condition, the sleep deprivation induced an increase and a decrease in posterior delta (2–4 Hz) and alpha (8–13 Hz) source activities, respectively. In the MODAFINIL condition, the vigilance enhancer partially recovered those source activities. Conclusions The present results suggest that posterior delta and alpha source activities may be both related to the regulation of human brain arousal and vigilance in quiet wakefulness. Significance Future research in healthy young adults may use this methodology to preselect new symptomatic drug candidates designed to normalize brain arousal and vigilance in seniors with dementia.

To this day, the pharmacological treatment of Alzheimer's disease remains limited to the temporary stabilisation of cognitive decline and the reduction of neuropsychiatric symptoms. It is moreover with great difficulty to predict and select promising drug candidates in the early stages of the discovery and developmental process. In this context, scientists have developed new experimental paradigms to artificially induce transient cognitive impairments in healthy volunteers akin to those observed in Alzheimer's disease, i.e. the Cognitive Challenge Models. In the last decade, a great amount of literature on Sleep Deprivation was published which mainly focused on the consequences of sleep loss for public health. However, sleep deprivation paradigm may also be regarded as a cognitive challenge model. It is commonly accepted that sleep deprivation induces cognitive impairments related to a global decrease in vigilance, while in fact, there is a controversial approach related to the selective effects on cognitive functions. The identification and validation of cognitive challenge models in healthy volunteers are suitable in early clinical development of drugs to determine the 'hint of efficacy' of drug candidates. The present review aims at exploring in detail the methods, designs and cognitive paradigms used in non pharmacological sleep deprivation studies. Sleep deprivation can be induced by different methods. Probing the four main cognitive functions will allow identifying the extent to which different sleep deprivation designs selectively compromise executive function, working memory, episodic memory and attention. Findings will be discussed in line with cognitive processing levels that are required according to the tasks.

Empirical evidence currently supports the idea that neurovascular dysfunction is involved in the neurodegenerative process of Alzheimer's disease (AD). In fact, epidemiological studies report that i) vascular risk factors are directly associated with an increased incidence of AD and ii) vascular lesions are frequently co-existent with AD. The neurovascular unit is a key control system for oxygen and nutrients exchange between neurons and microvessels so the integrity of this system is essential for neuronal activity and cell survival. This suggests that hypoxia arising from various vascular injuries may participate in the pathogenesis of AD and aggravate cognitive deficit. Moreover, hypoxia appears to have a direct effect on cognitive functions, in particular memory, by inducing a transient or definitive dysfunction of synaptic transmission. The interplay of hypoxic phenomenon and the development of AD-related pathologies support the use of hypoxia as a challenge model to assess symptomatic (i.e. cognitive enhancers) AD-treatment. Such challenge should be characterized and validated with current symptomatic drugs based on different mechanisms of action before being offered as alternative models for testing new drugs. To date, symptomatic treatments of AD including anticholinesterasic- (donepezil, rivastigmine and galantamine) and antiglutamatergic- (memantine) drugs target various neurotransmission impairments occurring at different stages of the disease. The first aim of the present review is to provide an overview of the methods used to achieve experimental hypoxia in rodents and to characterize the cognitive alterations induced by each method. The second objective is to summarize the main results from studies that have tested the effect of acetylcholinesterase inhibitors on hypoxiainduced cognitive impairment. Overall, the literature research yielded only a small number of studies investigating the effect of hypoxia on cognition in rodents and the different models described sometime differ substantially in terms of timing, severity and nature of cognitive impairment. Chronic exposure to intermittent normobaric or continuous hypobaric hypoxia induced persistent spatial reference and working memory alterations. In contrast, acute hypoxia exposure was shown to induce more transient associative and spatial memory impairments. Treatment with acetylcholinesterase inhibitors was shown to improve hypoxia-induced memory impairment in various hypoxia protocols.

The early assessment of new symptomatic drugs against Alzheimer's disease remains difficult because of the lack of a predictive end-point. The use of a battery including different parameters could improve this early development. In order to test the reverse effect of symptomatic drugs in healthy volunteers, scientists have developed new experimental paradigms to artificially induce transient cognitive impairments in healthy volunteers akin to those observed in Alzheimer's disease, i.e. Cognitive Challenge Models. In this context, transient hypoxia could be a relevant Cognitive Challenge Model. The deleterious effects of hypoxia on cognition, as described in the literature, should be considered carefully since they are usually assessed with different populations that do not have the same hypoxic sensitivity. Hypoxia can be obtained by the means of two different methods: normobaric and hypobaric hypoxia. In both designs, cognitive changes can be directly modulated by the severity of hypoxic levels. The purpose of this review is to gather existing support on the application of hypoxia within different cognitive domains and to highlight the scientific interests of such a model to predict and select promising drug candidates. We aimed at reviewing in detail the methods, designs and cognitive paradigms used in non-pharmacological hypoxia studies. Probing the four main cognitive functions will allow identifying the extent to which different hypoxia designs selectively compromise cognitive functioning. For each cognitive process, the convergent and divergent results are discussed in terms of paradigm differences whereas we will focus on defining the optimal methodology for obtaining the desired effects.

Transcranial Magnetic Stimulation (TMS) was proposed as a neurophysiological tool almost three decades ago. It now encompasses a very wide range of applications including clinical research and the treatment of psychiatric, neurologic and medical conditions such as depression, schizophrenia, addictions, post-traumatic stress disorders, pain, migraine, stroke, Alzheimer's disease, autism, multiple sclerosis and Parkinson's disease. By inducing electrical brain responses through the administration of magnetic pulses, TMS is in a unique position to painlessly modulate cortical regions and offers good spatial resolution and excellent temporal resolution, particularly when applied using single pulses. However, despite the impressive number of papers describing the use of TMS to modulate cognitive functions, the mechanisms underlying the behavioral changes observed after stimulation have not been fully identified. Here we present a review of the ability of TMS to transiently compromise brain function in humans. The primary aim was to investigate its capacity for use as a 'cognitive challenge model' in human pharmacological studies. The data reviewed include findings on executive function, attention and episodic memory. For each cognitive process, the convergent and divergent results are discussed in terms of paradigm differences and in order to define the optimal methodology for obtaining the desired effects.

Introduction The capacity of repetitive TMS to transiently interfere with cognitive processes in humans may offer an experimental platform for pharmacological studies. Developing compounds could then be tested to reverse artificially generated cognitive dysfunction, providing first hints of efficacy. In the FP7-IMI European ’Pharmacog’ Project, an rTMS protocol previously published in the literature, was adapted and validated as a ’cognitive challenge model’ to mimic episodic memory dysfunction occurring in early Alzheimer’s disease. However, it would be desirable to test whether the effects of TMS are comparable and reproducible across different centres and time-point assessments. Objectives Our main aims were, (1) to find out if visual memory interference through rTMS administration could be replicated using our specific experimental settings and task adaptations (Fig. 1), (2) to test if results are comparable in two centres and (3) to investigate if the effects obtained are reproducible when subjects are re-tested 15 days later. Methods 68 healthy young male subjects were included. Neuronavigated (Fig. 1) repetitive TMS was applied over the left dorsolateral prefrontal cortex (LDLPFC) or the Vertex area (control condition) during encoding of pictures, for latter memory recognition. Subjects attended one of two research centres in three main occasions: On visit 1, rTMS was applied using a sham coil and served as a baseline measure. On visit 2, real rTMS was administered. On visit 3, 15 days later, a subsample (N = 21) performed the same protocol to test for reproducibility of effects. Results A time (visit 1 vs visit 2) × TMS type (LDLPFC vs Vertex) ANOVA and posterior pairwise comparisons revealed that only rTMS delivered over the LDLPFC and during visit 2 day resulted in a significant decrease in subsequent memory recognition (F = 8.95, p = 0.004; Fig. 2a). No centre effect observed (F = 0.03, p = 0.96). Initial rTMS effects could not be replicated in the subsample (Fig. 2b). Conclusions Our findings offers positive evidence regarding the feasibility of adapting a rTMS cognitive interference protocol, to conduct new experimental research in separate independent institutions. The factors underlying the lack of test–retest reproducibility of the interference should be further investigated. Download : Download high-res image (345KB) Download : Download full-size image Download : Download high-res image (400KB) Download : Download full-size image

La survenue de crises chez des patients epileptiques n’est pas toujours un phenomene completement aleatoire. Parmi les facteurs favorisants, le stress et, d’une facon plus generale, le contexte emotionnel sont les circonstances le plus souvent rapportees par les patients. Nous avons plus particulierement etudie cette « vulnerabilite emotionnelle » a travers une approche clinique et cognitive. Nous avons pu montrer que bien que basee sur une appreciation subjective, cette vulnerabilite etait associee a des marqueurs de type « biais attentionnels » pour les informations emotionnelles. De plus, les patients vulnerables sont plus souvent des femmes et ont debute leur epilepsie apres un evenement emotionnel marquant.

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 5 mg donepezil or placebo for 15 days 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.

Very few studies in humans have quantified the effect obtained after direct electrical stimulation of the amygdala, in terms of both emotional and physiological responses. We tested patients with drug-resistant partial epilepsies who were explored with intracerebral electrodes in the setting of presurgical evaluation. We assessed the effects of direct electric stimulations in either the right or the left amygdala on verbally self-reported emotions (Izard scale) and on psychophysiological markers of emotions by recording skin conductance responses (SCRs) and by measuring the electromyographic responses of the corrugator supercilii (EMGc). According to responses on Izard scales, electrical stimulations of the right amygdala induced negative emotions, especially fear and sadness. In contrast, stimulations of the left amygdala were able to induce either pleasant (happiness) or unpleasant (fear, anxiety, sadness) emotions. Unpleasant states induced by electrical stimulations were accompanied by an increase in EMGc activity. In addition, when emotional changes were reported after electrical stimulation, SCR amplitude for the positively valenced emotions was larger than for the negative ones. These findings provide direct in vivo evidence that the human amygdala is involved in emotional experiences and strengthen the hypothesis of a functional asymmetry of the amygdala for valence and arousal processing.

International audience; The present proof-of-concept study investigated the feasibility of skin conductance biofeedback training in reducing seizures in adults with drug-resistant temporal lobe epilepsy (TLE), whose seizures are triggered by stress. Skin conductance biofeedback aims to increase levels of peripheral sympathetic arousal in order to reduce cortical excitability. This might seem somewhat counterintuitive, since such autonomic arousal may also be associated with increased stress and anxiety. Thus, this sought to verify that patients with TLE and stress-triggered seizures are not worsened in terms of stress, anxiety, and negative emotional response to this nonpharmacological treatment. Eleven patients with drug-resistant TLE with seizures triggered by stress were treated with 12 sessions of biofeedback. Patients did not worsen on cognitive evaluation of attentional biases towards negative emotional stimuli (P > .05) or on psychometric evaluation with state anxiety inventory (P = .059); in addition, a significant improvement was found in the Negative Affect Schedule (P = .014) and in the Beck Depression Inventory (P = .009). Biofeedback training significantly reduced seizure frequency with a mean reduction of −48.61% (SD = 27.79) (P = .005). There was a correlation between the mean change in skin conductance activity over the biofeedback treatment and the reduction of seizure frequency (r(11) = .62, P = .042). Thus, the skin conductance biofeedback used in the present study, which teaches patients to achieve an increased level of peripheral sympathetic arousal, was a well-tolerated nonpharmacological treatment. Further, well-controlled studies are needed to confirm the therapeutic value of this nonpharmacological treatment in reducing seizures in adults with drug-resistant TLE with seizures triggered by stress.

International audience; Background Recent investigations have suggested that the occurrence of epileptic seizures is not completely random. In particular, various types of psychological changes or life events may act as triggering factors. Objective To identify a possible link between self-perception of the impact of affective precipitants, cognitive responses modulated by aversive information and brain metabolic modifications in patients with temporal lobe epilepsy (TLE). Methods The extent to which seizures were elicited or not by emotional precipitants was estimated using a self-reported scale, allowing distinction of two groups: 'Emo-TLE' group (patients reporting to have seizures triggered by emotional events) and 'Other-TLE' group, which were compared with healthy individuals ('control' group). Attentional biases were investigated using the probe detection paradigm, using negative and neutral stimuli. Interictal brain metabolism was studied using FDG-PET, and comparison was made between controls, Emo-TLE and Other-TLE groups. Results Patients with emotional vulnerability (Emo-TLE) disclosed specific attentional biases towards negative stimuli compared with the Other-TLE and control groups. Patients with Emo-TLE also exhibited specific hypometabolism in the anterior temporal lobe, including amygdala and hippocampus. The degree of attentional biases correlated with decreased metabolism in these regions. Conclusions This investigation shows that the impact of affective events is the result of self-perception and also that it might be determined by specific cognitive and brain metabolic modifications in TLE.

Background Avoidance and hypervigilance to reminders of a traumatic event are among the main characteristics of post-traumatic stress disorder (PTSD). Attentional bias toward aversive cues in PTSD has been hypothesized as being part of the dysfunction causing etiology and maintenance of PTSD. The aim of the present study was to investigate the cognitive strategy underlying attentional bias in PTSD and whether normal cognitive processing is restored after a treatment suppressing core PTSD symptoms. Methods Nineteen healthy controls were matched for age, sex and education to 19 PTSD patients. We used the emotional stroop and detection of target tasks, before and after an average of 4.1 sessions of eye movement desensitization and reprocessing (EMDR) therapy. Results We found that on both tasks, patients were slower than controls in responding in the presence of emotionally negative words compared to neutral ones. After symptoms removal, patients no longer had attentional bias, and responded similarly to controls. Conclusion These results support the existence of an attentional bias in PTSD patients due to a disengagement difficulty. There was also preliminary evidence that the disengagement was linked to PTSD symptomatology. It should be further explored whether attentional bias and PTSD involve common brain mechanisms.

Emotional distress is one of the most frequently reported seizure precipitants in epilepsy, but little is known about its causes and processes. Interestingly, it is now accepted that emotional distress, such as anxiety, may be accompanied by evolutionary adaptation, or abnormal attentional vigilance toward threatening stimuli. The goal of this research was to study the link between emotional seizure precipitants and pathological attention-related biases toward threat in temporal lobe epilepsy (TLE). To this aim, patients were asked to report the extent to which seizures were elicited or not by emotional precipitants, allowing distinction of two groups: "Emo-TLE" group and "Other-TLE" group. Attentional biases were investigated by comparing patients' emotional Stroop and dot detection paradigms with those of healthy individuals (control group). We found that the Emo-TLE group was characterized by attentional bias toward threatening stimuli compared with neutral stimuli and compared with the other two groups. We thus hypothesize that attentional biases related to threat in patients with TLE may sustain emotional vulnerability and seizure occurrence.