Laura Lanteaume

Skin conductance biofeedback training in adults with drug-resistant temporal lobe epilepsy and stress-triggered seizures: A proof-of-concept study

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.

Cognitive and metabolic correlates of emotional vulnerability in patients with temporal lobe epilepsy

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.

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 donepezils 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 donepezils 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 Alzheimers disease in healthy volunteers prior to the initiation of Phase II/III clinical studies in patients.

Brain Networks are Independently Modulated by Donepezil, Sleep, and Sleep Deprivation

Resting-state connectivity has been widely studied in the healthy and pathological brain. Less well-characterized are the brain networks altered during pharmacological interventions and their possible interaction with vigilance. In the hopes of finding new biomarkers which can be used to identify cortical activity and cognitive processes linked to the effects of drugs to treat neurodegenerative diseases such as Alzheimer’s disease, the analysis of networks altered by medication would be particularly interesting. Eleven healthy subjects were recruited in the context of the European Innovative Medicines Initiative ‘PharmaCog’. Each underwent five sessions of simultaneous EEG-fMRI in order to investigate the effects of donepezil and memantine before and after sleep deprivation (SD). The SD approach has been previously proposed as a model for cognitive impairment in healthy subjects. By applying network based statistics (NBS), we observed altered brain networks significantly linked to donepezil intake and sleep deprivation. Taking into account the sleep stages extracted from the EEG data we revealed that a network linked to sleep is interacting with sleep deprivation but not with medication intake. We successfully extracted the functional resting-state networks modified by donepezil intake, sleep and SD. We observed donepezil induced whole brain connectivity alterations forming a network separated from the changes induced by sleep and SD, a result which shows the utility of this approach to check for the validity of pharmacological resting-state analysis of the tested medications without the need of taking into account the subject specific vigilance.

Neurobehavioral and Cognitive Changes Induced by Hypoxia in Healthy Volunteers.

The early assessment of new symptomatic drugs against Alzheimers 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 Alzheimers 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.

Translational Challenge Models in Support of Efficacy Studies: Effect of Cerebral Hypoxia on Cognitive Performances in Rodents

Empirical evidence currently supports the idea that neurovascular dysfunction is involved in the neurodegenerative process of Alzheimers 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.

Adaptability and reproducibility of a memory disruption rTMS protocol in the PharmaCog IMI European project

Transcranial magnetic stimulation (TMS) can interfere with cognitive processes, such as transiently impairing memory. As part of a multi-center European project, we investigated the adaptability and reproducibility of a previously published TMS memory interfering protocol in two centers using EEG or fMRI scenarios. Participants were invited to attend three experimental sessions on different days, with sham repetitive TMS (rTMS) applied on day 1 and real rTMS on days 2 and 3. Sixty-eight healthy young men were included. On each experimental day, volunteers were instructed to remember visual pictures while receiving neuronavigated rTMS trains (20 Hz, 900 ms) during picture encoding at the left dorsolateral prefrontal cortex (L-DLPFC) and the vertex. Mixed ANOVA model analyses were performed. rTMS to the L-DLPFC significantly disrupted recognition memory on experimental day 2. No differences were found between centers or between fMRI and EEG recordings. Subjects with lower baseline memory performances were more susceptible to TMS disruption. No stability of TMS-induced memory interference could be demonstrated on day 3. Our data suggests that adapted cognitive rTMS protocols can be implemented in multi-center studies incorporating standardized experimental procedures. However, our center and modality effects analyses lacked sufficient statistical power, hence highlighting the need to conduct further studies with larger samples. In addition, inter and intra-subject variability in response to TMS might limit its application in crossover or longitudinal studies.

BLOOD INFLAMMATORY PROFILES MEASURED BY THE ADFLAG® TEST ENABLE STRATIFICATION OF PRE-DEMENTIA ALZHEIMER’S DISEASE

P4-077 BLOOD INFLAMMATORY PROFILES MEASURED BY THE ADFLAG TEST ENABLE STRATIFICATION OF PREDEMENTIA ALZHEIMER’S DISEASE Nathalie A. Compagnone, Beatrice Blanc, Pauline Picamal, Samantha Galluzzi, Moira Marizzoni, Jorge Jovicich, Giovanni B. Frisoni, Gianluigi Forloni, Diego Albani, Jill Richardson, Lucilla Parnetti, Magda Tsolaki, Flavio Nobili, David Bartes-Faz, Mira Didic, Peter Schonknecht, Pierre Payoux, Andrea Soricelli, Paolo Rossini, Pieter Jelle Visser, R egis Bordet, Ute Fiedler, Olivier Blin, Joelle Micaleff, Laura Lanteaume, ICDD, Gemenos, France; Lab Alzheimer’s Neuroimaging and Epidemiology, Istituto di Ricovero e Cura a Carattere Scientifico, Fatebenefratelli, Brescia, Italy; Istituto di Ricovero e Cura a Carattere Scientifico, Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; University of Trento, Trento, Italy; Istituto di Ricovero e Cura a Carattere Scientifico, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy; GSK Research and Development, China-UK, Hertfordshire, United Kingdom; Lab of Clinical Neurochemistry, University of Perugia, Perugia, Italy; First Department of Neurology, AHEPA University Hospital, Makedonia, Thessaloniki, Greece; University of Genoa, Italy, Genoa, Italy; University of Barcelona, Barcelona, Spain; Service de Neurologie et Neuropsychologie, Marseille, France; Leipzig Research Center for Civilization Diseases, Leipzig, Germany; INSERM, Imagerie C er ebrale et Handicaps Neurologiques, Toulouse, France; SDN Istituto di Ricerca Diagnostica e Nucleare SpA per la Ricerca e l’Alta Formazione in Diagnostica Nucleare, Naples, Italy; Department of Gerontology, Neurosciences and Orthopedics, Catholic University, Rome, Italy; Alzheimer Center and Department of Neurology, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, Netherlands; Service de Pharmacologie-Hôpital Huriez-Centre Hospitalier R egional Universitaire, Lille, France; Institutes and Clinics of the University Duisburg-Essen, Essen, Germany; Aix-Marseille University, Centre National de la Recherche Scientifique, Marseille, France; Service de Neurologie et Neuropsychiatry, Centre Hospitalier Universitaire la Timone, Marseille, France; Assistance Publique Hôpitaux de Marseille, Marseille, France. Contact e-mail: ncompagnone@ icdd-sas.com

ADFLAG ® , A DIAGNOSTIC BLOOD TEST FOR PRE-DEMENTIA STAGES OF ALZHEIMER’S DISEASE

P3-214 ADFLAG , A DIAGNOSTIC BLOOD TEST FOR PRE-DEMENTIA STAGES OF ALZHEIMER’S DISEASE Beatrice Blanc, Nicolas Pelletier, Clotilde Biscarrat, Pauline Picamal, Nathalie Compagnone, Samantha Galluzzi, Moira Marizzoni, Jorge Jovicich, Giovanni B. Frisoni, Gianluigi Forloni, Diego Albani, Jill Richardson, Lucilla Parnetti, Magda Tsolaki, Flavio Nobili, David Bartrez-faz, Mira Didic, Peter Schoenknecht, Pierre Payoux, Andrea Soricelli, Paolo Rossini, Pieter Jelle Visser, Regis Bordet, Ute Fiedler, Olivier Blin, Julien Dupouey, Joelle Micallef, Laura Lanteaume, Bernard Michel, ICDD, Gemenos, France; IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; University of Trento, Trento, Italy; Memory Clinic and LANVIE Laboratory of Neuroimaging of Aging, University Hospitals and University of Geneva, Geneva, Switzerland; Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Milan, Italy; IRCCS, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy; GSK R&D, China-United Kingdom, Middlesex, United Kingdom; Lab of Clinical Neurochemistry, University of Perugia, Perugia, Italy; Aristotle University of Thessaloniki, Thessaloniki, Greece; University of Genoa, Italy, Genoa, Italy; Department of Psychiatry and Clinical Psychobiology, Faculty of Medicine, University of Barcelona and Institut d’Investigacions Biom ediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Service de Neurologie et Neuropsychologie, Marseille, France; Department of Psychiatry and Psychotherapy, University of Leipzig, Leipzig, Germany; INSERM, Imagerie C er ebrale et Handicaps Neurologiques, Toulouse, France; Fondazione SDN per la Ricerca e l’Alta Formazione in Diagnostica Nucleare, Naples, Italy; Department of Gerontology, Neurosciences & Orthopedics, Catholic University, Rome, Italy; VU University Medical Center, Amsterdam, Netherlands; Service de Pharmacologie-Hôpital Huriez-CHRU, Lille, France; Institutes and Clinics of the University Duisburg-Essen, Essen, Germany; Mediterranean Institute of Cognitive Neurosciences, Marseille, France; Service de Neurologie et Neuropsychologie, CHU la Timone, Marseille, France; Assistance Publique Hôpitaux de Marseille, Marseille, France; Service de Neurologie Comportementale, Hôpital Sainte Marguerite, Marseille, France, CNRS LNIAUMR 7260 FR3C FR 3512, Aix-Marseille Universit e, Marseille, France. Contact e-mail: bblanc@icdd-sas.com

La vulnérabilité émotionnelle dans les épilepsies temporales : un lien entre psychogenèse et épileptogenèse ?

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.