What Electrophysiology Tells Us About Alzheimer’s Disease::A Window into the Synchronization and Connectivity of Brain Neurons

Electrophysiology provides a real-time readout of neural functions and network capability in different brain states, on temporal (fractions of milliseconds) and spatial (micro, meso, and macro) scales unmet by other methodologies. However, current international guidelines do not endorse the use of electroencephalographic (EEG)/magnetoencephalographic (MEG) biomarkers in clinical trials performed in patients with Alzheimer’s disease (AD), despite a surge in recent validated evidence. This Position Paper of the ISTAART Electrophysiology Professional Interest Area endorses consolidated and translational electrophysiological techniques applied to both experimental animal models of AD and patients, to probe the effects of AD neuropathology (i.e., brain amyloidosis, tauopathy, and neurodegeneration) on neurophysiological mechanisms underpinning neural excitation/inhibition and neurotransmission as well as brain network dynamics, synchronization, and functional connectivity reflecting thalamocortical and cortico-cortical residual capacity. Converging evidence shows relationships between abnormalities in EEG/MEG markers and cognitive deficits in groups of AD patients at different disease stages. The supporting evidence for the application of electrophysiology in AD clinical research as well as drug discovery pathways warrants an international initiative to include the use of EEG/MEG biomarkers in the main multicentric projects planned in AD patients, to produce conclusive findings challenging the present regulatory requirements and guidelines for AD studies

Early diagnosis of Alzheimer's disease: the role of biomarkers including advanced EEG signal analysis. Report from the IFCN-sponsored panel of experts

Alzheimer's disease (AD) is the most common neurodegenerative disease among the elderly with a progressive decline in cognitive function significantly affecting quality of life. Both the prevalence and emotional and financial burdens of AD on patients, their families, and society are predicted to grow significantly in the near future, due to a prolongation of the lifespan. Several lines of evidence suggest that modifications of risk-enhancing life styles and initiation of pharmacological and non-pharmacological treatments in the early stage of disease, although not able to modify its course, helps to maintain personal autonomy in daily activities and significantly reduces the total costs of disease management. Moreover, many clinical trials with potentially disease-modifying drugs are devoted to prodromal stages of AD. Thus, the identification of markers of conversion from prodromal form to clinically AD may be crucial for developing strategies of early interventions. The current available markers, including volumetric magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebral spinal fluid (CSF) analysis are expensive, poorly available in community health facilities, and relatively invasive. Taking into account its low cost, widespread availability and non-invasiveness, electroencephalography (EEG) would represent a candidate for tracking the prodromal phases of cognitive decline in routine clinical settings eventually in combination with other markers. In this scenario, the present paper provides an overview of epidemiology, genetic risk factors, neuropsychological, fluid and neuroimaging biomarkers in AD and describes the potential role of EEG in AD investigation, trying in particular to point out whether advanced analysis of EEG rhythms exploring brain function has sufficient specificity/sensitivity/accuracy for the early diagnosis of AD

Backtranslation of EEG biomarkers of Alzheimer's disease from patients to mouse model

The present Ph.D. thesis has been mainly developed on the data of the project with the short name PharmaCog (2010-2015), granted by the European Framework Programme 7 with about 28 millions of Euro (i.e. Innovative Medicine Initiative, IMI, grant agreement n°115009; www.pharmacog.org). This project involved 15 academic institutions, 12 global pharmaceutical companies, and 5 small and medium sized enterprises (SMEs). The PharmaCog project aimed at improving the pathway of drug discovery in Alzheimer’s disease (AD), based on a major interest of pharma companies, namely the validation of electrophysiological, neuroimaging, and blood biomarkers possibly sensitive to the effect of disease-modifying drugs reducing Ab42 in the brain in AD patients at the prodromal stage of amnesic mild cognitive impairment (aMCI). The core concept of the PharmaCog project was that the pathway of drug discovery in AD may be enhanced by (1) the validation of biomarkers derived from blood, EEG, magnetic resonance imaging (MRI), and positron emission tomography (PET) in patients with aMCI due to AD diagnosed by in-vivo measurement of Ab42 and phospho-tau in the brain and (2) the evaluation of the translational value of those human biomarkers in wild type (WT) mice and animal models of AD including transgenic mice with the mutation of PS1 and/or APP (i.e. PDAPP and TASTPM strains). Those genetic factors induce an abnormal accumulation of Ab42 in the brain and related cognitive deficits. The expected results may be (1) the identification of a matrix of biomarkers sensitive to the prodromal AD (aMCI cognitive status) and its progression in patients and (2) the selection of similar biomarkers related to AD neuropathology and cognitive deficits in PDAPP and TASTPM strains. These biomarkers were expected to be very useful in clinical trials testing the efficacy and neurobiological impact of new disease-modifying drugs against prodromal AD. For the development of this Ph.D. thesis, the access to the experiments and the data of the PharmaCog project was allowed by Prof. Claudio Babiloni, leader of an Italian Unit (University of Foggia in 2010-2012 and Sapienza University of Rome in 2013-2015) of the PharmaCog Consortium and coordinator of study activities relative to biomarkers derived from electroencephalographic (EEG) signals recorded from human subjects and animals in that project. Specifically, Prof. Claudio Babiloni was in charge for the centralized qualification and analysis of EEG data recorded from aMCI patients (Work Package 5, WP5) and transgenic mouse models of AD such as PDAPP and TASTPM strains (WP6). The data of the present Ph.D. thesis mostly derived from the WP5 and WP6. This document illustrating the Ph.D. thesis is structured in three main Sections: ▪ An Introductive part illustrating concisely the AD neuropathology, the mouse models of AD used in this thesis, and basic concepts of EEG techniques useful to understand the present study results; ▪ An Experimental part describing the result of the four research studies led in the framework of this Ph.D. project. Two of these studies were published in international journals registered in ISI/PubMed with impact factor, while the other two are being currently under minor revisions in those journals; ▪ A Conclusion section

Neuroimaging Features of Adults With and Without Amnestic Mild Cognitive Impairment

Amnestic Mild Cognitive Impairment (aMCI), a condition in which the memory functions of cognition are significantly impaired, is an established risk factor for Alzheimer’s Dementia, a neurodegenerative disease that has no known cure. Electroencephalography’s (EEG) capability to measure the dynamics of the brain’s neuronal networks makes it a powerful tool for analyzing and understanding aMCI. In this study, I examined the brain activation patterns of four healthy subjects with those of thirteen aMCI diagnosed subjects during a one-hour afternoon sleep session by employing a 64-channel EEG data collection system. The power spectrum was analyzed to identify sleep stages, while spectral topography and source imaging techniques were employed to study the fluctuating patterns of the brain. Results of this study show distinct structures of the resting state patterns for aMCI subjects when compared to healthy controls. Furthermore, I compared the neuroimaging features from EEG to the neurological assessment of memory and additional cognitive measures in aMCI subjects. Results for source imaging analysis indicate a significant difference in the default mode network connectivities between more impaired versus less impaired aMCI diagnosed subjects. The results indicate that spatial topographies and electrophysiological networks measured by EEG may be used to characterize the neurological correlates of cognitive impairment in aMCI. In conclusion, this proof-of-concept study suggests that EEG may be used in place of fMRI for the evaluation of brain activations associated with aMCI and its degradation levels. This development could pave the way for cheaper, more accessible neuroimaging for subjects with aMCI

Event-related potentials associated to N-back test performance in schizophrenia

Producción CientíficaMapping of Event-Related Potentials (ERP) associated with auditory and visual odd-ball paradigms has shown consistent differences between healthy controls and schizophrenia patients. It may be hypothesized that higher task attentional/cognitive demand will result in larger differences in these paradigms, which may help understanding the substrates of cognitive deficits in this syndrome. To this aim, we performed an EEG study comparing the effects of increasing the attentional/cognitive load of an auditory N-back task on the Event-Related Potential in 50 subjects with schizophrenia (11 first episodes) and 35 healthy controls. We considered a post-target window of 1000 ms to explore possible between groups differences in N100, P300, and Late Slow Wave (LSW), and compared these components between 0-back (‘lower attentional/cognitive load) and 1-back (‘higher attentional/cognitive load’) conditions. Our results showed that N100 and LSW amplitude increase from 0- to 1-back condition was significantly larger in healthy controls compared to schizophrenia patients. Furthermore, LSW amplitude difference between 0- and 1-back conditions positively correlated with performance in the behavioral cognitive assessment. Taken together, these results support that higher task attentional/cognitive load (0-back vs. 1-back condition) increase N100 amplitude differences and reveal new findings related to the LSW component in schizophrenia.Junta de Castilla y León (project VA057P17)Instituto de Salud Carlos III (project PI18/00178

Dynamics of large-scale brain activity in health and disease

Tese de doutoramento em Engenharia Biomédica e Biofísica, apresentada à Universidade de Lisboa através da Faculdade de Ciências, 2008Cognition relies on the integration of information processed in widely distributed brain regions. Neuronal oscillations are thought to play an important role in the supporting local and global coordination of neuronal activity. This study aimed at investigating the dynamics of the ongoing healthy brain activity and early changes observed in patients with Alzheimer's disease (AD). Electro- and magnetoencephalography (EEG/MEG) were used due to high temporal resolution of these techniques. In order to evaluate the functional connectivity in AD, a novel algorithm based on the concept of generalized synchronization was improved by defining the embedding parameters as a function of the frequency content of interest. The time-frequency synchronization likelihood (TF SL) revealed a loss of fronto-temporal/parietal interactions in the lower alpha (8 10 Hz) oscillations measured by MEG that was not found with classical coherence. Further, long-range temporal (auto-) correlations (LRTC) in ongoing oscillations were assessed with detrended fluctuation analysis (DFA) on times scales from 1 25 seconds. Significant auto-correlations indicate a dependence of the underlying dynamical processes at certain time scales of separation, which may be viewed as a form of "physiological memory". We tested whether the DFA index could be related to the decline in cognitive memory in AD. Indeed, a significant decrease in the DFA exponents was observed in the alpha band (6 13 Hz) over temporo-parietal regions in the patients compared with the age-matched healthy control subjects. Finally, the mean level of SL of EEG signals was found to be significantly decreased in the AD patients in the beta (13 30 Hz) and in the upper alpha (10 13 Hz) and the DFA exponents computed as a measure of the temporal structure of SL time series were larger for the patients than for subjects with subjective memory complaint. The results obtained indicate that the study of spatio-temporal dynamics of resting-state EEG/MEG brain activity provides valuable information about the AD pathophysiology, which potentially could be developed into clinically useful indices for assessing progression of AD or response to medication

Эффекты когнитивной реабилитации с применением двойной задачи у пациентов в раннем послеоперационном периоде прямой реваскуляризации миокарда

Aim. To assess the effects of cognitive rehabilitation with dual-task training that involves a cognitive task combined with postural and walking control, as well as electroencephalogram indices in patients in the early postoperative period after direct myocardial revascularization.Methods. The study enrolled 48 patients scheduled for coronary artery bypass graft surgery. Subjects in this prospective, randomized study were randomized using envelopes to a postoperative cognitive training group (n = 23) and non-training group (n = 25). The cognitive training was carried out daily, starting 3-4 days after the procedure and until the discharge order. Dual tasks training (a cognitive task combined with postural and walking control) lasted 15-20 minutes. All patients were submitted to an extended neurophysiological assessment (psychometric tests and electroencephalogram study) and stabilography 3-5 days before and 8-11 days after coronary artery bypass grafting.Results. The patients who underwent cognitive training experienced postoperative cognitive dysfunction (POCD) in 39% cases in the early postoperative period after intervention, while the non-training group - in 64%. The relative risk of developing POCD in the non-training group was 2.77 (95% CI: 0.86-8.91, Z = 1.704, p = 0.08). The patients in cognitive training exhibited better cognitive state compared to the preoperative state (Z = 2.58; p = 0.01) in the absence of statistically significant differences in the non-training group. Moreover, type-1 theta power values increased in the non-training group in comparison to the preoperative values, while the cognitive training group did not have a statistically significant difference in theta power.Conclusion. Positive effects of dual task rehabilitation on the neurophysiological parameters of patients undergoing direct myocardial revascularization were demonstrated. Positive effects include lower frequency of POCD, improved cognitive state and less pronounced cortical dysfunction. The dual task training had proved a suitable training method for this category of patients. Additional studies are required to test the possibility of increasing the duration and intensity of dual task training for stronger recovery effect and improved cognitive and walking performance of patients in the postoperative period after direct myocardial revascularization.Цель. Оценить влияние когнитивной реабилитации с применением двойной задачи на когнитивные, постуральные функции и показатели электроэнцефалограммы у пациентов в раннем послеоперационном периоде прямой реваскуляризации миокарда.Материалы и методы. В проспективном рандомизированном исследовании участвовали 48 пациентов, подвергнутых коронарному шунтированию. Путем простой рандомизации (метод конвертов) сформированы группы послеоперационного когнитивного тренинга (n = 23) и сравнения (n = 25). Основной группе когнитивный тренинг проводили ежедневно, с 3-4-го дня после операции и до выписки из стационара в виде 15-20-минутных сессий с выполнением двойных заданий (постуральный тренинг и когнитивная задача). Всем больным оценены нейрофизиологический статус (психометрическое тестирование и электроэнцефалографическое исследование) и стабилография за 3-5 дней до и на 8-11-е сут после вмешательства.Результаты. В раннем послеоперационном периоде кардиохирургических вмешательств у пациентов, прошедших когнитивный тренинг, число случаев послеоперационной когнитивной дисфункции (ПОКД) составило 39%, тогда как в группе сравнения - 64%. Относительный риск развития ПОКД в группе без когнитивного тренинга - 2,77 (95% доверительный интервал 0,86-8,91; Z = 1,704; p = 0,08). В группе когнитивного тренинга наблюдалось увеличение                интегрального показателя когнитивного статуса по сравнению с предоперационным уровнем (Z = 2,58; p = 0,01) при отсутствии статистически значимых различий в группе сравнения. Также обнаружено, что мощность биопотенциалов тета-1-ритма увеличилась по сравнению с дооперационными показателями только у больных группы сравнения, тогда как у участников, прошедших программу когнитивного тренинга, не выявлено статистически значимого послеоперационного увеличения тета-активности.Заключение. Показано положительное влияние когнитивной реабилитации с применением двойной задачи на нейрофизиологические показатели пациентов, перенесших прямую реваскуляризацию миокарда, в виде меньшей частоты ПОКД, улучшения когнитивного статуса и менее выраженной корковой дисфункции, что позволяет говорить об эффективности этого когнитивного тренинга для анализируемой выборки. Необходимо дополнительно рассмотреть вопросы продолжительности и интенсивности тренинга с использованием двойных задач для повышения восстановительного эффекта на интеллектуальные ресурсы и постуральные функции больных в послеоперационном периоде прямой реваскуляризации миокарда

Advances in Clinical Neurophysiology

Including some of the newest advances in the field of neurophysiology, this book can be considered as one of the treasures that interested scientists would like to collect. It discusses many disciplines of clinical neurophysiology that are, currently, crucial in the practice as they explain methods and findings of techniques that help to improve diagnosis and to ensure better treatment. While trying to rely on evidence-based facts, this book presents some new ideas to be applied and tested in the clinical practice. Advances in Clinical Neurophysiology is important not only for the neurophysiologists but also for clinicians interested or working in wide range of specialties such as neurology, neurosurgery, intensive care units, pediatrics and so on. Generally, this book is written and designed to all those involved in, interpreting or requesting neurophysiologic tests

Keep calm and age well: Behavioural and electrophysiological investigations into the effects of cumulative stress exposure on ageing cognition

The research presented in this thesis comprises a body of work dedicated to continuing and enriching past exploration into the impact cumulative life stress exerts on ageing cognition. In order to extend previous work into this topic, behavioural measures were paired with electroencephalographic recordings of the cortical oscillatory activity thought to underlie cognitive operations. In a theoretical sense, work presented in this thesis strengthens past investigations highlighting the adverse effects of life stress on elderly peoples’ working memory abilities by replicating the effect under conditions of increased experimental rigour. It further provides evidence that the detrimental effects of cumulative stress extend to the domains of executive control and spatial memory. Electrophysiological findings obtained during task execution and at rest indicate pronounced changes in the oscillatory activity of aged high stress individuals’ delta, theta, alpha and gamma bands and are thus the first to demonstrate that cumulative stress affects the underlying neural processes related to successful task execution. As such, from a methodological standpoint, the current research strongly advocates the use of neuroscientific tools such as the electroencephalogram to gain an increased understanding of the mechanisms by which increased stress exposure evokes progressive cognitive decline in old age. Combined, the work presented in this thesis demonstrates the negative consequences of leading a highly stressful life for the integrity of multiple cognitive functions in old age and is the first to provide an indication of how cumulative stress affects both cortical and (indirectly) subcortical regions of the brain necessary for successful cognitive functioning