Phase and amplitude electroencephalography correlations change with disease progression in people with idiopathic rapid eye-movement sleep behavior disorder

Study Objectives Increased phase synchronization in electroencephalography (EEG) bands might reflect the activation of compensatory mechanisms of cognitive decline in people with neurodegenerative diseases. Here, we investigated whether altered large-scale couplings of brain oscillations could be linked to the balancing of cognitive decline in a longitudinal cohort of people with idiopathic rapid eye-movement sleep behavior disorder (iRBD). Methods We analyzed 18 patients (17 males, 69.7 +/- 7.5 years) with iRBD undergoing high-density EEG (HD-EEG), presynaptic dopaminergic imaging, and clinical and neuropsychological (NPS) assessments at two time points (time interval 24.2 +/- 5.9 months). We thus quantified the HD-EEG power distribution, orthogonalized amplitude correlation, and weighted phase-lag index at both time points and correlated them with clinical, NPS, and imaging data. Results Four patients phenoconverted at follow-up (three cases of parkinsonism and one of dementia). At the group level, NPS scores decreased over time, without reaching statistical significance. However, alpha phase synchronization increased and delta amplitude correlations decreased significantly at follow-up compared to baseline. Both large-scale network connectivity metrics were significantly correlated with NPS scores but not with sleep quality indices or presynaptic dopaminergic imaging data. Conclusions These results suggest that increased alpha phase synchronization and reduced delta amplitude correlation may be considered electrophysiological signs of an active compensatory mechanism of cognitive impairment in people with iRBD. Large-scale functional modifications may be helpful biomarkers in the characterization of prodromal stages of alpha-synucleinopathies.Peer reviewe

Alterations of Effective Connectivity Patterns in Mild Cognitive Impairment: An MEG Study

Producción CientíficaNeuroimaging techniques have demonstrated over the years their ability to characterize the brain abnormalities associated with different neurodegenerative diseases. Among all these techniques, magnetoencephalography (MEG) stands out by its high temporal resolution and noninvasiveness. The aim of the present study is to explore the coupling patterns of resting-state MEG activity in subjects with mild cognitive impairment (MCI). To achieve this goal, five minutes of spontaneous MEG activity were acquired with a 148- channel whole-head magnetometer from 18 MCI patients and 26 healthy controls. Interchannel relationships were investigated by means of two complementary coupling measures: coherence and Granger causality. Coherence is a classical method of functional connectivity, while Granger causality quantifies effective (or causal) connectivity. Both measures were calculated in the five conventional frequency bands: delta (d, 1-4 Hz), theta (q, 4-8 Hz), alpha (a, 8-13 Hz), beta (b, 13-30 Hz), and gamma (g, 30-45Hz). Our results showed that connectivity values were lower for MCI patients than for controls in all frequency bands. However, only Granger causality revealed statistically significant differences between groups (p-values < 0.05, FDR corrected Mann-Whitney U-test), mainly in the beta band. Our results support the role of MCI as a disconnection syndrome, which elicits early alterations in effective connectivity patterns. These findings can be helpful to identify the neural substrates involved in prodromal stages of dementia.This research was supported by ‘Ministerio de Economía y Competitividad’ and ‘European Regional Development Fund’ under project TEC2014-53196-R, by ‘European Commission’ and ‘European Regional Development Fund’ under project ‘Análisis y correlación entre el genoma completo y la actividad cerebral para la ayuda en el diagnóstico de la enfermedad de Alzheimer’ (‘Cooperation Programme Interreg V-A Spain-Portugal POCTEP 2014-2020’), and by ‘Consejería de Educación de la Junta de Castilla y León’ under project VA037U16. Pablo Núñez was in receipt of a ‘Promoción de empleo joven e implantación de la Garantía Juvenil en I+D+i’ grant from ‘Ministerio de Economía y Competitividad’ and University of Valladolid

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

Language impairments and resting-state EEG in brain tumour patients:Revealing connections

Intact language functions are crucial for everyday communication. A brain tumour can impair these functions. We studied language abilities and their relation to resting-state brain activity in low-grade brain tumour patients, in search for predictors of language outcome after surgery. The brain tumours in this thesis include gliomas, which originate in the brain, and meningiomas, which arise from the meninges. Glioma and meningioma patients underwent thorough language assessments and brain activity registrations by electroencephalography (EEG). Two aspects of brain activity were evaluated: slow-wave activity, concerning activity with a low frequency, and functional connectivity brain networks, reflecting the extent to which brain areas interact.It is concluded that low-grade gliomas can cause impairments in a variety of language abilities. Furthermore, meningiomas can induce language impairments (primarily in speech production and writing), despite that these tumours do not infiltrate brain tissue. Many glioma and meningioma patients are presented with language impairments 1 year after surgery, but there is large interpatient variation. Our findings underline the importance of extensive language testing before and after brain tumour surgery. With regard to the EEG analyses, the outcomes indicate that increased slow-wave activity and particular characteristics of the functional connectivity networks are associated with poorer language functioning before surgery in glioma patients, unlike in meningioma patients. Moreover, two predictors of language outcome after glioma surgery are identified. This line of research requires further investigation because it has the potential to improve clinical procedures, such as treatment planning, patient counselling, and language rehabilitation

Entropy and fractal analysis of brain-related neurophysiological signals in Alzheimer's and Parkinson's disease.

Brain-related neuronal recordings, such as local field potential, electroencephalogram and magnetoencephalogram, offer the opportunity to study the complexity of the human brain at different spatial and temporal scales. The complex properties of neuronal signals are intrinsically related to the concept of 'scale-free' behavior and irregular dynamic, which cannot be fully described through standard linear methods, but can be measured by nonlinear indexes. A remarkable application of these analysis methods on electrophysiological recordings is the deep comprehension of the pathophysiology of neurodegenerative diseases, that has been shown to be associated to changes in brain activity complexity. In particular, a decrease of global complexity has been associated to Alzheimer's disease, while a local increase of brain signals complexity characterizes Parkinson's disease. Despite the recent proliferation of studies using fractal and entropy-based analysis, the application of these techniques is still far from clinical practice, due to the lack of an agreement about their correct estimation and a conclusive and shared interpretation. Along with the aim of helping towards the realization of a multidisciplinary audience to approach nonlinear methods based on the concepts of fractality and irregularity, this survey describes the implementation and proper employment of the mostly known and applied indexes in the context of Alzheimer's and Parkinson's diseases

Mutant Tau knock-in mice display frontotemporal dementia relevant behaviour and histopathology

Peer reviewedPostprin

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

Evaluation and implementation of functional cerebral biomarkers in Alzheimer’s disease

The aim of this thesis was to evaluate and implement functional cerebral biomarkers in Alzheimer’s disease (AD) with respect to pathophysiology, disease severity, prognosis and treatment effect in medical trials. We focused on functional cerebral biomarkers that assess synaptic activity and functional connectivity using electroencephalography (EEG), magnetoencephalography (MEG) and 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET). In the different chapters a broad range of challenges associated with this topic was covered. We started by using FDG- PET to observe the effects of the experimental treatment of AD patients with the medical food Souvenaid, followed by EEG as treatment outcome measure in a trial with the drug PQ912. Next to the primary outcomes, the results of these studies revealed that more research was needed to observe which markers could observe reliable, reproducible and valid results and what the factors were that could influence their ability to do this. The EEG markers, rather than the FDG- PET markers, showed promising results. Therefore, we aimed to investigate the effects of sensitivity, reproducibility, heterogeneity of the population and treatment efficacy, while maintaining a well-defined study population and study design, on EEG biomarkers. We first investigated the reproducibility of AD related changes in functional connectivity captured by different measures in electroencephalography (EEG) and magnetoencephalography (MEG). Second, we evaluated the influence of subtypes of AD on various EEG measures and, on the other hand, we used EEG to find heterogeneity and to predict clinical progression

Bilateral upper-limb coordination in aging and stroke

Bilateral upper-limb coordination is an important ability for our living independency, since most of our daily tasks, such as lifting a box or using knife and fork, require the simultaneous use of both arms (Waller et al., 2006). However, bilateral coordination decline has been observed in both healthy aging and neurological groups (Pollock et al., 2014; Maes et al., 2017) , which often results in decreased quality of life (Broeks et al., 1999; Franceschini et al., 2010). Therefore, this dissertation sought to understand the characteristics and mechanisms of bilateral coordination and its impairments. The two fundamental bilateral movements in human upper limbs, i.e., in-phase (homologous muscles from bilateral arms activate simultaneously) and anti-phase (different muscle groups from bilateral arms activate simultaneously) movements, have been found to show different characteristics in behavioral and neural measurements (Swinnen and Wenderoth, 2004). Behaviorally, anti-phase movements are found to be performed with lower movement accuracy and higher phase variability between hands compared to in-phase movements (Wuyts et al., 1996; Byblow et al., 2000; Pollok et al., 2007). On the neural level, fMRI studies demonstrated that the left hemisphere shows larger task-related BOLD signal changes compared to the right hemisphere during in-phase movements (Aramaki et al., 2006), while the BOLD signal changes between the two hemispheres are similar during anti-phase movements (Walsh et al., 2008). These results suggest a left-dominated control of in-phase movements. However, a critical limitation in the literature is the lack of causal evidence supporting hemispherical specialization in bilateral coordination. Therefore, it is unclear whether the observed behavioral differences between anti-phase and in-phase movements were truly due to distinct hemispheric control. Another limitation of the literature is the design of existing paradigms. While most of our daily activities involve movements engaging multiple joints at the same time (Keenan et al., 2006; Murphy et al., 2006), previous studies mostly investigated single joint movements (e.g. index finger tapping, forearm pronation-supination). Contrary to single joint movements, bilateral movements engaging multiple joints require not only inter-limb coordination, but also additional intra-limb coordination. Therefore, it is unclear whether the previous findings from single joint movements could be directly applied to multiple joint movements. In this dissertation, we used a bilateral coordination paradigm involving both shoulder and elbow joints to investigate the neural mechanisms behind bilateral coordination and its decline. We designed three studies focusing on 1) the differences between bilateral in-phase and anti-phase movements from a human motion perspective, 2) how aging affects different bilateral coordination patterns and its neural correlates, as well as 3) how lesioned hemisphere affects bilateral coordination impairments and whether distinct rehabilitation treatments are needed after a left or right hemispheric stroke. In Study 1, we examined the two basic bilateral coordination modes, in-phase and anti-phase movements, in healthy young right-handed participants. We used a bilateral circle drawing task involving both shoulder and elbow joints. During the movements, we measured participants’ hand positions with high temporal and spatial precision, and developed intra-limb and inter-limb measures to differentiate movement characteristics during the two basic movement modes. For intra-limb coordination, we quantified trajectory variability of each hand during the movements. For inter-limb coordination, we computed the phase synchronization between hands. We found that intra-limb coordination was worse in the non-dominant hand during anti-phase compared to in-phase movements. In contrast, intra-limb coordination in the dominant hand did not differ between anti-phase and in-phase movements. Second, participants showed worse inter-limb synchronization during anti-phase compared to in-phase movements. Moreover, we examined the hand acceleration profile of both hands, and found that participants’ bilateral hands accelerated and decelerated in an in-phase manner during in-phase movements. In contrast, the acceleration and deceleration of the two hands were unrelated during anti-phase movements. These inter-limb acceleration profiles support the idea of differential neural mechanisms behind bilateral anti-phase and in-phase movements: during in-phase movements, the hands are governed by a common neural generator, while during anti-phase movements, the two hands are controlled by both hemispheres more independently. Taken together, Study 1 showed that the current experimental setup is able to differentiate the performance between bilateral in-phase and anti-phase movements engaging multiple joints. Therefore, we used the same paradigm combined with electroencephalography (EEG) to examine the presumed decline of bilateral coordination in aging. In Study 2, we investigated the effect of aging on the two basic bilateral movement modes. We used intra- and inter-limb measures as the behavioral measures, and EEG as a neural measure. Behaviorally, we found that older adults only showed significant impairments in anti-phase movements, but not in-phase movements, compared to young adults. On the neural level, we found that older adults showed different neural responses during anti-phase and in-phase movements compared to young adults. Specifically, during in-phase movements, young adults showed a more pronounced decrease of alpha power (8-12 Hz) over the left compared to the right hemisphere, while older adults showed similar levels of alpha power decrease over both hemispheres. Furthermore, in the older adults, we found a marginal correlation between the change in alpha power over the right hemisphere and the behavioral performance, which indicated a compensatory brain response. As for the anti-phase movements, we found that participants with stronger directional inter-hemispheric connectivity in the beta band (15-25 Hz) showed worse behavioral performance, and this effect was more pronounced in the older adults. This result implies that a balanced inter-hemispheric contribution is essential for executing a successful anti-phase movement. Our findings therefore show that the two hemispheres are differentially involved in the two basic bilateral coordination modes. These different neural characteristics may explain the distinct decline patterns of in-phase and anti-phase movements in older adults. However, causal evidence to support hemispherical specialization is needed to confirm our findings. Therefore, we conducted Study 3, where we used stroke as a lesion model to examine the influence of the lesioned hemisphere on bilateral coordination. In Study 3, we examined the bilateral coordination ability in patients with left (LHS) and right hemispheric stroke (RHS), as well as healthy controls. Given that healthy young participants show a left-dominant control in in-phase movements in Study 2 and in the previous literature (Aramaki et al., 2006; Maki et al., 2008), we expected that LHS patients would display a more pronounced impairment of in-phase movements compared to RHS patients. In contrast, since anti-phase movements require a more balanced inter-hemispheric contribution as shown in Study 2, and RHS patients show larger inter-hemispheric inhibition compared to healthy participants and LHS patients (Lewis and Perreault, 2007b), we expected that RHS patients would show more impairment in anti-phase movements compared to LHS patients. As predicted, we found that patients with RHS patients exhibited greater impairment during anti-phase movements (both intra- and inter-limb parameters) and LHS patients showed greater impairment during in-phase movements (intra-limb parameters only). Though LHS patients did not show greater impairment in inter-limb coordination during in-phase movements compared to RHS patients, our regression analysis revealed that only LHS patients swapped hand dominance during the task. We interpreted this result as a compensatory mechanism whereby bilateral in-phase movements in the LHS group switched from a left-dominated cortical control to a right-dominated cortical control. Our findings not only provide causal evidence for hemispheric specialization in bilateral movement coordination, but also characterize the differential impairments in bilateral coordination after a left or right hemispheric stroke. Taken together, this dissertation highlighted differential neural control processes involved in bilateral in-phase and anti-phase movements, and demonstrated how these distinct mechanisms lead to impaired bilateral coordination in aging and stroke. The present results could therefore advance the development of therapeutic strategies that seek to counteract bilateral coordination decline, such as differential treatment for patients with left and right hemispheric lesions, or the use of noninvasive brain stimulation at a target hemisphere.:List of abbreviations List of figures List of tables Chapter 1. General introduction 1.1. Introduction 1.2. Bilateral coordination in human upper extremities 1.3. Age-related motor decline 1.4. Stroke-induced motor impairments Chapter 2. Rationale of the Dissertation Chapter 3. Study I: Human motion characteristics during bilateral in-phase and anti-phase movements 3.1. Introduction 3.2. Materials and methods 3.3. Results 3.4. Discussion 3.5. Conclusion Chapter 4. Study II: The effect of aging on bilateral coordination 49 4.1. Introduction 4.2. Materials and methods 4.3. Results 4.4. Discussion 4.5. Conclusion Chapter 5. Study III: Effects of lesioned side on bilateral coordination after strokes 5.1. Introduction 5.2. Materials and methods 5.3. Results 5.4. Discussion 5.5. Conclusion Chapter 6. General discussion 6.1. Summary of research 6.2. Contributions and clinical implications 6.3. Outlook for future research Chapter 7. Summary of the dissertation References Appendix Appendix 1. Supplementary information for study 1 Appendix 2. Supplementary information for study 2 Appendix 3. Supplementary information for study 3 Appendix 4. Declaration of authenticit