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

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

Brain rhythms of pain

Pain is an integrative phenomenon that results from dynamic interactions between sensory and contextual (i.e., cognitive, emotional, and motivational) processes. In the brain the experience of pain is associated with neuronal oscillations and synchrony at different frequencies. However, an overarching framework for the significance of oscillations for pain remains lacking. Recent concepts relate oscillations at different frequencies to the routing of information flow in the brain and the signaling of predictions and prediction errors. The application of these concepts to pain promises insights into how flexible routing of information flow coordinates diverse processes that merge into the experience of pain. Such insights might have implications for the understanding and treatment of chronic pain

Disturbed resting state EEG synchronization in bipolar disorder: A graph-theoretic analysis

AbstractDisruption of functional connectivity may be a key feature of bipolar disorder (BD) which reflects disturbances of synchronization and oscillations within brain networks. We investigated whether the resting electroencephalogram (EEG) in patients with BD showed altered synchronization or network properties. Resting-state EEG was recorded in 57 BD type-I patients and 87 healthy control subjects. Functional connectivity between pairs of EEG channels was measured using synchronization likelihood (SL) for 5 frequency bands (δ, θ, α, β, and γ). Graph-theoretic analysis was applied to SL over the electrode array to assess network properties. BD patients showed a decrease of mean synchronization in the alpha band, and the decreases were greatest in fronto-central and centro-parietal connections. In addition, the clustering coefficient and global efficiency were decreased in BD patients, whereas the characteristic path length increased. We also found that the normalized characteristic path length and small-worldness were significantly correlated with depression scores in BD patients. These results suggest that BD patients show impaired neural synchronization at rest and a disruption of resting-state functional connectivity

Changes in MEG resting-state networks are related to cognitive decline in type 1 diabetes mellitus patients

OBJECTIVE: Integrity of resting-state functional brain networks (RSNs) is important for proper cognitive functioning. In type 1 diabetes mellitus (T1DM) cognitive decrements are commonly observed, possibly due to alterations in RSNs, which may vary according to microvascular complication status. Thus, we tested the hypothesis that functional connectivity in RSNs differs according to clinical status and correlates with cognition in T1DM patients, using an unbiased approach with high spatio-temporal resolution functional network.; METHODS: Resting-state magnetoencephalographic (MEG) data for T1DM patients with (n=42) and without (n=41) microvascular complications and 33 healthy participants were recorded. MEG time-series at source level were reconstructed using a recently developed atlas-based beamformer. Functional connectivity within classical frequency bands, estimated by the phase lag index (PLI), was calculated within eight commonly found RSNs. Neuropsychological tests were used to assess cognitive performance, and the relation with RSNs was evaluated.; RESULTS: Significant differences in terms of RSN functional connectivity between the three groups were observed in the lower alpha band, in the default-mode (DMN), executive control (ECN) and sensorimotor (SMN) RSNs. T1DM patients with microvascular complications showed the weakest functional connectivity in these networks relative to the other groups. For DMN, functional connectivity was higher in patients without microangiopathy relative to controls (all p<0.05). General cognitive performance for both patient groups was worse compared with healthy controls. Lower DMN alpha band functional connectivity correlated with poorer general cognitive ability in patients with microvascular complications.; DISCUSSION: Altered RSN functional connectivity was found in T1DM patients depending on clinical status. Lower DMN functional connectivity was related to poorer cognitive functioning. These results indicate that functional connectivity may play a key role in T1DM-related cognitive dysfunction

Functional connectivity in mild cognitive impairment during a memory task: implications for the disconnection hypothesis.

Mild cognitive impairment (MCI) has been considered an intermediate state between healthy aging and dementia. The early damage in anatomical connectivity and progressive loss of synapses that characterize early Alzheimer's disease suggest that MCI could also be a disconnection syndrome. Here, we compare the degree of synchronization of brain signals recorded with magnetoencephalography from patients (22) with MCI with that of healthy controls (19) during a memory task. Synchronization Likelihood, an index based on the theory of nonlinear dynamical systems, was used to measure functional connectivity. During the memory task patients showed higher interhemispheric synchronization than healthy controls between left and right -anterior temporo-frontal regions (in all studied frequency bands) and in posterior regions in the γ band. On the other hand, the connectivity pattern from healthy controls indicated two clusters of higher synchronization, one among left temporal sensors and another one among central channels. Both of them were found in all frequency bands. In the γ band, controls showed higher Synchronization Likelihood values than MCI patients between central-posterior and frontal-posterior channels and a high synchronization in posterior regions. The inter-hemispheric increased synchronization values could reflect a compensatory mechanism for the lack of efficiency of the memory networks in MCI patients. Therefore, these connectivity profiles support only partially the idea of MCI as a disconnection syndrome, as patients showed increased long distance inter-hemispheric connections but a decrease in antero-posterior functional connectivit

Synchronization during an internally directed cognitive state in healthy aging and mild cognitive impairment: a MEG study

Mild Cognitive Impairment (MCI) is a stage between healthy aging and dementia. Functional connectivity is widely used to study the brain activity during resting state or cognitive tasks. We aimed to determine the functional connectivity changes required to deal with an Internally Directed Cognitive State (IDICS) in healthy aging and MCI. This task differs from the most commonly employed in Magnetoencephalograpy (MEG)/ Electroencephalography (EEG), since inhibition from external stimuli is needed, and it allows the study of this control mechanism in healthy and pathological aging. To this end, MEG signals were acquired from 32 healthy individuals and 38 MCI patients, both in resting state and while performing a subtraction task of two levels of difficulty. Phase Locking Value (PLV) was calculated for five frequency bands: delta, theta, alpha, beta and gamma. Synchronization patterns changed in both groups while performing the task. MCI patients presented higher connectivity changes than those in the control group, and this was related to a lower cognitive performance. In particular, in MCIs a hypersynchronization in delta, theta, beta and gamma bands was found, which reveals an abnormal functioning in this group. Contrary to controls, MCIs presented a lack of synchronization in the alpha band which may denote an inhibition deficit. Additionally, the magnitude of connectivity changes rose with the task difficulty in controls but not in MCIs, in line with the CRUNCH model (Compensation-Related Utilization of Neural Circuits Hypothesis)

A novel method of early diagnosis of Alzheimer's disease based on EEG signals.

Studies have reported that electroencephalogram signals in Alzheimer's disease patients usually have less synchronization than those of healthy subjects. Changes in electroencephalogram signals start at early stage but, clinically, these changes are not easily detected. To detect this perturbation, three neural synchrony measurement techniques: phase synchrony, magnitude squared coherence, and cross correlation are applied to three different databases of mild Alzheimer's disease patients and healthy subjects. We have compared the right and left temporal lobes of the brain with the rest of the brain areas (frontal, central, and occipital) as temporal regions are relatively the first ones to be affected by Alzheimer's disease. Moreover, electroencephalogram signals are further classified into five different frequency bands (delta, theta, alpha beta, and gamma) because each frequency band has its own physiological significance in terms of signal evaluation. A new approach using principal component analysis before applying neural synchrony measurement techniques has been presented and compared with Average technique. The simulation results indicated that applying principal component analysis before synchrony measurement techniques shows significantly better results as compared to the lateral one. At the end, all the aforementioned techniques are assessed by a statistical test (Mann-Whitney U test) to compare the results

사람에서 점멸광자극을 이용한 성공적인 감마뇌파동조 유도의 결정 요인

학위논문(박사) -- 서울대학교대학원 : 자연과학대학 뇌인지과학과, 2023. 2. 김기웅.Background and Objectives: Although gamma entrainment using flickering light stimulus (FLS) of 40Hz was effective in reducing pathologies and enhancing cognitive function in mouse models of Alzheimers disease (AD), its efficacy was controversial in AD patients. The conflicting results in AD patients may be attributable to a couple of key factors. First, the optimal parameters of FLS for gamma entrainment may be different between diurnal humans and nocturnal mice. Second, the response to optimal FLS may be different between AD patients due to inter-individual difference in the microstructural integrity of white matter (WM) tracts. This study aimed to find the optimal parameters (color, luminal intensity and flickering frequency) of FLS for entraining gamma rhythms in diurnal humans and to examine the effect of fractional anisotropy (FA) of WM tracts on the entrainment and propagation of gamma rhythms. Methods: We first investigated the optimal color (white, red, green, and blue), luminal intensity (10 cd/m2, 100 cd/m2, 400 cd/m2, and 700 cd/m2), and frequency (32 - 50 Hz) of FLS for entraining gamma rhythms in visual cortex using event-related desynchronization/event-related synchronization (ERD/ERS) and for propagating gamma rhythm entrained in visual cortex to other brain regions using spectral Granger Causality (sGC) in 16 cognitively normal young adults (24.0 ± 3.7 yrs) and 35 cognitively normal older adults (70.0 ± 2.4 yrs). We also examined the adverse effects of FLS in both younger and older adults. Then we examined the effect of the FA of posterior thalamic radiations on the ERS of gamma rhythms entrained in visual cortex and that of and middle and superior longitudinal fasciculi on the sGC of the connectivity from visual cortex to temporal and frontal regions in 26 cognitively normal older adults using analysis of variance and linear regression analyses. Results: The FLSs using the lights of longer wavelengths such as white (p < 0.05) and red (p < 0.01) entrained and propagated gamma rhythms better than those of shorter wavelengths such as green and blue. The FLSs using stronger lights such as 700 cd/m2 (p < 0.001) and 400 cd/m2 (p < 0.01) entrained and propagated gamma rhythms better than weaker lights of 100 cd/m2 and 10 cd/m2. The FLSs flickering at 34-38 Hz were best for entraining and propagating gamma rhythm in younger adults (entrainment at Pz: p < 0.05, propagation: p < 0.05) while those flickering at 32-34 Hz were best for older adults (entrainment at Pz: p < 0.05, propagation: p < 0.001). In older adults, white FLSs of 700 cd/m2 flickering at 32–34 Hz entrained the gamma rhythms most strongly at visual cortex (p < 0.05) and propagated them most widely to other brain regions (p < 0.05). The FLSs of 700 cd/m2 flickering at 32 Hz entrained gamma rhythms worse in the visual cortex of the older adults whose FA of left posterior thalamic radiation was low than in those whose FA of left posterior thalamic radiation was not low (p 0.05), and their severity of adverse effects was milder than that in younger adults. Conclusion: In diurnal human, optimal flickering frequency for gamma entrainment was about 20% lower than that in nocturnal mice. Although the FLSs of stronger luminal intensity and the longer wavelength may entrain gamma rhythms better, they may result in more and severe adverse effects. In older adults, white or red FLSs of 700 cd/m2 flickering at 32-34 Hz may be optimal for entraining and propagating gamma rhythms. Since gamma rhythms were not properly entrained by optimal FLS in the older adults whose microstructural integrity of the white matter tracts was impaired, the integrity of the white matter tracts involved in the entrainment and propagation of gamma rhythm should be measured and considered in determining the indication of gamma entrainment using visual stimulation.연구배경 및 목적: 40Hz 점멸광자극 (flickering light stimulation, FLS)을 사용한 감마뇌파동조는 알츠하이머병 (Alzheimers disease, AD) 모델 쥐에서 병리를 감소시키고 인지 기능을 향상시키는 데 효과적이었지만 알츠하이머병 환자에서는 그 효능에 대해 논란이 있다. 알츠하이머병 환자의 상충되는 결과는 몇 가지 주요 요인에 기인할 수 있다. 첫째, 감마뇌파동조를 위한 FLS의 최적 매개변수는 일주 동물인 인간과 야행성 동물인 쥐 간에 다를 수 있다. 둘째, 최적의 FLS에 대한 반응은 백질 (white matter, WM) 섬유 다발 미세 구조적 무결성의 개인 간 차이로 인해 알츠하이머병 환자 간에 다를 수 있다. 이 연구는 일주 동물인 인간에서 감마뇌파를 동반하기 위한 FLS의 최적 매개변수 (색상, 밝기 및 점멸 주파수)를 찾고 감마뇌파의 동반 및 전파에 대한 백질 섬유 다발의 확산비등방성 (fractional anisotropy, FA)의 영향을 조사하는 것을 목표로 했다. 연구방법: 인지기능이 정상인 젊은 성인 16명과 노인 35명을 대상으로, 시각피질에 감마뇌파동조를 유도하고, 동조 된 시각피질의 감마뇌파를 다른 뇌 영역으로의 전파시킬 수 있는 FLS의 최적 색상 (백색, 적색, 녹색 및 청색), 밝기 (10 cd/m2, 100 cd/m2, 400 cd/m2 및 700 cd/m2) 및 점멸 주파수 (32-50 Hz)를 사건 관련 비 동기화/사건 관련 동기화 (event-related desynchronization/event-related synchronization, ERD/ERS)와 스펙트럼 그랜저 인과성 (spectral Granger Causality, sGC) 분석을 이용하여 조사했다. 아울러 젊은 성인과 노인에서 FLS의 부작용을 조사했다. 이어서 감마뇌파가 FLS에 의해 시각피질에 적절하게 동조 된 인지기능이 정상인 노인 26명을 대상으로, 시각피질에서 동조 된 감마뇌파의 ERS와 시각피질과 측두 및 전두 영역들 간 연결성인 sGC에 후방시상방사와 중간 및 상부 세로다발들의 확산비등방성이 미치는 영향을 회귀분석과 분산분석을 이용하여 조사했다. 연구결과: 사람에서는 백색 (p < 0.05) 및 적색 (p < 0.01)과 같은 장파장 FLS가 녹색 및 청색과 같은 단파장 FLS보다 감마뇌파동조를 더 강하게 유발하고, 동조 된 감마뇌파를 더 넓은 뇌 영역으로 전파시켰다. 또 700 cd/m2 (p < 0.001) 및 400 cd/m2 (p < 0.01)와 같은 강한 휘도 FLS는 100 cd/m2 및 10 cd/m2와 같은 약한 휘도 FLS보다 감마뇌파동조를 더 강하게 유발하고, 동조 된 감마뇌파를 더 넓은 뇌 영역으로 전파시켰다. 34-38 Hz에서 점멸하는 FLS는 젊은 성인에서 감마뇌파를 동반하고 전파하는 데 가장 효과적이었고 (Pz에서 동반: p < 0.05, 전파: p < 0.05) 32-34 Hz에서 점멸하는 FLS는 노인에게 가장 효과적이었다 (Pz에서 동반: p < 0.05, 전파: p < 0.001). 노인에서 32-34 Hz에서 점멸하는 700 cd/m2의 백색 FLS는 시각 피질에서 가장 강하게 감마뇌파를 동반하고 (p < 0.05) 다른 뇌 영역으로 가장 널리 전파했다 (p < 0.05). 32 Hz에서 점멸하는 700 cd/m2의 FLS는 좌후시상방사선의 FA가 낮지 않은 노인보다 낮은 노인에서 감마뇌파가 시각피질에 덜 동반된다 (p 0.05), 부작용의 심각성은 젊은 성인보다 경미했다. 결론: 주행성인 인간에서 감마 동조를 위한 최적의 점멸 주파수는 야행성 쥐보다 약 20% 낮았다. 더 강한 휘도와 더 긴 파장의 FLS가 감마뇌파를 더 잘 동조 시킬 수 있지만 더 크고 심각한 부작용을 초래할 수 있다. 노인의 경우 32-34 Hz에서 점멸하는 700 cd/m2의 백색 또는 적색 FLS가 감마뇌파를 동조하고 전파하는 데 최적일 수 있다. 감마뇌파는 백질 섬유 다발의 미세 구조적 무결성이 손상된 노인에서는 최적의 FLS에 의해 적절하게 동조 되지 않았기 때문에, 감마뇌파의 동조 및 전파와 관련된 백질 영역의 무결성은 시각적 자극을 사용하여 감마뇌파동조 적용을 결정할 때 측정되고 고려되어야 한다.1. Introduction 1 1.1. Background 1 1.2. Purpose 4 2. Methods 6 2.1. Study design 6 2.1.1. Study 1. Investigation on the optimal parameters of FLS for gamma entrainment in humans 6 2.1.2. Study 2. Investigation on the effect of WM microstructural integrity on the gamma entrainment by FLS in humans 7 2.2. Participants 7 2.2.1. Study 1. Investigation on the optimal parameters of FLS for gamma entrainment in humans 7 2.2.2. Study 2. Investigation on the effect of WM microstructural integrity on the gamma entrainment by FLS in humans 8 2.2.3. Clinical evaluation of the participants 8 2.3. Research ethics 9 2.4. FLS 9 2.5. Recording, preprocessing and analysis of EEG 10 2.6. Acquisition, preprocessing and analysis of DTI 13 2.7. Statistical analyses 14 3. Results 16 3.1. Effects of the rsEEG spectral band power on cognitive function 16 3.2. Entrainment and propagation of the gamma rhythms by FLS 16 3.3. Effects of the FLS color on gamma entrainment and propagation 17 3.4. Effects of the FLS intensity on gamma entrainment and propagation 18 3.5. Effects of the FLS frequency on gamma entrainment and propagation 18 3.6. Effects of the microstructural integrity of WM tracts on the gamma entrainment and propagation 20 3.7. Adverse effects 21 4. Discussions 23 5. Conclusions 35 Bibliography 66 국문초록 81박

Analysis of Magnetoencephalography Signals from Alzheimer’s Disease Patients Using Granger Causality

Producción CientíficaThe aim of this study was to analyze resting-state magnetoencephalography (MEG) activity in Alzheimer’s disease (AD) by means of Granger Causality (GC), an effective connectivity measure that provides an estimation of the information flow between brain regions. For this task, five minutes of MEG recordings were acquired with a 148-channel whole-head magnetometer from 36 AD patients and 26 healthy controls. Abnormalities in AD connectivity were found in the five typical frequency bands: delta (δ, 1-4 Hz), theta (θ, 4-8 Hz), alpha (α, 8-13 Hz), beta (β, 13-30 Hz), and gamma (γ, 30-65 Hz). Noteworthy increments in delta band and decrements in beta and gamma bands revealed disrupted connections in AD brain activity. Our analyses suggest that GC may be useful to characterize the brain impairment in AD.Ministerio de Economía y Competitividad (TEC2014-53196-R)Junta de Castilla y León (VA059U13 y BIO/VA08/15