Analysis of Respiratory Sinus Arrhythmia and Directed Information Flow between Brain and Body Indicate Different Management Strategies of fMRI-Related Anxiety.

BACKGROUND: Respiratory sinus arrhythmia (RSA) denotes decrease of cardiac beat-to-beat intervals (RRI) during inspiration and RRI increase during expiration, but an inverse pattern (termed negative RSA) was also found in healthy humans with elevated anxiety. It was detected using wave-by-wave analysis of cardiorespiratory rhythms and was considered to reflect a strategy of anxiety management involving the activation of a neural pacemaker. Results were consistent with slow breathing, but contained uncertainty at normal breathing rates (0.2-0.4 Hz). OBJECTIVES AND METHODS: We combined wave-by-wave analysis and directed information flow analysis to obtain information on anxiety management at higher breathing rates. We analyzed cardiorespiratory rhythms and blood oxygen level-dependent (BOLD) signals from the brainstem and cortex in 10 healthy fMRI participants with elevated anxiety. RESULTS: Three subjects with slow respiratory, RRI, and neural BOLD oscillations showed 57 ± 26% negative RSA and significant anxiety reduction by 54 ± 9%. Six participants with breathing rate of ~0.3 Hz showed 41 ± 16% negative RSA and weaker anxiety reduction. They presented significant information flow from RRI to respiration and from the middle frontal cortex to the brainstem, which may result from respiration-entrained brain oscillations, indicating another anxiety management strategy. CONCLUSIONS: The two analytical approaches applied here indicate at least two different anxiety management strategies in healthy subjects.

Respiration-entrained brain oscillations in healthy fMRI participants with high anxiety.

Brain-body interactions can be studied by using directed coupling measurements of fMRI oscillations in the low (0.1-0.2 Hz) and high frequency bands (HF; 0.2-0.4 Hz). Recently, a preponderance of oscillations in the information flow between the brainstem and the prefrontal cortex at around 0.15/0.16 Hz was shown. The goal of this study was to investigate the information flow between BOLD-, respiratory-, and heart beat-to-beat interval (RRI) signals in the HF band in healthy subjects with high anxiety during fMRI examinations. A multivariate autoregressive model was concurrently applied to the BOLD signals from the middle frontal gyrus (MFG), precentral gyrus and the brainstem, as well as to respiratory and RRI signals. Causal coupling between all signals was determined using the Directed Transfer Function (DTF). We found a salience of fast respiratory waves with a period of 3.1 s (corresponding to ~ 0.32 Hz) and a highly significant (p < 0.001) top-down information-flow from BOLD oscillations in the MFG to the brainstem. Additionally, there was a significant (p < 0.01) information flow from RRI to respiratory oscillations. We speculate that brain oscillations around 0.32 Hz, triggered by nasal breathing, are projected downwards to the brainstem. Particularly interesting is the driving force of cardiac to respiratory waves with a ratio of 1:1 or 1:2. These results support the binary hierarchy model with preferred respiratory frequencies at 0.32 Hz and 0.16 Hz.

Effect of learning on slow gamma propagation between hippocampus and cortex in the wild-type and AD mice.

Slow gamma oscillations (20-50 Hz) have been suggested to coordinate information transfer between brain structures involved in memory formation. Whereas the involvement of slow gamma in memory processing was studied by means of correlation between the gamma power and the occurrence of a given event (sharp wave ripples (SWRs), cortical transients), our approach consists of the analysis of the transmission of slow gamma itself. We use the method based on Granger causality principle-direct Directed Transfer Function, which allows to determine directed propagation of brain activity, including bidirectional flows. Four cortical sites along with CA1 ipsi- and contralateral were recorded in behaving wild-type and APP/PS1 mice before and after learning session of a spatial memory task. During slow wave sleep propagation of slow gamma was bidirectional, forming multiple loops of interaction which involved both CA1 and some of cortical sites. In episodes coincident with SWRs the number and strength of connectivity pathways increased in both groups compared to episodes without SWRs. The effect of learning was expressed only in APP/PS1 mice and consisted in strengthening of the slow gamma transmission from hippocampus to cortex as well as between both CA1 which may serve more efficient transmission of information from impaired CA1.

Processing of fMRI-related anxiety and information flow between brain and body revealed a preponderance of oscillations at 0.15/0.16 Hz.

Slow oscillations of different center frequencies and their coupling play an important role in brain-body interactions. The crucial question analyzed by us is, whether the low frequency (LF) band (0.05-0.15 Hz) or the intermediate frequency (IMF) band (0.1-0.2 Hz) is more eminent in respect of the information flow between body (heart rate and respiration) and BOLD signals in cortex and brainstem. A recently published study with the LF band in fMRI-naïve subjects revealed an intensive information flow from the cortex to the brainstem and a weaker flow from the brainstem to the cortex. The comparison of both bands revealed a significant information flow from the middle frontal gyrus (MFG) to the precentral gyrus (PCG) and from brainstem to PCG only in the IMF band. This pattern of directed coupling between slow oscillations in the cortex and brainstem not only supports the existence of a pacemaker-like structure in brainstem, but provides first evidence that oscillations centered at 0.15/0.16 Hz can also emerge in brain networks. BOLD oscillations in resting states are dominating at ~ 0.08 Hz and respiratory rates at ~ 0.32 Hz. Therefore, the frequency component at ~ 0.16 Hz (doubling-halving 0.08 Hz or 0.32 Hz) is of special interest, because phase coupled oscillations can reduce the energy demand.

From Coherence to Multivariate Causal Estimators of EEG Connectivity.

The paper concerns the development of methods of EEG functional connectivity estimation including short overview of the currently applied measures describing their advantages and flaws. Linear and non-linear, bivariate and multivariate methods are confronted. The performance of different connectivity measures in respect of robustness to noise, common drive effect and volume conduction is considered providing a guidance towards future developments in the field, which involve evaluation not only functional, but also effective (causal) connectivity. The time-varying connectivity measure making possible estimation of dynamical information processing in brain is presented. The methods of post-processing of connectivity results are considered involving application of advanced graph analysis taking into account community structure of networks and providing hierarchy of networks rather than the single, binary networks currently used.

Processing of fMRI-related anxiety and bi-directional information flow between prefrontal cortex and brain stem.

Brain-heart synchronization is fundamental for emotional-well-being and brain-heart desynchronization is characteristic for anxiety disorders including specific phobias. Recording BOLD signals with functional magnetic resonance imaging (fMRI) is an important noninvasive diagnostic tool; however, 1-2% of fMRI examinations have to be aborted due to claustrophobia. In the present study, we investigated the information flow between regions of interest (ROI's) in the cortex and brain stem by using a frequency band close to 0.1 Hz. Causal coupling between signals important in brain-heart interaction (cardiac intervals, respiration, and BOLD signals) was studied by means of Directed Transfer Function based on the Granger causality principle. Compared were initial resting states with elevated anxiety and final resting states with low or no anxiety in a group of fMRI-naïve young subjects. During initial high anxiety the results showed an increased information flow from the middle frontal gyrus (MFG) to the pre-central gyrus (PCG) and to the brainstem. There also was an increased flow from the brainstem to the PCG. While the top-down flow during increased anxiety was predominant, the weaker ascending flow from brainstem structures may characterize a rhythmic pacemaker-like activity that (at least in part) drives respiration. We assume that these changes in information flow reflect successful anxiety processing.

Measures of resting state EEG rhythms for clinical trials in Alzheimer's disease: Recommendations of an expert panel.

The Electrophysiology Professional Interest Area (EPIA) and Global Brain Consortium endorsed recommendations on candidate electroencephalography (EEG) measures for Alzheimer's disease (AD) clinical trials. The Panel reviewed the field literature. As most consistent findings, AD patients with mild cognitive impairment and dementia showed abnormalities in peak frequency, power, and "interrelatedness" at posterior alpha (8-12 Hz) and widespread delta (< 4 Hz) and theta (4-8 Hz) rhythms in relation to disease progression and interventions. The following consensus statements were subscribed: (1) Standardization of instructions to patients, resting state EEG (rsEEG) recording methods, and selection of artifact-free rsEEG periods are needed; (2) power density and "interrelatedness" rsEEG measures (e.g., directed transfer function, phase lag index, linear lagged connectivity, etc.) at delta, theta, and alpha frequency bands may be use for stratification of AD patients and monitoring of disease progression and intervention; and (3) international multisectoral initiatives are mandatory for regulatory purposes.

Reconfiguration of the cortical-hippocampal interaction may compensate for Sharp-Wave Ripple deficits in APP/PS1 mice and support spatial memory formation.

Hippocampal-cortical dialogue, during which hippocampal ripple oscillations support information transfer, is necessary for long-term consolidation of spatial memories. Whereas a vast amount of work has been carried out to understand the cellular and molecular mechanisms involved in the impairments of memory formation in Alzheimer's disease (AD), far less work has been accomplished to understand these memory deficiencies at the network-level interaction that may underlie memory processing. We recently demonstrated that freely moving 8 to 9-month-old APP/PS1 mice, a model of AD, are able to learn a spatial reference memory task despite a major deficit in Sharp-Wave Ripples (SWRs), the integrity of which is considered to be crucial for spatial memory formation. In order to test whether reconfiguration of hippocampal-cortical dialogue could be responsible for the maintenance of this ability for memory formation, we undertook a study to identify causal relations between hippocampal and cortical circuits in epochs when SWRs are generated in hippocampus. We analyzed the data set obtained from multielectrode intracranial recording of transgenic and wild-type mice undergoing consolidation of spatial memory reported in our previous study. We applied Directed Transfer Function, a connectivity measure based on Granger causality, in order to determine effective coupling between distributed circuits which express oscillatory activity in multiple frequency bands. Our results showed that hippocampal-cortical coupling in epochs containing SWRs was expressed in the two frequency ranges corresponding to ripple (130-180 Hz) and slow gamma (20-60 Hz) band. The general features of connectivity patterns were similar in the 8 to 9-month-old APP/PS1 and wild-type animals except that the coupling in the slow gamma range was stronger and spread to more cortical sites in APP/PS1 mice than in the wild-type group. During the occurrence of SWRs, the strength of effective coupling from the cortex to hippocampus (CA1) in the ripple band undergoes sharp increase, involving cortical areas that were different in the two groups of animals. In the wild-type group, retrosplenial cortex and posterior cingulate cortex interacted with the hippocampus most strongly, whereas in the APP/PS1 group more anterior structures interacted with the hippocampus, that is, anterior cingulate cortex and prefrontal cortex. This reconfiguration of cortical-hippocampal interaction pattern may be an adaptive mechanism responsible for supporting spatial memory consolidation in AD mice model.

International Federation of Clinical Neurophysiology (IFCN) - EEG research workgroup: Recommendations on frequency and topographic analysis of resting state EEG rhythms. Part 1: Applications in clinical research studies.

In 1999, the International Federation of Clinical Neurophysiology (IFCN) published "IFCN Guidelines for topographic and frequency analysis of EEGs and EPs" (Nuwer et al., 1999). Here a Workgroup of IFCN experts presents unanimous recommendations on the following procedures relevant for the topographic and frequency analysis of resting state EEGs (rsEEGs) in clinical research defined as neurophysiological experimental studies carried out in neurological and psychiatric patients: (1) recording of rsEEGs (environmental conditions and instructions to participants; montage of the EEG electrodes; recording settings); (2) digital storage of rsEEG and control data; (3) computerized visualization of rsEEGs and control data (identification of artifacts and neuropathological rsEEG waveforms); (4) extraction of "synchronization" features based on frequency analysis (band-pass filtering and computation of rsEEG amplitude/power density spectrum); (5) extraction of "connectivity" features based on frequency analysis (linear and nonlinear measures); (6) extraction of "topographic" features (topographic mapping; cortical source mapping; estimation of scalp current density and dura surface potential; cortical connectivity mapping), and (7) statistical analysis and neurophysiological interpretation of those rsEEG features. As core outcomes, the IFCN Workgroup endorsed the use of the most promising "synchronization" and "connectivity" features for clinical research, carefully considering the limitations discussed in this paper. The Workgroup also encourages more experimental (i.e. simulation studies) and clinical research within international initiatives (i.e., shared software platforms and databases) facing the open controversies about electrode montages and linear vs. nonlinear and electrode vs. source levels of those analyses.

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 corticocortical 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.

Coupling Between Brain Structures During Visual and Auditory Working Memory Tasks.

Transmission of EEG activity during a visual and auditory version of the working memory task based on the paradigm of linear syllogism was investigated. Our aim was to find possible similarities and differences in the synchronization patterns between brain structures during the same mental activity performed on different modality stimuli. The EEG activity transmission was evaluated by means of full frequency Directed Transfer Function (ffDTF) and short-time Directed Transfer Function (SDTF). SDTF provided information on dynamical propagation of EEG activity. The assortative mixing approach was applied to quantify coupling between regions of interest encompassing frontal, central and two posterior modules. The results showed similar schemes of coupling for both modalities with stronger coupling within the regions of interests than between them, which is concordant with the theories concerning efficient wiring and metabolic energy saving. The patterns of transmission showed main sources of activity in the anterior and posterior regions communicating intermittently in a broad frequency range. The differences between the patterns of transmission between the visual and auditory versions of working memory tasks were subtle and involved bigger propagation from the posterior electrodes towards the frontal ones during the visual task as well as from the temporal sites to the frontal ones during the auditory task.

Coupling of Oxy- and Deoxyhemoglobin concentrations with EEG rhythms during motor task.

A relationship between the brain rhythmic activity and the hemodynamic response was studied using the simultaneous measurement of electroencephalogram (EEG) and the functional near-infrared spectroscopy (fNIRS) during a motor task (self-paced right finger movements) for 10 subjects. An EEG recording with a 32-electrode (10-10) system was made and the hemodynamic response was obtained using 8 optodes placed over the sensorimotor cortex on both hemispheres. During the task an increase in oxyhemoglobine (HbO) was accompanied by a decrease in deoxyhemoglobine (HbR) concentration and a decrease in amplitudes (desynchronisation) of alpha (8-13 Hz) and beta (13-30 Hz) EEG rhythms. These phenomena were prominent in the hemisphere contralateral to the moving finger. The delays between the hemodynamic and electrophysiological variables were on average 2.8 s. Highly significant (p < 0.0001) negative Pearson correlations were found between HbO and alpha (r2 = -0.69) and HbO and beta (r2 = -0.54) rhythms. Positive correlations r2 = 0.5 between these rhythms and HbR were found.

Functional and effective brain connectivity for discrimination between Alzheimer's patients and healthy individuals: A study on resting state EEG rhythms.

OBJECTIVE: This exploratory study provided a proof of concept of a new procedure using multivariate electroencephalographic (EEG) topographic markers of cortical connectivity to discriminate normal elderly (Nold) and Alzheimer's disease (AD) individuals. METHOD: The new procedure was tested on an existing database formed by resting state eyes-closed EEG data (19 exploring electrodes of 10-20 system referenced to linked-ear reference electrodes) recorded in 42 AD patients with dementia (age: 65.9years±8.5 standard deviation, SD) and 42 Nold non-consanguineous caregivers (age: 70.6years±8.5 SD). In this procedure, spectral EEG coherence estimated reciprocal functional connectivity while non-normalized directed transfer function (NDTF) estimated effective connectivity. Principal component analysis and computation of Mahalanobis distance integrated and combined these EEG topographic markers of cortical connectivity. The area under receiver operating curve (AUC) indexed the classification accuracy. RESULTS: A good classification of Nold and AD individuals was obtained by combining the EEG markers derived from NDTF and coherence (AUC=86%, sensitivity=0.85, specificity=0.70). CONCLUSION: These encouraging results motivate a cross-validation study of the new procedure in age- and education-matched Nold, stable and progressing mild cognitive impairment individuals, and de novo AD patients with dementia. SIGNIFICANCE: If cross-validated, the new procedure will provide cheap, broadly available, repeatable over time, and entirely non-invasive EEG topographic markers reflecting abnormal cortical connectivity in AD patients diagnosed by direct or indirect measurement of cerebral amyloid ß and hyperphosphorylated tau peptides.

Measures of Coupling between Neural Populations Based on Granger Causality Principle.

This paper shortly reviews the measures used to estimate neural synchronization in experimental settings. Our focus is on multivariate measures of dependence based on the Granger causality (G-causality) principle, their applications and performance in respect of robustness to noise, volume conduction, common driving, and presence of a "weak node." Application of G-causality measures to EEG, intracranial signals and fMRI time series is addressed. G-causality based measures defined in the frequency domain allow the synchronization between neural populations and the directed propagation of their electrical activity to be determined. The time-varying G-causality based measure Short-time Directed Transfer Function (SDTF) supplies information on the dynamics of synchronization and the organization of neural networks. Inspection of effective connectivity patterns indicates a modular structure of neural networks, with a stronger coupling within modules than between them. The hypothetical plausible mechanism of information processing, suggested by the identified synchronization patterns, is communication between tightly coupled modules intermitted by sparser interactions providing synchronization of distant structures.

Matching Pursuit with Asymmetric Functions for Signal Decomposition and Parameterization.

The method of adaptive approximations by Matching Pursuit makes it possible to decompose signals into basic components (called atoms). The approach relies on fitting, in an iterative way, functions from a large predefined set (called dictionary) to an analyzed signal. Usually, symmetric functions coming from the Gabor family (sine modulated Gaussian) are used. However Gabor functions may not be optimal in describing waveforms present in physiological and medical signals. Many biomedical signals contain asymmetric components, usually with a steep rise and slower decay. For the decomposition of this kind of signal we introduce a dictionary of functions of various degrees of asymmetry--from symmetric Gabor atoms to highly asymmetric waveforms. The application of this enriched dictionary to Otoacoustic Emissions and Steady-State Visually Evoked Potentials demonstrated the advantages of the proposed method. The approach provides more sparse representation, allows for correct determination of the latencies of the components and removes the "energy leakage" effect generated by symmetric waveforms that do not sufficiently match the structures of the analyzed signal. Additionally, we introduced a time-frequency-amplitude distribution that is more adequate for representation of asymmetric atoms than the conventional time-frequency-energy distribution.

Functional brain networks: random, "small world" or deterministic?

Lately the problem of connectivity in brain networks is being approached frequently by graph theoretical analysis. In several publications based on bivariate estimators of relations between EEG channels authors reported random or "small world" structure of networks. The results of these works often have no relation to other evidence based on imaging, inverse solutions methods, physiological and anatomical data. Herein we try to find reasons for this discrepancy. We point out that EEG signals are very much interdependent, thus bivariate measures applied to them may produce many spurious connections. In fact, they may outnumber the true connections. Giving all connections equal weights, as it is usual in the framework of graph theoretical analysis, further enhances these spurious links. In effect, close to random and disorganized patterns of connections emerge. On the other hand, multivariate connectivity estimators, which are free of the artificial links, show specific, well determined patterns, which are in a very good agreement with other evidence. The modular structure of brain networks may be identified by multivariate estimators based on Granger causality and formalism of assortative mixing. In this way, the strength of coupling may be evaluated quantitatively. During working memory task, by means of multivariate Directed Transfer Function, it was demonstrated that the modules characterized by strong internal bonds exchange the information by weaker connections.