EEG connectivity patterns in response to gaming and learning-based cognitive stimulations in Rett syndrome.

BACKGROUND: Functional connectivity is scarcely studied in Rett syndrome (RTT). Explorations revealed associations between RTT's clinical, genetic profiles, and coherence measures, highlighting an unexplored frontier in understanding RTT's neural mechanisms and cognitive processes. AIMS: To evaluate the effects of diverse cognitive stimulations-learning-focused versus gaming-oriented-on electroencephalography brain connectivity in RTT. The comparison with resting states aimed to uncover potential biomarkers and insights into the neural processes associated with RTT. METHODS AND PROCEDURES: The study included 15 girls diagnosed with RTT. Throughout sessions lasting about 25 min, participants alternated between active and passive tasks, using an eyetracker device while their brain activity was recorded with a 20-channel EEG. Results revealed significant alterations during cognitive tasks, notably in delta, alpha and beta bands. Both tasks induced spectral pattern changes and connectivity shifts, hinting at enhanced neural processing. Hemispheric asymmetry decreased during tasks, suggesting more balanced neural processing. Linear and nonlinear connectivity alterations were observed in active tasks compared to resting state, while passive tasks showed no significant changes. CONCLUSIONS AND IMPLICATIONS: Results underscores the potential of cognitive stimulation for heightened cognitive abilities, promoting enhanced brain connectivity and information flow in Rett syndrome. These findings offer valuable markers for evaluating cognitive interventions and suggest gaming-related activities as effective tools for improving learning outcomes.

One size does not fit all: notable individual variation in brain activity correlates of antidepressant treatment response.

Introduction: To date, no robust electroencephalography (EEG) markers of antidepressant treatment response have been identified. Variable findings may arise from the use of group analyses, which neglect individual variation. Using a combination of group and single-participant analyses, we explored individual variability in EEG characteristics of treatment response. Methods: Resting-state EEG data and Montgomery-Åsberg Depression Rating Scale (MADRS) symptom scores were collected from 43 patients with depression before, at 1 and 12 weeks of pharmacotherapy. Partial least squares (PLS) was used to: 1) identify group differences in EEG connectivity (weighted phase lag index) and complexity (multiscale entropy) between eventual medication responders and non-responders, and 2) determine whether group patterns could be identified in individual patients. Results: Responders showed decreased alpha and increased beta connectivity, and early, widespread decreases in complexity over treatment. Non-responders showed an opposite connectivity pattern, and later, spatially confined decreases in complexity. Thus, as in previous studies, our group analyses identified significant differences between groups of patients with different treatment outcomes. These group-level EEG characteristics were only identified in ~40-60% of individual patients, as assessed quantitatively by correlating the spatiotemporal brain patterns between groups and individual results, and by independent raters through visualization. Discussion: Our single-participant analyses suggest that substantial individual variation exists, and needs to be considered when investigating characteristics of antidepressant treatment response for potential clinical applicability. Clinical trial registration: https://clinicaltrials.gov, identifier NCT00519428.

Potential biomarker for early detection of ADHD using phase-based brain connectivity and graph theory.

This research investigates an efficient strategy for early detection and intervention of attention-deficit hyperactivity disorder (ADHD) in children. ADHD is a neurodevelopmental condition characterized by inattention and hyperactivity/impulsivity symptoms, which can significantly impact a child's daily life. This study employed two distinct brain functional connectivity measurements to assess our approach across various local graph features. Six common classifiers are employed to distinguish between children with ADHD and healthy control. Based on the phase-based analysis, the study proposes two biomarkers that differentiate children with ADHD from healthy control, with a remarkable accuracy of 99.174%. Our findings suggest that subgraph centrality of phase-lag index brain connectivity within the beta and delta frequency bands could be a promising biomarker for ADHD diagnosis. Additionally, we identify node betweenness centrality of inter-site phase clustering connectivity within the delta and theta bands as another potential biomarker that warrants further exploration. These biomarkers were validated using a t-statistical test and yielded a p-value of under 0.05, which approved their significant difference in these two groups. Suggested biomarkers have the potential to improve the accuracy of ADHD diagnosis and could help identify effective intervention strategies for children with the condition.

Associating Functional Neural Connectivity and Specific Aspects of Sensorimotor Control in Chronic Stroke.

Hand sensorimotor deficits often result from stroke, limiting the ability to perform daily living activities. Sensorimotor deficits are heterogeneous among stroke survivors. Previous work suggests a cause of hand deficits is altered neural connectivity. However, the relationships between neural connectivity and specific aspects of sensorimotor control have seldom been explored. Understanding these relationships is important for developing personalized rehabilitation strategies to improve individual patients' specific sensorimotor deficits and, thus, rehabilitation outcomes. Here, we investigated the hypothesis that specific aspects of sensorimotor control will be associated with distinct neural connectivity in chronic stroke survivors. Twelve chronic stroke survivors performed a paretic hand grip-and-relax task while EEG was collected. Four aspects of hand sensorimotor grip control were extracted, including reaction time, relaxation time, force magnitude control, and force direction control. EEG source connectivity in the bilateral sensorimotor regions was calculated in α and ß frequency bands during grip preparation and execution. Each of the four hand grip measures was significantly associated with a distinct connectivity measure. These results support further investigations into functional neural connectivity signatures that explain various aspects of sensorimotor control, to assist the development of personalized rehabilitation that targets the specific brain networks responsible for the individuals' distinct sensorimotor deficits.

A review of critical brain oscillations in depression and the efficacy of transcranial magnetic stimulation treatment.

Repetitive transcranial magnetic stimulation (rTMS) and intermittent theta burst stimulation (iTBS) have been proven effective non-invasive treatments for patients with drug-resistant major depressive disorder (MDD). However, some depressed patients do not respond to these treatments. Therefore, the investigation of reliable and valid brain oscillations as potential indices for facilitating the precision of diagnosis and treatment protocols has become a critical issue. The current review focuses on brain oscillations that, mostly based on EEG power analysis and connectivity, distinguish between MDD and controls, responders and non-responders, and potential depression severity indices, prognostic indicators, and potential biomarkers for rTMS or iTBS treatment. The possible roles of each biomarker and the potential reasons for heterogeneous results are discussed, and the directions of future studies are proposed.

EEG Connectivity in ADHD Compared to a Normative Database: A Cohort Analysis of 120 Subjects from the ICAN Study.

This study explores how EEG connectivity measures in children with ADHD ages 7-10 (n = 140) differ from an age-matched nonclinical database. We differentiated connectivity in networks, Brodmann area pairs, and frequencies. Subjects were in the International Collaborative ADHD Neurofeedback study, which explored neurofeedback for ADHD. Inclusion criteria were mainly rigorously diagnosed ADHD and a theta/beta power ratio (TBR) ≤ 4.5. Using statistical and machine learning algorithms, connectivity values were extracted in coherence, phase, and lag coherence at all Brodmann, subcortical, and cerebellar areas within the main networks in all EEG frequencies and then compared with a normative database. There is a higher rate of dysregulation (more than ± 1.97SD), in some cases as much as 75%, of the Brodmann pairs observed in coherence and phase between BAs 7, 10, and 11 with secondary connections from these areas to BAs 21, 30, 35, 37, 39, and 40 in the ADHD children as compared to the normative database. Left and right Brodmann areas 10 and 11 are highly disconnected to each other. The most dysregulated Brodmann Areas in ADHD are 7, 10, and 11, relevant to ADHD executive-function deficits and provide important considerations when developing interventions for ADHD children.

Who's driving? The default mode network in healthy elderly individuals at risk of cognitive decline.

Introduction: Age is the main risk factor for the development of neurocognitive disorders, with Alzheimer's disease being the most common. Its physiopathological features may develop decades before the onset of clinical symptoms. Quantitative electroencephalography (qEEG) is a promising and cost-effective tool for the prediction of cognitive decline in healthy older individuals that exhibit an excess of theta activity. The aim of the present study was to evaluate the feasibility of brain connectivity variable resolution electromagnetic tomography (BC-VARETA), a novel source localization algorithm, as a potential tool to assess brain connectivity with 19-channel recordings, which are common in clinical practice. Methods: We explored differences in terms of functional connectivity among the nodes of the default mode network between two groups of healthy older participants, one of which exhibited an EEG marker of risk for cognitive decline. Results: The risk group exhibited increased levels of delta, theta, and beta functional connectivity among nodes of the default mode network, as well as reversed directionality patterns of connectivity among nodes in every frequency band when compared to the control group. Discussion: We propose that an ongoing pathological process may be underway in healthy elderly individuals with excess theta activity in their EEGs, which is further evidenced by changes in their connectivity patterns. BC-VARETA implemented on 19-channels EEG recordings appears to be a promising tool to detect dysfunctions at the connectivity level in clinical settings.

Hyperconnectivity matters in early-onset Alzheimer's disease: a resting-state EEG connectivity study.

OBJECTIVES: The aim of this study was to differentiate individuals with early-onset Alzheimer's disease (EOAD) and identify differences of functional connectivity in resting-state EEG between individuals with EOAD and late-onset AD (LOAD) in comparison with both healthy young and elderly individuals. METHODS: Forty EOAD and 56 LOAD patients were included along with 51 demographically matched young, and 54 elderly healthy individuals as controls to the EOAD and LOAD groups. Four minutes of resting-state EEG were recorded during the eyes-closed condition. The absolute value of imaginary coherence (ICoh) was measured for connectivity. The maximum values of ICoh were measured at delta (0.5-3.5 Hz), theta (4-7.5Hz), alpha (8-13 Hz), alpha-1 (8-10 Hz), alpha-2 (10.5-13 Hz), beta (13-30 Hz), beta-1 (13-20 Hz), and beta-2 (20.5-30 Hz) frequency bands. RESULTS: Individuals with EOAD showed higher coherence values in all frequency bands than LOAD patients. Compared to young healthy controls (YHC), EOAD had increased ICoh values in theta and beta-2 bands, whereas LOAD had lower ICoh values in the alpha-1 band than elderly healthy controls (EHC). Lastly, patients with EOAD demonstrated negative moderate correlations between language domains and beta-1 ICoh values. CONCLUSION: To the authors' knowledge, this is the first study evaluating coherence alterations among early-and late-onset AD patients and the diagnostic value of coherence measures. It was suggested that EOAD patients had more severe pathological changes compared with LOAD.

Brain Activity Characteristics of Patients With Disorders of Consciousness in the EEG Resting State Paradigm: A Review.

The assessment of the level of consciousness in disorders of consciousness (DoC) is still one of the most challenging problems in contemporary medicine. Nevertheless, based on the multitude of studies conducted over the last 20 years on resting states based on electroencephalography (EEG) in DoC, it is possible to outline the brain activity profiles related to both patients without preserved consciousness and minimally conscious ones. In the case of patients without preserved consciousness, the dominance of low, mostly delta, frequency, and the marginalization of the higher frequencies were observed, both in terms of the global power of brain activity and in functional connectivity patterns. In turn, the minimally conscious patients revealed the opposite brain activity pattern-the characteristics of higher frequency bands were preserved both in global power and in functional long-distance connections. In this short review, we summarize the state of the art of EEG-based research in the resting state paradigm, in the context of providing potential support to the traditional clinical assessment of the level of consciousness.

Electroencephalographic Connectivity: A Fundamental Guide and Checklist for Optimal Study Design and Evaluation.

Brain connectivity can be estimated through many analyses applied to electroencephalography (EEG) data. However, substantial heterogeneity in the implementation of connectivity methods exists. Heterogeneity in conceptualization of connectivity measures, data collection, or data preprocessing may be associated with variability in robustness of measurement. While it is difficult to compare the results of studies using different EEG connectivity measures, standardization of processing and reporting may facilitate the task. We discuss how factors such as referencing, epoch length and number, controls for volume conduction, artifact removal, and statistical control of multiple comparisons influence the EEG connectivity estimate for connectivity measures, and what can be done to control for potential confounds associated with these factors. Based on the results reported in previous literature, this article presents recommendations and a novel checklist developed for quality assessment of EEG connectivity studies. This checklist and its recommendations are made in an effort to draw attention to factors that may influence connectivity estimates and factors that need to be improved in future research. Standardization of procedures and reporting in EEG connectivity may lead to EEG connectivity studies being made more synthesizable and comparable despite variations in the methodology underlying connectivity estimates.

Evaluation of Directed Causality Measures and Lag Estimations in Multivariate Time-Series.

The detection of causal effects among simultaneous observations provides knowledge about the underlying network, and is a topic of interests in many scientific areas. Over the years different causality measures have been developed, each with their own advantages and disadvantages. However, an extensive evaluation study is missing. In this work we consider some of the best-known causality measures i.e., cross-correlation, (conditional) Granger causality index (CGCI), partial directed coherence (PDC), directed transfer function (DTF), and partial mutual information on mixed embedding (PMIME). To correct for noise-related spurious connections, each measure (except PMIME) is tested for statistical significance based on surrogate data. The performance of the causality metrics is evaluated on a set of simulation models with distinct characteristics, to assess how well they work in- as well as outside of their "comfort zone." PDC and DTF perform best on systems with frequency-specific connections, while PMIME is the only one able to detect non-linear interactions. The varying performance depending on the system characteristics warrants the use of multiple measures and comparing their results to avoid errors. Furthermore, lags between coupled variables are inherent to real-world systems and could hold essential information on the network dynamics. They are however often not taken into account and we lack proper tools to estimate them. We propose three new methods for lag estimation in multivariate time series, based on autoregressive modelling and information theory. One of the autoregressive methods and the one based on information theory were able to reliably identify the correct lag value in different simulated systems. However, only the latter was able to maintain its performance in the case of non-linear interactions. As a clinical application, the same methods are also applied on an intracranial recording of an epileptic seizure. The combined knowledge from the causality measures and insights from the simulations, on how these measures perform under different circumstances and when to use which one, allow us to recreate a plausible network of the seizure propagation that supports previous observations of desynchronisation and synchronisation during seizure progression. The lag estimation results show absence of a relationship between connectivity strength and estimated lag values, which contradicts the line of thinking in connectivity shaped by the neuron doctrine.

Robust EEG Based Biomarkers to Detect Alzheimer's Disease.

Biomarkers to detect Alzheimer's disease (AD) would enable patients to gain access to appropriate services and may facilitate the development of new therapies. Given the large numbers of people affected by AD, there is a need for a low-cost, easy to use method to detect AD patients. Potentially, the electroencephalogram (EEG) can play a valuable role in this, but at present no single EEG biomarker is robust enough for use in practice. This study aims to provide a methodological framework for the development of robust EEG biomarkers to detect AD with a clinically acceptable performance by exploiting the combined strengths of key biomarkers. A large number of existing and novel EEG biomarkers associated with slowing of EEG, reduction in EEG complexity and decrease in EEG connectivity were investigated. Support vector machine and linear discriminate analysis methods were used to find the best combination of the EEG biomarkers to detect AD with significant performance. A total of 325,567 EEG biomarkers were investigated, and a panel of six biomarkers was identified and used to create a diagnostic model with high performance (≥85% for sensitivity and 100% for specificity).

EEG Assessment in Patients With Disorders of Consciousness: Aims, Advantages, Limits, and Pitfalls.

This study presents a brief review of literature exploring simple EEG-polygraphic examinations and procedures that can be carried out at a patient's bedside. These include EEG with a common electrode array and sleep evaluation. The review briefly discusses more complex analytical techniques, such as the application of advanced EEG signal processing methods developed by our research group, to define what type of consistent markers are suitable for clinical use or to better understand complex patient conditions. These advanced analytical techniques aim to detect relevant EEG-based markers that could be useful in evaluating patients and predicting outcomes. These data could contribute to future developments in research.

Statistical Analysis of Graph-Theoretic Indices to Study EEG-TMS Connectivity in Patients With Depression.

AIM: The objective of this work was to demonstrate the usefulness of a novel statistical method to study the impact of transcranial magnetic stimulation (TMS) on brain connectivity in patients with depression using different stimulation protocols, i.e., 1 Hz repetitive TMS over the right dorsolateral prefrontal cortex (DLPFC) (protocol G1), 10 Hz repetitive TMS over the left DLPFC (G2), and intermittent theta burst stimulation (iTBS) consisting of three 50 Hz burst bundle repeated at 5 Hz frequency (G3). METHODS: Electroencephalography (EEG) connectivity analysis was performed using Directed Transfer Function (DTF) and a set of 21 indices based on graph theory. The statistical analysis of graph-theoretic indices consisted of a combination of the k-NN rule, the leave-one-out method, and a statistical test using a 2 × 2 contingency table. RESULTS: Our new statistical approach allowed for selection of the best set of graph-based indices derived from DTF, and for differentiation between conditions (i.e., before and after TMS) and between TMS protocols. The effects of TMS was found to differ based on frequency band. CONCLUSION: A set of four brain asymmetry measures were particularly useful to study protocol- and frequency-dependent effects of TMS on brain connectivity. SIGNIFICANCE: The new approach would allow for better evaluation of the therapeutic effects of TMS and choice of the most appropriate stimulation protocol.

Electroencephalographic correlates of body shape concerns: an eLORETA functional connectivity study.

The main aim of the present study was to investigate the association between body shape concerns and electroencephalography (EEG) functional connectivity within body image network in a sample of university students (N = 68). EEG was recorded during 5 min of resting state. All participants were asked to complete self-report measures assessing certain psychopathological dimensions (i.e., body shape concerns, depression, anxiety, obsessive-compulsive symptoms). EEG analyses were conducted by means of the exact low-resolution electromagnetic tomography software (eLORETA). Our results showed that body shape concerns were positively associated with increased gamma functional connectivity between the left and right prefrontal cortex (PFC). Furthermore, our data revealed that this EEG pattern was independently associated with body shape concerns after controlling for potential socio-demographic and clinical confounding variables. This finding seems to suggest that increased EEG gamma connectivity between the left and right PFC might be a relevant neurophysiological alteration involved in the development and/or maintenance of dysfunctional concerns about one's body.

Genetic Association Between Alzheimer's Disease Risk Variant of the PICALM Gene and EEG Functional Connectivity in Non-demented Adults.

Genome wide association studies (GWAS) have identified and validated the association of the PICALM genotype with Alzheimer's disease (AD). The PICALM rs3851179 A allele is thought to have a protective effect, whereas the G allele appears to confer risk for AD. The influence of the PICALM genotype on brain functional connectivity in non-demented subjects remains largely unknown. We examined the association of the PICALM rs3851179 genotype with the characteristics of lagged linear connectivity (LLC) of resting EEG sources in 104 non-demented adults younger than 60 years of age. The EEG analysis was performed using exact low-resolution brain electromagnetic tomography (eLORETA) freeware (Pascual-Marqui et al., 2011). We found that the carriers of the A PICALM allele (PICALM AA and AG genotypes) had higher widespread interhemispheric LLC of alpha sources compared to the carriers of the GG PICALM allele. An exploratory correlation analysis showed a moderate positive association between the alpha LLC interhemispheric characteristics and the corpus callosum size and between the alpha interhemispheric LLC characteristics and the Luria word memory scores. These results suggest that the PICALM rs3851179 A allele provides protection against cognitive decline by facilitating neurophysiological reserve capacities in non-demented adults. In contrast, lower functional connectivity in carriers of the AD risk variant, PICALM GG, suggests early functional alterations in alpha rhythm networks.

Altered neural oscillations and connectivity in the beta band underlie detail-oriented visual processing in autism.

Sensory and perceptual anomalies may have a major impact on basic cognitive and social skills in humans. Autism Spectrum Disorder (ASD) represents a special perspective to explore this relationship, being characterized by both these features. The present study employed electroencephalography (EEG) to test whether detail-oriented visual perception, a recognized hallmark of ASD, is associated with altered neural oscillations and functional connectivity in the beta frequency band, considering its role in feedback and top-down reentrant signalling in the typical population. Using a visual crowding task, where participants had to discriminate a peripheral target letter surrounded by flankers at different distances, we found that detail-oriented processing in children with ASD, as compared to typically developing peers, could be attributed to anomalous oscillatory activity in the beta band (15-30 Hz), while no differences emerged in the alpha band (8-12 Hz). Altered beta oscillatory response reflected in turn atypical functional connectivity between occipital areas, where the initial stimulus analysis is accomplished, and infero-temporal regions, where objects identity is extracted. Such atypical beta connectivity predicted both ASD symptomatology and their detail-oriented processing. Overall, these results might be explained by an altered feedback connectivity within the visual system, with potential cascade effects in visual scene parsing and higher order functions.

Electroencephalogram Source Connectivity in the Prediction of Electroconvulsive Therapy Outcome in Major Depressive Disorder.

Objectives. Major depressive disorder (MDD) is a common and potentially lethal disorder affecting up to 14% of all persons worldwide. However, one-third to thwo-thirds of patients are nonresponders to first-line therapy. Even the electroconvulsive therapy (ECT) as the option of choice in therapy-resistant MDD still shows a high proportion of nonresponders. In case of a predicted nonresponse to ECT, for example, by means of electrophysiological electroencephalogram (EEG) parameters, other therapies of MDD (eg, augmentation, polypharmacy etc) could be chosen. Methods. In this study, we retrospectively analyzed 2-minute resting state EEGs from patients with MDD who underwent ECT (6-12 sessions with 3 sessions per week) between 2006 and 2015 at the University Hospital of Zurich. Following several lines of evidence, we hypothesized altered linear EEG connectivity within the alpha band being predictive for treatment outcome. We used a network-based statistics (NBS) approach to compare connectivity measures between responders and nonresponders. Source estimates and connectivity measures were mapped using low-resolution brain tomography (LORETA). As the main outcome parameter served the retrospectively assessed efficacy index (CGI-E) from the Clinical Global Impression (CGI) rating scale. Results. Responders in comparison with non-responders showed a significant lower linear lagged connectivity in widespread cortical areas within the EEG alpha 2 band. Additionally, there were strong correlations between CGI ratings and connectivity strength mainly within frontal cortices. Conclusions. Pretreatment EEG-connectivity within the alpha 2 band has a predictive value for the efficacy of ECT treatment.

Unmixing EEG Inverse Solutions Based on Brain Segmentation.

Due to its low resolution, any EEG inverse solution provides a source estimate at each voxel that is a mixture of the true source values over all the voxels of the brain. This mixing effect usually causes notable distortion in estimates of source connectivity based on inverse solutions. To lessen this shortcoming, an unmixing approach is introduced for EEG inverse solutions based on piecewise approximation of the unknown source by means of a brain segmentation formed by specified Regions of Interests (ROIs). The approach is general and flexible enough to be applied to any inverse solution with any specified family of ROIs, including point, surface and 3D brain regions. Two of its variants are elaborated in detail: arbitrary piecewise constant sources over arbitrary regions and sources with piecewise constant intensity of known direction over cortex surface regions. Numerically, the approach requires just solving a system of linear equations. Bounds for the error of unmixed estimates are also given. Furthermore, insights on the advantages and of variants of this approach for connectivity analysis are discussed through a variety of designed simulated examples.

A Comparative Study of Different EEG Reference Choices for Diagnosing Unipolar Depression.

The choice of an electroencephalogram (EEG) reference has fundamental importance and could be critical during clinical decision-making because an impure EEG reference could falsify the clinical measurements and subsequent inferences. In this research, the suitability of three EEG references was compared while classifying depressed and healthy brains using a machine-learning (ML)-based validation method. In this research, the EEG data of 30 unipolar depressed subjects and 30 age-matched healthy controls were recorded. The EEG data were analyzed in three different EEG references, the link-ear reference (LE), average reference (AR), and reference electrode standardization technique (REST). The EEG-based functional connectivity (FC) was computed. Also, the graph-based measures, such as the distances between nodes, minimum spanning tree, and maximum flow between the nodes for each channel pair, were calculated. An ML scheme provided a mechanism to compare the performances of the extracted features that involved a general framework such as the feature extraction (graph-based theoretic measures), feature selection, classification, and validation. For comparison purposes, the performance metrics such as the classification accuracies, sensitivities, specificities, and F scores were computed. When comparing the three references, the diagnostic accuracy showed better performances during the REST, while the LE and AR showed less discrimination between the two groups. Based on the results, it can be concluded that the choice of appropriate reference is critical during the clinical scenario. The REST reference is recommended for future applications of EEG-based diagnosis of mental illnesses.