Bayesian vector autoregressive model for multi-subject effective connectivity inference using multi-modal neuroimaging data.

In this article a multi-subject vector autoregressive (VAR) modeling approach was proposed for inference on effective connectivity based on resting-state functional MRI data. Their framework uses a Bayesian variable selection approach to allow for simultaneous inference on effective connectivity at both the subject- and group-level. Furthermore, it accounts for multi-modal data by integrating structural imaging information into the prior model, encouraging effective connectivity between structurally connected regions. They demonstrated through simulation studies that their approach resulted in improved inference on effective connectivity at both the subject- and group-level, compared with currently used methods. It was concluded by illustrating the method on temporal lobe epilepsy data, where resting-state functional MRI and structural MRI were used. Hum Brain Mapp 38:1311-1332, 2017. © 2016 Wiley Periodicals, Inc.

Time-dependence of graph theory metrics in functional connectivity analysis.

Brain graphs provide a useful way to computationally model the network structure of the connectome, and this has led to increasing interest in the use of graph theory to quantitate and investigate the topological characteristics of the healthy brain and brain disorders on the network level. The majority of graph theory investigations of functional connectivity have relied on the assumption of temporal stationarity. However, recent evidence increasingly suggests that functional connectivity fluctuates over the length of the scan. In this study, we investigate the stationarity of brain network topology using a Bayesian hidden Markov model (HMM) approach that estimates the dynamic structure of graph theoretical measures of whole-brain functional connectivity. In addition to extracting the stationary distribution and transition probabilities of commonly employed graph theory measures, we propose two estimators of temporal stationarity: the S-index and N-index. These indexes can be used to quantify different aspects of the temporal stationarity of graph theory measures. We apply the method and proposed estimators to resting-state functional MRI data from healthy controls and patients with temporal lobe epilepsy. Our analysis shows that several graph theory measures, including small-world index, global integration measures, and betweenness centrality, may exhibit greater stationarity over time and therefore be more robust. Additionally, we demonstrate that accounting for subject-level differences in the level of temporal stationarity of network topology may increase discriminatory power in discriminating between disease states. Our results confirm and extend findings from other studies regarding the dynamic nature of functional connectivity, and suggest that using statistical models which explicitly account for the dynamic nature of functional connectivity in graph theory analyses may improve the sensitivity of investigations and consistency across investigations.

Functional connectivity homogeneity correlates with duration of temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is often associated with progressive changes to seizures, memory, and mood during its clinical course. However, the cerebral changes related to this progression are not well understood. Because the changes may be related to changes in brain networks, we used functional connectivity MRI (fcMRI) to determine whether brain network parameters relate to the duration of TLE. Graph theory-based analysis of the sites of reported regions of TLE abnormality was performed on resting-state fMRI data in 48 subjects: 24 controls, 13 patients with left TLE, and 11 patients with right TLE. Various network parameters were analyzed including betweenness centrality (BC), clustering coefficient (CC), path length (PL), small-world index (SWI), global efficiency (GE), connectivity strength (CS), and connectivity diversity (CD). These were compared for patients with TLE as a group, compared to controls, and for patients with left and right TLE separately. The association of changes in network parameters with epilepsy duration was also evaluated. We found that CC, CS, and CD decreased in subjects with TLE compared to control subjects. Analyzed according to epilepsy duration, patients with TLE showed a progressive reduction in CD. In conclusion, we found that several network parameters decreased in patients with TLE compared to controls, which suggested reduced connectivity in TLE. Reduction in CD associated with epilepsy duration suggests a homogenization of connections over time in TLE, indicating a reduction of the normal repertoire of stronger and weaker connections to other brain regions.

Functional connectivity of hippocampal networks in temporal lobe epilepsy.

OBJECTIVE: Temporal lobe epilepsy (TLE) affects brain areas beyond the temporal lobes due to connections of the hippocampi and other temporal lobe structures. Using functional connectivity magnetic resonance imaging (MRI), we determined the changes of hippocampal networks in TLE to assess for a more complete distribution of abnormality. METHODS: Regions of interest (ROIs) were defined in the right and left hippocampi in three groups of participants: left TLE (n = 13), right TLE (n = 11), and healthy controls (n = 16). Brain regions functionally connected to these ROIs were identified by correlating resting-state low-frequency functional MRI (fMRI) blood oxygenation level-dependent (BOLD) signal fluctuations. The grouped results were compared using independent sample t-test. RESULTS: TLE was associated with increased hippocampal connectivity involving several key areas of the limbic network (temporal lobe, insula, thalamus), frontal lobes, angular gyrus, basal ganglia, brainstem, and cerebellum, along with reduced connectivity involving areas of the sensorimotor cortex (visual, somatosensory, auditory, primary motor) and the default mode network (precuneus). Left TLE had more marked connectivity changes than right TLE. SIGNIFICANCE: The observed connectivity changes in TLE indicate dysfunctional networks that underlie widespread brain involvement in TLE. There are identifiable differences in the connectivity of the hippocampi between left and right TLE.

High-rate leading spikes in propagating spike sequences predict seizure outcome in surgical patients with temporal lobe epilepsy.

Inter-ictal spikes aid in the diagnosis of epilepsy and in planning surgery of medication-resistant epilepsy. However, the localizing information from spikes can be unreliable because spikes can propagate, and the burden of spikes, often assessed as a rate, does not always correlate with the seizure onset zone or seizure outcome. Recent work indicates identifying where spikes regularly emerge and spread could localize the seizure network. Thus, the current study sought to better understand where and how rates of single and coupled spikes, and especially brain regions with high-rate and leading spike of a propagating sequence, informs the extent of the seizure network. In 37 patients with medication-resistant temporal lobe seizures, who had surgery to treat their seizure disorder, an algorithm detected spikes in the pre-surgical depth inter-ictal EEG. A separate algorithm detected spike propagation sequences and identified the location of leading and downstream spikes in each sequence. We analysed the rate and power of single spikes on each electrode and coupled spikes between pairs of electrodes, and the proportion of sites with high-rate, leading spikes in relation to the seizure onset zone of patients seizure free (n = 19) and those with continuing seizures (n = 18). We found increased rates of single spikes in mesial temporal seizure onset zone (ANOVA, P < 0.001, η2 = 0.138), and increased rates of coupled spikes within, but not between, mesial-, lateral- and extra-temporal seizure onset zone of patients with continuing seizures (P < 0.001; η2 = 0.195, 0.113 and 0.102, respectively). In these same patients, there was a higher proportion of brain regions with high-rate leaders, and each sequence contained a greater number of spikes that propagated with a higher efficiency over a longer distance outside the seizure onset zone than patients seizure free (Wilcoxon, P = 0.0172). The proportion of high-rate leaders in and outside the seizure onset zone could predict seizure outcome with area under curve = 0.699, but not rates of single or coupled spikes (0.514 and 0.566). Rates of coupled spikes to a greater extent than single spikes localize the seizure onset zone and provide evidence for inter-ictal functional segregation, which could be an adaptation to avert seizures. Spike rates, however, have little value in predicting seizure outcome. High-rate spike sites leading propagation could represent sources of spikes that are important components of an efficient seizure network beyond the clinical seizure onset zone, and like the seizure onset zone these, too, need to be removed, disconnected or stimulated to increase the likelihood for seizure control.

Effect of lateralized temporal lobe epilepsy on the default mode network.

The default mode network (DMN) is composed of cerebral regions involved in conscious, resting state cognition. The hippocampus is an essential component of this network. Here, the DMN in TLE is compared to control subjects to better understand its involvement in TLE. We performed resting state connectivity analysis using regions of interest (ROIs) in the retrosplenium/precuneus (Rsp/PCUN) and the ventro-medial pre-frontal cortex (vmPFC) in 36 subjects (11 with right TLE, 12 with left TLE, 13 controls) to delineate the posterior and anterior DMN regions respectively. We found reduced connectivity of the posterior to the anterior DMN in patients with both right and left TLE. However, the posterior and anterior networks were found to be individually preserved. Lateralization of TLE affects the DMN with left TLE demonstrating more extensive networks. These DMN changes may be relevant to altered cognition and memory in TLE and may be relevant to right vs. left TLE differences in cognitive involvement.

Interictal Gamma Event Connectivity Differentiates the Seizure Network and Outcome in Patients after Temporal Lobe Epilepsy Surgery.

Studies of interictal EEG functional connectivity in the epileptic brain seek to identify abnormal interactions between brain regions involved in generating seizures, which clinically often is defined by the seizure onset zone (SOZ). However, there is evidence for abnormal connectivity outside the SOZ (NSOZ), and removal of the SOZ does not always result in seizure control, suggesting, in some cases, that the extent of abnormal connectivity indicates a larger seizure network than the SOZ. To better understand the potential differences in interictal functional connectivity in relation to the seizure network and outcome, we computed event connectivity in the theta (4-8 Hz, ThEC), low-gamma (30-55 Hz, LGEC), and high-gamma (65-95 Hz, HGEC) bands from interictal depth EEG recorded in surgical patients with medication-resistant seizures suspected to begin in the temporal lobe. Analysis finds stronger LGEC and HGEC in SOZ than NSOZ of seizure-free (SF) patients (p = 1.10e-9, 0.0217), but no difference in not seizure-free (NSF) patients. There were stronger LGEC and HGEC between mesial and lateral temporal SOZ of SF than NSF patients (p = 0.00114, 0.00205), and stronger LGEC and ThEC in NSOZ of NSF than SF patients (p = 0.0089, 0.0111). These results show that event connectivity is sensitive to differences in the interactions between regions in SOZ and NSOZ and SF and NSF patients. Patients with differential strengths in event connectivity could represent a well-localized seizure network, whereas an absence of differences could indicate a larger seizure network than the one localized by the SOZ and higher likelihood for seizure recurrence.

Temporal and spectral characteristics of dynamic functional connectivity between resting-state networks reveal information beyond static connectivity.

Estimation of functional connectivity (FC) has become an increasingly powerful tool for investigating healthy and abnormal brain function. Static connectivity, in particular, has played a large part in guiding conclusions from the majority of resting-state functional MRI studies. However, accumulating evidence points to the presence of temporal fluctuations in FC, leading to increasing interest in estimating FC as a dynamic quantity. One central issue that has arisen in this new view of connectivity is the dramatic increase in complexity caused by dynamic functional connectivity (dFC) estimation. To computationally handle this increased complexity, a limited set of dFC properties, primarily the mean and variance, have generally been considered. Additionally, it remains unclear how to integrate the increased information from dFC into pattern recognition techniques for subject-level prediction. In this study, we propose an approach to address these two issues based on a large number of previously unexplored temporal and spectral features of dynamic functional connectivity. A Generalized Autoregressive Conditional Heteroskedasticity (GARCH) model is used to estimate time-varying patterns of functional connectivity between resting-state networks. Time-frequency analysis is then performed on dFC estimates, and a large number of previously unexplored temporal and spectral features drawn from signal processing literature are extracted for dFC estimates. We apply the investigated features to two neurologic populations of interest, healthy controls and patients with temporal lobe epilepsy, and show that the proposed approach leads to substantial increases in predictive performance compared to both traditional estimates of static connectivity as well as current approaches to dFC. Variable importance is assessed and shows that there are several quantities that can be extracted from dFC signal which are more informative than the traditional mean or variance of dFC. This work illuminates many previously unexplored facets of the dynamic properties of functional connectivity between resting-state networks, and provides a platform for dynamic functional connectivity analysis that facilitates its usage as an investigative measure for healthy as well as abnormal brain function.

Functional MRI Correlates of Resting-State Temporal Theta and Delta EEG Rhythms.

PURPOSE: The EEG rhythms demonstrate changes in frequency and power with spontaneous changes in behavioral state that do not have well-understood metabolic correlates within the brain. To investigate this question and compare the temporal lobe theta and delta rhythms, resting-state functional MRI was obtained with simultaneous EEG. METHODS: Simultaneous EEG-functional MRI was recorded from 14 healthy sleep-deprived subjects in awake and drowsy states. Scalp electrodes corresponding to bilateral temporal lobes were used to calculate delta and theta band power. The resulting time series was used as input in a general linear model, and the final power curves were convolved with the standard hemodynamic response function. Resulting images were thresholded at Z > 2.0. RESULTS: Positive and negative correlations for unilateral theta and delta rhythms were present bilaterally in different structures and with differing correlation signs. Theta rhythm positive correlation was present in hindbrain, peri-opercular, and frontoparietal regions and subcortical gray structures, whereas negative correlation was present in parietooccipital cortex. Delta rhythm positive correlation was present in parietooccipital cortex, and negative correlation roughly resembled positive correlations for the theta rhythm. CONCLUSIONS: Temporal lobe theta and delta rhythms are correlated with functional MRI signal in an almost mutually exclusive distribution. The different distributions indicate different corresponding networks. These normal findings supplement the understanding of theta and delta rhythm significance.

A Hierarchical Bayesian Model for the Identification of PET Markers Associated to the Prediction of Surgical Outcome after Anterior Temporal Lobe Resection.

We develop an integrative Bayesian predictive modeling framework that identifies individual pathological brain states based on the selection of fluoro-deoxyglucose positron emission tomography (PET) imaging biomarkers and evaluates the association of those states with a clinical outcome. We consider data from a study on temporal lobe epilepsy (TLE) patients who subsequently underwent anterior temporal lobe resection. Our modeling framework looks at the observed profiles of regional glucose metabolism in PET as the phenotypic manifestation of a latent individual pathologic state, which is assumed to vary across the population. The modeling strategy we adopt allows the identification of patient subgroups characterized by latent pathologies differentially associated to the clinical outcome of interest. It also identifies imaging biomarkers characterizing the pathological states of the subjects. In the data application, we identify a subgroup of TLE patients at high risk for post-surgical seizure recurrence after anterior temporal lobe resection, together with a set of discriminatory brain regions that can be used to distinguish the latent subgroups. We show that the proposed method achieves high cross-validated accuracy in predicting post-surgical seizure recurrence.

Network analysis of the default mode network using functional connectivity MRI in Temporal Lobe Epilepsy.

Functional connectivity MRI (fcMRI) is an fMRI method that examines the connectivity of different brain areas based on the correlation of BOLD signal fluctuations over time. Temporal Lobe Epilepsy (TLE) is the most common type of adult epilepsy and involves multiple brain networks. The default mode network (DMN) is involved in conscious, resting state cognition and is thought to be affected in TLE where seizures cause impairment of consciousness. The DMN in epilepsy was examined using seed based fcMRI. The anterior and posterior hubs of the DMN were used as seeds in this analysis. The results show a disconnection between the anterior and posterior hubs of the DMN in TLE during the basal state. In addition, increased DMN connectivity to other brain regions in left TLE along with decreased connectivity in right TLE is revealed. The analysis demonstrates how seed-based fcMRI can be used to probe cerebral networks in brain disorders such as TLE.

Functional MRI of sleep spindles and K-complexes.

OBJECTIVE: Sleep spindles and K-complexes are EEG hallmarks of non-REM sleep. However, the brain regions generating these discharges and the functional connections of their generators to other regions are not fully known. We investigated the neuroanatomical correlates of spindles and K-complexes using simultaneous EEG and fMRI. METHODS: EEGs recorded during EEG-fMRI studies of 7 individuals were used for fMRI analysis. Higher-level group analyses were performed, and images were thresholded at Z ≥ 2.3. RESULTS: fMRI of 106 spindles and 60 K-complexes was analyzed. Spindles corresponded to increased signal in thalami and posterior cingulate, and right precuneus, putamen, paracentral cortex, and temporal lobe. K-complexes corresponded to increased signal in thalami, superior temporal lobes, paracentral gyri, and medial regions of the occipital, parietal and frontal lobes. Neither corresponded to regions of decreased signal. CONCLUSIONS: fMRI of both spindles and K-complexes depicts signal subjacent to the vertex, which likely indicates each discharges' source. The thalamic signal is consistent with thalamic involvement in sleep homeostasis. The limbic region's signal is consistent with roles in memory consolidation. Unlike the spindle, the K-complex corresponds to extensive signal in primary sensory cortices. SIGNIFICANCE: Identification of these active regions contributes to the understanding of sleep networks and the physiology of awareness and memory during sleep.

Functional imaging of sleep vertex sharp transients.

OBJECTIVE: The vertex sharp transient (VST) is an electroencephalographic (EEG) discharge that is an early marker of non-REM sleep. It has been recognized since the beginning of sleep physiology research, but its source and function remain mostly unexplained. We investigated VST generation using functional MRI (fMRI). METHODS: Simultaneous EEG and fMRI were recorded from seven individuals in drowsiness and light sleep. VST occurrences on EEG were modeled with fMRI using an impulse function convolved with a hemodynamic response function to identify cerebral regions correlating to the VSTs. A resulting statistical image was thresholded at Z>2.3. RESULTS: Two hundred VSTs were identified. Significantly increased signal was present bilaterally in medial central, lateral precentral, posterior superior temporal, and medial occipital cortex. No regions of decreased signal were present. CONCLUSION: The regions are consistent with electrophysiologic evidence from animal models and functional imaging of human sleep, but the results are specific to VSTs. The regions principally encompass the primary sensorimotor cortical regions for vision, hearing, and touch. SIGNIFICANCE: The results depict a network comprising the presumed VST generator and its associated regions. The associated regions functional similarity for primary sensation suggests a role for VSTs in sensory experience during sleep.

Neural correlates of two imagined egocentric transformations.

Two egocentric spatial transformation tasks, hand and perspective rotation, were compared using the same visual stimulus within both block and event-related functional magnetic resonance imaging (fMRI) paradigms. Both involved body-relative judgments but were predicted to vary in the recruitment of the body schema and a motor execution system. The Hand task required the imagined rotation of one's own hand to make a left-right handedness decision. In contrast, the Viewer task required a perspective transformation and updating of the parts of a hand as an object. Previous behavioral and neuroimaging work suggested that hand rotations would rely on dynamic and biomechanical processing of body-part relations recruiting a motor processing system, whereas perspective transformations and the updating of object-self relations would be supported by primarily visual-spatial mechanisms. There was a common neural substrate found for both tasks including the lateral occipital areas, inferior and superior parietal cortex, and the cerebellum. Direct comparisons between the two tasks revealed greater activation in the Hand task in left superior and inferior parietal and premotor cortex and cerebellum, whereas the Viewer task showed greater activation only in the right lingual and fusiform gyri. Degree of rotation also modulated activity in the Hand task in bilateral superior parietal and premotor cortex, but not in the Viewer task. Implications of these regions for the role of dynamic body schema and motor processing in egocentric transformations are discussed.