Sharon Chiang

Graph theory findings in the pathophysiology of temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is the most common form of adult epilepsy. Accumulating evidence has shown that TLE is a disorder of abnormal epileptogenic networks, rather than focal sources. Graph theory allows for a network-based representation of TLE brain networks, and has potential to illuminate characteristics of brain topology conducive to TLE pathophysiology, including seizure initiation and spread. We review basic concepts which we believe will prove helpful in interpreting results rapidly emerging from graph theory research in TLE. In addition, we summarize the current state of graph theory findings in TLE as they pertain its pathophysiology. Several common findings have emerged from the many modalities which have been used to study TLE using graph theory, including structural MRI, diffusion tensor imaging, surface EEG, intracranial EEG, magnetoencephalography, functional MRI, cell cultures, simulated models, and mouse models, involving increased regularity of the interictal network configuration, altered local segregation and global integration of the TLE network, and network reorganization of temporal lobe and limbic structures. As different modalities provide different views of the same phenomenon, future studies integrating data from multiple modalities are needed to clarify findings and contribute to the formation of a coherent theory on the pathophysiology of TLE.

Clinical correlates of graph theory findings in temporal lobe epilepsy.

PURPOSE Temporal lobe epilepsy (TLE) is considered a brain network disorder, additionally representing the most common form of pharmaco-resistant epilepsy in adults. There is increasing evidence that seizures in TLE arise from abnormal epileptogenic networks, which extend beyond the clinico-radiologically determined epileptogenic zone and may contribute to the failure rate of 30-50% following epilepsy surgery. Graph theory allows for a network-based representation of TLE brain networks using several neuroimaging and electrophysiologic modalities, and has potential to provide clinicians with clinically useful biomarkers for diagnostic and prognostic purposes. METHODS We performed a review of the current state of graph theory findings in TLE as they pertain to localization of the epileptogenic zone, prediction of pre- and post-surgical seizure frequency and cognitive performance, and monitoring cognitive decline in TLE. RESULTS Although different neuroimaging and electrophysiologic modalities have yielded occasionally conflicting results, several potential biomarkers have been characterized for identifying the epileptogenic zone, pre-/post-surgical seizure prediction, and assessing cognitive performance. For localization, graph theory measures of centrality have shown the most potential, including betweenness centrality, outdegree, and graph index complexity, whereas for prediction of seizure frequency, measures of synchronizability have shown the most potential. The utility of clustering coefficient and characteristic path length for assessing cognitive performance in TLE is also discussed. CONCLUSIONS Future studies integrating data from multiple modalities and testing predictive models are needed to clarify findings and develop graph theory for its clinical utility.

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.

Differences in graph theory functional connectivity in left and right temporal lobe epilepsy

PURPOSE To investigate lateralized differences in limbic system functional connectivity between left and right temporal lobe epilepsy (TLE) using graph theory. METHODS Interictal resting state fMRI was performed in 14 left TLE patients, 11 right TLE patients, and 12 controls. Graph theory analysis of 10 bilateral limbic regions of interest was conducted. Changes in edgewise functional connectivity, network topology, and regional topology were quantified, and then left and right TLE were compared. RESULTS Limbic edgewise functional connectivity was predominantly reduced in both left and right TLE. More regional connections were reduced in right TLE, most prominently involving reduced interhemispheric connectivity between the bilateral insula and bilateral hippocampi. A smaller number of limbic connections were increased in TLE, more so in left than in right TLE. Topologically, the most pronounced change was a reduction in average network betweenness centrality and concurrent increase in left hippocampal betweenness centrality in right TLE. In contrast, left TLE exhibited a weak trend toward increased right hippocampal betweenness centrality, with no change in average network betweenness centrality. CONCLUSION Limbic functional connectivity is predominantly reduced in both left and right TLE, with more pronounced reductions in right TLE. In contrast, left TLE exhibits both edgewise and topological changes that suggest a tendency toward reorganization. Network changes in TLE and lateralized differences thereof may have important diagnostic and prognostic implications.

CCR2 Gene Deletion and Pharmacologic Blockade Ameliorate a Severe Murine Experimental Autoimmune Neuritis Model of Guillain-Barré Syndrome

The molecular determinants and signaling pathways responsible for hematogenous leukocyte trafficking during peripheral neuroinflammation are incompletely elucidated. Chemokine ligand/receptor pair CCL2/CCR2 has been pathogenically implicated in the acute inflammatory demyelinating polyradiculoneuropathy variant of Guillain-Barré syndrome (GBS). We evaluated the role of CCR2 in peripheral neuroinflammation utilizing a severe murine experimental autoimmune neuritis (sm-EAN) model. Sm-EAN was induced in 8–12 week old female SJL CCR2 knockout (CCR2KO), heterozygote (CCR2HT) and wild type (CCR2WT) mice, and daily neuromuscular severity scores and weights recorded. In vitro and in vivo splenocyte proliferation and cytokine expression assays, and sciatic nerve Toll-like receptor (TLR) 2, TLR4 and CCL2 expression assays were performed to evaluate systemic and local innate immune activation at disease onset. Motor nerve electrophysiology and sciatic nerve histology were also performed to characterize the inflammatory neuropathy at expected peak severity. To further determine the functional relevance of CCR2 in sm-EAN, 20 mg/kg CCR2 antagonist, RS 102895 was administered daily for 5 days to a cohort of CCR2WT mice following sm-EAN disease onset, with efficacy compared to 400 mg/kg human intravenous immunoglobulin (IVIg). CCR2KO mice were relatively resistant to sm-EAN compared to CCR2WT and CCR2HT mice, associated with attenuated peripheral nerve demyelinating neuritis. Partial CCR2 gene deletion did not confer any protection against sm-EAN. CCR2KO mice demonstrated similar splenocyte activation or proliferation profiles, as well as TLR2, TLR4 and CCL2 expression to CCR2WT or CCR2HT mice, implying a direct role for CCR2 in sm-EAN pathogenesis. CCR2 signaling blockade resulted in rapid, near complete recovery from sm-EAN following disease onset. RS 102895 was significantly more efficacious than IVIg. CCR2 mediates pathogenic hematogenous monocyte trafficking into peripheral nerves, with consequential demyelination in sm-EAN. CCR2 is amenable to pharmacologic blockade, making it a plausible drug target for GBS.

White matter structural connectivity changes correlate with epilepsy duration in temporal lobe epilepsy

PURPOSE Temporal lobe epilepsy (TLE) is thought to be a network disease and structural changes using diffusion tensor imaging (DTI) have been shown. However, lateralized differences in the structural integrity of TLE, as well as changes in structural integrity with longer disease duration, have not been well defined. METHODS We examined the fractional anisotropy (FA) and mean diffusivity (MD) in the hippocampus, as well as its primary (cingulum and fornix) and remote (uncinate and external capsule) connections in both right and left TLE. Changes in diffusion measures over the disease course were examined by correlating FA and MD in the various structures with epilepsy duration. The potential for each measure of anisotropy and diffusivity as a marker of TLE laterality was investigated using random forest (RF) analysis. RESULTS MD was increased in the bilateral hippocampus, cingulum, fornix and the right external capsule in both left and right TLE compared to controls. In addition, left TLE exhibited an increased MD in the ipsilateral uncinate fasciculus and bilateral external capsules. A decrease in FA was seen in the left cingulum in left TLE. RF analysis demonstrated that MD of the right hippocampus and FA of the left external capsule were important predictors of TLE laterality. An association of increased MD with epilepsy duration was seen in the left hippocampus in left TLE. CONCLUSION Evidence of disrupted white matter architecture in the hippocampus and its primary and remote connections were demonstrated in TLE. While changes in the hippocampus and cingulum were more prominent in right TLE, remote changes were more prominent in left TLE. MD of the right hippocampus and FA of the left external capsule were found to be the strongest structural predictors of TLE laterality. Changes associated with duration of epilepsy indicated that changes in structural integrity may be progressive over the disease course. This study illustrates the potential of structural diffusion tensor imaging in elucidating pathophysiology, enhancing diagnosis and assisting prognostication.

Brain Graph Topology Changes Associated with Anti-Epileptic Drug Use.

Neuroimaging studies of functional connectivity using graph theory have furthered our understanding of the network structure in temporal lobe epilepsy (TLE). Brain network effects of anti-epileptic drugs could influence such studies, but have not been systematically studied. Resting-state functional MRI was analyzed in 25 patients with TLE using graph theory analysis. Patients were divided into two groups based on anti-epileptic medication use: those taking carbamazepine/oxcarbazepine (CBZ/OXC) (n=9) and those not taking CBZ/OXC (n=16) as a part of their medication regimen. The following graph topology metrics were analyzed: global efficiency, betweenness centrality (BC), clustering coefficient, and small-world index. Multiple linear regression was used to examine the association of CBZ/OXC with graph topology. The two groups did not differ from each other based on epilepsy characteristics. Use of CBZ/OXC was associated with a lower BC. Longer epilepsy duration was also associated with a lower BC. These findings can inform graph theory-based studies in patients with TLE. The changes observed are discussed in relation to the anti-epileptic mechanism of action and adverse effects of CBZ/OXC.

The role of chemokines in Guillain-Barré syndrome.

Introduction: Chemokines and their receptors are important mediators of inflammation. Guillain–Barré syndrome (GBS) is the most common cause of acute paralysis worldwide. Despite current treatments, outcomes are suboptimal. Specific chemokine receptor antagonists have the potential to be efficacious against pathogenic leukocyte trafficking in GBS. Methods: A 36‐year literature review was performed to summarize available data on chemokine expression in GBS and its representative animal model, experimental autoimmune neuritis (EAN). Results: Although there were a few observational human and animal studies demonstrating chemokine ligand/receptor expression in GBS and EAN, in vitro and in vivo functional studies using gene knockouts, neutralizing antibodies, or small molecular antagonists were limited. CCL2–CCR2, CCL5–CCR5, and CXCL10–CXCR3 have been most strongly implicated in EAN and GBS pathogenesis, providing targets for molecular blockade. Conclusions: Preclinical human in vitro and in vivo EAN studies are needed to evaluate the potential efficacy of chemokine signaling inhibition in GBS. Muscle Nerve 48: 320–330, 2013

Computer‐automated focus lateralization of temporal lobe epilepsy using fMRI

To compare the performance of computer‐automated diagnosis using functional magnetic resonance imaging (fMRI) interictal graph theory (CADFIG) to that achieved in standard clinical practice with MRI, for lateralizing the affected hemisphere in temporal lobe epilepsy (TLE).

Structural–functional coupling changes in temporal lobe epilepsy

Alterations in both structural connectivity (SC) and functional connectivity (FC) have been reported in temporal lobe epilepsy (TLE). However, the relationship between FC and SC remains less understood. This study used functional connectivity MRI and diffusion tensor imaging to examine coupling of FC and SC within the limbic network of TLE, as well as its relation to epilepsy duration, regional changes, and disease laterality in 14 patients with left TLE, 10 with right TLE, and 11 healthy controls. Structural and functional networks were separately constructed and the correlation estimated between structural and functional connectivity. This measure of SC-FC coupling was compared between left/right TLE and controls, and correlated with epilepsy duration. Elastic net regression was used to investigate regional structural and functional changes associated with SC-FC coupling. SC-FC coupling was decreased in left TLE compared to controls, and accompanied by reductions in FC for left and right TLE and in SC for left TLE. When examined in relation to disease duration, an increase in SC-FC coupling with longer epilepsy duration was observed, associated predominantly with structural loss of the fusiform and frontal inferior orbital gyrus in left TLE and functional hub redistribution in right TLE. These results suggest that decoupling between structural and functional networks in TLE is modulated by several factors, including epilepsy duration and regional changes in the fusiform, frontal inferior orbital gyrus, posterior cingulate, and hippocampus. SC-FC coupling may provide a more sensitive biomarker of disease burden in TLE than biomarkers based on single imaging modalities.