Boris C. Bernhardt

Graph-Theoretical Analysis Reveals Disrupted Small-World Organization of Cortical Thickness Correlation Networks in Temporal Lobe Epilepsy

Temporal lobe epilepsy (TLE) is the most common drug-resistant epilepsy in adults. As morphometric studies have shown widespread structural damage in TLE, this condition is often referred to as a system disorder with disrupted structural networks. Studies based on univariate statistical comparisons can only indirectly test such hypothesis. Graph theory provides a new approach to formally analyze large-scale networks. Using graph-theoretical analysis of magnetic resonance imaging-based cortical thickness correlations, we investigated the structural basis of the organization of such networks in 122 TLE patients and 47 age- and sex-matched healthy controls. Networks in patients and controls were characterized by a short path length between anatomical regions and a high degree of clustering, suggestive of a small-world topology. However, compared with controls, patients showed increased path length and clustering, altered distribution of network hubs, and higher vulnerability to targeted attacks, suggesting a reorganization of cortical thickness correlation networks. Longitudinal analysis demonstrated that network alterations intensify over time. Bootstrap simulations showed high reproducibility of network parameters across random subsamplings, indicating that altered network topology in TLE is a consistent finding. Increased network disruption was associated with unfavorable postoperative seizure outcome, implying adverse effects of epileptogenesis on large-scale network organization.

Longitudinal and cross-sectional analysis of atrophy in pharmacoresistant temporal lobe epilepsy

Background: Whether recurrent epileptic seizures induce brain damage is debated. Disease progression in epilepsy has been evaluated only in a few community-based studies involving patients with seizures well controlled by medication. These studies concluded that epilepsy does not inevitably lead to global cerebral damage. Objective: To track the progression of neocortical atrophy in pharmacoresistant temporal lobe epilepsy (TLE) using longitudinal and cross-sectional designs. Methods: Using a fully automated measure of cortical thickness on MRI, we studied a homogeneous sample of patients with pharmacoresistant TLE. In the longitudinal analysis (n = 18), fixed-effect models were used to quantify cortical atrophy over a mean interscan interval of 2.5 years (range = 7 to 90 months). In the cross-sectional analysis (n = 121), we correlated epilepsy duration and thickness. To dissociate normal aging from pathologic progression, we compared aging effects in TLE to healthy controls. Results: The longitudinal analysis mapped progression in ipsilateral temporopolar and central and contralateral orbitofrontal, insular, and angular regions. In patients with more than 14 years of disease, atrophy progressed more rapidly in frontocentral and parietal regions that in those with shorter duration. The cross-sectional study showed progressive atrophy in the mesial and superolateral frontal, and parietal cortices. Conclusions: Our combined cross-sectional and longitudinal analysis in patients with pharmacoresistant temporal lobe epilepsy demonstrated progressive neocortical atrophy over a mean interval of 2.5 years that is distinct from normal aging, likely representing seizure-induced damage. The cumulative character of atrophy underlies the importance of early surgical treatment in this group of patients.

Impulse Control and Underlying Functions of the Left DLPFC Mediate Age-Related and Age-Independent Individual Differences in Strategic Social Behavior

Human social exchange is often characterized by conflicts of interest requiring strategic behavior for their resolution. To investigate the development of the cognitive and neural mechanisms underlying strategic behavior, we studied childrens decisions while they played two types of economic exchange games with differing demands of strategic behavior. We show an increase of strategic behavior with age, which could not be explained by age-related changes in social preferences but instead by developmental differences in impulsivity and associated brain functions of the left dorsolateral prefrontal cortex (DLPFC). Furthermore, observed differences in cortical thickness of lDLPFC were predictive of differences in impulsivity and strategic behavior irrespective of age. We conclude that egoistic behavior in younger children is not caused by a lack of understanding right or wrong, but by the inability to implement behavioral control when tempted to act selfishly; a function relying on brain regions maturing only late in ontogeny.

Mapping limbic network organization in temporal lobe epilepsy using morphometric correlations: insights on the relation between mesiotemporal connectivity and cortical atrophy.

Temporal lobe epilepsy (TLE) is considered primarily a limbic disorder. Our purpose was to map limbic network organization in TLE and to statistically relate it to neocortical atrophy. We performed MRI-based cortical thickness analysis in 110 TLE patients (including 68 patients with hippocampal atrophy and 42 patients with normal hippocampal volume) and 46 healthy controls. Limbic connectivity was statistically inferred by correlating mean thickness of the entorhinal cortex (EC) with thickness at each vertex across the entire neocortex. The EC was chosen as seed region since it is the link between the neocortex and the hippocampal formation. Patients showed cortical thinning mainly in temporal and fronto-central neocortices, with a prevalence of atrophy in up to 35%. In controls, EC networks corresponded closely to known anatomical connections. In TLE the pattern of correlations was similar to controls, suggesting that pathological processes in the EC affect the same networks that co-vary with the EC in the healthy brain. Nevertheless, we found decreases in correlations mainly in the temporal lobe and increases mainly in orbitofrontal cortices. Although our analysis indicated alterations in the temporo-limbic network in TLE, there was no association between mesiotemporal connectivity and atrophy across the entire cortical surface. This divergence underlines the complexity of the pathophysiological mechanisms leading to neocortical atrophy in TLE.

Cortical thickness analysis in temporal lobe epilepsy: reproducibility and relation to outcome.

Objective: To assess the reproducibility of neocortical atrophy and its clinical significance across the spectrum of temporal lobe epilepsy (TLE), in particular with respect to postsurgical outcome. Methods: MRI-based cortical thickness measurement was obtained in 105 patients. A total of 58 had hippocampal atrophy on magnetic resonance volumetry (TLE-HA) and 47 had normal hippocampal volumes (TLE-NV). Twenty-seven patients had repeated scans with a mean interval of 28 months. Patients were compared to 48 age- and sex-matched healthy controls. We used linear models to assess cortical thinning and the effect of seizure control after surgery. Reproducibility of finding cortical atrophy was statistically evaluated using bootstrap simulations. Results: Cross-sectional and longitudinal analyses revealed highly similar topology and rates of neocortical thinning in both TLE groups, predominantly in frontocentral, temporal, and cingulate regions. Bootstrap methods showed that at least 20 subjects per group were necessary to reliably observe these patterns of atrophy in TLE. Moreover, power analysis showed that even with sample sizes of 80 subjects per group, differences in thickness between TLE-HA and TLE-NV would be marginal. With respect to postsurgical outcome, we found an association between residual seizures and atrophy in temporopolar and insular cortices in TLE-HA, and in the posterior quadrant in TLE-NV. Conclusion: We demonstrated with a high degree of confidence that static and dynamic effects of epilepsy impact similarly the neocortex of patients with hippocampal atrophy and patients with normal hippocampal volumes. On the contrary, areas predicting unfavorable postsurgical outcome were distinct, suggesting different configurations of epileptogenic networks in these 2 groups.

Imaging structural and functional brain networks in temporal lobe epilepsy

Early imaging studies in temporal lobe epilepsy (TLE) focused on the search for mesial temporal sclerosis, as its surgical removal results in clinically meaningful improvement in about 70% of patients. Nevertheless, a considerable subgroup of patients continues to suffer from post-operative seizures. Although the reasons for surgical failure are not fully understood, electrophysiological and imaging data suggest that anomalies extending beyond the temporal lobe may have negative impact on outcome. This hypothesis has revived the concept of human epilepsy as a disorder of distributed brain networks. Recent methodological advances in non-invasive neuroimaging have led to quantify structural and functional networks in vivo. While structural networks can be inferred from diffusion MRI tractography and inter-regional covariance patterns of structural measures such as cortical thickness, functional connectivity is generally computed based on statistical dependencies of neurophysiological time-series, measured through functional MRI or electroencephalographic techniques. This review considers the application of advanced analytical methods in structural and functional connectivity analyses in TLE. We will specifically highlight findings from graph-theoretical analysis that allow assessing the topological organization of brain networks. These studies have provided compelling evidence that TLE is a system disorder with profound alterations in local and distributed networks. In addition, there is emerging evidence for the utility of network properties as clinical diagnostic markers. Nowadays, a network perspective is considered to be essential to the understanding of the development, progression, and management of epilepsy.

Thalamo-cortical network pathology in idiopathic generalized epilepsy: insights from MRI-based morphometric correlation analysis.

Epileptic activity underlying idiopathic generalized epilepsy (IGE) is related to abnormal thalamo-cortical interactions. Our purpose was to map in vivo the organization of the thalamo-cortical network in IGE. We measured cortical thickness and thalamic volumes on MRI in 23 IGE patients with generalized tonic-clonic seizures only and 46 healthy controls. Significant correlations between thalamic volumes and cortical thickness were interpreted as thalamo-cortical network connections. In controls, thickness of frontal, limbic, and occipital regions was positively correlated with the thalamic volumes, corresponding to known anatomical connections from sacrificial tracer studies in primates and human in vivo DTI data. In patients, thalamo-cortical network correlations increased in fronto-central and parietal regions, but decreased in limbic areas. Group analysis revealed that, compared to controls, IGE patients had bilateral thalamic atrophy and widespread cortical thinning that was most prominent in fronto-central areas, with a prevalence of up to 40%. Duration of epilepsy affected negatively thalamic volumes and thickness of fronto-central and limbic cortices. These effects were significantly different from aging in controls. Patients with poorly controlled seizures showed an even faster progression in these neocortical regions. Fronto-centro-parietal atrophy in IGE is likely the effect of generalized seizure activity inducing thalamo-cortical network remodeling. On the other hand, limbic abnormalities may take place secondary to thalamic disconnection.

MRI analysis in temporal lobe epilepsy: Cortical thinning and white matter disruptions are related to side of seizure onset

Purpose:  Past studies reported more widespread structural brain abnormalities in patients with left compared to right temporal lobe epilepsy (TLE), but the profile of these differences remains unknown. This study investigated the relationship between cortical thinning, white matter compromise, epilepsy variables, and the side of seizure onset, in patients with TLE.

Selective Disruption of Sociocognitive Structural Brain Networks in Autism and Alexithymia

Autism spectrum conditions (ASC) are neurodevelopmental disorders characterized by abnormal social cognition. A core feature of ASC is disrupted Theory of Mind (ToM), our ability to take the mental perspective of others. ASC is also associated with alexithymia, a trait characterized by altered emotional interoception and empathy. Here, we applied structural MRI covariance analysis to assess whether ASC and alexithymia differentially affect structural brain networks associated with sociocognitive and socioaffective functions. Based on previous functional MRI findings, we expected disrupted ToM networks (centered on dorsomedial prefontal cortex [dmPFC], and temporo-parietal junction [TPJ]) in ASC, while alexithymia would affect networks centered on fronto-insular cortex (FI), regions associated with interoception of emotion and empathy. Relative to controls, ASC indeed showed reduced covariance in networks centered on dmPFC and TPJ, but not within FI networks. Irrespective of ASC, covariance was negatively modulated by alexithymia in networks extending from FI to posterior regions. Network findings were complemented by self-reports, indicating decreased perspective taking but normal empathic concern in ASC. Our results show divergent effects of ASC and alexithymia on inter-regional structural networks, suggesting that networks mediating socioaffective processes may be separable from networks mediating sociocognitive processing.

Mapping thalamocortical network pathology in temporal lobe epilepsy

Objective: Although experimental work has provided evidence that the thalamus is a crucial relay structure in temporal lobe epilepsy (TLE), the relation of the thalamus to neocortical pathology remains unclear. To assess thalamocortical network pathology in TLE, we mapped pointwise patterns of thalamic atrophy and statistically related them to neocortical thinning. Methods: We studied cross-sectionally 36 patients with drug-resistant TLE and 19 age- and sex-matched healthy control subjects using high-resolution MRI. To localize thalamic pathology, we converted manual labels into surface meshes using the spherical harmonic description and calculated local deformations relative to a template. In addition, we measured cortical thickness by means of the constrained Laplacian anatomic segmentation using proximity algorithm. Results: Compared with control subjects, patients with TLE showed ipsilateral thalamic atrophy that was located along the medial surface, encompassing anterior, medial, and posterior divisions. Unbiased analysis correlating the degree of medial thalamic atrophy with cortical thickness measurements mapped bilateral frontocentral, lateral temporal, and mesiotemporal cortices. These areas overlapped with those of cortical thinning found when patients were compared with control subjects. Thalamic atrophy intensified with a longer duration of epilepsy and was more severe in patients with a history of febrile convulsions. Conclusion: The degree and distribution of thalamic pathology relates to the topography and extent of neocortical atrophy, lending support to the concept that the thalamus is an important hub in the pathologic network of TLE.