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Our goal was to assess the effects of long-term mental training in socio-affective skills on structural brain networks. We studied a group of long-term meditation practitioners (LTMs) who have focused on cultivating socio-affective skills using loving-kindness and compassion meditation for an average of 40k h, comparing these to meditation-naïve controls. To maximize homogeneity of prior practice, LTMs were included only if they had undergone extensive full-time meditation retreats in the same center. MRI-based cortical thickness analysis revealed increased thickness in the LTM cohort relative to meditation-native controls in fronto-insular cortices. To identify functional networks relevant for the generation of socio-affective states, structural imaging analysis were complemented by fMRI analysis in LTMs, showing amplitude increases during a loving-kindness meditation session relative to non-meditative rest in multiple prefrontal and insular regions bilaterally. Importantly, functional findings partially overlapped with regions of cortical thickness increases in the left ventrolateral prefrontal cortex and anterior insula, suggesting that these regions may play a central role in the generation of emotional states relevant for the meditative practice. Our multi-modal MRI approach revealed structural changes in LTMs who have cultivated loving-kindness and compassion for a significant period of their life in functional networks activated by these practices. These preliminary cross-sectional findings motivate future longitudinal work studying brain plasticity following the regular practice of skills aiming at enhancing human altruism and prosocial motivation., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: In drug-resistant temporal lobe epilepsy (TLE), relative to the large number of whole-brain morphological studies, neocortical T2 changes have not been systematically investigated. The aim of this study was to assess the anatomical principles that govern the distribution of neocortical T2-weighted fluid-attenuated inversion recovery (FLAIR) signal intensity and uncover its topographic principles., Methods: Using a surface-based sampling scheme, we mapped neocortical FLAIR intensity of 61 TLE patients relative to 38 healthy controls imaged at 3 T. To address topographic principles of the susceptibility to FLAIR signal changes in TLE, we assessed associations with normative data on tissue composition using 2 complementary approaches. First, we evaluated whether the degree of TLE-related FLAIR intensity changes differed across cytoarchitectonic classes as defined by Von Economo-Koskinas taxonomy. Second, as a proxy to map regions with similar intracortical composition, we carried out a FLAIR intensity covariance paradigm in controls by seeding systematically from all cortical regions, and identified those networks that were the best spatial predictors of the between-group FLAIR changes., Results: Increased intensities were observed in bilateral limbic and paralimbic cortices (hippocampus, parahippocampus, cingulate, temporopolar, insular, orbitofrontal). Effect sizes were highest in periallocortical limbic and insular classes as defined by the Von Economo-Koskinas cytoarchitectonic taxonomy. Furthermore, systematic FLAIR intensity covariance analysis in healthy controls revealed that similarity patterns characteristic of limbic cortices, most notably the hippocampus, served as sensitive predictors for the topography of FLAIR hypersignal in patients. FLAIR intensity findings were robust against correction for morphological confounds. Patients with a history of febrile convulsions showed more marked signal changes in parahippocampal and retrosplenial cortices, known to be strongly connected to the hippocampus., Significance: FLAIR intensity mapping and covariance analysis provide a model of TLE gray matter pathology based on shared vulnerability of periallocortical and limbic cortices., (Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.)

Progressive functional decline in the epilepsies is largely unexplained. We formed the ENIGMA-Epilepsy consortium to understand factors that influence brain measures in epilepsy, pooling data from 24 research centres in 14 countries across Europe, North and South America, Asia, and Australia. Structural brain measures were extracted from MRI brain scans across 2149 individuals with epilepsy, divided into four epilepsy subgroups including idiopathic generalized epilepsies (n =367), mesial temporal lobe epilepsies with hippocampal sclerosis (MTLE; left, n = 415; right, n = 339), and all other epilepsies in aggregate (n = 1026), and compared to 1727 matched healthy controls. We ranked brain structures in order of greatest differences between patients and controls, by meta-analysing effect sizes across 16 subcortical and 68 cortical brain regions. We also tested effects of duration of disease, age at onset, and age-by-diagnosis interactions on structural measures. We observed widespread patterns of altered subcortical volume and reduced cortical grey matter thickness. Compared to controls, all epilepsy groups showed lower volume in the right thalamus (Cohen's d = -0.24 to -0.73; P < 1.49 × 10-4), and lower thickness in the precentral gyri bilaterally (d = -0.34 to -0.52; P < 4.31 × 10-6). Both MTLE subgroups showed profound volume reduction in the ipsilateral hippocampus (d = -1.73 to -1.91, P < 1.4 × 10-19), and lower thickness in extrahippocampal cortical regions, including the precentral and paracentral gyri, compared to controls (d = -0.36 to -0.52; P < 1.49 × 10-4). Thickness differences of the ipsilateral temporopolar, parahippocampal, entorhinal, and fusiform gyri, contralateral pars triangularis, and bilateral precuneus, superior frontal and caudal middle frontal gyri were observed in left, but not right, MTLE (d = -0.29 to -0.54; P < 1.49 × 10-4). Contrastingly, thickness differences of the ipsilateral pars opercularis, and contralateral transverse temporal gyrus, were observed in right, but not left, MTLE (d = -0.27 to -0.51; P < 1.49 × 10-4). Lower subcortical volume and cortical thickness associated with a longer duration of epilepsy in the all-epilepsies, all-other-epilepsies, and right MTLE groups (beta, b < -0.0018; P < 1.49 × 10-4). In the largest neuroimaging study of epilepsy to date, we provide information on the common epilepsies that could not be realistically acquired in any other way. Our study provides a robust ranking of brain measures that can be further targeted for study in genetic and neuropathological studies. This worldwide initiative identifies patterns of shared grey matter reduction across epilepsy syndromes, and distinctive abnormalities between epilepsy syndromes, which inform our understanding of epilepsy as a network disorder, and indicate that certain epilepsy syndromes involve more widespread structural compromise than previously assumed., (© The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Growing evidence highlights the importance of white matter in the pathogenesis of focal epilepsy. Ex vivo and post-mortem studies show pathological changes in epileptic patients in white matter myelination, axonal integrity, and cellular composition. Diffusion-weighted MRI and its analytical extensions, particularly diffusion tensor imaging (DTI), have been the most widely used technique to image the white matter in vivo for the last two decades, and have shown microstructural alterations in multiple tracts both in the vicinity and at distance from the epileptogenic focus. These techniques have also shown promising ability to predict cognitive status and response to pharmacological or surgical treatments. More recently, the hypothesis that focal epilepsy may be more adequately described as a system-level disorder has motivated a shift towards the study of macroscale brain connectivity. This review will cover emerging findings contributing to our understanding of white matter alterations in focal epilepsy, studied by means of histological and ultrastructural analyses, diffusion MRI, and large-scale network analysis. Focus is put on temporal lobe epilepsy and focal cortical dysplasia. This topic was addressed in a special interest group on neuroimaging at the 70th annual meeting of the American Epilepsy Society, held in Houston December 2-6, 2016., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Although neuroscientific research has revealed experience-dependent brain changes across the life span in sensory, motor, and cognitive domains, plasticity relating to social capacities remains largely unknown. To investigate whether the targeted mental training of different cognitive and social skills can induce specific changes in brain morphology, we collected longitudinal magnetic resonance imaging (MRI) data throughout a 9-month mental training intervention from a large sample of adults between 20 and 55 years of age. By means of various daily mental exercises and weekly instructed group sessions, training protocols specifically addressed three functional domains: (i) mindfulness-based attention and interoception, (ii) socio-affective skills (compassion, dealing with difficult emotions, and prosocial motivation), and (iii) socio-cognitive skills (cognitive perspective-taking on self and others and metacognition). MRI-based cortical thickness analyses, contrasting the different training modules against each other, indicated spatially diverging changes in cortical morphology. Training of present-moment focused attention mostly led to increases in cortical thickness in prefrontal regions, socio-affective training induced plasticity in frontoinsular regions, and socio-cognitive training included change in inferior frontal and lateral temporal cortices. Module-specific structural brain changes correlated with training-induced behavioral improvements in the same individuals in domain-specific measures of attention, compassion, and cognitive perspective-taking, respectively, and overlapped with task-relevant functional networks. Our longitudinal findings indicate structural plasticity in well-known socio-affective and socio-cognitive brain networks in healthy adults based on targeted short daily mental practices. These findings could promote the development of evidence-based mental training interventions in clinical, educational, and corporate settings aimed at cultivating social intelligence, prosocial motivation, and cooperation.

Neuroimaging studies of malformations of cortical development have mainly focused on the characterization of the primary lesional substrate, while whole-brain investigations remain scarce. Our purpose was to assess large-scale brain organization in prevalent cortical malformations. Based on experimental evidence suggesting that distributed effects of focal insults are modulated by stages of brain development, we postulated differential patterns of network anomalies across subtypes of malformations. We studied a cohort of patients with focal cortical dysplasia type II (n = 63), subcortical nodular heterotopia (n = 44), and polymicrogyria (n = 34), and compared them to 82 age- and sex-matched controls. Graph theoretical analysis of structural covariance networks indicated a consistent rearrangement towards a regularized architecture characterized by increased path length and clustering, as well as disrupted rich-club topology, overall suggestive of inefficient global and excessive local connectivity. Notably, we observed a gradual shift in network reconfigurations across subgroups, with only subtle changes in focal cortical dysplasia type II, moderate effects in heterotopia and maximal effects in polymicrogyria. Analysis of resting state functional connectivity also revealed gradual network changes, with most marked rearrangement in polymicrogyria; contrary to findings in the structural domain, however, functional architecture was characterized by decreases in both local and global parameters. Diverging results in the structural and functional domain were supported by formal structure-function coupling analysis. Our findings support the concept that time of insult during corticogenesis impacts the severity of topological network reconfiguration. Specifically, late-stage malformations, typified by polymicrogyria, may selectively disrupt the formation of large-scale cortico-cortical networks and thus lead to a more profound impact on whole-brain organization than early stage disturbances of predominantly radial migration patterns observed in cortical dysplasia type II, which likely affect a relatively confined cortical territory., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: It remains unclear whether drug-resistant temporal lobe epilepsy (TLE) is associated with cumulative brain damage, with no expert consensus and no quantitative syntheses of the available evidence., Methods: We conducted a systematic review and meta-analysis of MRI studies on progressive atrophy, searching PubMed and Ovid MEDLINE databases for cross-sectional and longitudinal quantitative MRI studies on drug-resistant TLE., Results: We screened 2,976 records and assessed eligibility of 248 full-text articles. Forty-two articles met the inclusion criteria for quantitative evaluation. We observed a predominance of cross-sectional studies, use of different clinical indices of progression, and high heterogeneity in age-control procedures. Meta-analysis of 18/1 cross-sectional/longitudinal studies on hippocampal atrophy (n = 979 patients) yielded a pooled effect size of r = -0.42 for ipsilateral atrophy related to epilepsy duration (95% confidence interval [CI] -0.51 to -0.32; p < 0.0001; I 2 = 65.22%) and r = -0.35 related to seizure frequency (95% CI -0.47 to -0.22; p < 0.0001; I 2 = 61.97%). Sensitivity analyses did not change the results. Narrative synthesis of 25/3 cross-sectional/longitudinal studies on whole brain atrophy (n = 1,504 patients) indicated that >80% of articles reported duration-related progression in extratemporal cortical and subcortical regions. Detailed analysis of study design features yielded low to moderate levels of evidence for progressive atrophy across studies, mainly due to dominance of cross-sectional over longitudinal investigations, use of diverse measures of seizure estimates, and absence of consistent age control procedures., Conclusions: While the neuroimaging literature is overall suggestive of progressive atrophy in drug-resistant TLE, published studies have employed rather weak designs to directly demonstrate it. Longitudinal multicohort studies are needed to unequivocally differentiate aging from disease progression., (© 2017 American Academy of Neurology.)

The hippocampus contributes to episodic, spatial and semantic aspects of memory, yet individual differences within and between these functions are not well-understood. In 136 healthy individuals, we investigated whether these differences reflect variation in the strength of connections between functionally-specialised segments of the hippocampus and diverse cortical regions that participate in different aspects of memory. Better topographical memory was associated with stronger connectivity between lingual gyrus and left anterior, rather than posterior, hippocampus. Better semantic memory was associated with increased connectivity between the intracalcarine/cuneus and left, rather than right, posterior hippocampus. Notably, we observed a double dissociation between semantic and topographical memory: better semantic memory was associated with stronger connectivity between left temporoparietal cortex and left anterior hippocampus, while better topographic memory was linked to stronger connectivity with right anterior hippocampus. Together these data support a division-of-labour account of hippocampal functioning: at the population level, differences in connectivity across the hippocampus reflect functional specialisation for different facets of memory, while variation in these connectivity patterns across individuals is associated with differences in the capacity to retrieve different types of information. In particular, within-hemisphere connectivity between hippocampus and left temporoparietal cortex supports conceptual processing at the expense of spatial ability., (Copyright © 2017. Published by Elsevier Inc.)

Objective: To characterize in vivo MRI signatures of focal cortical dysplasia (FCD) type IIA and type IIB through combined analysis of morphology, intensity, microstructure, and function., Methods: We carried out a multimodal 3T MRI profiling of 33 histologically proven FCD type IIA (9) and IIB (24) lesions. A multisurface approach operating on manual consensus labels systematically sampled intracortical and subcortical lesional features. Geodesic distance mapping quantified the same features in the lesion perimeter. Logistic regression assessed the relationship between MRI and histology, while supervised pattern learning was used for individualized subtype prediction., Results: FCD type IIB was characterized by abnormal morphology, intensity, diffusivity, and function across all surfaces, while type IIA lesions presented only with increased fluid-attenuated inversion recovery signal and reduced diffusion anisotropy close to the gray-white matter interface. Similar to lesional patterns, perilesional anomalies were more marked in type IIB extending up to 16 mm. Structural MRI markers correlated with categorical histologic characteristics. A profile-based classifier predicted FCD subtypes with equal sensitivity of 85%, while maintaining a high specificity of 94% against healthy and disease controls., Conclusions: Image processing applied to widely available MRI contrasts has the ability to dissociate FCD subtypes at a mesoscopic level. Integrating in vivo staging of pathologic traits with automated lesion detection is likely to provide an objective definition of lesional boundary and assist emerging approaches, such as minimally invasive thermal ablation, which do not supply tissue specimen., (© 2017 American Academy of Neurology.)

The capacity to imagine situations that have already happened or fictitious events that may take place in the future is known as mental time travel (MTT). Studies have shown that MTT is an important aspect of spontaneous thought, yet we lack a clear understanding of how the neurocognitive architecture of the brain constrains this element of human cognition. Previous functional magnetic resonance imaging (MRI) studies have shown that MTT involves the coordination between multiple regions that include mesiotemporal structures such as the hippocampus, as well as prefrontal and parietal regions commonly associated with the default mode network (DMN). The current study used a multimodal neuroimaging approach to identify the structural and functional brain organisation that underlies individual differences in the capacity to spontaneously engage in MTT. Using regionally unconstrained diffusion tractography analysis, we found increased diffusion anisotropy in right lateralised temporo-limbic, corticospinal, inferior fronto-occipital tracts in participants who reported greater MTT. Probabilistic connectivity mapping revealed a significantly higher connection probability of the right hippocampus with these tracts. Resting-state functional MRI connectivity analysis using the right hippocampus as a seed region revealed greater functional coupling to the anterior regions of the DMN with increasing levels of MTT. These findings demonstrate that the interactions between the hippocampus and regions of the cortex underlie the capacity to engage in MTT, and support contemporary theoretical accounts that suggest that the integration of the hippocampus with the DMN provides the neurocognitive landscape that allows us to imagine distant times and places., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Functional neuroimaging studies have suggested the existence of 2 largely distinct social cognition networks, one for theory of mind (taking others' cognitive perspective) and another for empathy (sharing others' affective states). To address whether these networks can also be dissociated at the level of brain structure, we combined behavioral phenotyping across multiple socio-cognitive tasks with 3-Tesla MRI cortical thickness and structural covariance analysis in 270 healthy adults, recruited across 2 sites. Regional thickness mapping only provided partial support for divergent substrates, highlighting that individual differences in empathy relate to left insular-opercular thickness while no correlation between thickness and mentalizing scores was found. Conversely, structural covariance analysis showed clearly divergent network modulations by socio-cognitive and -affective phenotypes. Specifically, individual differences in theory of mind related to structural integration between temporo-parietal and dorsomedial prefrontal regions while empathy modulated the strength of dorsal anterior insula networks. Findings were robust across both recruitment sites, suggesting generalizability. At the level of structural network embedding, our study provides a double dissociation between empathy and mentalizing. Moreover, our findings suggest that structural substrates of higher-order social cognition are reflected rather in interregional networks than in the the local anatomical markup of specific regions per se., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Mind-wandering has a controversial relationship with cognitive control. Existing psychological evidence supports the hypothesis that episodes of mind-wandering reflect a failure to constrain thinking to task-relevant material, as well the apparently alternative view that control can facilitate the expression of self-generated mental content. We assessed whether this apparent contradiction arises because of a failure to consider differences in the types of thoughts that occur during mind-wandering, and in particular, the associated level of intentionality. Using multi-modal magnetic resonance imaging (MRI) analysis, we examined the cortical organisation that underlies inter-individual differences in descriptions of the spontaneous or deliberate nature of mind-wandering. Cortical thickness, as well as functional connectivity analyses, implicated regions relevant to cognitive control and regions of the default-mode network for individuals who reported high rates of deliberate mind-wandering. In contrast, higher reports of spontaneous mind-wandering were associated with cortical thinning in parietal and posterior temporal regions in the left hemisphere (which are important in the control of cognition and attention) as well as heightened connectivity between the intraparietal sulcus and a region that spanned limbic and default-mode regions in the ventral inferior frontal gyrus. Finally, we observed a dissociation in the thickness of the retrosplenial cortex/lingual gyrus, with higher reports of spontaneous mind-wandering being associated with thickening in the left hemisphere, and higher repots of deliberate mind-wandering with thinning in the right hemisphere. These results suggest that the intentionality of the mind-wandering state depends on integration between the control and default-mode networks, with more deliberation being associated with greater integration between these systems. We conclude that one reason why mind-wandering has a controversial relationship with control is because it depends on whether the thoughts emerge in a deliberate or spontaneous fashion., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Recent advances in neuroimaging have offered a rich array of structural and functional markers to probe the organization of regional and large-scale brain networks. The current chapter provides a brief introduction into these techniques and overviews their contribution to the understanding of autism spectrum disorder (ASD), a neurodevelopmental condition associated with atypical social cognition, language function, and repetitive behaviors/interests. While it is generally recognized that ASD relates to structural and functional network anomalies, the extent and overall pattern of reported findings have been rather heterogeneous. Indeed, while several attempts have been made to label the main neuroimaging phenotype of ASD (e.g., 'early brain overgrowth hypothesis', 'amygdala theory', 'disconnectivity hypothesis'), none of these frameworks has been without controversy. Methodological sources of inconsistent results may include differences in subject inclusion criteria, variability in image processing, and analysis methodology. However, inconsistencies may also relate to high heterogeneity across the autism spectrum itself. It, therefore, remains to be investigated whether a consistent imaging phenotype that adequately describes the entire autism spectrum can, in fact, be established. On the other hand, as previous findings clearly emphasize the value of neuroimaging in identifying atypical brain morphology, function, and connectivity, they ultimately support its high potential to identify biologically and clinically relevant endophenotypes.

Efficient semantic cognition depends on accessing and selecting conceptual knowledge relevant to the current task or context. This study explored the neurocognitive architecture that supports this function by examining how individual variation in functional brain organisation predicts comprehension and semantic generation. Participants underwent resting state functional magnetic resonance imaging (fMRI) and, on separate days, performed written synonym judgement, and letter and category fluency tasks. We found that better synonym judgement for high frequency items was linked to greater functional coupling between posterior fusiform and anterior superior temporal cortex (aSTG), which might index orthographic-to-semantic access. However, stronger coupling between aSTG and ventromedial prefrontal cortex was associated with poor performance on the same trials, potentially reflecting greater difficulty in focussing retrieval on relevant features for high frequency items that appear in a greater range of contexts. Fluency performance was instead linked to variations in the functional coupling of the inferior frontal gyrus (IFG); anterior IFG was more coupled to regions of primary visual cortex for individuals who were good at category fluency, while poor letter fluency was predicted by stronger coupling between posterior IFG and retrosplenial cortex. These results show that individual differences in functional connectivity at rest predict semantic performance and are consistent with a component process account of semantic cognition in which representational information is shaped by control processes to fit the current requirements, in both comprehension and fluency tasks., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Humans have the ability to reflect upon their perception, thoughts, and actions, known as metacognition (MC). The brain basis of MC is incompletely understood, and it is debated whether MC on different processes is subserved by common or divergent networks. We combined behavioral phenotyping with multi-modal neuroimaging to investigate whether structural substrates of individual differences in MC on higher-order cognition (MC-C) are dissociable from those underlying MC on perceptual accuracy (MC-P). Motivated by conceptual work suggesting a link between MC and cognitive perspective taking, we furthermore tested for overlaps between MC substrates and mentalizing networks. In a large sample of healthy adults, individual differences in MC-C and MC-P did not correlate. MRI-based cortical thickness mapping revealed a structural basis of this independence, by showing that individual differences in MC-P related to right prefrontal cortical thickness, while MC-C scores correlated with measures in lateral prefrontal, temporo-parietal, and posterior midline regions. Surface-based superficial white matter diffusivity analysis revealed substrates resembling those seen for cortical thickness, confirming the divergence of both MC faculties using an independent imaging marker. Despite their specificity, substrates of MC-C and MC-P fell clearly within networks known to participate in mentalizing, confirmed by task-based fMRI in the same subjects, previous meta-analytical findings, and ad-hoc Neurosynth-based meta-analyses. Our integrative multi-method approach indicates domain-specific substrates of MC; despite their divergence, these nevertheless likely rely on component processes mediated by circuits also involved in mentalizing. Hum Brain Mapp 37:3388-3399, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Drug-resistant temporal lobe epilepsy is increasingly recognized as a system-level disorder affecting the structure and function of large-scale grey matter networks. While diffusion magnetic resonance imaging studies have demonstrated deep fibre tract alterations, the superficial white matter immediately below the cortex has so far been neglected despite its proximity to neocortical regions and key role in maintaining cortico-cortical connectivity. Using multi-modal 3 T magnetic resonance imaging, we mapped the topography of superficial white matter diffusion alterations in 61 consecutive temporal lobe epilepsy patients relative to 38 healthy controls and studied the relationship to large-scale structural as well as functional networks. Our approach continuously sampled mean diffusivity and fractional anisotropy along surfaces running 2 mm below the cortex. Multivariate statistics mapped superficial white matter diffusion anomalies in patients relative to controls, while correlation and mediation analyses evaluated their relationship to structural (cortical thickness, mesiotemporal volumetry) and functional parameters (resting state functional magnetic resonance imaging amplitude) and clinical variables. Patients presented with overlapping anomalies in mean diffusivity and anisotropy, particularly in ipsilateral temporo-limbic regions. Diffusion anomalies did not relate to cortical thinning; conversely, they mediated large-scale functional amplitude decreases in patients relative to controls in default mode hub regions (i.e. anterior and posterior midline regions, lateral temporo-parietal cortices), and were themselves mediated by hippocampal atrophy. With respect to clinical variables, we observed more marked diffusion anomalies in patients with a history of febrile convulsions and those with longer disease duration. Similarly, more marked diffusion alterations were associated with seizure-free outcome. Bootstrap analyses indicated high reproducibility of our findings, suggesting generalizability. The temporo-limbic distribution of superficial white matter anomalies, together with the mediation-level findings, suggests that this so far neglected region serves a key link between the hippocampal atrophy and large-scale default mode network alterations in temporal lobe epilepsy., (© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Making sense of the world around us depends upon selectively retrieving information relevant to our current goal or context. However, it is unclear whether selective semantic retrieval relies exclusively on general control mechanisms recruited in demanding non-semantic tasks, or instead on systems specialised for the control of meaning. One hypothesis is that the left posterior middle temporal gyrus (pMTG) is important in the controlled retrieval of semantic (not non-semantic) information; however this view remains controversial since a parallel literature links this site to event and relational semantics. In a functional neuroimaging study, we demonstrated that an area of pMTG implicated in semantic control by a recent meta-analysis was activated in a conjunction of (i) semantic association over size judgements and (ii) action over colour feature matching. Under these circumstances the same region showed functional coupling with the inferior frontal gyrus - another crucial site for semantic control. Structural and functional connectivity analyses demonstrated that this site is at the nexus of networks recruited in automatic semantic processing (the default mode network) and executively demanding tasks (the multiple-demand network). Moreover, in both task and task-free contexts, pMTG exhibited functional properties that were more similar to ventral parts of inferior frontal cortex, implicated in controlled semantic retrieval, than more dorsal inferior frontal sulcus, implicated in domain-general control. Finally, the pMTG region was functionally correlated at rest with other regions implicated in control-demanding semantic tasks, including inferior frontal gyrus and intraparietal sulcus. We suggest that pMTG may play a crucial role within a large-scale network that allows the integration of automatic retrieval in the default mode network with executively-demanding goal-oriented cognition, and that this could support our ability to understand actions and non-dominant semantic associations, allowing semantic retrieval to be 'shaped' to suit a task or context., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Although most temporal lobe epilepsy (TLE) patients show marked hippocampal sclerosis (HS) upon pathological examination, 40% present with no significant cell loss but gliotic changes only. To evaluate effects of hippocampal pathology on brain structure and functional networks, we aimed at dissociating multimodal magnetic resonance imaging (MRI) characteristics in patients with HS (TLE-HS) and those with gliosis only (TLE-G)., Methods: In 20 TLE-HS, 19 TLE-G, and 25 healthy controls, we carried out a novel MRI-based hippocampal subfield surface analysis that integrated volume, T2 signal intensity, and diffusion markers with seed-based hippocampal functional connectivity., Results: Compared to controls, TLE-HS presented with marked ipsilateral atrophy, T2 hyperintensity, and mean diffusivity increases across all subfields, whereas TLE-G presented with dentate gyrus hypertrophy, focal increases in T2 intensity and mean diffusivity. Multivariate assessment confirmed a more marked ipsilateral load of anomalies across all subfields in TLE-HS, whereas anomalies in TLE-G were restricted to the subiculum. A between-cohort dissociation was independently suggested by resting-state functional connectivity analysis, revealing marked hippocampal decoupling from anterior and posterior default mode hubs in TLE-HS, whereas TLE-G did not differ from controls. Back-projection connectivity analysis from cortical targets revealed consistently decreased network embedding across all subfields in TLE-HS, while changes in TLE-G were limited to the subiculum. Hippocampal disconnectivity strongly correlated to T2 hyperintensity and marginally to atrophy., Interpretation: Multimodal MRI reveals diverging structural and functional connectivity profiles across the TLE spectrum. Pathology-specific modulations of large-scale functional brain networks lend novel evidence for a close interplay of structural and functional disruptions in focal epilepsy. Ann Neurol 2016;80:142-153., (© 2016 American Neurological Association.)

Temporal lobe epilepsy (TLE) is the most frequent drug-resistant epilepsy in adults and commonly associated with variable degrees of mesiotemporal atrophy on magnetic resonance imaging (MRI). Analyses of inter-regional connectivity have unveiled disruptions in large-scale cortico-cortical networks; little is known about the topological organization of the mesiotemporal lobe, the limbic subnetwork central to the disorder. We generated covariance networks based on high-resolution MRI surface-shape descriptors of the hippocampus, entorhinal cortex, and amygdala in 134 TLE patients and 45 age- and sex-matched controls. Graph-theoretical analysis revealed increased path length and clustering in patients, suggesting a shift toward a more regularized arrangement; findings were reproducible after split-half assessment and across 2 parcellation schemes. Analysis of inter-regional correlations and module participation showed increased within-structure covariance, but decreases between structures, particularly with regards to the hippocampus and amygdala. While higher clustering possibly reflects topological consequences of axonal sprouting, decreases in interstructure covariance may be a consequence of disconnection within limbic circuitry. Preoperative network parameters, specifically the segregation of the ipsilateral hippocampus, predicted long-term seizure freedom after surgery., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Our aim is to assess the subfield-specific histopathological correlates of hippocampal volume and intensity changes (T1, T2) as well as diff!usion MRI markers in TLE, and investigate the efficacy of quantitative MRI measures in predicting histopathology in vivo., Experimental Design: We correlated in vivo volumetry, T2 signal, quantitative T1 mapping, as well as diffusion MRI parameters with histological features of hippocampal sclerosis in a subfield-specific manner. We made use of on an advanced co-registration pipeline that provided a seamless integration of preoperative 3 T MRI with postoperative histopathological data, on which metrics of cell loss and gliosis were quantitatively assessed in CA1, CA2/3, and CA4/DG., Principal Observations: MRI volumes across all subfields were positively correlated with neuronal density and size. Higher T2 intensity related to increased GFAP fraction in CA1, while quantitative T1 and diffusion MRI parameters showed negative correlations with neuronal density in CA4 and DG. Multiple linear regression analysis revealed that in vivo multiparametric MRI can predict neuronal loss in all the analyzed subfields with up to 90% accuracy., Conclusion: Our results, based on an accurate co-registration pipeline and a subfield-specific analysis of MRI and histology, demonstrate the potential of MRI volumetry, diffusion, and quantitative T1 as accurate in vivo biomarkers of hippocampal pathology., (© 2015 Wiley Periodicals, Inc.)

Objective: To perform whole-brain morphometry in patients with frontal lobe epilepsy and evaluate the utility of group-level patterns for individualized diagnosis and prognosis., Methods: We compared MRI-based cortical thickness and folding complexity between 2 frontal lobe epilepsy cohorts with histologically verified focal cortical dysplasia (FCD) (13 type I; 28 type II) and 41 closely matched controls. Pattern learning algorithms evaluated the utility of group-level findings to predict histologic FCD subtype, the side of the seizure focus, and postsurgical seizure outcome in single individuals., Results: Relative to controls, FCD type I displayed multilobar cortical thinning that was most marked in ipsilateral frontal cortices. Conversely, type II showed thickening in temporal and postcentral cortices. Cortical folding also diverged, with increased complexity in prefrontal cortices in type I and decreases in type II. Group-level findings successfully guided automated FCD subtype classification (type I: 100%; type II: 96%), seizure focus lateralization (type I: 92%; type II: 86%), and outcome prediction (type I: 92%; type II: 82%)., Conclusion: FCD subtypes relate to diverse whole-brain structural phenotypes. While cortical thickening in type II may indicate delayed pruning, a thin cortex in type I likely results from combined effects of seizure excitotoxicity and the primary malformation. Group-level patterns have a high translational value in guiding individualized diagnostics., (© 2016 American Academy of Neurology.)

In drug-resistant temporal lobe epilepsy (TLE), MRI studies have shown consistent mesiotemporal and neocortical structural alterations when comparing patients to healthy controls. It remains, however, relatively unclear whether the side of seizure focus differentially impacts the degree of structural damage. This work performed a comprehensive surface-based analysis of mesiotemporal and neocortical morphology on preoperative 1.5 T MRI in 25/35 LTLE/RTLE patients that achieved seizure freedom after surgery (i.e., Engel-I outcome; 7 ± 2 years follow-up), an imaging-independent confirmation of focus lateralization. Compared to 46 age- and sex-matched controls, both TLE groups displayed marked ipsilateral atrophy in mesiotemporal regions, while cortical thinning was bilateral. Direct contrasts between LTLE and RTLE did not reveal significant differences. Bootstrap simulations indicated low reproducibility of observing a between-cohort difference; power analysis revealed that more than 110 patients would be necessary to detect subtle differences. No difference between LTLE and RTLE was confirmed when using voxel-based morphometry, an independent proxy of gray matter volume. Similar results were obtained analyzing a separate 3 T dataset (15/15 LTLE/RTLE patients; Engel-I after 4 ± 2 years follow-up; 42 controls). Our results strongly support equivalent gray matter compromise in left and right TLE. The morphological profile of seizure-free patients, presenting with ipsilateral mesiotemporal and bilateral cortical atrophy, motivates the development of neuromarkers of outcome that consider both mesiotemporal and neocortical structures. Hum Brain Mapp 37:515-524, 2016. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)

The hippocampus is composed of distinct anatomical subregions that participate in multiple cognitive processes and are differentially affected in prevalent neurological and psychiatric conditions. Advances in high-field MRI allow for the non-invasive identification of hippocampal substructure. These approaches, however, demand time-consuming manual segmentation that relies heavily on anatomical expertise. Here, we share manual labels and associated high-resolution MRI data (MNI-HISUB25; submillimetric T1- and T2-weighted images, detailed sequence information, and stereotaxic probabilistic anatomical maps) based on 25 healthy subjects. Data were acquired on a widely available 3 Tesla MRI system using a 32 phased-array head coil. The protocol divided the hippocampal formation into three subregions: subicular complex, merged Cornu Ammonis 1, 2 and 3 (CA1-3) subfields, and CA4-dentate gyrus (CA4-DG). Segmentation was guided by consistent intensity and morphology characteristics of the densely myelinated molecular layer together with few geometry-based boundaries flexible to overall mesiotemporal anatomy, and achieved excellent intra-/inter-rater reliability (Dice index ≥90/87%). The dataset can inform neuroimaging assessments of the mesiotemporal lobe and help to develop segmentation algorithms relevant for basic and clinical neurosciences.

Recent years have witnessed a paradigm shift in the study and conceptualization of epilepsy, which is increasingly understood as a network-level disorder. An emblematic case is temporal lobe epilepsy (TLE), the most common drug-resistant epilepsy that is electroclinically defined as a focal epilepsy and pathologically associated with hippocampal sclerosis. In this review, we will summarize histopathological, electrophysiological, and neuroimaging evidence supporting the concept that the substrate of TLE is not limited to the hippocampus alone, but rather is broadly distributed across multiple brain regions and interconnecting white matter pathways. We will introduce basic concepts of graph theory, a formalism to quantify topological properties of complex systems that has recently been widely applied to study networks derived from brain imaging and electrophysiology. We will discuss converging graph theoretical evidence indicating that networks in TLE show marked shifts in their overall topology, providing insight into the neurobiology of TLE as a network-level disorder. Our review will conclude by discussing methodological challenges and future clinical applications of this powerful analytical approach., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Autism spectrum disorders (ASD) are a group of neurodevelopmental conditions primarily characterized by abnormalities in social cognition. Abundant previous functional MRI studies have shown atypical activity in networks encompassing medial prefrontal cortex (mPFC) and medial parietal regions corresponding to posterior cingulate cortex and precuneus (PCC/PCU). Conversely, studies assessing structural brain anomalies in ASD have been rather inconsistent. The current work evaluated whether structural changes in ASD can be reliability detected in a large multicenter dataset. Our comprehensive structural MRI framework encompassed cortical thickness mapping and structural covariance analysis based on three independent samples comprising individuals with ASD and controls (n = 220), selected from the Autism Brain Imaging Data Exchange open-access database. Surface-based analysis revealed increased cortical thickness in ASD relative to controls in mPFC and lateral prefrontal cortex. Clusters encompassing mPFC were embedded in altered inter-regional covariance networks, showing decreased covariance in ASD relative to controls primarily to PCC/PCU and inferior parietal regions. Cortical thickness increases and covariance reductions in ASD were consistent, yet of variable effect size, across the different sites evaluated and measurable both in children and adults. Our multisite study shows regional and network-level structural alterations in mPFC in ASD that, possibly, relate to atypical socio-cognitive functions in this condition., (© 2015 Wiley Periodicals, Inc.)

Objective: In temporal lobe epilepsy (TLE), although hippocampal atrophy lateralizes the focus, the value of magnetic resonance imaging (MRI) to predict postsurgical outcome is rather modest. Prediction solely based on the hippocampus may be hampered by widespread mesiotemporal structural damage shown by advanced imaging. Increasingly complex and high-dimensional representation of MRI metrics motivates a shift to machine learning to establish objective, data-driven criteria for pathogenic processes and prognosis., Methods: We applied clustering to 114 consecutive unilateral TLE patients using 1.5T MRI profiles derived from surface morphology of hippocampus, amygdala, and entorhinal cortex. To evaluate the diagnostic validity of the classification, we assessed its yield to predict outcome in 79 surgically treated patients. Reproducibility of outcome prediction was assessed in an independent cohort of 27 patients evaluated on 3.0T MRI., Results: Four similarly sized classes partitioned our cohort; in all, alterations spanned over the 3 mesiotemporal structures. Compared to 46 controls, TLE-I showed marked bilateral atrophy; in TLE-II atrophy was ipsilateral; TLE-III showed mild bilateral atrophy; whereas TLE-IV showed hypertrophy. Classes differed with regard to histopathology and freedom from seizures. Classwise surface-based classifiers accurately predicted outcome in 92 ± 1% of patients, outperforming conventional volumetry. Predictors of relapse were distributed bilaterally across structures. Prediction accuracy was similarly high in the independent cohort (96%), supporting generalizability., Interpretation: We provide a novel description of individual variability across the TLE spectrum. Class membership was associated with distinct patterns of damage and outcome predictors that did not spatially overlap, emphasizing the ability of machine learning to disentangle the differential contribution of morphology to patient phenotypes, ultimately refining the prognosis of epilepsy surgery., (© 2014 American Neurological Association.)

Humans often judge others egocentrically, assuming that they feel or think similarly to themselves. Emotional egocentricity bias (EEB) occurs in situations when others feel differently to oneself. Using a novel paradigm, we investigated the neurocognitive mechanisms underlying the developmental capacity to overcome such EEB in children compared with adults. We showed that children display a stronger EEB than adults and that this correlates with reduced activation in right supramarginal gyrus (rSMG) as well as reduced coupling between rSMG and left dorsolateral prefrontal cortex (lDLPFC) in children compared with adults. Crucially, functional recruitment of rSMG was associated with age-related differences in cortical thickness of this region. Although in adults the mere presence of emotional conflict occurs between self and other recruited rSMG, rSMG-lDLPFC coupling was only observed when implementing empathic judgements. Finally, resting state analyses comparing connectivity patterns of rSMG with that of right temporoparietal junction suggested a unique role of rSMG for self-other distinction in the emotional domain for adults as well as for children. Thus, children's difficulties in overcoming EEB may be due to late maturation of regions distinguishing between conflicting socio-affective information and relaying this information to regions necessary for implementing accurate judgments., (© The Author (2014). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.)

The advent of MRI has revolutionized the evaluation and management of drug-resistant epilepsy by allowing the detection of the lesion associated with the region that gives rise to seizures. Recent evidence indicates marked chronic alterations in the functional organization of lesional tissue and large-scale cortico-subcortical networks. In this review, we focus on recent methodological developments in functional MRI (fMRI) analysis techniques and their application to the two most common drug-resistant focal epilepsies, i.e., temporal lobe epilepsy related to mesial temporal sclerosis and extra-temporal lobe epilepsy related to focal cortical dysplasia. We put particular emphasis on methodological developments in the analysis of task-free or "resting-state" fMRI to probe the integrity of intrinsic networks on a regional, inter-regional, and connectome-wide level. In temporal lobe epilepsy, these techniques have revealed disrupted connectivity of the ipsilateral mesiotemporal lobe, together with contralateral compensatory reorganization and striking reconfigurations of large-scale networks. In cortical dysplasia, initial observations indicate functional alterations in lesional, peri-lesional, and remote neocortical regions. While future research is needed to critically evaluate the reliability, sensitivity, and specificity, fMRI mapping promises to lend distinct biomarkers for diagnosis, presurgical planning, and outcome prediction.

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., (© The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Many powerful human emotional thoughts are generated in the absence of a precipitating event in the environment. Here, we tested whether we can decode the valence of internally driven, self-generated thoughts during task-free rest based on neural similarities with task-related affective mental states. We acquired functional magnetic resonance imaging (fMRI) data while participants generated positive and negative thoughts as part of an attribution task (Session A) and while they reported the occurrence of comparable mental states during task-free rest periods (Session B). With the use of multivariate pattern analyses (MVPA), we identified response patterns in the medial orbitofrontal cortex (mOFC) that encode the affective content of thoughts that are generated in response to an external experimental cue. Importantly, these task driven response patterns reliably predicted the occurrence of affective thoughts generated during unconstrained rest periods recorded one week apart. This demonstrates that at least certain elements of task-cued and task-free affective experiences rely on a common neural code. Furthermore, our findings reveal the role that the mOFC plays in determining the affective tone of unconstrained thoughts. More generally, our results suggest that MVPA is an important methodological tool for attempts to understand unguided subject driven mental states such as mind-wandering and daydreaming based on neural similarities with task-based experiences., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Previous functional imaging studies have shown key roles of the dorsal anterior insula (dAI) and anterior midcingulate cortex (aMCC) in empathy for the suffering of others. The current study mapped structural covariance networks of these regions and assessed the relationship between networks and individual differences in empathic responding in 94 females. Individual differences in empathy were assessed through average state measures in response to a video task showing others' suffering, and through questionnaire-based trait measures of empathic concern. Overall, covariance patterns indicated that dAI and aMCC are principal hubs within prefrontal, temporolimbic, and midline structural covariance networks. Importantly, participants with high empathy state ratings showed increased covariance of dAI, but not aMCC, to prefrontal and limbic brain regions. This relationship was specific for empathy and could not be explained by individual differences in negative affect ratings. Regarding questionnaire-based empathic trait measures, we observed a similar, albeit weaker modulation of dAI covariance, confirming the robustness of our findings. Our analysis, thus, provides novel evidence for a specific contribution of frontolimbic structural covariance networks to individual differences in social emotions beyond negative affect., (© The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objective: To detect automatically focal cortical dysplasia (FCD) type II in patients with extratemporal epilepsy initially diagnosed as MRI-negative on routine inspection of 1.5 and 3.0T scans., Methods: We implemented an automated classifier relying on surface-based features of FCD morphology and intensity, taking advantage of their covariance. The method was tested on 19 patients (15 with histologically confirmed FCD) scanned at 3.0T, and cross-validated using a leave-one-out strategy. We assessed specificity in 24 healthy controls and 11 disease controls with temporal lobe epilepsy. Cross-dataset classification performance was evaluated in 20 healthy controls and 14 patients with histologically verified FCD examined at 1.5T., Results: Sensitivity was 74%, with 100% specificity (i.e., no lesions detected in healthy or disease controls). In 50% of cases, a single cluster colocalized with the FCD lesion, while in the remaining cases a median of 1 extralesional cluster was found. Applying the classifier (trained on 3.0T data) to the 1.5T dataset yielded comparable performance (sensitivity 71%, specificity 95%)., Conclusion: In patients initially diagnosed as MRI-negative, our fully automated multivariate approach offered a substantial gain in sensitivity over standard radiologic assessment. The proposed method showed generalizability across cohorts, scanners, and field strengths. Machine learning may assist presurgical decision-making by facilitating hypothesis formulation about the epileptogenic zone., Classification of Evidence: This study provides Class II evidence that automated machine learning of MRI patterns accurately identifies FCD among patients with extratemporal epilepsy initially diagnosed as MRI-negative., (© 2014 American Academy of Neurology.)

When deprived of compelling perceptual input, the mind is often occupied with thoughts unrelated to the immediate environment. Previous behavioral research has shown that this self-generated task-unrelated thought (TUT), especially under non-demanding conditions, relates to cognitive capacities such as creativity, planning, and reduced temporal discounting. Despite the frequency and importance of this type of cognition, little is known about its structural brain basis. Using MRI-based cortical thickness measures in 37 participants, we were able to show that individuals with a higher tendency to engage in TUT under low-demanding conditions (but not under high-demanding conditions) show an increased thickness of medial prefrontal cortex (mPFC) and anterior/midcingulate cortex. Thickness of these regions also related to less temporal discounting (TD) of monetary rewards in an economic task, indicative of more patient decision-making. The findings of a shared structural substrate in mPFC and anterior/midcingulate cortex underlying both TUT and TD suggest an important role of these brain regions in supporting the self-generation of information that is unrelated to the immediate environment and which may be adaptive in nature., (Copyright © 2013 Elsevier Inc. All rights reserved.)

We propose a multispectral MRI-based clinical decision support approach to carry out automated seizure focus lateralization in patients with temporal lobe epilepsy (TLE). Based on high-resolution T1- and T2-weighted MRI with hippocampal subfield segmentations, our approach samples MRI features along the medial sheet of each subfield to minimize partial volume effects. To establish correspondence of sampling points across subjects, we propagate a spherical harmonic parameterization derived from the hippocampal boundary along a Laplacian gradient field towards the medial sheet. Volume and intensity data sampled on the medial sheet are finally fed into a supervised classifier. Testing our approach in TLE patients in whom the seizure focus could not be lateralized using conventional MR volumetry, the proposed approach correctly lateralized all patients and outperformed classification performance based on global subfield volumes or mean T2-intensity (100% vs. 68%). Moreover, statistical group-level comparisons revealed patterns of subfield abnormalities that were not evident in the global measurements and that largely agree with known histopathological changes.

Objective: Evidence for disease progression in the mesiotemporal lobe is mainly derived from global volumetry of the hippocampus. In this study, we tracked progressive structural changes in the hippocampus, amygdala, and entorhinal cortex in drug-resistant temporal lobe epilepsy at a subregional level. Furthermore, we evaluated the relation between disease progression and surgical outcome., Methods: We combined cross-sectional modeling of disease duration in a large cohort of patients (n = 134) and longitudinal analysis in a subset that delayed surgery (n = 31). To track subregional pathology, we applied surface-shape analysis techniques on manual mesiotemporal labels., Results: Longitudinal and cross-sectional designs showed consistent patterns of progressive atrophy in hippocampal CA1, anterolateral entorhinal, and the amygdalar laterobasal group bilaterally. These regions also exhibited more marked age-related volume loss in patients compared with controls. We found a faster progression of hippocampal atrophy in patients with a seizure frequency ≥6 per month. High rates of contralateral entorhinal cortex atrophy predicted postsurgical seizure relapse., Conclusion: We observed progressive atrophy in hippocampal, amygdalar, and entorhinal subregions that frequently display neuronal loss on histology. The bilateral character of cumulative atrophy highlights the importance of early surgery. In patients who nevertheless delay this procedure, serial scanning may provide markers of surgical outcome.

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.

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 children's 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., (Copyright © 2012 Elsevier Inc. All rights reserved.)

In drug-resistant temporal lobe epilepsy (TLE), detecting hippocampal atrophy on MRI is important as it allows defining the surgical target. The performance of automatic segmentation in TLE has so far been considered unsatisfactory. In addition to atrophy, about 40% of patients present with developmental abnormalities (referred to as malrotation) characterized by atypical morphologies of the hippocampus and collateral sulcus. Our purpose was to evaluate the impact of malrotation and atrophy on the performance of three state-of-the-art automated algorithms. We segmented the hippocampus in 66 patients and 35 sex- and age-matched healthy subjects using a region-growing algorithm constrained by anatomical priors (SACHA), a freely available atlas-based software (FreeSurfer) and a multi-atlas approach (ANIMAL-multi). To quantify malrotation, we generated 3D models from manual hippocampal labels and automatically extracted collateral sulci. The accuracy of automated techniques was evaluated relative to manual labeling using the Dice similarity index and surface-based shape mapping, for which we computed vertex-wise displacement vectors between automated and manual segmentations. We then correlated segmentation accuracy with malrotation features and atrophy. ANIMAL-multi demonstrated similar accuracy in patients and healthy controls (p > 0.1), whereas SACHA and FreeSurfer were less accurate in patients (p < 0.05). Surface-based analysis of contour accuracy revealed that SACHA over-estimated the lateral border of malrotated hippocampi (r = 0.61; p < 0.0001), but performed well in the presence of atrophy (|r |< 0.34; p > 0.2). Conversely, FreeSurfer and ANIMAL-multi were affected by both malrotation (FreeSurfer: r = 0.57; p = 0.02, ANIMAL-multi: r = 0.50; p = 0.05) and atrophy (FreeSurfer: r = 0.78, p < 0.0001, ANIMAL-multi: r = 0.61; p < 0.0001). Compared to manual volumetry, automated procedures underestimated the magnitude of atrophy (Cohen's d: manual: 1.68; ANIMAL-multi: 1.11; SACHA: 1.10; FreeSurfer: 0.90, p < 0.0001). In addition, they tended to lateralize the seizure focus less accurately in the presence of malrotation (manual: 64%; ANIMAL-multi: 55%, p = 0.4; SACHA: 50%, p = 0.1; FreeSurfer: 41%, p = 0.05). Hippocampal developmental anomalies and atrophy had a negative impact on the segmentation performance of three state-of-the-art automated methods. These shape variants should be taken into account when designing segmentation algorithms., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Empathy--the ability to share the feelings of others--is fundamental to our emotional and social lives. Previous human imaging studies focusing on empathy for others' pain have consistently shown activations in regions also involved in the direct pain experience, particularly anterior insula and anterior and midcingulate cortex. These findings suggest that empathy is, in part, based on shared representations for firsthand and vicarious experiences of affective states. Empathic responses are not static but can be modulated by person characteristics, such as degree of alexithymia. It has also been shown that contextual appraisal, including perceived fairness or group membership of others, may modulate empathic neuronal activations. Empathy often involves coactivations in further networks associated with social cognition, depending on the specific situation and information available in the environment. Empathy-related insular and cingulate activity may reflect domain-general computations representing and predicting feeling states in self and others, likely guiding adaptive homeostatic responses and goal-directed behavior in dynamic social contexts.

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., Methods: We performed diffusion tensor imaging tractography and cortical thickness analyses of 18 patients with left TLE (LTLE), 18 patients with right TLE (RTLE), and 36 controls. We investigated the relationship among brain structural abnormalities, side of seizure onset, age of seizure onset, and disease duration., Key Findings: Patients with TLE displayed cortical thinning and white matter compromise, predominately on the side ipsilateral to the seizure onset. Relative to RTLE, patients with LTLE showed more widespread abnormalities, particularly in white matter fiber tracts. Greater compromise in white matter integrity was associated with earlier age of seizure onset, whereas cortical thinning was marginally associated with disease duration., Significance: These data support previous findings of LTLE showing greater structural compromise than RTLE, and suggest that mechanisms may not be uniform for gray and white matter compromise in patients with LTLE and RTLE. These results may indicate that LTLE is different from RTLE, possibly due to greater vulnerability of the left hemisphere to early injury and the progressive effects of seizures., (Wiley Periodicals, Inc. © 2011 International League Against 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.

Nearly one-third of patients with focal epilepsy experience disabling seizures that are refractory to pharmacotherapy. Drug-resistant focal epilepsy is, however, potentially curable by surgery. Although lesions associated with the epileptic focus can often be accurately detected by MRI, in many patients conventional imaging based on visual evaluation is unable to pinpoint the surgical target. Patients with so-called cryptogenic epilepsy represent one of the greatest clinical challenges in many tertiary epilepsy centers. In recent years, it has become increasingly clear that epilepsies that are considered cryptogenic are not necessarily nonlesional, the primary histopathological substrate being subtle cortical dysplasia. This Review considers the application of new advances in brain imaging, such as MRI morphometry, computational modeling and diffusion tensor imaging. By revealing dysplastic lesions that previously eluded visual assessments, quantitative structural MRI methods such as these have clearly demonstrated an increased diagnostic yield of epileptic lesions, and have provided successful surgical options to an increasing number of patients with 'cryptogenic' epilepsy.

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.

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.

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.