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Neuronal dysfunction due to iron accumulation in conjunction with reactive oxygen species (ROS) could represent an important, yet underappreciated, component of the epileptogenic process. However, to date, alterations in iron metabolism in the epileptogenic brain have not been addressed in detail. Iron-related neuropathology and antioxidant metabolic processes were investigated in resected brain tissue from patients with temporal lobe epilepsy and hippocampal sclerosis (TLE-HS), post-mortem brain tissue from patients who died after status epilepticus (SE) as well as brain tissue from the electrically induced SE rat model of TLE. Magnetic susceptibility of the presumed seizure-onset zone from three patients with focal epilepsy was compared during and after seizure activity. Finally, the cellular effects of iron overload were studied in vitro using an acute mouse hippocampal slice preparation and cultured human fetal astrocytes. While iron-accumulating neurons had a pyknotic morphology, astrocytes appeared to acquire iron-sequestrating capacity as indicated by prominent ferritin expression and iron retention in the hippocampus of patients with SE or TLE. Interictal to postictal comparison revealed increased magnetic susceptibility in the seizure-onset zone of epilepsy patients. Post-SE rats had consistently higher hippocampal iron levels during the acute and chronic phase (when spontaneous recurrent seizures are evident). In vitro, in acute slices that were exposed to iron, neurons readily took up iron, which was exacerbated by induced epileptiform activity. Human astrocyte cultures challenged with iron and ROS increased their antioxidant and iron-binding capacity, but simultaneously developed a pro-inflammatory phenotype upon chronic exposure. These data suggest that seizure-mediated, chronic neuronal iron uptake might play a role in neuronal dysfunction/loss in TLE-HS. On the other hand, astrocytes sequester iron, specifically in chronic epilepsy. This function might transform astrocytes into a highly resistant, pro-inflammatory phenotype potentially contributing to pro-epileptogenic inflammatory processes. [ABSTRACT FROM AUTHOR]

Objective: Using multimodal imaging, we tested the hypothesis that patients after hemispherotomy recruit non‐primary motor areas and non‐pyramidal descending motor fibers to restore motor function of the impaired limb. Methods: Functional and structural MRI data were acquired in a group of 25 patients who had undergone hemispherotomy and in a matched group of healthy controls. Patients' motor impairment was measured using the Fugl‐Meyer Motor Assessment. Cortical areas governing upper extremity motor‐control were identified by task‐based functional MRI. The resulting areas were used as nodes for functional and structural connectivity analyses. Results: In hemispherotomy patients, movement of the impaired upper extremity was associated to widespread activation of non‐primary premotor areas, whereas movement of the unimpaired one and of the control group related to activations prevalently located in the primary motor cortex (all p ≤ 0.05, FWE‐corrected). Non‐pyramidal tracts originating in premotor/supplementary motor areas and descending through the pontine tegmentum showed relatively higher structural connectivity in patients (p < 0.001, FWE‐corrected). Significant correlations between structural connectivity and motor impairment were found for non‐pyramidal (p = 0.023, FWE‐corrected), but not for pyramidal connections. Interpretation: A premotor/supplementary motor network and non‐pyramidal fibers seem to mediate motor function in patients after hemispherotomy. In case of hemispheric lesion, the homologous regions in the contralesional hemisphere may not compensate the resulting motor deficit, but the functionally redundant premotor network. [ABSTRACT FROM AUTHOR]

Objective: Focal cortical dysplasias (FCDs) are a common cause of drug‐resistant focal epilepsy but frequently remain undetected by conventional magnetic resonance imaging (MRI) assessment. The visual detection can be facilitated by morphometric analysis of T1‐weighted images, for example, using the Morphometric Analysis Program (v2018; MAP18), which was introduced in 2005, independently validated for its clinical benefits, and successfully integrated in standard presurgical workflows of numerous epilepsy centers worldwide. Here we aimed to develop an artificial neural network (ANN) classifier for robust automated detection of FCDs based on these morphometric maps and probe its generalization performance in a large, independent data set. Methods: In this retrospective study, we created a feed‐forward ANN for FCD detection based on the morphometric output maps of MAP18. The ANN was trained and cross‐validated on 113 patients (62 female, mean age ± SD =29.5 ± 13.6 years) with manually segmented FCDs and 362 healthy controls (161 female, mean age ± SD =30.2 ± 9.6 years) acquired on 13 different scanners. In addition, we validated the performance of the trained ANN on an independent, unseen data set of 60 FCD patients (28 female, mean age ± SD =30 ± 15.26 years) and 70 healthy controls (42 females, mean age ± SD = 40.0 ± 12.54 years). Results: In the cross‐validation, the ANN achieved a sensitivity of 87.4% at a specificity of 85.4% on the training data set. On the independent validation data set, our method still reached a sensitivity of 81.0% at a comparably high specificity of 84.3%. Significance: Our method shows a robust automated detection of FCDs and performance generalizability, largely independent of scanning site or MR‐sequence parameters. Taken together with the minimal input requirements of a standard T1 image, our approach constitutes a clinically viable and useful tool in the presurgical diagnostic routine for drug‐resistant focal epilepsy. [ABSTRACT FROM AUTHOR]

Selective amygdalohippocampectomy is an effective treatment for patients with therapy-refractory temporal lobe epilepsy but may cause visual field defect (VFD). Here, we aimed to describe tissue-specific pre- and postoperative imaging correlates of the VFD severity using whole-brain analyses from voxel- to network-level. Twenty-eight patients with temporal lobe epilepsy underwent pre- and postoperative MRI (T1-MPRAGE and Diffusion Tensor Imaging) as well as kinetic perimetry according to Goldmann standard. We probed for whole-brain gray matter (GM) and white matter (WM) correlates of VFD using voxel-based morphometry and tract-based spatial statistics, respectively. We furthermore reconstructed individual structural connectomes and conducted local and global network analyses. Two clusters in the bihemispheric middle temporal gyri indicated a postsurgical GM volume decrease with increasing VFD severity (FWE-corrected p < 0.05). A single WM cluster showed a fractional anisotropy decrease with increasing severity of VFD in the ipsilesional optic radiation (FWE-corrected p < 0.05). Furthermore, patients with (vs. without) VFD showed a higher number of postoperative local connectivity changes. Neither in the GM, WM, nor in network metrics we found preoperative correlates of VFD severity. Still, in an explorative analysis, an artificial neural network meta-classifier could predict the occurrence of VFD based on presurgical connectomes above chance level. [ABSTRACT FROM AUTHOR]

Limbic encephalitis (LE) forms a spectrum of autoimmune diseases involving temporal lobe epilepsy and memory impairment. Imaging features of LE are known to depend on the associated antibody and to occur on the brain network level. However, first studies investigating brain networks in LE have either focused on one distinct antibody subgroup or on distinct anatomical regions. In this study, brain graphs of 17 LE patients with autoantibodies against glutamic acid decarboxylase 65 (GAD‐LE), four LE patients with autoantibodies against leucine‐rich glioma‐inactivated 1, five LE patients with autoantibodies against contactin‐associated protein‐like 2, 26 age‐ and gender‐matched healthy control subjects, and 20 epilepsy control patients with hippocampal sclerosis were constructed based on T1‐weighted structural magnetic resonance imaging scans and diffusion tensor imaging. GAD‐LE showed significantly altered global network topology in terms of integration and segregation as compared to healthy controls and patients with hippocampal sclerosis (P <.01, analysis of variance with Tukey‐Kramer post hoc tests). Linear regression linked global network measures with amygdala volume and verbal memory performance (P <.05). Alterations of local network topology show serotype dependence in hippocampus, amygdala, insula, and various cortical regions. Our findings reveal serotype‐dependent patterns of structural connectivity and prove the relevance of in silico network measures on clinical grounds. [ABSTRACT FROM AUTHOR]

Summary: Rasmussen encephalitis (RE) is an immune‐mediated brain disease with progressive unihemispheric atrophy. Although it is regarded as a strictly one‐sided pathology, volumetric magnetic resonance imaging (MRI) studies have revealed atrophy in the so‐called unaffected hemisphere. In contrast to previous studies, we hypothesized that the contralesional hemisphere would show increased gray matter volume in response to the ipsilesional atrophy. We assessed the gray matter volume differences among 21 patients with chronic, late‐stage RE and 89 age‐ and gender‐matched healthy controls using voxel‐based morphometry. In addition, 11 patients with more than one scan were tested longitudinally. Compared to controls, the contralesional hemisphere of the patients revealed a higher cortical volume but a lower subcortical gray matter volume (all P < 0.001, unpaired t test). Progressive gray matter volume losses in bilateral subcortical gray matter structures were observed (P < 0.05, paired t test). The comparatively higher cortical volume in the contralesional hemisphere can be interpreted as a result of compensatory structural remodeling in response to atrophy of the ipsilesional hemisphere. Contralesional subcortical gray matter volume loss may be due to the pathology or its treatment. Because MRI provides the best marker for determining the progression of RE, an accurate description of its MRI features is clinically relevant. [ABSTRACT FROM AUTHOR]

Epilepsy has been associated with a dysfunction of the blood-brain barrier. While there is ample evidence that a dysfunction of the blood-brain barrier contributes to epileptogenesis, blood-brain barrier dysfunction as a consequence of single epileptic seizures has not been systematically investigated. We hypothesized that blood-brain barrier dysfunction is temporally and anatomically associated with epileptic seizures in patients and used a newly-established quantitative MRI protocol to test our hypothesis. Twenty-three patients with epilepsy undergoing inpatient monitoring as part of their presurgical evaluation were included in this study (10 females, mean age ± standard deviation: 28.78 ± 8.45). For each patient, we acquired quantitative T1 relaxation time maps (qT1) after both ictal and interictal injection of gadolinium-based contrast agent. The postictal enhancement of contrast agent was quantified by subtracting postictal qT1 from interictal qT1 and the resulting ΔqT1 was used as a surrogate imaging marker of peri-ictal blood-brain barrier dysfunction. Additionally, the serum concentrations of MMP9 and S100, both considered biomarkers of blood-brain barrier dysfunction, were assessed in serum samples obtained prior to and after the index seizure. Fifteen patients exhibited secondarily generalized tonic-clonic seizures and eight patients exhibited focal seizures at ictal injection of contrast agent. By comparing ΔqT1 of the generalized tonic-clonic seizures and focal seizures groups, the anatomical association between ictal epileptic activity and postictal enhancement of contrast agent could be probed. The generalized tonic-clonic seizures group showed significantly higher ΔqT1 in the whole brain as compared to the focal seizures group. Specific analysis of scans acquired later than 3 h after the onset of the seizure revealed higher ΔqT1 in the generalized tonic-clonic seizures group as compared to the focal seizures group, which was strictly lateralized to the hemisphere of seizure onset. Both MMP9 and S100 showed a significantly increased postictal concentration. The current study provides evidence for the occurrence of a blood-brain barrier dysfunction, which is temporally and anatomically associated with epileptic seizures. qT1 after ictal contrast agent injection is rendered as valuable imaging marker of seizure-associated blood-brain barrier dysfunction and may be measured hours after the seizure. The observation of the strong anatomical association of peri-ictal blood-brain barrier dysfunction may spark the development of new functional imaging modalities for the post hoc visualization of brain areas affected by the seizure. [ABSTRACT FROM AUTHOR]

The blood–brain barrier (BBB) is a physiological barrier maintaining a specialized brain micromilieu that is necessary for proper neuronal function. Endothelial tight junctions and specific transcellular/efflux transport systems provide a protective barrier against toxins, pathogens, and immune cells. The barrier function is critically supported by other cell types of the neurovascular unit, including pericytes, astrocytes, microglia, and interneurons. The dysfunctionality of the BBB is a hallmark of neurological diseases, such as ischemia, brain tumors, neurodegenerative diseases, infections, and autoimmune neuroinflammatory disorders. Moreover, BBB dysfunction is critically involved in epilepsy, a brain disorder characterized by spontaneously occurring seizures because of abnormally synchronized neuronal activity. While resistance to antiseizure drugs that aim to reduce neuronal hyperexcitability remains a clinical challenge, drugs targeting the neurovasculature in epilepsy patients have not been explored. The use of novel imaging techniques permits early detection of BBB leakage in epilepsy; however, the detailed mechanistic understanding of causes and consequences of BBB compromise remains unknown. Here, we discuss the current knowledge of BBB involvement in temporal lobe epilepsy with the emphasis on the neurovasculature as a therapeutic target. [ABSTRACT FROM AUTHOR]

Objective Methods Results Significance Focal cortical dysplasia (FCD) is a common cause of drug‐resistant focal epilepsy but can be challenging to detect visually on magnetic resonance imaging. Three artificial intelligence models for automated FCD detection are publicly available (MAP18, deepFCD, MELD) but have only been compared on single‐center data. Our first objective is to compare them on independent multicenter test data. Additionally, we train and compare three new models and make them publicly available.We retrospectively collected FCD cases from four epilepsy centers. We chose three novel models that take two‐dimensional (2D) slices (2D‐nnUNet), 2.5D slices (FastSurferCNN), and large 3D patches (3D‐nnUNet) as inputs and trained them on a subset of Bonn data. As core evaluation metrics, we used voxel‐level Dice similarity coefficient (DSC), cluster‐level F1 score, subject‐level detection rate, and specificity.We collected 329 subjects, 244 diagnosed with FCD (27.7 ± 14.4 years old, 54% male) and 85 healthy controls (7.1 ± 2.4 years old, 51% female). We used 118 subjects for model training and kept the remaining subjects as an independent test set. 3D‐nnUNet achieved the highest F1 score of .58, the highest DSC of .36 (95% confidence interval [CI] = .30–.41), a detection rate of 55%, and a specificity of 86%. deepFCD showed the highest detection rate (82%) but had the lowest specificity (0%) and cluster‐level precision (.03, 95% CI = .03–.04, F1 score = .07). MELD showed the least performance variation across centers, with detection rates between 46% and 54%.This study shows the variance in performance for FCD detection models in a multicenter dataset. The two models with 3D input data showed the highest sensitivity. The 2D models performed worse than all other models, suggesting that FCD detection requires 3D data. The greatly improved precision of 3D‐nnUNet may make it a sensible choice to aid FCD detection. [ABSTRACT FROM AUTHOR]

Progressive inflammation of one hemisphere characterises Rasmussen's encephalitis (RE), but contralesional epileptiform activity has been repeatedly reported. We aimed to quantify contralesional epileptiform activity in RE and uncover its functional and structural underpinnings. We retrospectively ascertained people with RE treated between 2000 and 2018 at a tertiary centre (Centre 1) and reviewed all available EEG datasets. The temporal occurrence of preoperative contralesional epileptiform activity (interictal/ictal) was evaluated using mixed-effects logistic regression. Cases with/without contralesional epileptiform activity were compared for cognition, inflammation (ipsilesional brain biopsies), and MRI (cortical and fixel-based morphometry). EEG findings were validated in a second cohort treated at another tertiary centre (Centre 2) between 1995 and 2020. We included 127 people with RE and 687 EEG samples. Preoperatively, contralesional epileptiform activity was seen in 30/68 (44%, Centre 1) and 8/59 (14%, Centre 2). In both cohorts, this activity was associated with younger onset age (OR = 0.9; 95% CI 0.83–0.97; P = 0.006). At centre 1, contralesional epileptiform activity was associated with contralesional MRI alterations, lower intelligence (OR = 5.19; 95% CI 1.28–21.08; P = 0.021), and impaired verbal memory (OR = 10.29; 95% CI 1.97–53.85; P = 0.006). After hemispherotomy, 11/17 (65%, Centre 1) and 28/37 (76%, Centre 2) were seizure-free. Contralesional epileptiform activity was persistent postoperatively in 6/12 (50%, Centre 1) and 2/34 (6%, Centre 2). Preoperative contralesional epileptiform activity reduced the chance of postoperative seizure freedom in both cohorts (OR = 0.69; 95% CI 0.50–0.95; P = 0.029). Our findings question the concept of strict unilaterality of RE and provide the evidence of contralesional epileptiform activity as a possible EEG predictor for persisting postoperative seizures. [ABSTRACT FROM AUTHOR]

Objective: Interictal blood–brain barrier dysfunction in chronic epilepsy has been demonstrated in animal models and pathological specimens. Ictal blood–brain barrier dysfunction has been shown in humans in vivo using an experimental quantitative magnetic resonance imaging (MRI) protocol. Here, we hypothesized that interictal blood–brain barrier dysfunction is also present in people with drug‐resistant epilepsy. Methods: Thirty‐nine people (21 females, mean age at MRI ± SD = 30 ± 8 years) with drug‐resistant epilepsy were prospectively recruited and underwent interictal T1‐relaxometry before and after administration of a paramagnetic contrast agent. Likewise, quantitative T1 was acquired in 29 people without epilepsy (12 females, age at MRI = 48 ± 18 years). Quantitative T1 difference maps were calculated and served as a surrogate imaging marker for blood–brain barrier dysfunction. Values of quantitative T1 difference maps inside hemispheres ipsilateral to the presumed seizure onset zone were then compared, on a voxelwise level and within presumed seizure onset zones, to the contralateral side of people with epilepsy and to people without epilepsy. Results: Compared to the contralateral side, ipsilateral T1 difference values were significantly higher in white matter (corrected p <.05), gray matter (uncorrected p <.05), and presumed seizure onset zones (p =.04) in people with epilepsy. Compared to people without epilepsy, significantly higher T1 difference values were found in the anatomical vicinity of presumed seizure onset zones (p =.004). A subgroup of people with hippocampal sclerosis demonstrated significantly higher T1 difference values in the ipsilateral hippocampus and in regions strongly interconnected with the hippocampus compared to people without epilepsy (corrected p <.01). Finally, z‐scores reflecting the deviation of T1 difference values within the presumed seizure onset zone were associated with verbal memory performance (p =.02) in people with temporal lobe epilepsy. Significance: Our results indicate a blood–brain barrier dysfunction in drug‐resistant epilepsy that is detectable interictally in vivo, anatomically related to the presumed seizure onset zone, and associated with cognitive deficits. [ABSTRACT FROM AUTHOR]

Third-party altruistic decision-making has been shown to be modulated by other-regarding attention (e.g., focusing on the offender's crime or the victim's situation especially in judicial judgment). However, the neural mechanisms underlying this modulation remain poorly understood. In this fMRI study, participants voluntarily decided if they wanted to punish the first-party offender or help the second-party victim using their own monetary endowment in an unfair context. Particularly, before deciding they were asked to focus on the (un)fairness of the offender proposing the offer (offender-focused block, OB), the feeling of the victim receiving this offer (victim-focused block, VB), or without any specific focus (baseline block, BB). We found that compared to BB participants punished more frequently and prolonged help choices in OB, whereas they helped more frequently in VB. These findings were accompanied by an increased activation in the temporo-parietal junction (TPJ) during decision making in OB and VB. Moreover, regions relevant to cognitive control (esp. IFG/AI and the dorsal anterior cingulate cortex) were strongly recruited during specific choices conflicting the attention focus (e.g., choosing help in OB). Our findings revealed how other-regarding attention modulates third-party altruistic decision-making at the neural level. [ABSTRACT FROM AUTHOR]

Focal cortical dysplasias (FCDs) are malformations of cortical development and one of the most common pathologies causing pharmacoresistant focal epilepsy. Resective neurosurgery yields high success rates, especially if the full extent of the lesion is correctly identified and completely removed. The visual assessment of magnetic resonance imaging does not pinpoint the FCD in 30%–50% of cases, and half of all patients with FCD are not amenable to epilepsy surgery, partly because the FCD could not be sufficiently localized. Computational approaches to FCD detection are an active area of research, benefitting from advancements in computer vision. Automatic FCD detection is a significant challenge and one of the first clinical grounds where the application of artificial intelligence may translate into an advance for patients' health. The emergence of new methods from the combination of health and computer sciences creates novel challenges. Imaging data need to be organized into structured, well‐annotated datasets and combined with other clinical information, such as histopathological subtypes or neuroimaging characteristics. Algorithmic output, that is, model prediction, requires a technically correct evaluation with adequate metrics that are understandable and usable for clinicians. Publication of code and data is necessary to make research accessible and reproducible. This critical review introduces the field of automatic FCD detection, explaining underlying medical and technical concepts, highlighting its challenges and current limitations, and providing a perspective for a novel research environment. [ABSTRACT FROM AUTHOR]

Motor function after hemispheric lesions has been associated with the structural integrity of either the pyramidal tract (PT) or alternate motor fibers (aMF). In this study, we aimed to differentially characterize the roles of PT and aMF in motor compensation by relating diffusion-tensor-imaging-derived parameters of white matter microstructure to measures of proximal and distal motor function in patients after hemispherotomy. Twenty-five patients (13 women; mean age: 21.1 years) after hemispherotomy (at mean age: 12.4 years) underwent Diffusion Tensor Imaging and evaluation of motor function using the Fugl-Meyer Assessment and the index finger tapping test. Regression analyses revealed that fractional anisotropy of the PT explained (p = 0.050) distal motor function including finger tapping rate (p = 0.027), whereas fractional anisotropy of aMF originating in the contralesional cortex and crossing to the ipsilesional hemisphere in the pons explained proximal motor function (p = 0.001). Age at surgery was found to be the only clinical variable to explain motor function (p < 0.001). Our results are indicative of complementary roles of the PT and of aMF in motor compensation of hemispherotomy mediating distal and proximal motor compensation of the upper limb, respectively. [ABSTRACT FROM AUTHOR]

Cognitive effort and self-control are exhausting. Although evidence is ambiguous, behavioural studies have repeatedly suggested that control-demanding tasks seem to deplete a limited cache of self-regulatory resources leading to performance degradations and fatigue. While resource depletion has indirectly been associated with a decline in right prefrontal cortex capacity, its precise neural underpinnings have not yet been revealed. This study consisted of two independent experiments, which set out to investigate the causal role of the right dorsolateral prefrontal cortex (DLPFC) in a classic dual phase depletion paradigm employing non-invasive brain stimulation. In Experiment 1 we demonstrated a general depletion effect, which was significantly eliminated by anodal transcranial Direct Current Stimulation to the right DLPFC. In Experiment 2, however, we failed to replicate the basic psychological depletion effect within a second independent sample. The dissimilar results are discussed in the context of the current ‘replication crisis’ and suggestions for future studies are offered. While our current results do not allow us to firmly argue for or against the existence of resource depletion, we outline why it is crucial to further clarify which specific external and internal circumstances lead to limited replicability of the described effect. We showcase and discuss the current inter-lab replication problem based on two independent samples tested within one research group (intra-lab). [ABSTRACT FROM AUTHOR]

[Display omitted] • Eigenvalues of the Laplace–Beltrami operator on 3D mesh = Shape ("BrainPrint"). • Shape is complementary to volume in limbic encephalitis classification. • In lesional temporal lobe epilepsy shape is redundant to volume. • Shape explains memory performance in limbic encephalitis. Shape-based markers have entered the field of morphometric neuroimaging analysis as a second mainstay alongside conventional volumetric approaches. We aimed to assess the added value of shape description for the analysis of lesional and autoimmune temporal lobe epilepsy (TLE) focusing on hippocampus and amygdala. We retrospectively investigated MRI and clinical data from 65 patients with lesional TLE (hippocampal sclerosis (HS) and astrogliosis) and from 62 patients with limbic encephalitis (LE) with serologically proven autoantibodies. Surface reconstruction and volumetric segmentation were performed with FreeSurfer. For the shape analysis, we used BrainPrint , a tool that utilizes eigenvalues of the Laplace–Beltrami operator on triangular meshes to calculate intra-subject asymmetry. Psychometric tests of memory performance were ascertained, to evaluate clinical relevance of the shape descriptor. The potential benefit of shape in addition to volumetric information for classification was assessed by five-fold repeated cross validation and logistic regression. For the LE group, the best performing classification model consisted of a combination of volume and shape asymmetry (mean AUC = 0.728), the logistic regression model was significantly improved considering both modalities instead of just volume asymmetry. For lesional TLE, the best model only considered volumetric information (mean AUC = 0.867). Shape asymmetry of the hippocampus was largely associated with verbal memory performance only in LE patients (OR = 1.07, p = 0.02). For lesional TLE, shape description is robust, but redundant when compared to volumetric approaches. For LE, in contrast, shape asymmetry as a complementary modality significantly improves the detection of subtle morphometric changes and is further associated with memory performance, which underscores the clinical relevance of shape asymmetry as a novel imaging biomarker. [ABSTRACT FROM AUTHOR]