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Objective: Psychiatric comorbidities are frequent in people with epilepsy (PWE) or psychogenic nonepileptic seizures (PNES), and the use of validated screening instruments to identify respective symptoms is recommended. Our aim was to investigate the recommendations resulting from routine screening for depression, anxiety and suicidality with the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) and the Generalized Anxiety Disorder Scale (GAD-7) in the outpatient clinic of a tertiary epilepsy center., Methods: We retrospectively analyzed NDDI-E and GAD-7 scores (German versions) of 264 outpatients at a tertiary epilepsy center and extracted recommendations regarding psychopathology from the outpatient letters., Results: The screening revealed a likely major depression (NDDI-E ≥17) in 15.2% of PWE (without PNES, 30/197) and an NDDI-E score ≥17 in 51.2% of patients with PNES ± epilepsy (21/41), moderate to severe symptoms of generalized anxiety (GAD-7 ≥10) in 20.3% of PWE (40/197) and 56.1% of patients with PNES (23/41), and a high risk of suicidality (NDDI-E item 4 ≥3) in 8.1% of PWE (16/197) and in 24.4% of patients with PNES (10/41). The most frequently given recommendations regarding depression or anxiety were a psychiatric/psychotherapeutic treatment for PWE and an admission to the psychotherapy ward of the epilepsy center for patients with PNES. No evidence for active suicidal tendencies was found in any of the patients with a positive screening for suicidality., Conclusion: Routine screening with NDDI-E and GAD-7 for depression, anxiety and suicidality is efficient and feasible and leads to individual recommendations for further assessment and treatment., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CB has received support from and/or has served as a paid consultant for Angelini, Jazz Pharmaceuticals, Johnson & Johnson, Marinus and Xenon Pharma. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Early Alzheimer's disease diagnosis is crucial for preventive therapy development. Standard neuropsychological evaluation does not identify clinically normal individuals with brain amyloidosis, the first stage of the pathology, defined as preclinical Alzheimer's disease. Spatial navigation assessment, in particular path integration, appears promising to detect preclinical symptoms, as the medial temporal lobe plays a key role in navigation and is the first cortical region affected by tau pathology., Methods: We have conducted a cross-sectional study. We related the path integration performance of 102 individuals without dementia, aged over 50, to amyloid and tau pathologies, measured using positron emission tomography. We included 75 clinically normal individuals (19 with brain amyloidosis, 56 without) and 27 individuals with mild cognitive impairment (18 with brain amyloidosis, 9 without). We fitted linear mixed models to predict the path integration performances according to amyloid status or tau pathology in the medial temporal lobal, adjusting for age, gender, cognitive status, education, and video game experience. We decomposed the error into rotation and distance errors., Results: We observed that clinically normal adults with brain amyloidosis (preclinical Alzheimer's disease) had spatial navigation deficits when relying only on self-motion cues. However, they were able to use a landmark to reduce their errors. Individuals with mild cognitive impairment had deficits in path integration that did not improve when a landmark was added in the environment. The amyloid status did not influence performance among individuals with mild cognitive impairment. Among all individuals, rotation, but not distance, errors increased with the level of tau pathology in the medial temporal lobe., Conclusion: Our results suggest that path integration performance in an environment without external cues allows identifying individuals with preclinical Alzheimer's disease, before overt episodic memory impairment is noticeable. Specifically, we demonstrated that poor angular estimation is an early cognitive marker of tau pathology, whereas distance estimation relates to older ages, not to Alzheimer's disease., Trial Registration: Eudra-CT 2018-003473-94., Competing Interests: Declarations. Ethics approval and consent to participate: This study was conducted in accordance with the Declaration of Helsinki and approved by the institution’s Ethics Committee (UCL-2016–121). All participants provided written informed consent. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background and Objectives: The influence of the age at which complete corpus callosotomy (CC) surgery is performed on seizure outcomes remains unclear. This study aimed to evaluate the age-dependent aspects of long-term seizure outcomes after complete CC., Methods: We reviewed 41 patients who underwent one-stage complete CC. Seizure outcomes were analyzed for age at epilepsy onset and at complete CC, focal MRI abnormality, and etiology., Results: The median age was 7 months at epilepsy onset and 93 months at complete CC. The median follow-up duration was 67 months. Sixteen patients had focal MRI lesions and 4 had only general atrophy. Etiology was identified in 20 patients. For overall seizure outcomes (N = 41), complete seizure freedom was achieved in 5 patients, excellent seizure reduction (>80%) in 11, good (50%-80%) in 5, and poor (<50%) in 20. Freedom was correlated with younger age at complete CC and unknown etiology ( P ≤ .05). Freedom was only achieved in patients aged younger than 7 years. Worthwhile (≥50%, freedom, excellent, and good) and not worthwhile (<50%, poor) overall seizure reduction showed no statistical difference in age at complete CC. No related factor was found for worthwhile overall seizure reduction. For drop attack outcomes (N = 31), freedom was achieved in 22 cases, excellent in 5, and poor in 4. Freedom was correlated with younger age at complete CC ( P < .05) although freedom was achieved in 4 of 7 patients older than 20 years. Age at complete CC showed no statistical difference between worthwhile (≥50%) and not worthwhile (<50%) drop attack reduction. Worthwhile drop attack reduction was correlated with unknown etiology ( P < .05). Complications were mild and transient., Conclusion: Complete CC is an excellent surgical option based on favorable seizure outcomes and acceptable complications in our present study., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Congress of Neurological Surgeons.)

Summary: Precise localization of peripheral nerve injuries and evaluation of their prognosis based on clinical and electrodiagnostic examinations are particularly challenging in the acute phase. High-resolution ultrasound (HRUS) may offer a viable and cost-effective imaging option for assessing the morphology of nerve injuries. Consequently, a systematic review and meta-analysis of studies on the use of ultrasound for diagnosing traumatic nerve injuries were conducted. A total of 15 studies were included, reporting the most recent findings on using HRUS in the diagnosis of traumatic nerve injury. These studies assessed the diagnostic test accuracy of ultrasound for the detection of traumatic nerve injury in 272 participants, with the cross-sectional area at the site of traumatic nerve injury also reported in 1,249 participants. The pooled sensitivity and specificity of the included studies were 92% confidence interval (CI) (0.89-0.95) and 86% CI (0.82-0.89), respectively. The positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were 13.76 CI (1.41-134.34), 0.08 CI (0.03-0.18), and 286.23 CI (21.22-3,860.40), respectively. In the summary of the receiver operating characteristic curve, the area under the curve was 0.986, and the Q* index was 0.949. Based on the current literature, HRUS has shown promising results in addition to its availability and feasibility. HRUS can serve as a valuable complement to clinical and electrodiagnostic examinations for diagnosing traumatic peripheral nerve injuries. Further research is recommended to better understand the ultrasound characteristics of these injuries., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 by the American Clinical Neurophysiology Society.)

Objective: Lennox-Gastaut syndrome (LGS) is typically characterized by drug-resistant epilepsy and subsequent cognitive deterioration. Surgery is a rare but viable option for the control of seizures in a subset of patients with LGS. This study aimed to describe the organization of the epileptogenic zone network (EZN) in patients with LGS using stereoelectroencephalography (SEEG) and to report the outcome of post-SEEG treatment., Methods: A quantitative SEEG signal analysis was conducted in 14 consecutive patients with LGS, in whom a potentially localized EZN was suggested based on a comprehensive noninvasive evaluation. The EZN and the irritative zone network were identified using relevant biomarkers during ictal (epileptogenicity index and connectivity epileptogenicity index) and interictal (spikes and high-frequency oscillations) recordings. The applied post-SEEG treatments were assessed, including SEEG-guided radiofrequency thermocoagulation (RF-TC), surgery, and neurostimulation., Results: The seizure onset patterns showed some specificity by seizure type, with 84% of tonic seizures involving low-voltage fast activity. The EZN of patients with LGS was often, but not always, complex and extensive, involving two or more lobes (79%) and both hemispheres (64%). The lateral neocortical structures, particularly the lateral premotor and dorsolateral prefrontal cortices, were identified as being most frequently involved in the EZN. Among the explored subcortical structures, only the pulvinar, central-lateral thalamic nucleus, and hypothalamic hamartoma belonged to the EZN. Twelve patients (86%) underwent SEEG-guided RF-TC, with 50% experiencing a >50% reduction in baseline seizure frequency. Four patients (29%) underwent curative surgery for significant involvement of a lesion in the EZN, and one case achieved an Engel class I outcome., Significance: This is the first quantitative SEEG study in patients with LGS to demonstrate the utility of SEEG in identifying patients who may benefit from surgery and to perform SEEG-guided RF-TC. Nevertheless, the indications for SEEG should be carefully assessed, as localized EZN is uncommon in LGS., (© 2025 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

In vitro and ex vivo studies on drug metabolism and stability are vital for drug development and pre-clinical safety assessment. Traditional in vitro models, such as liver enzyme (S9) fractions and microsomes, often fail to account for individual variability. Personalized models, including 3D cell models and organoids, offer promising alternatives but may not fully replicate physiological processes, especially for Cytochrome P450 (CYP) families involved in extrahepatic metabolism. A major challenge in these studies is the low stability and expression of CYP enzymes. This study aimed to stabilize native CYP activity in vitro by developing an optimized buffer formulation. Initial experiments using recombinant CYP supersomes and liver microsomes identified 45 μM cysteine, 4 mM dithiothreitol (DTT), and 300 μM phosphocholine (PC) as the most effective stabilizers. The applicability of these stabilizers was subsequently confirmed in primary human brain tissue, where they enabled the successful determination of CYP2D6 activity. This highlights the stabilizing buffer's utility for enhancing CYP functionality in diverse tissue types, including the brain, which plays a critical role in cerebral detoxification and drug metabolism. These findings suggest that specific enzyme stabilization can enable comprehensive evaluations of CYP function in ex vivo tissue samples, advancing the development of organoid human tissue models and supporting drug metabolism research., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2024. Published by Elsevier B.V.)

Despite decades of advancements in diagnostic MRI, 30-50% of temporal lobe epilepsy (TLE) patients remain categorized as "non-lesional" (i.e., MRI negative or MRI-) based on visual assessment by human experts. MRI- patients face diagnostic uncertainty and significant delays in treatment planning. Quantitative MRI studies have demonstrated that MRI- patients often exhibit a TLE-specific pattern of temporal and limbic atrophy that may be too subtle for the human eye to detect. This signature pattern could be successfully translated into clinical use via artificial intelligence (AI) advances in computer-aided MRI interpretation, thereby improving the detection of brain "lesional" patterns associated with TLE. Here, we tested this hypothesis by employing a three-dimensional convolutional neural network (3D CNN) applied to a dataset of 1,178 scans from 12 different centers. 3D CNN was able to differentiate TLE from healthy controls with high accuracy (85.9% ± 2.8), significantly outperforming support vector machines based on hippocampal (74.4% ± 2.6) and whole-brain (78.3% ± 3.3) volumes. Our analysis subsequently focused on a subset of patients who achieved sustained seizure freedom post-surgery as a gold standard for confirming TLE. Importantly, MRI- patients from this cohort were accurately identified as TLE 82.7% ± 0.9 of the time, an encouraging finding since clinically these were all patients considered to be MRI- (i.e., not radiographically different than controls). The saliency maps from the CNN revealed that limbic structures, particularly medial temporal, cingulate, and orbitofrontal areas, were most influential in classification, confirming the importance of the well-established TLE signature atrophy pattern for diagnosis. Indeed, the saliency maps were similar in MRI+ and MRI- TLE groups, suggesting that even when humans cannot distinguish more subtle levels of atrophy, these MRI- patients are on the same continuum common across all TLE patients. As such, AI can identify TLE lesional patterns and AI-aided diagnosis has the potential to greatly enhance the neuroimaging diagnosis of TLE and redefine the concept of "lesional" TLE., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Musicogenic epilepsy (ME) is characterized by seizures triggered by music. The epileptogenic focus in this rare reflex epilepsy is often in the temporal lobe, although the precise localization is still unclear. A correlation between ME and the presence of GAD65 antibodies indicates a potential immunological pathogenic mechanism. We evaluated a 32-year-old woman with drug-resistant temporal lobe epilepsy as a candidate for epilepsy surgery. In the absence of clear clinical lateralizing signs, video-EEG monitoring with intracranial electrodes inserted through the foramen ovale was performed to record from the amygdalo-hippocampal regions. The foramen ovale electrodes revealed bilateral, asynchronous, and independent seizure onsets in the mesial temporal regions triggered by music. Testing for GAD65 antibodies confirmed high-titer positivity. The efficacy of epilepsy surgery in antiGAD65-positive ME patients remains limited. We highlight the use of semi-invasive recording with foramen ovale electrodes in ME, as it can reveal bilateral seizures of mesial origin that contraindicate surgery and support the consideration of immunotherapy options. PLAIN LANGUAGE SUMMARY: Musicogenic epilepsy is a type of epilepsy in which music triggers seizures. Our understanding of its origin and cause is still limited. We assessed a patient with music-induced seizures to see if surgery was an option. Since noninvasive tests before surgery were not clear, we used a minimally invasive method with electrodes inserted through a small opening in the skull called the foramen ovale to record the seizures. Thus, we found that the seizures started independently from both temporal lobes, contraindicating epilepsy surgery. We also found high levels of GAD65 antibodies indicating an immunological pathogenic mechanism., (© 2025 The Author(s). Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) is associated with a complex genetic architecture, but the translation from genetic risk factors to brain vulnerability remains unclear. Here, we examined associations between epilepsy-related polygenic risk scores for HS (PRS-HS) and brain structure in a large sample of neurotypical children, and correlated these signatures with case-control findings in in multicentric cohorts of patients with TLE-HS. Imaging-genetic analyses revealed PRS-related cortical thinning in temporo-parietal and fronto-central regions, strongly anchored to distinct functional and structural network epicentres. Compared to disease-related effects derived from epilepsy case-control cohorts, structural correlates of PRS-HS mirrored atrophy and epicentre patterns in patients with TLE-HS. By identifying a potential pathway between genetic vulnerability and disease mechanisms, our findings provide new insights into the genetic underpinnings of structural alterations in TLE-HS and highlight potential imaging-genetic biomarkers for early risk stratification and personalized interventions., Competing Interests: POTENTIAL CONFLICTS OF INTEREST All authors declare no competing conflicts of interest.

In light of the growing interest in the bidirectional relationship between epilepsy and dementia, this review aims to provide an overview of the role of hyperphosphorylated tau (pTau) in cognition in human epilepsy. A literature search identified five relevant studies. All of them examined pTau burden in surgical biopsy specimens from patients with temporal lobe epilepsy. The prevalence of pTau reported across the five studies, encompassing a total of 142 patients, ranged from 3.5% to 95%. Findings also varied regarding the location of pTau in the hippocampus and/or temporal cortex. Two of five studies (40%) demonstrated an inverse relationship between pTau burden and cognitive performance, one study with regard to executive functions and the other with regard to naming and verbal short-term memory. The only longitudinal study found a significant link between pTau and cognitive decline in verbal learning and memory, and in part also in naming, from the pre- to the postoperative assessment and from three to 12 months postoperatively. Given the heterogeneity of the study cohorts and the neuropsychological and neuropathological methodologies and findings, no clear picture emerges regarding the association between pTau and cognition in temporal lobe epilepsy. Added to this is the multifactorial etiology of cognitive impairment in epilepsy, including the active epilepsy, the underlying and sometimes dynamic pathology, and anti-seizure medication. Some of these factors may affect pTau expression. Further research should aim to investigate pTau longitudinally and noninvasively on a whole-brain level, using targeted neuropsychological outcome measures and controlling for age and other factors potentially influencing cognitive trajectories in epilepsy.

Objective: Epilepsy is considered as a network disorder of interacting brain regions. The propagation of local epileptic activity from the seizure onset zone (SOZ) along neuronal networks determines the semiology of seizures. However, in highly interconnected brain regions such as the insula, the association between the SOZ and semiology is blurred necessitating invasive stereoelectroencephalography (SEEG). Normative connectomes on MRI data enable to link different symptoms and lesion locations to a common functional network. The present study applied connectomics to disentangle epilepsy networks from insular SEEG recordings and to describe their relationship to seizure semiology., Methods: We retrospectively extracted functional networks by normative connectome analysis from 118 insular contacts depicting epileptic discharges during SEEG in 20 epilepsy patients. The resulting epilepsy networks were correlated to the corresponding semiology by voxel-wise regression and multivariate analyses of variances., Results: Epileptic foci were found in the posterior insula for somatosensory, other sensory and motor seizures, while cognitive and autonomic symptoms were related to the anterior insula. We identified insular connections to the superior temporal gyrus and heschl gyrus in sensory seizures and projections to the somatosensory cortex in somatosensory seizures. Insula-basal ganglia pathways were found in cognitive seizure manifestations, while insular connectivity to fronto-basal regions were strongest in patients with autonomic seizures., Conclusion: The semiology of seizures is mirrored in the functional connectivity of insular epileptic discharges. Combining SEEG and connectomics could provide additional information about seizure propagation within the epilepsy network and might enable new treatment options in the future like deep brain stimulation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Machetanz, Weinbrenner, Wuttke, Ethofer, Helfrich, Kegele, Lauxmann, Alber, Rona, Tatagiba, Lerche, Honegger and Naros.)

Objective: This study aimed to evaluate the quality of life (QOL) in children with epilepsy and their caregivers, as well as the caregiver burden, through a secondary analysis of a cross-sectional online survey in Japan., Methods: Eligible participants were caregivers of children (aged < 18 years) diagnosed with epilepsy. Children's QOL was measured using the daily living subset of the Japanese version of the Quality of Life in Children with Epilepsy (QOLCE-Js52). Caregiver QOL and burden were measured using the physical component summary (PCS) and mental component summary (MCS) of the Short Form-8 (SF-8) and the short Japanese version of the Zarit Caregiver Burden Interview (J-ZBI&#95;8)., Results: Between March 2023 and May 2023, 1,147 caregivers completed the survey. Most caregivers (n = 1,144, 99.7 %) were parents. The mean (standard deviation [SD]) QOLCE-Js52 score was 68.3 (14.2). The mean (SD) scores of the PCS and MCS of the SF-8 were 46.5 (4.5) and 43.7 (5.1), respectively, which were significantly lower than those of the general Japanese population (p < 0.001 for both means). The mean (SD) J-ZBI&#95;8 score was 4.9 (7.1), with 13.2 % of caregivers scoring at least 13, a predictor of depression. Multivariable regression analysis showed that disability was a significant risk factor for lower QOL and increased caregiver burden (p < 0.001). Frequent seizures, emergency transportation, and longer epilepsy duration were associated with poorer QOL in children and caregivers., Conclusion: Risk factors, such as emergency transport, may be mitigated by rescue medication in non-hospital settings., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Shinichi Nishiuma and Takuya Kumagai are employees of Aculys Pharma, Inc. Healthcare Consulting, Inc. has received research funding from Aculys Pharma, Inc. Kinya Kokubo is the representative director of Healthcare Consulting, Inc. Katsuhiko Iwasaki and Kazuaki Yamamoto are employees of Healthcare Consulting, Inc. Knock on the Door, Inc. has received research funding from Aculys Pharma, Inc. Hiroomi Hayashi is a representative director of Knock on the Door, Inc. Eiji Nakagawa and Shin Okazaki has received advisory fees from Aculys Pharma, Inc. for this research. Beyond these declared interests, there are no conflicts of interest to disclose regarding this study., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: 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., Methods: 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 F 1 score, subject-level detection rate, and specificity., Results: 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 F 1 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, F 1 score = .07). MELD showed the least performance variation across centers, with detection rates between 46% and 54%., Significance: 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., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Post-traumatic stress disorder (PTSD) is more common in patients with drug-resistant epilepsy. Some of these patients experience PTSD due to early psychotraumatic events. This study aims to assess the influence of PTSD on interictal functional connectivity using stereoelectroencephalography (SEEG) recordings in patients with temporal lobe DRE (TDRE). Two groups were considered: TDRE patients with PTSD (PTSD+, N = 11) and TDRE patients without PTSD (PTSD-, N = 12). All subjects had questionnaires measuring anxiety, depression, PTSD symptoms related to seizures, a diagnostic PTSD questionnaire, and a childhood trauma questionnaire. Resting state functional connectivity (FC) was evaluated on SEEG signals to analyze network characteristics. We mainly focused on brain regions involved in PTSD (amygdala, orbitofrontal cortex, hippocampus, insula, rhinal cortex, anterior cingulate cortex). Results revealed increased FC in PTSD + subjects in the brain regions involved in PTSD, but only in the hemisphere ipsilateral to the epileptogenic zone. In contrast, a decreased FC in the contralateral hemisphere was observed in the hippocampus. These findings support the existence of a PTSD-epilepsy-reinforced network, leading to FC alterations dependent on the epilepsy side and the region. Our study is the first to offer insights into the intricate dynamic linking PTSD and epilepsy and highlights the need for accounting for the influence of comorbidities on epileptogenic networks., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Time-frequency analysis of focal seizure electroencephalographic signals performed with depth electrodes in human temporal lobe structures has revealed the occurrence at onset of oscillations at approximately 30-100 Hz that feature a monotonic rapid decay in frequency content. This seizure onset pattern, referred to as chirp, has been identified as a highly specific and sensitive marker of focal seizures that are characterized by low-voltage fast activity. We report that this chirp pattern is also observed in animal models of temporal lobe epilepsy in both in vivo and in vitro preparations. We propose here that chirps mirror the involvement of synchronous interneuron firing that is known to represent a specific cellular mechanism leading to the initiation of focal seizures, in particular those characterized by low-voltage fast activity., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: To evaluate the effects of changes in group delay from a click signal to a chirp signal on the 40-Hz Auditory Steady-State Response (ASSR) using magnetoencephalography (MEG)., Design: In this study, each participant was exposed to 10 chirp signals with gradually varying group delays from the CE chirp to the click at 60 dB nHL. The 40-Hz ASSR was measured using MEG and evaluated for amplitude and latency in the maximum signal channel at the click signal measured in each hemisphere., Study Sample: Ten native Japanese speakers without histories of auditory diseases (8 males and 2 females, mean age 28.4 ± 5.70 years) participated in the study., Results: The 40-Hz ASSR amplitude increased with the group delay of the chirp signal, was most efficient with the CE-chirp (longest group delay) and was significantly larger in the contralateral hemisphere for the CE-chirp than with the click signal. No significant differences were observed in ipsilateral hemispheres. The latency of the 40-Hz ASSR decreased as the group delay of the chirp signal increased., Conclusions: This study demonstrated that chirp signals, particularly the CE chirp, are more efficient than click signals in eliciting a 40-Hz ASSR, especially in the contralateral hemisphere.

Objective: This study aims to evaluate the efficacy and safety of deep brain stimulation (DBS) of the medial pulvinar nucleus (PuM) in reducing seizure frequency and addressing comorbidities in patients with drug and vagal nerve-resistant focal epilepsy., Methods: This is an open-label prospective treatment trial with a planned enrollment of 12 patients suffering from medically refractory epilepsy (Clinical trial gov NCT04692701), for which the interim 12-month post-implantation results for the first 6 patients are being reported. Inclusion criteria were focal epilepsy not suitable for or after failed surgical intervention and previous failure of neurostimulation therapies (vagus nerve stimulation or anterior thalamic nucleus DBS). Evaluations included seizure diaries, neuropsychological assessments, and scales for depression, anxiety, quality of life, and seizure severity. PuM DBS was performed using ROSA robotic assistance, with follow-ups every 3 months for 1 year., Results: Out of six patients, five completed 1-year follow-up (one patient died prematurely). A non-significant trend toward seizure reduction was observed at 6 months, becoming more pronounced at 1 year (mean reduction: 45%; responders: 2/5). Seizure severity significantly improved ( p  = 0.02), with a reduction in the NHS3 scale scores. Quality of life improved significantly at 1 year ( p  = 0.03). Psychiatric assessments indicated a non-significant trend toward improvement in depression (mean improvement: 26%) and anxiety (mean improvement: 20%) scores. Neuropsychological testing showed stable or improved cognitive performance in three out of five patients. Adverse events included one case of cerebral hemorrhage, one infection leading to device removal, and one possible SUDEP., Significance: Preliminary results suggest that PuM DBS may offer a promising therapeutic option for reducing seizure severity and improving quality of life and cognitive functions in patients with drug-resistant epilepsy. Despite the small sample size and the presence of serious adverse events, the findings warrant further investigation with larger cohorts to confirm these trends and optimize the treatment protocol., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Pizzo, Carron, Laguitton, Clement, Giusiano and Bartolomei.)

Objective: Resistance to antiseizure medications (ASMs) is a major challenge in the treatment of patients with epilepsy. Despite numerous newly marketed ASMs, the proportion of drug-resistant people with epilepsy has not significantly decreased over the years. Therefore, novel and innovative seizure models for preclinical drug screening are highly desirable. Here, we explore the efficacy of a broad spectrum of ASMs in suppressing seizure activity in two established Drosophila melanogaster bang-sensitive mutants. These mutants respond with seizures to mechanical stimulation, providing a promising platform for screening novel ASMs., Methods: Seven frequently used ASMs (brivaracetam, cenobamate, lacosamide, lamotrigine, levetiracetam, phenytoin, and valproate) were administered to the bang-sensitive mutants easily shocked 2F ( eas 2F ). After 48 h of treatment, the flies were vortexed to induce mechanical stimulation. The seizure probability (i.e., ratio of seizing and non-seizing flies) as well as the seizure duration were analyzed.paralytic bss1 ( para bss1 ). After 48 h of treatment, the flies were vortexed to induce mechanical stimulation. The seizure probability (i.e., ratio of seizing and non-seizing flies) as well as the seizure duration were analyzed., Results: In case of eas mutants, treatment with the sodium channel blockers phenytoin and lamotrigine resulted in a robust reduction of seizure probability, whereas flies treated with lacosamide showed a decrease in seizure duration. Treatment with valproate resulted in both a reduction in seizure probability and in seizure duration. In contrast, levetiracetam, brivaracetam and cenobamate had no effect on the bang-sensitive phenotype of 2F flies. In case of eas flies, none of the tested medications significantly reduced seizure activity, supporting its role as a model of intractable epilepsy. 2F flies. In case of para bss1 flies, none of the tested medications significantly reduced seizure activity, supporting its role as a model of intractable epilepsy., Significance: Our results show that particularly sodium channel blockers as well as valproate are effective in suppressing seizure activity in the bang-sensitive mutant eas . These findings demonstrate the usability of 2F . These findings demonstrate the usability of Drosophila might provide an attractive and innovative high-throughput model for the discovery of novel antiseizure compounds.Drosophila might provide an attractive and innovative high-throughput model for the discovery of novel antiseizure compounds., Competing Interests: SW has received travel support and speaker honoraria from Angelini Pharma. YW is member of an advisory board of Angelini Pharma. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Fischer, Karge, Koch, Voigt, Weber and Wolking.)

The neuromuscular circuit mechanisms of freezing of gait in Parkinson's disease have received little study. Technological progress enables researchers chronically to sense local field potential activity of the basal ganglia in patients while walking. To study subthalamic activity and the circuit processes of supraspinal contributions to spinal motor integration, we recorded local field potentials, surface EMG of antagonistic leg muscles and gait kinematics in patients while walking and freezing. To evaluate the specificity of our findings, we controlled our findings to internally generated volitional stops. We found specific activation-deactivation abnormalities of oscillatory activity of the subthalamic nucleus both before and during a freeze. Furthermore, we were able to show with synchronization analyses that subthalamo-spinal circuits entrain the spinal motor neurons to a defective timing and activation pattern. The main neuromuscular correlates when turning into freezing were as follows: (i) disturbed reciprocity between antagonistic muscles; (ii) increased co-contraction of the antagonists; (iii) defective activation and time pattern of the gastrocnemius muscle; and (iv) increased subthalamo-muscular coherence with the gastrocnemius muscles before the freeze. Beyond the pathophysiological insights into the supraspinal mechanisms contributing to freezing of gait, our findings have potential to inform the conceptualization of future neurorestorative therapies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: In this study, we isolated a cohort of patients who have refractory epilepsy who underwent surgery with frontobasal focus. This work aimed to develop prognostic factors associated with a better seizure outcome and identify risk factors determining postoperative morbidity., Methods: We identified all patients with frontobasal epilepsy who underwent surgery due to refractory epilepsy at the University Hospital Bonn over 22 years. Although this is a retrospective study, all data sets were collected prospectively. We evaluated both surgical and functional outcomes., Results: In total, 32 patients were identified for inclusion in this study. With a long and stable postoperative seizure outcome averaging 109 months, we were able to show that patients with frontobasal epilepsy can achieve a better outcome (53 % seizure-free, ILAE1) than patients with frontal epilepsy. In contrast to other brain regions, the resection size (isolated or extended) did not influence the outcome. Low-grade tumors, on the other hand, were associated with a better seizure outcome, and gliosis or non-specific histological findings with a worse seizure outcome. Stereo-EEG with depth electrodes is more suitable for invasive diagnostics at the frontal base than strip or grid electrodes. Patients who did not become seizure-free after surgery and underwent a second surgery did not profit significantly concerning seizure outcome., Conclusion: Patients with frontobasal epilepsy who are operated on early in the course of the disease, are MRI-positive, and have a tumor as an epileptogenic pathology have the best chance of seizure freedom., Competing Interests: Declaration of competing interest On behalf of all authors, I hereby declare that there is no conflict of interest concerning the manuscript “Epilepsy-surgery for fronto-basal lesions: Management, Outcome, and Review of Literature.”, (Copyright © 2024 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Objective: To assess whether arterial spin labeling perfusion images of healthy controls can enhance ictal single-photon emission computed tomography analysis and whether the acquisition of the interictal image can be omitted., Methods: We developed 2 pipelines: The first uses ictal and interictal images and compares these to single-photon emission computed tomography and arterial spin labeling of healthy controls. The second pipeline uses only the ictal image and the analogous healthy controls. Both pipelines were compared to the gold standard analysis and evaluated on data of individuals with epilepsy who underwent ictal single-photon emission computed tomography imaging during presurgical evaluation between 2010 and 2022. Fifty healthy controls prospectively underwent arterial spin labeling imaging. The correspondence between the detected hyperperfusion and the postoperative resection cavity or the presumably affected lobe was assessed using Dice score and mean Euclidean distance. Additionally, the outcomes of the pipelines were automatically assigned to 1 of 5 concordance categories., Results: Inclusion criteria were met by 43 individuals who underwent epilepsy surgery and by 73 non-surgical individuals with epilepsy. Compared to the gold standard analysis, both pipelines resulted in significantly higher Dice scores and lower mean distances (p < 0.05). The combination of both provided localizing results in 85/116 cases, compared to 54/116 generated by the current gold standard analysis and the ictal image alone produced localizing results in 60/116 (52%) cases., Interpretation: We propose a new ictal single-photon emission computed tomography protocol; it finds relevantly more ictal hyperperfusion, and halves the radiation dose in about half of the individuals. ANN NEUROL 2024;96:1160-1173., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objective: High-field magnetic resonance imaging (MRI) is a standard in the diagnosis of epilepsy. However, high costs and technical barriers have limited adoption in low- and middle-income countries. Even in high-income nations, many individuals with epilepsy face delays in undergoing MRI. Recent advancements in ultra-low-field (ULF) MRI technology, particularly the development of portable scanners, offer a promising solution to the limited accessibility of MRI. In this study, we present and evaluate the imaging capability of ULF MRI in detecting structural abnormalities typically associated with epilepsy and compare it to high-field MRI at 3 T., Methods: Data collection was conducted within 3 consecutive weeks at the University Hospital Bonn. Inclusion criteria were a minimum age of 18 years, diagnosed epilepsy, and clinical high-field MRI with abnormalities. We used a .064 T Swoop portable MR Imaging System. Both high-field MRI and ULF MRI scans were evaluated independently by two experienced neuroradiologists as part of their clinical routine, comparing pathology detection and diagnosis completeness., Results: Twenty-three individuals with epilepsy were recruited. One subject presented with a dual pathology. Across the entire cohort, in 17 of 24 (71%) pathologies, an anomaly colocalizing with the actual lesion was observed on ULF MRI. For 11 of 24 (46%) pathologies, the full diagnosis could be made based on ULF MRI. Tumors and posttraumatic lesions could be diagnosed best on ULF MRI, whereas cortical dysplasia and other focal pathologies were the least well diagnosed., Significance: This single-center series of individuals with epilepsy demonstrates the feasibility and utility of ULF MRI for the field of epileptology. Its integration into epilepsy care offers transformative potential, particularly in resource-limited settings. Further research is needed to position ULF MRI within imaging modalities in the diagnosis of epilepsy., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: Neurological autoimmune peripheral and central nervous system disorders can be associated with anti-sulfatide antibodies. These antibodies are considered potential diagnostic biomarkers, although their additional diagnostic value in neurological fields has been increasingly questioned. Given the little evidence of anti-sulfatide antibodies' frequency and diagnostic value in neurology, we aimed to fill this knowledge gap by investigating 10 years of data., Methods: This retrospective study analyzed the results of the anti-ganglioside dot kits (GA Generic Assays GmbH) from 1318 serum samples and 462 cerebrospinal fluid (CSF) samples for the frequency, sensitivity, and specificity of anti-sulfatide antibodies in neurological disorders., Results: Although anti-sulfatide antibodies are rarely present in neurological autoimmune disorders (serum IgM 2.5%, IgG 4.6%), they are also present in non-autoimmune diseases (serum IgM 1.2%, IgG 2.5%) and lack sensitivity and specificity towards being a diagnostic marker. Furthermore, anti-sulfatide antibodies are rarely found in CSF (e.g., no positive results for IgM), and including so-called borderline results ((+)) increases sensitivity and the false-positive rate in serum and CSF., Discussion: While anti-sulfatide antibodies appear more frequently in neurological autoimmune diseases, they are rare overall and provide very limited diagnostic value in determining specific neurological diseases and-more importantly-if a neurological disease has a potential autoimmune etiology., Competing Interests: Declarations. Conflicts of interest: None of the authors has any conflict of interest to disclose. Ethical publication statement: We confirm that we have read the journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Standard protocol approvals, registrations, and patient consents: The study was performed according to the Declaration of Helsinki and was approved by the local ethics committee (project number approval no. 189/2023B O2, 25th April 2023). Declaration of generative artificial intelligence and artificial intelligence-assisted technologies in the writing process: After writing the draft of our manuscript, we utilized Large Language Models (LLMs, here ChatGPT and Grammarly) to correct for grammar and scientific rigor. After using this tool, the authors reviewed and edited the content as needed., (© 2024. The Author(s).)

Background and Objective: Despite recent performance advancements, deep learning models are not yet adopted in clinical practice on a wide scale. The intrinsic intransparency of such systems is commonly cited as one major reason for this reluctance. This has motivated methods that aim to provide explanations of model functioning. Known limitations of feature-based explanations have led to an increased interest in concept-based interpretability. Testing with Concept Activation Vectors (TCAV) employs human-understandable, abstract concepts to explain model behavior. The method has previously been applied to the medical domain in the context of electronic health records, retinal fundus images and magnetic resonance imaging., Methods: We explore the usage of TCAV for building interpretable models on physiological time series, using an example of abnormality detection in electroencephalography (EEG). For this purpose, we adopt the XceptionTime model, which is suitable for multi-channel physiological data of variable sizes. The model provides state-of-the-art performance on raw EEG data and is publically available. We propose and test several ideas regarding concept definition through metadata mining, using additional labeled EEG data and extracting interpretable signal characteristics in the form of frequencies. By including our own hospital data with analog labeling, we further evaluate the robustness of our approach., Results: The tested concepts show a TCAV score distribution that is in line with the clinical expectations, i.e. concepts known to have strong links with EEG pathologies (such as epileptiform discharges) received higher scores than the neutral concepts (e.g. sex). The scores were consistent across the applied concept generation strategies., Conclusions: TCAV has the potential to improve interpretability of deep learning applied to multi-channel signals as well as to detect possible biases in the data. Still, further work on developing the strategies for concept definition and validation on clinical physiological time series is needed to better understand how to extract clinically relevant information from the concept sensitivity scores., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Given two unidirectionally coupled nonlinear systems, we speak of generalized synchronization when the responder "follows" the driver. Mathematically, this situation is implemented by a map from the driver state space to the responder state space termed the synchronization map. In nonlinear times series analysis, the framework of the present work, the existence of the synchronization map amounts to the invertibility of the so-called cross map, which is a continuous map that exists in the reconstructed state spaces for typical time-delay embeddings. The cross map plays a central role in some techniques to detect functional dependencies between time series. In this paper, we study the changes in the "noiseless scenario" just described when noise is present in the driver, a more realistic situation that we call the "noisy scenario." Noise will be modeled using a family of driving dynamics indexed by a finite number of parameters, which is sufficiently general for practical purposes. In this approach, it turns out that the cross and synchronization maps can be extended to the noisy scenario as families of maps that depend on the noise parameters, and only for "generic" driver states in the case of the cross map. To reveal generalized synchronization in both the noiseless and noisy scenarios, we check the existence of synchronization maps of higher periods (introduced in this paper) using recurrent neural networks and predictability. The results obtained with synthetic and real-world data demonstrate the capability of our method., (© 2024 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International (CC BY-NC-ND) license (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Lesional focal epilepsy (LFE) is a common and severe seizure disorder caused by epileptogenic lesions, including malformations of cortical development (MCD) and low-grade epilepsy-associated tumors (LEAT). Understanding the genetic etiology of these lesions can inform medical and surgical treatment. We conducted a somatic variant enrichment mega-analysis in brain tissue from 1386 individuals who underwent epilepsy surgery, including 599 previously unpublished individuals with ultra-deep ( > 1600x) targeted panel sequencing. Here we confirm four known associations (BRAF, SLC35A2, MTOR, PTPN11), support eight associations without prior statistical support (FGFR1, PIK3CA, AKT3, NF1, PTEN, RHEB, KRAS, NRAS), and identify novel associations for two genes, DYRK1A and EGFR. Both novel genes show specific histopathological phenotypes, interact with LFE genes and pathways, and may represent promising candidates as biomarkers and potentially druggable targets., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Herein, we present a case of idiopathic generalized epilepsy (IGE) manifesting as de novo late-onset absence status epilepticus (ASE) following mild coronavirus disease 2019 (COVID-19). A woman in her 40s presented with persistent 3-5.5 Hz generalized spike-wave complexes (SWCs) on electroencephalography (EEG). She experienced a generalized tonic-clonic seizure (GTCS) 10 days after the COVID-19 infection. She was diagnosed with epilepsy at 40 years of age, after which she was started on levetiracetam (LEV) 1,000 mg/day. After the medication was started, she experienced three other GTCSs. We performed a long-term video EEG of the patient, leading to a diagnosis of late-onset IGE with de novo late-onset ASE. She achieved seizure freedom for over a year with a combination of valproic acid (VPA) and lamotrigine (LTG), although her EEG continued to demonstrate persistent generalized SWCs. This case suggests that late-onset IGE accompanied by de novo late-onset status epilepticus may have been triggered by COVID-19. Persistent neuroinflammation may be reflected in persistent EEG abnormalities, even after epileptic seizures are well controlled with medications. LTG and VPA are believed to be effective for clinical management, and EEG is an essential modality for recording epileptic activity in outpatient settings., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. National Center Hospital, National Center of Neurology and Psychiatry, Japan issued approval A2024-065. This report has been approved by the Ethics Review Committee of National Center Hospital, National Center of Neurology and Psychiatry, Japan. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Otake et al.)

Recurring utterances (RUs) are a distinct language symptom observed in severe aphasia, known to be associated with global or Broca's aphasia, though their neural basis remains unclear. We present a case of RU induced by selective left frontal suppression using a novel technique named the super-selective Wada test (ssWada), which involves temporary anesthetization of specific brain regions through super-selective catheterization of cerebral arteries. This method allows for precise simulation of localized brain dysfunction. We applied this technique on a 49-year-old right-handed man with drug-resistant epilepsy as a preoperative examination. Propofol administration to the superior branch of the left middle cerebral artery (MCA), supplying the pars triangularis, pars opercularis, middle frontal gyrus, and part of the precentral gyrus, induced Broca's aphasia with RUs. The RU content was the phrase uttered at anesthesia administration. Notably, the anesthetic did not affect the temporal language area or basal ganglia. The patient showed minimal awareness of his abnormal speech despite preserved receptive language function and memory, aligning with previous observations of anosognosia in patients with RU. Contrastingly, anesthetic infusion into the inferior branch of the left MCA resulted in mixed aphasia, while right MCA infusion induced no language impairments. This case demonstrates that RUs can arise without deficits in the posterior language area or basal ganglia. It illustrates the potential of ssWada in investigating neural substrates of neuropsychological symptoms through temporary, localized brain disruption. This approach offers novel insights into brain-behavior relationships in language processing and cognition., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: Myositis-specific antibodies (MSAs) and myositis-associated antibodies (MAAs) are assessed in clinical neurology, serving as a non-invasive tool for the differential diagnosis of autoimmune myopathies. However, the presence of MSAs and MAAs in neurological disorders remains uncertain., Methods: Retrospective analysis was conducted on 878 serum samples from the neurological laboratory of the University Hospital Tübingen, Germany. The EUROLINE Myositis Profil 3 (IgG) Line Blot was used for antibody evaluation (anti-Mi2, -Ku, -PM-Scl100, -PM-Scl75, -Jo1, -SRP, -PL7, -PL12, -EJ, -OJ, and -Ro52). Samples were categorized into 19 disease groups, with consideration for myositis-linked and non-myositis-linked diseases. Then, the distribution of positive findings and the concurrent presence of more than one MAA/MSA were analyzed., Results: Among 727 included line blots, 84 could be assigned to myositis-linked diseases (thereof 44 positive for MAA/MSA). MAA and MSA taken together were more frequently positive for the main group of myositis-linked disease (52.4 %) compared to the non-myositis-linked group (14.6 %, overall specificity 85.4 %). However, individual antibodies were specific, ranging above 97.5 %. False positive antibody results can also occur in neurological differential diagnoses such as muscle dystrophy or cramp fasciculation syndrome. Furthermore, the concurrent presence of more than one MAA/MSA does not show a significant association with the presence of a myositis-linked disease for antibody-positive samples (p = 0.136)., Discussion: Testing MSA and MAA simultaneously may not be suitable as a primary screening method for myositis-linked diseases in clinical neurological groups. However, MSAs and MAAs may offer valuable diagnostic support, particularly in cases where myositis is strongly considered., Competing Interests: Declaration of competing interest None of the authors has any conflict of interest to disclose., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Hippocampal sclerosis (HS), the most common pathology associated with temporal lobe epilepsy (TLE), is not always visible on magnetic resonance imaging (MRI), causing surgical delays and reduced postsurgical seizure-freedom. We developed an open-source software to characterize and localize HS to aid the presurgical evaluation of children and adults with suspected TLE., Methods: We included a multicenter cohort of 365 participants (154 HS; 90 disease controls; 121 healthy controls). HippUnfold was used to extract morphological surface-based features and volumes of the hippocampus from T1-weighted MRI scans. We characterized pathological hippocampi in patients by comparing them to normative growth charts and analyzing within-subject feature asymmetries. Feature asymmetry scores were used to train a logistic regression classifier to detect and lateralize HS. The classifier was validated on an independent multicenter cohort of 275 patients with HS and 161 healthy and disease controls., Results: HS was characterized by decreased volume, thickness, and gyrification alongside increased mean and intrinsic curvature. The classifier detected 90.1% of unilateral HS patients and lateralized lesions in 97.4%. In patients with MRI-negative histopathologically-confirmed HS, the classifier detected 79.2% (19/24) and lateralized 91.7% (22/24). The model achieved similar performances on the independent cohort, demonstrating its ability to generalize to new data. Individual patient reports contextualize a patient's hippocampal features in relation to normative growth trajectories, visualise feature asymmetries, and report classifier predictions., Interpretation: Automated and Interpretable Detection of Hippocampal Sclerosis (AID-HS) is an open-source pipeline for detecting and lateralizing HS and outputting clinically-relevant reports. ANN NEUROL 2024., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objectives: Artificial intelligence (AI) is thought to improve lesion detection. However, a lack of knowledge about human performance prevents a comparative evaluation of AI and an accurate assessment of its impact on clinical decision-making. The objective of this work is to quantitatively evaluate the ability of humans to detect focal cortical dysplasia (FCD), compare it to state-of-the-art AI, and determine how it may aid diagnostics., Materials and Methods: We prospectively recorded the performance of readers in detecting FCDs using single points and 3-dimensional bounding boxes. We acquired predictions of 3 AI models for the same dataset and compared these to readers. Finally, we analyzed pairwise combinations of readers and models., Results: Twenty-eight readers, including 20 nonexpert and 5 expert physicians, reviewed 180 cases: 146 subjects with FCD (median age: 25, interquartile range: 18) and 34 healthy control subjects (median age: 43, interquartile range: 19). Nonexpert readers detected 47% (95% confidence interval [CI]: 46, 49) of FCDs, whereas experts detected 68% (95% CI: 65, 71). The 3 AI models detected 32%, 51%, and 72% of FCDs, respectively. The latter, however, also predicted more than 13 false-positive clusters per subject on average. Human performance was improved in the presence of a transmantle sign ( P < 0.001) and cortical thickening ( P < 0.001). In contrast, AI models were sensitive to abnormal gyration ( P < 0.01) or gray-white matter blurring ( P < 0.01). Compared with single experts, expert-expert pairs detected 13% (95% CI: 9, 18) more FCDs ( P < 0.001). All AI models increased expert detection rates by up to 19% (95% CI: 15, 24) ( P < 0.001). Nonexpert+AI pairs could still outperform single experts by up to 13% (95% CI: 10, 17)., Conclusions: This study pioneers the comparative evaluation of humans and AI for FCD lesion detection. It shows that AI and human predictions differ, especially for certain MRI features of FCD, and, thus, how AI may complement the diagnostic workup., Competing Interests: Conflicts of interest and sources of funding: A.R. has received fees as a speaker from UCB Pharma and travel support from the Elisabeth und Helmut Uhl Stiftung. U.A. has received fees as a speaker for Siemens Healthineers and as clinical consultant for Bayer. A.R. lectures for Guerbet and Bayer, and is part of the Advisory Board for GE, Bracco, and Guerbet. R.S. has received personal fees as speaker or for serving on advisory boards from Angelini, Arvelle, Bial, Desitin, Eisai, Jazz Pharmaceuticals Germany GmbH, Janssen-Cilag GmbH, LivaNova, LivAssured B.V., Novartis, Precisis GmbH, Rapport Therapeutics, Tabuk Pharmaceuticals, UCB Pharma, UNEEG, and Zogenix. T.R. has received fees as a speaker from Eisai. None of the previously mentioned activities were related to the content of this manuscript. The remaining authors have nothing to declare. No external funding was received for this work., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Learning never stops. As we navigate life, we continuously acquire and update knowledge to optimize memory-guided action, with a gradual shift from the former to the latter as we master our environment. How are these learning dynamics expressed in the brain and in behavioral patterns? Here, we devised a spatiotemporal image learning task ("Memory Arena") in which participants learn a set of 50 items to criterion across repeated exposure blocks. Critically, brief task-free periods between successive image presentations allowed us to assess multivariate electroencephalogram (EEG) patterns representing the previous and/or upcoming image identity, as well as anticipatory eye movements toward the upcoming image location. As expected, participants eventually met the performance criterion, albeit with different learning rates. During task-free periods, we were able to readily decode representations of both previous and upcoming image identities. Importantly though, decoding strength followed opposing slopes for previous vs. upcoming images across time, with a gradual decline of evidence for the previous image and a gradual increase of evidence for the upcoming image. Moreover, the ratio of upcoming vs. previous image evidence directly followed behavioral learning rates. Finally, eye movement data revealed that participants increasingly used the task-free period to anticipate upcoming image locations, with target-precision slopes paralleling both behavioral performance measures as well as EEG decodability of the upcoming image across time. Together, these results unveil the neural and behavioral dynamics underlying the gradual transition from learning to memory-guided action., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The differences in clinical bioethics between the Mediterranean and Latin American cultures have not been analyzed. The objective of the study is to compare the ethical conflicts that internists in Spain, Mexico and Argentina have., Methods: Cross-sectional observational study through a survey directed at internists from Spain, Argentina and Mexico. The survey was administered to affiliated members of the National Societies of Internal Medicine across three countries via an online platform., Results: 762 internists participated, 261 from Spain, 154 from Argentina and 347 from Mexico. The main ethical conflicts that internists in Spain, Argentina and Mexico have are related (in order) to the end of life, to the clinical relationship and to the patient's autonomy. Withholding and withdrawing life-sustaining treatment is the most frequent conflict in Spain and Argentina and the second in Mexico., Conclusions: Internists from Spain and Argentina identify very similar ethical conflicts. Furthermore, they consider them more frequent and difficult than in Mexico. In Argentina they are less satisfied with the way they are resolved. To explain these differences, socio-cultural factors are postulated, among others: paternalism, individualism, masculinity, organization of the health system, formal training in bioethics and assessment of death., (© 2024. The Author(s).)

Introduction: The purpose of this epidemiological study was to assess the prevalence, comorbidities, and real-world management of childhood epilepsy to provide insights for enhancing epilepsy management and medical resource planning., Materials and Methods: The study encompassed insured individuals aged 0-17 years as of December 2018 who were registered at any point in 2018, for at least part of the year, in a Japanese health claims database spanning January-December 2018. Epilepsy was defined as a diagnosis of epilepsy based on the International Classification of Diseases, 10th Revision codes, and a claimed management fee for epilepsy or an anti-seizure medication (ASM) prescription for longer than 4 weeks. The prevalence of epilepsy, patient characteristics, including comorbidities, and management status, such as prescription of ASMs, were evaluated., Results: Among 1528,905 registered children, 9279 were identified as having epilepsy. The prevalence of epilepsy was the lowest at 1.97 per 1000 population (95 % confidence interval [CI] 1.80-2.15) in the 0-2-year age group and increased with age to 9.34 per 1000 population (95 % CI 8.98-9.72) in the 15-17-year age group, with a significantly higher prevalence in boys than in girls in the ≥12-year age group. ASMs were prescribed to 88.3 %-91.9 % of the patients. Moreover, 27 (0.29 %) patients underwent epilepsy surgery. The frequency of claiming intravenous ASMs and long-term electroencephalogram fees increased with a decrease in age., Conclusions: Our findings indicate that young children receive more medical resources than adolescents and that epilepsy surgery is underutilized. Further investigations will help improve the management of and develop measures against epilepsy., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Malformations of the brain are common and vary in severity, from negligible to potentially fatal. Their causes have not been fully elucidated. Here, we report pathogenic variants in the core protein-folding machinery TRiC/CCT in individuals with brain malformations, intellectual disability, and seizures. The chaperonin TRiC is an obligate hetero-oligomer, and we identify variants in seven of its eight subunits, all of which impair function or assembly through different mechanisms. Transcriptome and proteome analyses of patient-derived fibroblasts demonstrate the various consequences of TRiC impairment. The results reveal an unexpected and potentially widespread role for protein folding in the development of the central nervous system and define a disease spectrum of "TRiCopathies."

The epileptogenic network in temporal lobe epilepsy (TLE) contains structures of the primary and secondary olfactory cortex such as the piriform and entorhinal cortex, the amygdala, and the hippocampus. Olfactory auras and olfactory dysfunction are relevant symptoms of TLE. This study aims to characterize olfactory function in TLE using olfactory testing and olfactory functional magnetic resonance imaging (fMRI). We prospectively enrolled 20 individuals with unilateral TLE (age 45 ± 20 years [mean ± SD], 65% female, 90% right-handed) and 20 healthy individuals (age 33 ± 15 years [mean ± SD], 35% female, 90% right-handed). In the TLE group, the presumed seizure onset zone was left-sided in 75%; in 45% of the individuals with TLE limbic encephalitis was the presumed etiology; and 15% of the individuals with TLE reported olfactory auras. Olfactory function was assessed with a Screening Sniffin' Sticks Test (Burkhart, Wedel, Germany) during a pre-assessment. During a pre-testing, all individuals were asked to rate the intensity, valence, familiarity, and associated memory of five different odors (eugenol, vanillin, phenethyl alcohol, decanoic acid, valeric acid) and a control solution. During the fMRI experiment, all individuals repeatedly smelled eugenol (positively valenced odor), valeric acid (negatively valenced odor), and the control solution and were asked to rate odor intensity on a five-point Likert scale. We acquired functional EPI sequences and structural images (T1, T2, FLAIR). Compared to healthy individuals, individuals with TLE rated the presented odors as more neutral (two-sided Mann-Whitney U tests, FDR-p < 0.05) and less familiar (two-sided Mann-Whitney U tests, FDR-p < 0.05). fMRI data analysis revealed a reduced response contrast in secondary olfactory areas (e.g., hippocampus) connected to the limbic system when comparing eugenol and valeric acid in individuals with TLE when compared with healthy individuals. However, no lateralization effect was obtained when calculating a lateralization index by the number of activated voxels in the olfactory system (two-sided Mann-Whitney U test; U = 176.0; p = 0.525). TLE is characterized by olfactory dysfunction and associated with hypoactivation of secondary olfactory structures connected to the limbic system. These findings contribute to our understanding of the pathophysiology of TLE. This study was preregistered on OSF Registries (www.osf.io)., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Background: The decision to disclose epilepsy in the workplace is complex, as it entails both advantages and disadvantages. In this study, we aimed to identify the factors associated with disclosure of epilepsy in the workplace based on the disclosure decision-making model for patients who required underwent comprehensive assessment in the Epilepsy Monitoring Unit (EMU)., Methods: This retrospective study included 193 patients with epilepsy (112 men, aged 18-66 years) who underwent comprehensive assessment, including long-term video-EEG monitoring, neuroimaging studies, and neuropsychological and psychosocial assessment in the Tohoku University Hospital EMU. Data were obtained from the medical records and self-reported questionnaires at our EMU. The outcome variable was disclosure of epilepsy. Predictive variables were selected based on the disclosure decision-making model: individual factors (i.e., age, sex, age at onset of epilepsy, seizure frequency, generalized tonic-clonic seizures or focal to bilateral tonic-clonic seizures in the last 2 years, experiences of viewing own seizure, and felt stigma), and relational factors (i.e., experiences of discrimination, enacted stigma, and social support). Data were analyzed using a logistic regression analysis model., Results: Our results indicated that 43.5% of patients disclosed epilepsy to their employer. The factors that associated with disclosure of epilepsy were experiences of discrimination (odds ratio [OR], 7.78; 95% confidence interval [CI], 2.84-21.34, p < 0.01), experiences of viewing own seizure (OR, 3.51; 95% CI, 1.27-9.72, p < 0.05), and level of enacted stigma (OR, 0.69; 95% CI, 0.48-0.99, p < 0.05)., Conclusion: This study indicated that the decision to disclose epilepsy was associated with both individual factors, such as experience of viewing own seizures, and relational factors, such as experience of discrimination and enacted stigma., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: We analyzed the dose-dependent effects of Sevoflurane anesthesia on high-frequency oscillations (HFOs) and spike discharges at non-epileptic sites and evaluated their effectiveness in identifying the epileptogenic zone., Methods: We studied 21 children with drug-resistant focal epilepsy who achieved seizure control after focal resective surgery. Open-source detectors quantified HFO and spike rates during extraoperative and intraoperative intracranial EEG recordings performed before resection. We determined under which anesthetic conditions HFO and spike rates differentiated the seizure onset zone (SOZ) within the resected area from non-epileptic sites., Results: We analyzed 925 artifact-free electrodes, including 867 at non-epileptic sites and 58 at SOZ sites. Higher Sevoflurane doses significantly increased HFO and spike rates at non-epileptic sites, exhibiting spatial variability among different detectors. These biomarkers were elevated in the SOZ more than in non-epileptic sites under 2-4 vol% Sevoflurane anesthesia, with Cohen's d effect sizes above 3.0 and Mann-Whitney U-Test r effect sizes above 0.5., Conclusions: We provided normative atlases of HFO and spike rates under different Sevoflurane anesthesia conditions. Sevoflurane elevates HFO and spike rates preferentially in the epileptogenic zone., Significance: Assessing the relative severity of biomarker levels across sites may be relevant for localizing the epileptogenic zone under Sevoflurane anesthesia., Competing Interests: Declarations of interest None of the authors have potential conflicts of interest to be disclosed., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Purpose: Rasmussen syndrome (RS) is marked by progressive unihemispheric atrophy, resulting in hemiparesis, refractory epilepsy, and cognitive/language decline. Detailed diagnostic and treatment algorithms are currently lacking. We aimed to survey medical providers on their current practices in the diagnosis and treatment of RS., Methods: A steering committee was formed to create the survey, which was disseminated to the international medical community. One hundred twelve surveys were completed. Descriptive statistics, as well as comparisons by level of experience, patient age group cared for, and geographic region using Fisher's exact test, were conducted., Results: Analysis of cerebrospinal fluid (82 %) and serum (78 %) for autoimmune encephalitis (AE) are completed by most, while approximately one-third obtain genetic and metabolic studies in all patients (36 % and 38 %, respectively). Providers in US and Europe more readily pursue serum AE antibody panels (85 % and 85 %, respectively, versus 67 %, p = 0.019) and genetic testing (56 % and 47 %, respectively, versus 14 %, p < 0.001) than the rest of the world. Thirty-six percent proceed to biopsy in patients otherwise meeting diagnostic criteria, and US providers are more likely to suggest this than others (73 % versus 14-41 %, p < 0.001). Opinions differed on the prioritization of hemispherectomy/hemispherotomy versus immunotherapy in 14 clinical scenarios with various neurologic deficit severity provided. Preferred immunotherapy regimens also varied, with US providers more often choosing IVIG as first-line (67 %) compared to others (28 %-32 %, p = 0.030). Surgical standard of care was identified as functional hemispherectomy or hemispherotomy by 90 %., Conclusion: The survey highlights trends but also significant variations in clinical practice that can serve as targets for future research and expert consensus guidelines., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Suresh Pujar has received honoraria for serving on advisory board for UCB, and speaker's fees from UCB and Danone. Coral M. Stredny receives grant support from the Pediatric Epilepsy Research Foundation. She is an unpaid member of the medical and scientific advisory boards of the Autoimmune Encephalitis Alliance and NORSE Institute. Claude Steriade receives institutional salary support from The Epilepsy Study Consortium, on behalf of Alterity, Cerebral, Cerevel, Eliem, Equilibre, Janssen, Longboard, Marinus, Neurocrine, Neuroelectrics, Receptor, SK Life Sciences, Supernus, UCB, and Xenon, serves as an Editor for Dynamed, receives grants from NINDS, Parekh Institute for Interdisciplinary Neurology, NORD, and UCB, has served as an Expert Witness for the DOJ, has received compensation for speakers bureau for SK Life Sciences and consulted for Epitel Inc. and Jazz Pharmaceuticals. Ronny Wickström has received honoraria for serving on advisory boards for Jazz Pharmaceuticals, GW Pharma and Octapharma and speaker's fees from EISAI, UCB, Sobi, Jazz Pharmaceuticals and Sanofi-Genzyme. Medical treatments discussed represent off-label uses., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Rasmussen's encephalitis (RE) is a rare neurologic disorder characterized by progressive seizures and unilateral cerebral atrophy with onset during childhood and unknown etiology. When medical therapy appears refractory, surgical disconnection of the affected hemisphere is indicated. Quality of life after functional hemispherectomy is largely good, affected females may therefore pursue pregnancy. However, data on pregnancy and delivery in RE post hemispherectomy is extremely rare., Case Presentation: We present the case of a patient with left functional hemispherectomy for RE at the age of seven, who experienced two successful pregnancies. In both pregnancies, her post-surgical symptoms including right-sided spasticity, cephalgia, dizziness, and impairment of vision and speech deteriorated but improved to pre-pregnancy level after delivery. Neurologic sequelae post-hemispherectomy overlapped with clinical signs of preeclampsia and required close diagnostic surveillance during both pregnancies., Conclusion: There are no data on the interaction between RE, hemispherectomy and pregnancy, making maternal and fetal risk assessment difficult. Due to the complexity of the condition and symptoms, management of RE in pregnancy remains highly challenging and requires an interdisciplinary approach. This is the first case description of two successful pregnancies in a woman with RE and status post-hemispherectomy. Further evidence is urgently required to improve counseling and management of affected women., (© 2024. The Author(s).)

The number zero holds a special status among numbers, indispensable for developing a comprehensive number theory. 1 Despite its importance in mathematics, the neuronal foundation of zero in the human brain is unknown. We conducted single-neuron recordings in neurosurgical patients , while they made judgments involving nonsymbolic number representations (dot numerosity), including the empty set, and symbolic numbers (Arabic numerals), including numeral zero. Neurons showed responsiveness to either the empty set or numeral zero, but not both. Neuronal activity to zero in both nonsymbolic and symbolic formats exhibited a numerical distance effect, indicating that zero representations are integrated together with countable numerosities and positive integers at the low end of the number line. 2 A boundary in neuronal coding existed between the nonsymbolic empty set and small numerosities, correlating with the relative difficulty in discriminating numerosity zero behaviorally. Conversely, no such boundary was found for symbolic zero activity, suggesting that symbolic representations integrate zero with other numerals along the number line, reconciling its outlier role. The status of zero as a special nonsymbolic numerical quantity is reflected in the activity of neurons in the human brain, which seems to serve as a scaffold for more advanced representations of zero as a symbolic number., 3 , 4 Despite its importance in mathematics, the neuronal foundation of zero in the human brain is unknown. We conducted single-neuron recordings in neurosurgical patients 5 , 6 , 7 while they made judgments involving nonsymbolic number representations (dot numerosity), including the empty set, and symbolic numbers (Arabic numerals), including numeral zero. Neurons showed responsiveness to either the empty set or numeral zero, but not both. Neuronal activity to zero in both nonsymbolic and symbolic formats exhibited a numerical distance effect, indicating that zero representations are integrated together with countable numerosities and positive integers at the low end of the number line. 8 , 9 A boundary in neuronal coding existed between the nonsymbolic empty set and small numerosities, correlating with the relative difficulty in discriminating numerosity zero behaviorally. Conversely, no such boundary was found for symbolic zero activity, suggesting that symbolic representations integrate zero with other numerals along the number line, reconciling its outlier role. The status of zero as a special nonsymbolic numerical quantity is reflected in the activity of neurons in the human brain, which seems to serve as a scaffold for more advanced representations of zero as a symbolic number., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Magnetoencephalography (MEG) provides crucial information in diagnosing focal epilepsy. However, dipole estimation, a commonly used analysis method for MEG, can be time-consuming since it necessitates neurophysiologists to manually identify epileptic spikes. To reduce this burden, we developed the automatic detection of spikes using deep learning in single center. In this study, we performed a multi-center study using six MEG centers to improve the performance of the automated detection of neuromagnetically recorded epileptic spikes, which we previously developed using deep learning. Data from four centers were used for training and evaluation (internal data), and the remaining two centers were used for evaluation only (external data). We used a five-fold subject-wise cross-validation technique to train and evaluate the models. A comparison showed that the multi-center model outperformed the single-center model in terms of performance. The multi-center model achieved an average ROC-AUC of 0.9929 and 0.9426 for the internal and external data, respectively. The median distance between the neurophysiologist-analyzed and automatically analyzed dipoles was 4.36 and 7.23 mm for the multi-center model for internal and external data, respectively, indicating accurate detection of epileptic spikes. By training data from multiple centers, automated analysis can improve spike detection and reduce the analysis workload for neurophysiologists. This study suggests that the multi-center model has the potential to detect spikes within 1 cm of a neurophysiologist's analysis. This multi-center model can significantly reduce the number of hours required by neurophysiologists to detect spikes., (© 2024. The Author(s).)