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In this review, we (i) describe the nomenclature of Broca's area and show how the circumscribed definition of Broca's area is disassociated from Broca's aphasia, (ii) describe in detail how the gross anatomy of Broca's area varies between people, and how the definitions vary between studies, (iii) attempt to reconcile the findings of structural asymmetry of Broca's area with the differences in methodological approaches, (iv) consider the functional significance of cytoarchitectonic definitions of Broca's area, and (v) critically elucidate the significance of circumscribed regions of cortex for language lateralisation and language development. Contrary to what has previously been reported in the literature, asymmetry of Broca's area has not been reproducibly demonstrated, particularly on a gross morphological level. This may be due to major inconsistencies in methodology (including different anatomical boundaries, measurement techniques and samples studied) or that the sulcal contours defining Broca's area are so naturally variable between people making a standard definition difficult. Cytoarchitectonic analyses more often than not report leftward asymmetry of some component of area 44 and/or area 45. If a structural asymmetry of Broca's area does exist, it is variable, which differs from that of the functional asymmetry of language, which is more consistent. One reason for this might be that the link between cellular architecture, connectivity and language function still remains to be elucidated. There is currently no convincing explanation to associate asymmetry of Broca's area with the lateralisation of language. [ABSTRACT FROM AUTHOR]

Gel electrolytes have emerged as a versatile solution to address numerous limitations associated with liquid electrolytes in electrical energy storage (EES) devices, in terms of safety, flexibility, and affordability. Aqueous gel electrolytes, in particular, exhibit exceptional features by offering one of the highest ion solvation capacities and ionic conductivities. The two main challenges with hydrogel electrolytes are their easy freezing at subzero temperatures and rapid dehydration under open conditions, leading to the failure of the EES device. In response, we present an uncomplicated and quick-to-make hydrogel electrolyte system offering impressive mechanical properties (205.5 kPa tensile strength, 2880 kJ/m 3 toughness, and 3030% strain at the break), along with antifreezing and antiflammability attributes. Notably, the hydrogel electrolyte demonstrates high ionic conductivity and superior performance in supercapacitor cells over a wide range of temperatures (-40 to 80 °C) and under various deformations. The hydrogel electrolyte maintains its capabilities under open conditions over an extended period of time, even at 50 °C, showcased by powering a wristwatch. The atmospheric stability of the hydrogel electrolyte demonstrated in this study introduces promising prospects for the future of EES devices spanning from production to end-user consumption.

Patients with chronic focal epilepsy commonly exhibit subcortical atrophy, particularly of the thalamus. The timing of these alterations remains uncertain, though preliminary evidence suggests that observable changes may already be present at diagnosis. It is also not yet known how these morphological changes are linked to the coherence of white matter pathways throughout the brain, or to neuropsychological function often compromised before antiseizure medication treatment. This study investigates localized atrophy in subcortical regions using surface shape analysis in individuals with newly diagnosed focal epilepsy (NDfE) and assesses their implications on brain connectivity and cognitive function. We collected structural (T1w) and diffusion-weighted MRI and neuropsychological data from 104 patients with NDfE and 45 healthy controls (HCs) matched for age, sex, and education. A vertex-based shape analysis was performed on subcortical structures to compare patients with NDfE and HC, adjusting for age, sex, and intracranial volume. The mean deformation of significance areas (pcor < 0.05) was used to identify white matter pathways associated with overall shape alterations in patients relative to controls using correlational tractography. Additionally, the relationship between significant subcortical shape values and neuropsychological outcomes was evaluated using a generalized canonical correlation approach. Shape analysis revealed bilateral focal inward deformation (a proxy for localized atrophy) in anterior areas of the right and left thalamus and right pallidum in patients with NDfE compared to HC (FWE corrected). No structures showed areas of outward deformation in patients. The connectometry analysis revealed that fractional anisotropy (FA) was positively correlated with thalamic and pallidal shape deformation, that is, reduced FA was associated with inward deformation in tracts proximal to and or connecting with the thalamus including the fornix, frontal, parahippocampal, and corticothalamic pathways. Thalamic and pallidal shape changes were also related to increased depression and anxiety and reduced memory and cognitive function. These findings suggest that atrophy of the thalamus, which has previously been associated with the generation and maintenance of focal seizures, may present at epilepsy diagnosis and relate to alterations in both white matter connectivity and cognitive performance. We suggest that at least some alterations in brain structure and consequent impact on cognitive and affective processes are the result of early epileptogenic processes rather than exclusively due to the chronicity of longstanding epilepsy, recurrent seizures, and treatment with antiseizure medication., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Microbial electrosynthesis of H 2 O 2 offers an economical and eco-friendly alternative to the costly and environmentally detrimental anthraquinone process. Three-dimensional (3D) electrodes fabricated through additive manufacturing demonstrate significant advantages over carbon electrodes with two-dimensional (2D) surfaces in microbial electrosynthesis of H 2 O 2 . Nevertheless, the presence of oxygen-containing free acidic groups on the prototype electrode surface imparts hydrophilic properties to the electrode, which affects the efficiency of the two-electron oxygen reduction reaction for H 2 O 2 generation. In this study, we elucidated that the efficiency of microbial H 2 O 2 synthesis is markedly enhanced by utilizing oxygen-free 3D electrodes produced via additive manufacturing techniques followed by surface modifications to eradicate oxygen-containing functional groups. These oxygen-free 3D electrodes exhibit superior hydrophobicity compared to traditional carbon electrodes with 2D surfaces and their 3D printed analogues. The oxygen-free 3D electrode is capable of generating up to 130.2 mg L -1 of H 2 O 2 within a 6-h time frame, which is 2.4 to 13.6 times more effective than conventional electrodes (such as graphite plates) and pristine 3D printed electrodes. Additionally, the reusability of the oxygen-free 3D electrode underscores its practical viability for large-scale applications. Furthermore, this investigation explored the role of the oxygen-free 3D electrode in the bioelectro-Fenton process, affirming its efficacy as a tertiary treatment technology for the elimination of micropollutants. This dual functionality accentuates the versatility of the oxygen-free 3D electrode in facilitating both the synthesis of valuable chemicals and advancing environmental remediation. This research introduces an innovative electrode design that fosters efficient and sustainable H 2 O 2 synthesis while concurrently enabling subsequent environmental restoration., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Convolutional neural networks (CNN) show great promise for translating decades of research on structural abnormalities in temporal lobe epilepsy into clinical practice. Three-dimensional CNNs typically outperform two-dimensional CNNs in medical imaging. Here we explore for the first time whether a three-dimensional CNN outperforms a two-dimensional CNN for identifying temporal lobe epilepsy-specific features on MRI. Using 1178 T1-weighted images (589 temporal lobe epilepsy, 589 healthy controls) from 12 surgical centres, we trained 3D and 2D CNNs for temporal lobe epilepsy versus healthy control classification, using feature visualization to identify important regions. The 3D CNN was compared to the 2D model and to a randomized model (comparison to chance). Further, we explored the effect of sample size with subsampling, examined model performance based on single-subject clinical characteristics, and tested the impact of image harmonization on model performance. Across 50 datapoints (10 runs with 5-folds each) the 3D CNN median accuracy was 86.4% (35.3% above chance) and the median F 1-score was 86.1% (33.3% above chance). The 3D model yielded higher accuracy compared to the 2D model on 84% of datapoints (median 2D accuracy, 83.0%), a significant outperformance for the 3D model (binomial test: P < 0.001). This advantage of the 3D model was only apparent at the highest sample size. Saliency maps exhibited the importance of medial-ventral temporal, cerebellar, and midline subcortical regions across both models for classification. However, the 3D model had higher salience in the most important regions, the ventral-medial temporal and midline subcortical regions. Importantly, the model achieved high accuracy (82% accuracy) even in patients without MRI-identifiable hippocampal sclerosis. Finally, applying ComBat for harmonization did not improve performance. These findings highlight the value of 3D CNNs for identifying subtle structural abnormalities on MRI, especially in patients without clinically identified temporal lobe epilepsy lesions. Our findings also reveal that the advantage of 3D CNNs relies on large sample sizes for model training., Competing Interests: None of the authors have any conflict of interest to disclose., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Interhemispheric anatomical differences have long been thought to be related to language lateralisation. Previous studies have explored whether asymmetries in the diffusion characteristics of white matter language tracts are consistent with language lateralisation. These studies, typically with smaller cohorts, yielded mixed results. This study investigated whether connectomic analysis of quantitative anisotropy (QA) and shape features of white matter tracts across the whole brain are associated with language lateralisation. We analysed 1040 healthy individuals (562 females) from the Human Connectome Project database. Hemispheric language dominance for each participant was quantified using a laterality quotient (LQ) derived from fMRI activation in regions of interest (ROIs) associated with a language comprehension task compared against a math task. A linear regression model was used to examine the relationship between structural asymmetry and functional lateralisation. Connectometry revealed a significant negative correlation between LQs and QA of corpus callosum tracts, indicating that higher QA in these regions is associated with bilateral and right-hemisphere language representation in frontal and temporal regions, respectively. Left language laterality in temporal lobe was significantly associated with longer right inferior fronto-occipital fasciculus (IFOF) and forceps minor tracts. These results suggest that diffusion measures of microstructural architecture as well as geometrical features of reconstructed white matter tracts play a role in language lateralisation. People with increased dependence on right or both frontal hemispheres for language processing may have more developed commissural fibres, which may support more efficient interhemispheric communication. Significance statement The left cerebral hemisphere is dominant for language functions in most people. In some healthy people, language functions are lateralised to the right hemisphere or distributed across both hemispheres. The anatomy underlying patterns of hemispheric language dominance are not well established. Emerging evidence suggests that white matter connectivity and architecture is an important feature of cortical functional organisation. In this work, we report that people who have language functions distributed across both hemispheres have greater inter-hemispheric connectivity compared to lateralised people. Our findings provide further insights into the anatomical basis of language function and may have wider clinical implications., (Copyright © 2024 Andrulyte et al.)

Peracetic acid (PAA) has received increasing attention as an alternative oxidant for wastewater treatment. However, existing processes for PAA activation to generate reactive species typically require external energy input (e.g., electrically and UV-mediated activation) or catalysts (e.g., Co 2+ ), inevitably increasing treatment costs or introducing potential new contaminants that necessitate additional removal. In this work, we developed a catalyst-free, self-sustaining bioelectrochemical approach within a two-chamber bioelectrochemical system (BES), where a cathode electrode in-situ activates PAA using renewable biogenic electrons generated by anodic exoelectrogens (e.g., Geobacter) degrading biodegradable organic matter (e.g., acetic acid) in wastewater at the anode. This innovative BES-PAA technique achieved 98 % and 81 % removal of 2 µM sulfamethoxazole (SMX) in two hours at pH 2 (cation exchange membrane) and pH 6 (bipolar membrane) using 100 μM PAA without external voltage. Mechanistic studies, including radical quenching, molecular probe validation, electron spin resonance (ESR) experiments, and density functional theory (DFT) calculations, revealed that SMX degradation was driven by reactive species generated via biogenic electron-mediated OO cleavage of PAA, with CH 3 C(O)OO• contributing 68.1 %, •OH of 18.4 %, and CH 3 C(O)O• of 9.4 %, where initial formation of •OH and CH 3 C(O)O• rapidly reacts with PAA to produce CH 3 C(O)OO•. The presence of common water constituents such as anions (e.g., Cl - , NO 3 - , and H 2 PO 4 - ) and humic acid (HA) significantly hinders SMX removal via the BES-PAA technique, whereas CO 3 2- and HCO 3 - ions have a comparatively minor impact. Additionally, the study investigated the removal of various pharmaceuticals present in secondary treated municipal wastewater, attributing differences in removal efficiency to the selective action of CH 3 C(O)OO•. This research demonstrates a novel PAA activation method that is ecologically benign, inexpensive, and capable of overcoming catalyst deactivation and secondary pollution issues., 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 Ltd.. All rights reserved.)

Anxiety is the most common form of mental health disorder, affecting millions of people worldwide. Psychosocial interventions such as mindfulness and cognitive behavioral therapy (CBT) have been suggested as an effective treatment in the management of general anxiety and anxiety disorders, with emerging evidence also suggesting the effectiveness of hypnosis. Moreover, anxiety has shown to be linked to the onset and development of several cardiovascular diseases (CVD), which are the leading cause of global death. In this paper, we review the current literature to examine the role that anxiety has on the onset and development of CVD and summarize the current knowledge on the role that hypnosis and hypnotherapy have in reducing anxiety, also explaining how this can impact the cardiovascular system and the prevention of CVD. Review of the evidence suggests that hypnosis and hypnotherapy are effective in treating anxiety and may positively affect the heart and the cardiovascular system, reducing sympathetic activation and increasing parasympathetic tone, potentially preventing the onset of CVD related to increased sympathetic activation. However, further studies are required to further understand how hypnosis and hypnotherapy affect the cardiovascular system through investigation of the neurophysiological components of the hypnotic state and of the mind-body relationship. Healthcare systems should embed mental health screening in patients at risk of developing CVD as part of the clinical pathway and consider the role that hypnosis and hypnotherapy may play in the management of CVD., 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 Leo, Keller and Proietti.)

Up to 35% of individuals diagnosed with epilepsy continue to have seizures despite treatment, commonly referred to as drug-resistant epilepsy. Uncontrolled seizures can directly, or indirectly, negatively impact an individual's quality of life. To inform clinical management and life decisions, it is important to be able to predict the likelihood of seizure control. Those likely to achieve seizure control will be able to return sooner to their usual work and leisure activities and require less follow-up, whereas those with a poor prognosis will need more frequent clinical attendance and earlier consideration of epilepsy surgery. This is a systematic review aimed at identifying demographic, clinical, physiological (e.g., electroencephalographic), and imaging (e.g., magnetic resonance imaging) factors that may be predictive of treatment outcomes in patients with newly diagnosed epilepsy (NDE). MEDLINE and Embase were searched for prediction models of treatment outcomes in patients with NDE. Study characteristics were extracted and subjected to assessment of risk of bias (and applicability concerns) using the PROBAST (Prediction Model Risk of Bias Assessment Tool) tool. Baseline variables associated with treatment outcomes are reported as prognostic factors. After screening, 48 models were identified in 32 studies, which generally scored low for concerns of applicability, but universally scored high for susceptibility to bias. Outcomes reported fit broadly into four categories: drug resistance, short-term treatment response, seizure remission, and mortality. Prognostic factors were also heterogenous, but the predictors that were commonly significantly associated with outcomes were those related to seizure characteristics/types, epilepsy history, and age at onset. Antiseizure medication response was often included as a baseline variable, potentially obscuring other factor relationships at baseline. Currently, outcome prediction models for NDE demonstrate a high risk of bias. Model development could be improved with a stronger adherence to recommended TRIPOD (Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis) practices. Furthermore, we outline actionable changes to common practices that are intended to improve the overall quality of prediction model development in NDE., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Rapid removal of toxic substances is crucial to restore the normal functions of our body and ensure survival. Due to their high substrate specificity and catalytic efficiency, enzymes are unique candidates to deplete toxic compounds. While enzymes display several limitations including low stability and high immunogenicity, these can be overcome by entrapping them in a diverse range of carriers. The resulting micro/nanoreactors shield the enzymes from their surroundings, preventing their misfolding or denaturation thus allowing them to conduct their function. The micro/nanoreactors must circulate in the blood stream for extended periods of time to ensure complete depletion of the toxic agents. Surprisingly, while it is widely acknowledged that non-spherical carriers exhibit longer residence time in the bloodstream than their spherical counterparts, so far, all the reported micro/nanoreactors have been assembled with a spherical architecture. Herein, we address this important issue by pioneering the first shape-specific microreactors. We use UV-assisted punching to create rod-like microgel shapes with dimensions of 8 μm × 1 μm × 2 μm and demonstrate their biocompatibility by conducting hemolysis and cell viability assays with a macrophage and an endothelial cell line. Upon encapsulation of the model enzyme β-lactamase, the successful fabrication of rod-shaped microreactors is demonstrated by their ability to convert the yellow nitrocefin substrate into its hydrolyzed product.

Recent advances in the use of nano- and microparticles in drug delivery, cell therapy, and tissue engineering have led to increasing attention towards nanostructured microparticulate formulations for maximum benefit from both nano- and micron sized features. Scalable manufacturing of monodisperse nanostructured microparticles with tunable size, shape, content, and release rate remains a big challenge. Current technology, mainly comprises complex multi-step chemical procedures with limited control over these aspects. Here, we demonstrate a novel technique for high-yield fabrication of monodisperse monolayer and multilayer nanofibrous microparticles (MoNami and MuNaMi respectively). The fabrication procedure includes sequential electrospinning followed by micro-cutting at room temperature and transfer of particles for collection. The big advantage of the introduced technique is the potential to apply several polymer-drug combinations forming multilayer microparticles enjoying extracellular matrix (ECM)-mimicking architecture with tunable release profile. We demonstrate the fabrication and study the factors affecting the final three-dimensional structure. A model drug is encapsulated into a three-layer sheet (PLGA-pullulan-PLGA), and we demonstrate how the release profile changes from burst to sustain by simply cutting particles out of the electrospun sheet. We believe our fabrication method offers a unique and facile platform for realizing advanced microparticles for oral drug delivery applications., Competing Interests: The authors declare no competing interests. However, we would like to disclose that the Technical University of Denmark has filed a patent (PCT/EP2024/055263) entitled “Monodisperse nanofibrous microparticles for delivery of one or more active substances” where the inventors are Ajalloueian F., Thamdrup L.H.E. and Boisen A., (© 2024 The Authors.)

Producing H 2 O 2 via microbial electrosynthesis is a cost-effective and environmentally favorable alternative to the costly and environmentally hazardous anthraquinone method. However, most studies have relied on carbon electrodes with two-dimensional (2D) surfaces (e.g., graphite), which have limited surface area and active sites, resulting in suboptimal H 2 O 2 production. In this study, we demonstrate the enhanced efficiency of microbial H 2 O 2 synthesis using three-dimensional (3D) electrodes produced through additive manufacturing technology due to their larger surface area than conventional carbon electrodes with 2D surfaces. This work innovatively combines 3D printed pyrolytic carbon (3D PyrC) electrodes with highly defined outer geometry and internal mesh structures derived from additive manufacturing with high-temperature resin precursors followed by pyrolysis with microbial electrochemical platform technology to achieve efficient H 2 O 2 synthesis. The 3D PyrC electrode produced a maximum of 129.2 mg L -1 of H 2 O 2 in 12 h, which was 2.3-6.9 times greater than conventional electrodes (e.g., graphite and carbon felt). Furthermore, the scalability, reusability and mechanical properties of the 3D PyrC electrode were exemplary, showcasing its practical viability for large-scale applications. Beyond H 2 O 2 synthesis, the study explored the application of the 3D PyrC electrode in the bio-electro-Fenton process, demonstrating its efficacy as a tertiary treatment technology for the removal of micropollutants. This dual functionality underscores the versatility of the 3D PyrC electrode in addressing both the synthesis of valuable chemicals and environmental remediation. This study shows a novel electrode design for efficient, sustainable synthesis of H 2 O 2 and subsequent environmental remediation., 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 B.V. All rights reserved.)

Objective: The intricate neuroanatomical structure of the cerebellum is of longstanding interest in epilepsy, but has been poorly characterized within the current corticocentric models of this disease. We quantified cross-sectional regional cerebellar lobule volumes using structural magnetic resonance imaging in 1602 adults with epilepsy and 1022 healthy controls across 22 sites from the global ENIGMA-Epilepsy working group., Methods: A state-of-the-art deep learning-based approach was employed that parcellates the cerebellum into 28 neuroanatomical subregions. Linear mixed models compared total and regional cerebellar volume in (1) all epilepsies, (2) temporal lobe epilepsy with hippocampal sclerosis (TLE-HS), (3) nonlesional temporal lobe epilepsy, (4) genetic generalized epilepsy, and (5) extratemporal focal epilepsy (ETLE). Relationships were examined for cerebellar volume versus age at seizure onset, duration of epilepsy, phenytoin treatment, and cerebral cortical thickness., Results: Across all epilepsies, reduced total cerebellar volume was observed (d = .42). Maximum volume loss was observed in the corpus medullare (d max  = .49) and posterior lobe gray matter regions, including bilateral lobules VIIB (d max  = .47), crus I/II (d max  = .39), VIIIA (d max  = .45), and VIIIB (d max  = .40). Earlier age at seizure onset ( η ρ max 2  = .05) and longer epilepsy duration ( η ρ max 2  = .06) correlated with reduced volume in these regions. Findings were most pronounced in TLE-HS and ETLE, with distinct neuroanatomical profiles observed in the posterior lobe. Phenytoin treatment was associated with reduced posterior lobe volume. Cerebellum volume correlated with cerebral cortical thinning more strongly in the epilepsy cohort than in controls., Significance: We provide robust evidence of deep cerebellar and posterior lobe subregional gray matter volume loss in patients with chronic epilepsy. Volume loss was maximal for posterior subregions implicated in nonmotor functions, relative to motor regions of both the anterior and posterior lobe. Associations between cerebral and cerebellar changes, and variability of neuroanatomical profiles across epilepsy syndromes argue for more precise incorporation of cerebellar subregional damage into neurobiological models of epilepsy., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: Diabetes mellitus (DM) is associated with structural grey matter alterations in the brain, including changes in the somatosensory and pain processing regions seen in association with diabetic peripheral neuropathy. In this case-controlled biobank study, we aimed to ascertain differences in grey and white matter anatomy in people with DM compared with non-diabetic controls (NDC)., Methods: This study utilises the UK Biobank prospective, population-based, multicentre study of UK residents. Participants with diabetes and age/gender-matched controls without diabetes were selected in a three-to-one ratio. We excluded people with underlying neurological/neurodegenerative disease. Whole brain, cortical, and subcortical volumes (188 regions) were compared between participants with diabetes against NDC corrected for age, sex, and intracranial volume using univariate regression models, with adjustment for multiple comparisons. Diffusion tensor imaging analysis of fractional anisotropy (FA) was performed along the length of 50 white matter tracts., Results: We included 2404 eligible participants who underwent brain magnetic resonance imaging (NDC, n = 1803 and DM, n = 601). Participants with DM had a mean (±standard deviation) diagnostic duration of 18 ± 11 years, with adequate glycaemic control (HbA1 C 52 ± 13 mmol/mol), low prevalence of microvascular complications (diabetic retinopathy prevalence, 5.8%), comparable cognitive function to controls but greater self-reported pain. Univariate volumetric analyses revealed significant reductions in grey matter volume (whole brain, total, and subcortical grey matter), with mean percentage differences ranging from 2.2% to 7% in people with DM relative to NDC (all p < 0.0002). The subcortical (bilateral cerebellar cortex, brainstem, thalamus, central corpus callosum, putamen, and pallidum) and cortical regions linked to sensorimotor (bilateral superior frontal, middle frontal, precentral, and postcentral gyri) and visual functions (bilateral middle and superior occipital gyri), all had lower grey matter volumes in people with DM relative to NDC. People with DM had significantly reduced FA along the length of the thalamocortical radiations, thalamostriatal projections, and commissural fibres of the corpus callosum (all; p < 0·001)., Interpretation: This analysis suggests that anatomic differences in brain regions are present in a cohort with adequately controlled glycaemia without prevalent microvascular disease when compared with volunteers without diabetes. We hypothesise that these differences may predate overt end-organ damage and complications such as diabetic neuropathy and retinopathy. Central nervous system alterations/neuroplasticity may occur early in the natural history of microvascular complications; therefore, brain imaging should be considered in future mechanistic and interventional studies of DM., (© 2024 The Authors. Diabetes/Metabolism Research and Reviews published by John Wiley & Sons Ltd.)

Implantable cell replacement therapies promise to completely restore the function of neural structures, possibly changing how we currently perceive the onset of neurodegenerative diseases. One of the major clinical hurdles for the routine implementation of stem cell therapies is poor cell retention and survival, demanding the need to better understand these mechanisms while providing precise and scalable approaches to monitor these cell-based therapies in both pre-clinical and clinical scenarios. This poses significant multidisciplinary challenges regarding planning, defining the methodology and requirements, prototyping and different stages of testing. Aiming toward an optogenetic neural stem cell implant controlled by a smart wireless electronic frontend, we show how an iterative development methodology coupled with a modular design philosophy can mitigate some of these challenges. In this study, we present a miniaturized, wireless-controlled, modular multisensor platform with fully interfaced electronics featuring three different modules: an impedance analyzer, a potentiostat and an optical stimulator. We show the application of the platform for electrical impedance spectroscopy-based cell monitoring, optical stimulation to induce dopamine release from optogenetically modified neurons and a potentiostat for cyclic voltammetry and amperometric detection of dopamine release. The multisensor platform is designed to be used as an opto-electric headstage for future in vivo animal experiments.

Collaborative efforts between basic scientists, engineers, and clinicians are enabling translational epileptology. In this article, we summarize the recent advances presented at the International Conference for Technology and Analysis of Seizures (ICTALS 2022): (1) novel developments of structural magnetic resonance imaging; (2) latest electroencephalography signal-processing applications; (3) big data for the development of clinical tools; (4) the emerging field of hyperdimensional computing; (5) the new generation of artificial intelligence (AI)-enabled neuroprostheses; and (6) the use of collaborative platforms to facilitate epilepsy research translation. We highlight the promise of AI reported in recent investigations and the need for multicenter data-sharing initiatives., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Recently, microneedle-based sensors have been introduced as novel strategy for in situ monitoring of biomarkers in the skin. Here, in-plane silicon microneedles with different dimensions and shapes are fabricated and their ability to penetrate skin is evaluated. Arrays with flat, triangular, hypodermic, lancet and pencil-shaped microneedles, with lengths of 500-1000 μm, widths of 200-400 μm and thickness of 180-500 μm are considered. Fracture force is higher than 20 N for all microneedle arrays (MNA) confirming a high mechanical stability of the microneedles. Penetration force in skin-simulating hydrogels, excised rat abdominal skin and porcine ear skin is at least five times lower than the fracture force for all MNA designs. The lowest force for skin penetration is required for triangular microneedles with a low width and thickness. Skin tissue staining and histological analysis of rat abdominal skin and porcine ear skin confirm successful penetration of the epidermis for all MNA designs. However, the penetration depth is between 100 and 300 μm, which is considerably lower than the microneedle length. Tissue damage estimated by visual analysis of the penetration hole is smallest for triangular microneedles. Penetration ability and tissue damage are compared to the skin prick test (SPT) needle applied in allergy testing., 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 © 2023. Published by Elsevier B.V.)

Brain organoid technology has transformed both basic and applied biomedical research and paved the way for novel insights into developmental processes and disease states of the human brain. While the use of brain organoids has been rapidly growing in the past decade, the accompanying bioengineering and biofabrication solutions have remained scarce. As a result, most brain organoid protocols still rely on commercially available tools and culturing platforms that had previously been established for different purposes, thus entailing suboptimal culturing conditions and excessive use of plasticware. To address these issues, we developed a 3D printing pipeline for the fabrication of tailor-made culturing platforms for fluidically connected but spatially separated brain organoid array culture. This all-in-one platform allows all culturing steps-from cellular aggregation, spheroid growth, hydrogel embedding, and organoid maturation-to be performed in a single well plate without the need for organoid manipulation or transfer. Importantly, the approach relies on accessible materials and widely available 3D printing equipment. Furthermore, the developed design principles are modular and highly customizable. As such, we believe that the presented technology can be easily adapted by other research groups and fuel further development of culturing tools and platforms for brain organoids and other 3D cellular systems., (Creative Commons Attribution license.)

Background and Objectives: A new frontier in diagnostic radiology is the inclusion of machine-assisted support tools that facilitate the identification of subtle lesions often not visible to the human eye. Structural neuroimaging plays an essential role in the identification of lesions in patients with epilepsy, which often coincide with the seizure focus. In this study, we explored the potential for a convolutional neural network (CNN) to determine lateralization of seizure onset in patients with epilepsy using T1-weighted structural MRI scans as input., Methods: Using a dataset of 359 patients with temporal lobe epilepsy (TLE) from 7 surgical centers, we tested whether a CNN based on T1-weighted images could classify seizure laterality concordant with clinical team consensus. This CNN was compared with a randomized model (comparison with chance) and a hippocampal volume logistic regression (comparison with current clinically available measures). Furthermore, we leveraged a CNN feature visualization technique to identify regions used to classify patients., Results: Across 100 runs, the CNN model was concordant with clinician lateralization on average 78% (SD = 5.1%) of runs with the best-performing model achieving 89% concordance. The CNN outperformed the randomized model (average concordance of 51.7%) on 100% of runs with an average improvement of 26.2% and outperformed the hippocampal volume model (average concordance of 71.7%) on 85% of runs with an average improvement of 6.25%. Feature visualization maps revealed that in addition to the medial temporal lobe, regions in the lateral temporal lobe, cingulate, and precentral gyrus aided in classification., Discussion: These extratemporal lobe features underscore the importance of whole-brain models to highlight areas worthy of clinician scrutiny during temporal lobe epilepsy lateralization. This proof-of-concept study illustrates that a CNN applied to structural MRI data can visually aid clinician-led localization of epileptogenic zone and identify extrahippocampal regions that may require additional radiologic attention., Classification of Evidence: This study provides Class II evidence that in patients with drug-resistant unilateral temporal lobe epilepsy, a convolutional neural network algorithm derived from T1-weighted MRI can correctly classify seizure laterality., (© 2023 American Academy of Neurology.)

Atrial fibrillation (AF) is the most common form of cardiac arrhythmia, affecting 2%-3% of the world's population. Mental and emotional stress, as well as some mental health conditions (e.g., depression) have been shown to significantly impact the heart and have been suggested to act both as independent risk factors and triggers in the onset of AF. In this paper, we review the current literature to examine the role that mental and emotional stress have in the onset of AF and summarise the current knowledge on the interaction between the brain and heart, and the cortical and subcortical pathways involved in the response to stress. Review of the evidence suggests that mental and emotional stress negatively affect the cardiac system, potentially increasing the risk for developing and/or triggering AF. Further studies are required to further understand the cortical and sub-cortical structures involved in the mental stress response and how these interact with the cardiac system, which may help in defining new strategies and interventions to prevent the development of, and improve the management of AF., Competing Interests: DAL has received investigator-initiated educational grants from Bristol Myers Squibb (BMS) and Pfizer; been a speaker for Boehringer Ingelheim, Bayer, and BMS/Pfizer and consulted for Boehringer Ingelheim and BMS/Pfizer; all outside the submitted work. GYHL: Consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, Anthem. No fees are received personally. 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., (© 2023 Leo, Ozdemir, Lane, Lip, Keller and Proietti.)

The piriform cortex (PC) is located at the junction of the temporal and frontal lobes. It is involved physiologically in olfaction as well as memory and plays an important role in epilepsy. Its study at scale is held back by the absence of automatic segmentation methods on MRI. We devised a manual segmentation protocol for PC volumes, integrated those manually derived images into the Hammers Atlas Database (n = 30) and used an extensively validated method (multi-atlas propagation with enhanced registration, MAPER) for automatic PC segmentation. We applied automated PC volumetry to patients with unilateral temporal lobe epilepsy with hippocampal sclerosis (TLE; n = 174 including n = 58 controls) and to the Alzheimer's Disease Neuroimaging Initiative cohort (ADNI; n = 151, of whom with mild cognitive impairment (MCI), n = 71; Alzheimer's disease (AD), n = 33; controls, n = 47). In controls, mean PC volume was 485 mm 3 on the right and 461 mm 3 on the left. Automatic and manual segmentations overlapped with a Jaccard coefficient (intersection/union) of ~0.5 and a mean absolute volume difference of ~22 mm 3 in healthy controls, ~0.40/ ~28 mm 3 in patients with TLE, and ~ 0.34/~29 mm 3 in patients with AD. In patients with TLE, PC atrophy lateralised to the side of hippocampal sclerosis (p < .001). In patients with MCI and AD, PC volumes were lower than those of controls bilaterally (p < .001). Overall, we have validated automatic PC volumetry in healthy controls and two types of pathology. The novel finding of early atrophy of PC at the stage of MCI possibly adds a novel biomarker. PC volumetry can now be applied at scale., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Patients with movement disorders treated by deep brain stimulation do not always achieve successful therapeutic alleviation of motor symptoms, even in cases where surgery is without complications. Magnetic resonance imaging (MRI) offers methods to investigate structural brain-related factors that may be predictive of clinical motor outcomes. This review aimed to identify features which have been associated with variability in clinical post-operative motor outcomes in patients with Parkinson's disease, dystonia, and essential tremor from structural MRI modalities. We performed a literature search for articles published between 1 January 2000 and 1 April 2022 and identified 5197 articles. Following screening through our inclusion criteria, we identified 60 total studies (39 = Parkinson's disease, 11 = dystonia syndromes and 10 = essential tremor). The review captured a range of structural MRI methods and analysis techniques used to identify factors related to clinical post-operative motor outcomes from deep brain stimulation. Morphometric markers, including volume and cortical thickness were commonly identified in studies focused on patients with Parkinson's disease and dystonia syndromes. Reduced metrics in basal ganglia, sensorimotor and frontal regions showed frequent associations with reduced motor outcomes. Increased structural connectivity to subcortical nuclei, sensorimotor and frontal regions was also associated with greater motor outcomes. In patients with tremor, increased structural connectivity to the cerebellum and cortical motor regions showed high prevalence across studies for greater clinical motor outcomes. In addition, we highlight conceptual issues for studies assessing clinical response with structural MRI and discuss future approaches towards optimizing individualized therapeutic benefits. Although quantitative MRI markers are in their infancy for clinical purposes in movement disorder treatments, structural features obtained from MRI offer the powerful potential to identify candidates who are more likely to benefit from deep brain stimulation and provide insight into the complexity of disorder pathophysiology., Competing Interests: The authors have no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: Temporal lobe epilepsy (TLE) is the most common type of focal epilepsy. An increasingly identified subset of patients with TLE consists of those who show bilaterally independent temporal lobe seizures. The purpose of this study was to leverage network neuroscience to better understand the interictal whole brain network of bilateral TLE (BiTLE)., Methods: In this study, using a multicenter resting state functional magnetic resonance imaging (rs-fMRI) data set, we constructed whole-brain functional networks of 19 patients with BiTLE, and compared them to those of 75 patients with unilateral TLE (UTLE). We quantified resting-state, whole-brain topological properties using metrics derived from network theory, including clustering coefficient, global efficiency, participation coefficient, and modularity. For each metric, we computed an average across all brain regions, and iterated this process across network densities. Curves of network density vs each network metric were compared between groups. Finally, we derived a combined metric, which we term the "integration-segregation axis," by combining whole-brain average clustering coefficient and global efficiency curves, and applying principal component analysis (PCA)-based dimensionality reduction., Results: Compared to UTLE, BiTLE had decreased global efficiency (p = .031), and decreased whole brain average participation coefficient across a range of network densities (p = .019). Modularity maximization yielded a larger number of smaller communities in BiTLE than in UTLE (p = .020). Differences in network properties separate BiTLE and UTLE along the integration-segregation axis, with regions within the axis having a specificity of up to 0.87 for BiTLE. Along the integration-segregation axis, UTLE patients with poor surgical outcomes were distributed in the same regions as BiTLE, and network metrics confirmed similar patterns of increased segregation in both BiTLE and poor outcome UTLE., Significance: Increased interictal whole-brain network segregation, as measured by rs-fMRI, is specific to BiTLE, as well as poor surgical outcome UTLE, and may assist in non-invasively identifying this patient population prior to intracranial electroencephalography or device implantation., (© 2023 International League Against Epilepsy.)

Neurocysticercosis (NCC)-a parasitic CNS infection endemic to developing nations-has been called the leading global cause of acquired epilepsy yet remains understudied. It is currently unknown why a large proportion of patients develop recurrent seizures, often following the presentation of acute seizures. Furthermore, the presentation of NCC is heterogenous and the features that predispose to the development of an epileptogenic state remain uncertain. Perilesional factors (such as oedema and gliosis) have been implicated in NCC-related ictogenesis, but the effects of cystic factors, including lesion load and location, seem not to play a role in the development of habitual epilepsy. In addition, the cytotoxic consequences of the cyst's degenerative stages are varied and the majority of research, relying on retrospective data, lacks the necessary specificity to distinguish between acute symptomatic and unprovoked seizures. Previous research has established that epileptogenesis can be the consequence of abnormal network connectivity, and some imaging studies have suggested that a causative link may exist between NCC and aberrant network organisation. In wider epilepsy research, network approaches have been widely adopted; studies benefiting predominantly from the rich, multimodal data provided by advanced MRI methods are at the forefront of the field. Quantitative MRI approaches have the potential to elucidate the lesser-understood epileptogenic mechanisms of NCC. This review will summarise the current understanding of the relationship between NCC and epilepsy, with a focus on MRI methodologies. In addition, network neuroscience approaches with putative value will be highlighted, drawing from current imaging trends in epilepsy research., Competing Interests: Declaration of Competing Interest None, (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Objectives: Chronic poststroke language impairment is typically worse in older individuals or those with large stroke lesions. However, there is unexplained variance that likely depends on intact tissue beyond the lesion. Brain age is an emerging concept, which is partially independent from chronologic age. Advanced brain age is associated with cognitive decline in healthy older adults; therefore, we aimed to investigate the relationship with stroke aphasia. We hypothesized that advanced brain age is a significant factor associated with chronic poststroke language impairments, above and beyond chronologic age, and lesion characteristics., Methods: This cohort study retrospectively evaluated participants from the Predicting Outcomes of Language Rehabilitation in Aphasia clinical trial (NCT03416738), recruited through local advertisement in South Carolina (US). Primary inclusion criteria were left hemisphere stroke and chronic aphasia (≥12 months after stroke). Participants completed baseline behavioral testing including the Western Aphasia Battery-Revised (WAB-R), Philadelphia Naming Test (PNT), Pyramids and Palm Trees Test (PPTT), and Wechsler Adult Intelligence Scale Matrices subtest, before completing 6 weeks of language therapy. The PNT was repeated 1 month after therapy. We leveraged modern neuroimaging techniques to estimate brain age and computed a proportional difference between chronologic age and estimated brain age. Multiple linear regression models were used to evaluate the relationship between proportional brain age difference (PBAD) and behavior., Results: Participants (N = 93, 58 males and 35 females, average age = 61 years) had estimated brain ages ranging from 14 years younger to 23 years older than chronologic age. Advanced brain age predicted performance on semantic tasks (PPTT) and language tasks (WAB-R). For participants with advanced brain aging (n = 47), treatment gains (improvement on the PNT) were independently predicted by PBAD (T = -2.0474, p = 0.0468, 9% of variance explained)., Discussion: Through the application of modern neuroimaging techniques, advanced brain aging was associated with aphasia severity and performance on semantic tasks. Notably, therapy outcome scores were also associated with PBAD, albeit only among participants with advanced brain aging. These findings corroborate the importance of brain age as a determinant of poststroke recovery and underscore the importance of personalized health factors in determining recovery trajectories, which should be considered during the planning or implementation of therapeutic interventions., (© 2022 American Academy of Neurology.)

Background: Structural and functional neuroimaging studies often overlook lower basal ganglia structures located in and adjacent to the midbrain due to poor contrast on clinically acquired T1-weighted scans. Here, we acquired T1-weighted, T2-weighted, and resting-state fMRI scans to investigate differences in volume, estimated myelin content and functional connectivity of the substantia nigra (SN), subthalamic nuclei (SubTN) and red nuclei (RN) of the midbrain in IGE., Methods: Thirty-three patients with IGE (23 refractory, 10 non-refractory) and 39 age and sex-matched healthy controls underwent MR imaging. Midbrain structures were automatically segmented from T2-weighted images and structural volumes were calculated. The estimated myelin content for each structure was determined using a T1-weighted/T2-weighted ratio method. Resting-state functional connectivity analysis of midbrain structures (seed-based) was performed using the CONN toolbox., Results: An increased volume of the right RN was found in IGE and structural volumes of the right SubTN differed between patients with non-refractory and refractory IGE. However, no volume findings survived corrections for multiple comparisons. No myelin alterations of midbrain structures were found for any subject groups. We found functional connectivity alterations including significantly decreased connectivity between the left SN and the thalamus and significantly increased connectivity between the right SubTN and the superior frontal gyrus in IGE., Conclusions: We report volumetric and functional connectivity alterations of the midbrain in patients with IGE. We postulate that potential increases in structural volumes are due to increased iron deposition that impacts T2-weighted contrast. These findings are consistent with previous studies demonstrating pathophysiological abnormalities of the lower basal ganglia in animal models of generalised epilepsy., 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 © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Radiological identification of temporal lobe epilepsy (TLE) is crucial for diagnosis and treatment planning. TLE neuroimaging abnormalities are pervasive at the group level, but they can be subtle and difficult to identify by visual inspection of individual scans, prompting applications of artificial intelligence (AI) assisted technologies., Method: We assessed the ability of a convolutional neural network (CNN) algorithm to classify TLE vs. patients with AD vs. healthy controls using T1-weighted magnetic resonance imaging (MRI) scans. We used feature visualization techniques to identify regions the CNN employed to differentiate disease types., Results: We show the following classification results: healthy control accuracy = 81.54% (SD = 1.77%), precision = 0.81 (SD = 0.02), recall = 0.85 (SD = 0.03), and F1-score = 0.83 (SD = 0.02); TLE accuracy = 90.45% (SD = 1.59%), precision = 0.86 (SD = 0.03), recall = 0.86 (SD = 0.04), and F1-score = 0.85 (SD = 0.04); and AD accuracy = 88.52% (SD = 1.27%), precision = 0.64 (SD = 0.05), recall = 0.53 (SD = 0.07), and F1 score = 0.58 (0.05). The high accuracy in identification of TLE was remarkable, considering that only 47% of the cohort had deemed to be lesional based on MRI alone. Model predictions were also considerably better than random permutation classifications (p < 0.01) and were independent of age effects., Conclusions: AI (CNN deep learning) can classify and distinguish TLE, underscoring its potential utility for future computer-aided radiological assessments of epilepsy, especially for patients who do not exhibit easily identifiable TLE associated MRI features (e.g., hippocampal sclerosis)., (© 2023. The Author(s).)

Aims: Generalised epilepsy is thought to involve distributed brain networks. However, the molecular and cellular factors that render different brain regions more vulnerable to epileptogenesis remain largely unknown. We aimed to investigate epilepsy-related morphometric similarity network (MSN) abnormalities at the macroscale level and their relationships with microscale gene expressions at the microscale level., Methods: We compared the MSN of genetic generalised epilepsy with generalised tonic-clonic seizure patients (GGE-GTCS, n = 101) to demographically matched healthy controls (HC, n = 150). Cortical MSNs were estimated by combining seven morphometric features derived from structural magnetic resonance imaging for each individual. Regional gene expression profiles were derived from brain-wide microarray measurements provided by the Allen Human Brain Atlas., Results: GGE-GTCS patients exhibited decreased regional MSNs in primary motor, prefrontal and temporal regions and increases in occipital, insular and posterior cingulate cortices, when compared with the HC. These case-control neuroimaging differences were validated using split-half analyses and were not affected by medication or drug response effects. When assessing associations with gene expression, genes associated with GGE-GTCS-related MSN differences were enriched in several biological processes, including 'synapse organisation', 'neurotransmitter transport' pathways and excitatory/inhibitory neuronal cell types. Collectively, the GGE-GTCS-related cortical vulnerabilities were associated with chromosomes 4, 5, 11 and 16 and were dispersed bottom-up at the cellular, pathway and disease levels, which contributed to epileptogenesis, suggesting diverse neurobiologically relevant enrichments in GGE-GTCS., Conclusions: By bridging the gaps between transcriptional signatures and in vivo neuroimaging, we highlighted the importance of using MSN abnormalities of the human brain in GGE-GTCS patients to investigate disease-relevant genes and biological processes., (© 2022 British Neuropathological Society.)

The pathophysiological progress of Parkinson's disease leads through degeneration of dopaminergic neurons in the substantia nigra to complete cell death and lack of dopamine in the striatum where it modulates motor functions. Transplantation of dopaminergic stem cell-derived neurons is a possible therapy to restore dopamine levels. We have previously presented multifunctional pyrolytic carbon coated leaky optoelectrical fibers (LOEFs) with laser ablated micro-optical windows (µOWs) as carriers for channelrhodopsin-2 modified optogenetically active neurons for light-induced on-demand dopamine release and amperometric real-time detection. To increase the dopamine release by stimulating a larger neuronal population with light, we present here a novel approach to generate µOWs through laser ablation around the entire circumference of optical fibers to obtain Omni-LOEFs. Cyclic voltammetric characterization of the pyrolytic carbon showed that despite the increased number of µOWs, the electrochemical properties were not deteriorated. Finally, we demonstrate that the current recorded during real-time detection of dopamine upon light-induced stimulation of neurons differentiated on Omni-LOEFs is significantly higher compared to recordings from the same number of cells seeded on LOEFs with µOWs only on one side. Moreover, by varying the cell seeding density, we show that the recorded current is proportional to the dimension of the cell population., 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 © 2022. Published by Elsevier B.V.)

Introduction: A first unprovoked seizure is a common presentation, reliably identifying those that will have recurrent seizures is a challenge. This study will be the first to explore the combined utility of serum biomarkers, quantitative electroencephalogram (EEG) and quantitative MRI to predict seizure recurrence. This will inform patient stratification for counselling and the inclusion of high-risk patients in clinical trials of disease-modifying agents in early epilepsy., Methods and Analysis: 100 patients with first unprovoked seizure will be recruited from a tertiary neuroscience centre and baseline assessments will include structural MRI, EEG and a blood sample. As part of a nested pilot study, a subset of 40 patients will have advanced MRI sequences performed that are usually reserved for patients with refractory chronic epilepsy. The remaining 60 patients will have standard clinical MRI sequences. Patients will be followed up every 6 months for a 24-month period to assess seizure recurrence. Connectivity and network-based analyses of EEG and MRI data will be carried out and examined in relation to seizure recurrence. Patient outcomes will also be investigated with respect to analysis of high-mobility group box-1 from blood serum samples., Ethics and Dissemination: This study was approved by North East-Tyne & Wear South Research Ethics Committee (20/NE/0078) and funded by an Association of British Neurologists and Guarantors of Brain clinical research training fellowship. Findings will be presented at national and international meetings published in peer-reviewed journals., Trial Registration Number: NIHR Clinical Research Network's (CRN) Central Portfolio Management System (CPMS)-44976., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Seizures can occur unpredictably in patients with acute encephalitis syndrome (AES), and many suffer from poor long-term neurological sequelae. Establishing factors associated with acute seizures risk and poor outcomes could support clinical care. We aimed to conduct regional and volumetric analysis of cerebral oedema on magnetic resonance imaging (MRI) in patients with AES. We assessed the relationship of brain oedema with acute seizure activity and long-term neurological outcome., Methods: In a multi-centre cohort study, adults and children presenting with an AES were recruited in the UK. The clinical and brain MRI data were retrospectively reviewed. The outcomes variables were inpatient acute seizure activity and neurological disability at six-months post-discharge. A poor outcome was defined as a Glasgow outcome score (GOS) of 1-3. We quantified regional brain oedema on MRI through stereological examination of T2-weighted images using established methodology by independent and blinded assessors. Clinical and neuroimaging variables were analysed by multivariate logistic regression to assess for correlation with acute seizure activity and outcome., Results: The study cohort comprised 69 patients (mean age 31.8 years; 53.6% female), of whom 41 (59.4%) had acute seizures as inpatients. A higher Glasgow coma scale (GCS) score on admission was a negative predictor of seizures (OR 0.61 [0.46-0.83], p = 0.001). Even correcting for GCS on admission, the presence of cortical oedema was a significant risk factor for acute seizure activity (OR 5.48 [1.62-18.51], p = 0.006) and greater volume of cerebral oedema in these cortical structures increased the risk of acute seizures (OR 1.90 [1.12-3.21], p = 0.017). At six-month post-discharge, 21 (30.4%) had a poor neurological outcome. Herpes simplex virus encephalitis was associated with higher risk of poor outcomes in univariate analysis (OR 3.92 [1.08-14.20], p = 0.038). When controlling for aetiology, increased volume of cerebral oedema was an independent risk factor for adverse neurological outcome at 6 months (OR 1.73 [1.06-2.83], p = 0.027)., Conclusions: Both the presence and degree of cerebral oedema on MRIs of patients with AES may help identify patients at risk of acute seizure activity and subsequent long-term morbidity., (© 2022. The Author(s).)

Objective: Recent work has shown that people with common epilepsies have characteristic patterns of cortical thinning, and that these changes may be progressive over time. Leveraging a large multicenter cross-sectional cohort, we investigated whether regional morphometric changes occur in a sequential manner, and whether these changes in people with mesial temporal lobe epilepsy and hippocampal sclerosis (MTLE-HS) correlate with clinical features., Methods: We extracted regional measures of cortical thickness, surface area, and subcortical brain volumes from T1-weighted (T1W) magnetic resonance imaging (MRI) scans collected by the ENIGMA-Epilepsy consortium, comprising 804 people with MTLE-HS and 1625 healthy controls from 25 centers. Features with a moderate case-control effect size (Cohen d ≥ .5) were used to train an event-based model (EBM), which estimates a sequence of disease-specific biomarker changes from cross-sectional data and assigns a biomarker-based fine-grained disease stage to individual patients. We tested for associations between EBM disease stage and duration of epilepsy, age at onset, and antiseizure medicine (ASM) resistance., Results: In MTLE-HS, decrease in ipsilateral hippocampal volume along with increased asymmetry in hippocampal volume was followed by reduced thickness in neocortical regions, reduction in ipsilateral thalamus volume, and finally, increase in ipsilateral lateral ventricle volume. EBM stage was correlated with duration of illness (Spearman ρ = .293, p = 7.03 × 10 -16 ), age at onset (ρ = -.18, p = 9.82 × 10 -7 ), and ASM resistance (area under the curve = .59, p = .043, Mann-Whitney U test). However, associations were driven by cases assigned to EBM Stage 0, which represents MTLE-HS with mild or nondetectable abnormality on T1W MRI., Significance: From cross-sectional MRI, we reconstructed a disease progression model that highlights a sequence of MRI changes that aligns with previous longitudinal studies. This model could be used to stage MTLE-HS subjects in other cohorts and help establish connections between imaging-based progression staging and clinical features., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Introduction: Idiopathic generalized epilepsy (IGE) is a collection of generalized nonlesional epileptic network disorders. Around 20-40% of patients with IGE are refractory to antiseizure medication, and mechanisms underlying refractoriness are poorly understood. Here, we characterize structural brain network alterations and determine whether network alterations differ between patients with refractory and nonrefractory IGE. Methods: Thirty-three patients with IGE (10 nonrefractory and 23 refractory) and 39 age- and sex-matched healthy controls were studied. Network nodes were segmented from T1-weighted images, while connections between these nodes (edges) were reconstructed from diffusion magnetic resonance imaging (MRI). Diffusion networks of fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and streamline count (Count) were studied. Differences between all patients, refractory, nonrefractory, and control groups were computed using network-based statistics. Nodal volume differences between groups were computed using Cohen's d effect size calculation. Results: Patients had significantly decreased bihemispheric FA and Count networks and increased MD and RD networks compared with controls. Alterations in network architecture, with respect to controls, differed depending on treatment outcome, including predominant FA network alterations in refractory IGE and increased nodal volume in nonrefractory IGE. Diffusion MRI networks were not influenced by nodal volume. Discussion: Although a nonlesional disorder, patients with IGE have bihemispheric structural network alterations that may differ between patients with refractory and nonrefractory IGE. Given that distinct nodal volume and FA network alterations were observed between treatment outcome groups, a multifaceted network analysis may be useful for identifying imaging biomarkers of refractory IGE.