A WORLDWIDE ENIGMA STUDY ON EPILEPSY-RELATED GRAY AND WHITE MATTER COMPROMISE ACROSS THE ADULT LIFESPAN.

Objectives: Temporal lobe epilepsy (TLE) is commonly associated with mesiotemporal pathology and widespread alterations of grey and white matter structures. Evidence supports a progressive condition although the temporal evolution of TLE is poorly defined. This ENIGMA-Epilepsy study utilized multimodal magnetic resonance imaging (MRI) data to investigate structural alterations in TLE patients across the adult lifespan. We charted both grey and white matter changes and explored the covariance of age-related alterations in both compartments. Methods: We studied 769 TLE patients and 885 healthy controls across an age range of 17-73 years, from multiple international sites. To assess potentially non-linear lifespan changes in TLE, we harmonized data and combined median split assessments with cross-sectional sliding window analyses of grey and white matter age-related changes. Covariance analyses examined the coupling of grey and white matter lifespan curves. Results: In TLE, age was associated with a robust grey matter thickness/volume decline across a broad cortico-subcortical territory, extending beyond the mesiotemporal disease epicentre. White matter changes were also widespread across multiple tracts with peak effects in temporo-limbic fibers. While changes spanned the adult time window, changes accelerated in cortical thickness, subcortical volume, and fractional anisotropy (all decreased), and mean diffusivity (increased) after age 55 years. Covariance analyses revealed strong limbic associations between white matter tracts and subcortical structures with cortical regions. Conclusions: This study highlights the profound impact of TLE on lifespan changes in grey and white matter structures, with an acceleration of aging-related processes in later decades of life. Our findings motivate future longitudinal studies across the lifespan and emphasize the importance of prompt diagnosis as well as intervention in patients.

Patterns of subregional cerebellar atrophy across epilepsy syndromes: An ENIGMA-Epilepsy study.

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 (dmax = .49) and posterior lobe gray matter regions, including bilateral lobules VIIB (dmax = .47), crus I/II (dmax = .39), VIIIA (dmax = .45), and VIIIB (dmax = .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.

MP2RAGE vs. MPRAGE surface-based morphometry in focal epilepsy.

In drug-resistant focal epilepsy, detecting epileptogenic lesions using MRI poses a critical diagnostic challenge. Here, we assessed the utility of MP2RAGE-a T1-weighted sequence with self-bias correcting properties commonly utilized in ultra-high field MRI-for the detection of epileptogenic lesions using a surface-based morphometry pipeline based on FreeSurfer, and compared it to the common approach using T1w MPRAGE, both at 3T. We included data from 32 patients with focal epilepsy (5 MRI-positive, 27 MRI-negative with lobar seizure onset hypotheses) and 94 healthy controls from two epilepsy centres. Surface-based morphological measures and intensities were extracted and evaluated in univariate GLM analyses as well as multivariate unsupervised 'novelty detection' machine learning procedures. The resulting prediction maps were analyzed over a range of possible thresholds using alternative free-response receiver operating characteristic (AFROC) methodology with respect to the concordance with predefined lesion labels or hypotheses on epileptogenic zone location. We found that MP2RAGE performs at least comparable to MPRAGE and that especially analysis of MP2RAGE image intensities may provide additional diagnostic information. Secondly, we demonstrate that unsupervised novelty-detection machine learning approaches may be useful for the detection of epileptogenic lesions (maximum AFROC AUC 0.58) when there is only a limited lesional training set available. Third, we propose a statistical method of assessing lesion localization performance in MRI-negative patients with lobar hypotheses of the epileptogenic zone based on simulation of a random guessing process as null hypothesis. Based on our findings, it appears worthwhile to study similar surface-based morphometry approaches in ultra-high field MRI (≥ 7 T).

Long-term efficacy and safety of nusinersen in adults with 5q spinal muscular atrophy: a prospective European multinational observational study.

Background: Evidence for the efficacy of nusinersen in adults with 5q-associated spinal muscular atrophy (SMA) has been demonstrated up to a period of 16 months in relatively large cohorts but whereas patients reach a plateau over time is still to be demonstrated. We investigated the efficacy and safety of nusinersen in adults with SMA over 38 months, the longest time period to date in a large cohort of patients from multiple clinical sites. Methods: Our prospective, observational study included adult patients with SMA from Germany, Switzerland, and Austria (July 2017 to May 2022). All participants had genetically-confirmed, 5q-associated SMA and were treated with nusinersen according to the label. The total Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM) scores, and 6-min walk test (6 MWT; metres), were recorded at baseline and 14, 26, and 38 months after treatment initiation, and pre and post values were compared. Adverse events were also recorded. Findings: Overall, 389 patients were screened for eligibility and 237 were included. There were significant increases in all outcome measures compared with baseline, including mean HFMSE scores at 14 months (mean difference 1.72 [95% CI 1.19-2.25]), 26 months (1.20 [95% CI 0.48-1.91]), and 38 months (1.52 [95% CI 0.74-2.30]); mean RULM scores at 14 months (mean difference 0.75 [95% CI 0.43-1.07]), 26 months (mean difference 0.65 [95% CI 0.27-1.03]), and 38 months (mean difference 0.72 [95% CI 0.25-1.18]), and 6 MWT at 14 months (mean difference 30.86 m [95% CI 18.34-43.38]), 26 months (mean difference 29.26 m [95% CI 14.87-43.65]), and 38 months (mean difference 32.20 m [95% CI 10.32-54.09]). No new safety signals were identified. Interpretation: Our prospective, observational, long-term (38 months) data provides further real-world evidence for the continuous efficacy and safety of nusinersen in a large proportion of adult patients with SMA. Funding: Financial support for the registry from Biogen, Novartis and Roche.

Ploidy-specific transcriptomes shed light on the heterogeneous identity and metabolism of developing tomato pericarp cells.

Endoreduplication, during which cells increase their DNA content through successive rounds of full genome replication without cell division, is the major source of endopolyploidy in higher plants. Endoreduplication plays pivotal roles in plant growth and development and is associated with the activation of specific transcriptional programmes that are characteristic of each cell type, thereby defining their identity. In plants, endoreduplication is found in numerous organs and cell types, especially in agronomically valuable ones, such as the fleshy fruit (pericarp) of tomato presenting high ploidy levels. We used the tomato pericarp tissue as a model system to explore the transcriptomes associated with endoreduplication progression during fruit growth. We confirmed that expression globally scales with ploidy level and identified sets of differentially expressed genes presenting only developmental-specific, only ploidy-specific expression patterns or profiles resulting from an additive effect of ploidy and development. When comparing ploidy levels at a specific developmental stage, we found that non-endoreduplicated cells are defined by cell division state and cuticle synthesis while endoreduplicated cells are mainly defined by their metabolic activity changing rapidly over time. By combining this dataset with publicly available spatiotemporal pericarp expression data, we proposed a map describing the distribution of ploidy levels within the pericarp. These transcriptome-based predictions were validated by quantifying ploidy levels within the pericarp tissue. This in situ ploidy quantification revealed the dynamic progression of endoreduplication and its cell layer specificity during early fruit development. In summary, the study sheds light on the complex relationship between endoreduplication, cell differentiation and gene expression patterns in the tomato pericarp.

Patterns of subregional cerebellar atrophy across epilepsy syndromes: An ENIGMA-Epilepsy study.

Objective: The intricate neuroanatomical structure of the cerebellum is of longstanding interest in epilepsy, but has been poorly characterized within the current cortico-centric models of this disease. We quantified cross-sectional regional cerebellar lobule volumes using structural MRI in 1,602 adults with epilepsy and 1,022 healthy controls across twenty-two 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 i) all epilepsies; ii) temporal lobe epilepsy with hippocampal sclerosis (TLE-HS); iii) non-lesional temporal lobe epilepsy (TLE-NL); iv) genetic generalised epilepsy; and (v) extra-temporal 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=0.42). Maximum volume loss was observed in the corpus medullare (dmax=0.49) and posterior lobe grey matter regions, including bilateral lobules VIIB (dmax= 0.47), Crus I/II (dmax= 0.39), VIIIA (dmax=0.45) and VIIIB (dmax=0.40). Earlier age at seizure onset (ηρ2max=0.05) and longer epilepsy duration (ηρ2max=0.06) 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 grey matter volume loss in patients with chronic epilepsy. Volume loss was maximal for posterior subregions implicated in non-motor 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 cerebellum subregions into neurobiological models of epilepsy.

Multi-spectral diffusion MRI mega-analysis in genetic generalized epilepsy: Relation to outcomes.

BACKGROUND AND OBJECTIVES: Genetic generalized epilepsy (GGE) is the most common form of generalized epilepsy. Although individual patients with GGE typically present without structural alterations, group differences have been demonstrated in GGE and some GGE subtypes like juvenile myoclonic epilepsy (GGE-JME). Previous studies usually involved only small cohorts from single centers and therefore could not assess imaging markers of multiple GGE subtypes. METHODS: We performed a diffusion MRI mega-analysis in 192 participants consisting of 126 controls and 66 patients with GGE from four different cohorts and two different epilepsy centers. We applied whole-brain multi-site harmonization and analyzed fractional anisotropy (FA), as well as mean, radial and axial diffusivity (MD/RD/AD) to assess differences between controls, patients with GGE and the common GGE subtypes, i.e. GGE with generalized tonic-clonic seizures only (GGE-GTCS), GGE-JME and absence epilepsy (GGE-AE). We also analyzed relationships with patients' response to anti-seizure-medication (ASM). RESULTS: Relative to controls, we identified decreased anisotropy and increased RD in patients with GGE. We found no significant effects of disease duration, age of onset or seizure frequency on diffusion metrics. Patients with JME had increased MD and RD when compared to controls, while patients with GGE-GTCS showed decreased MD/AD when compared to controls. Compared to patients with GGE-AE, patients with GGE-GTCS had lower AD/MD. Compared to patients with GGE-GTCS, patients with GGE-JME had higher MD/RD and AD. Moreover, we found lower FA in patients with refractory when compared to patients with non-refractory GGE in the right cortico-spinal tract, but no significant differences in patients with active versus controlled epilepsy. DISCUSSION: We provide evidence that clinically defined GGE as a whole and GGE-subtypes harbor marked microstructural differences detectable with diffusion MRI. Moreover, we found an association between microstructural changes and treatment resistance. Our findings have important implications for future full-resolution multi-site studies when assessing GGE, its subtypes and ASM refractoriness.

Thermally Switchable Nanogate Based on Polymer Phase Transition.

Mimicking and extending the gating properties of biological pores is of paramount interest for the fabrication of membranes that could be used in filtration or drug processing. Here, we build a selective and switchable nanopore for macromolecular cargo transport. Our approach exploits polymer graftings within artificial nanopores to control the translocation of biomolecules. To measure transport at the scale of individual biomolecules, we use fluorescence microscopy with a zero-mode waveguide set up. We show that grafting polymers that exhibit a lower critical solution temperature creates a toggle switch between an open and closed state of the nanopore depending on the temperature. We demonstrate tight control over the transport of DNA and viral capsids with a sharp transition (∼1 °C) and present a simple physical model that predicts key features of this transition. Our approach provides the potential for controllable and responsive nanopores in a range of applications.

Big Field of View MRI T1w and FLAIR Template - NMRI225.

Image templates are a common tool for neuroscience research. Often, they are used for spatial normalization of magnetic resonance imaging (MRI) data, which is a necessary procedure for analyzing brain morphology and function via voxel-based analysis. This allows the researcher to reduce individual shape differences across images and make inferences across multiple subjects. Many templates have a small field-of-view typically focussed on the brain, limiting the use for applications requiring detailed information about other extra-cranial structures in the head and neck area. However, there are several applications where such information is important, for example source reconstruction of electroencephalography (EEG) and/or magnetoencephalography (MEG). We have constructed a new template based on 225 T1w and FLAIR images with a big field-of-view that can serve both as target for across subject spatial normalization as well as a basis to build high-resolution head models. This template is based on and iteratively re-registered to the MNI152 space to provide maximal compatibility with the most commonly used brain MRI template.

Clinical Significance of Diffusion Tensor Imaging in Metachromatic Leukodystrophy.

BACKGROUND: Metachromatic leukodystrophy (MLD) is a lysosomal enzyme deficiency disorder leading to progressive demyelination and, consecutively, to cognitive and motor decline. Brain magnetic resonance imaging (MRI) can detect affected white matter as T2 hyperintense areas but cannot quantify the gradual microstructural process of demyelination more accurately. Our study aimed to investigate the value of routine MR diffusion tensor imaging in assessing disease progression. METHODS: MR diffusion parameters (apparent diffusion coefficient [ADC] and fractional anisotropy [FA]) were in the frontal white matter, central region (CR), and posterior limb of the internal capsule in 111 MR datasets from a natural history study of 83 patients (age: 0.5-39.9 years; 35 late-infantile, 45 juvenile, 3 adult, with clinical diffusion sequences of different scanner manufacturers) as well as 120 controls. Results were correlated with clinical parameters reflecting motor and cognitive function. RESULTS: ADC values increase and FA values decrease depending on disease stage/severity. They show region-specific correlations with clinical parameters of motor and cognitive symptoms, respectively. Higher ADC levels in CR at diagnosis predicted a disease course with more rapid motor deterioration in juvenile MLD patients. In highly organized tissues such as the corticospinal tract, in particular, diffusion MR parameters were highly sensitive to MLD-associated changes and did not correlate with the visual quantification of T2 hyperintensities. CONCLUSION: Our results show that diffusion MRI can deliver valuable, robust, clinically meaningful, and easily obtainable/accessible/available parameters in the assessment of prognosis and progression of MLD. Therefore, it provides additional quantifiable information to established methods such as T2 hyperintensity.

MR-spectroscopy in metachromatic leukodystrophy: A model free approach and clinical correlation.

BACKGROUND AND PURPOSE: Metachromatic leukodystrophy (MLD) is a lysosomal enzyme deficiency disorder leading to demyelination and subsequently to a progressive decline in cognitive and motor function. It affects mainly white matter where changes during the course of the disease can be visualized on T2-weighted MRI as hyperintense areas. Associated changes in brain metabolism can be quantified by MR spectroscopy (MRS) and may give complementary information as biomarkers for disease characterisation and progression. Our study aimed to further investigate the correlation of MRS with clinical parameters for motor and cognitive function by using a model free MRS analysis approach that would be precise and straightforward to implement. MATERIALS AND METHODS: 53 MRS datasets derived from 29 patients (10 late-infantile, 19 juvenile) and 12 controls were acquired using a semi-LASER CSI sequence covering a slice through the centrum semiovale above the corpus callosum. We defined four regions of interest in the white matter (frontal white matter [FWM] and the cortico-spinal tract [CST] area, each left and right) and one in cortical grey matter. Spectra were analysed using a model and fitting free approach by calculating the definite integral of 10 intervals which were distributed along the whole spectrum. These 10 intervals were orientated towards the main peaks of the metabolites N-acetylaspartate (NAA), creatine, myo-inositol, choline, glutamine/glutamate and aspartate to approximately attribute changes in the intervals to corresponding metabolites. Their ratios to the main creatine peak integral were correlated with clinical parameters assessing motor and cognitive abilities. Furthermore, in a post-hoc analysis, NAA levels of a subset of 21 MR datasets were correlated to NAA levels in urine measured by 1H (proton) nuclear magnetic resonance (NMR) spectroscopy. The applied interval integration method was validated in the control cohort against the standard approach, using spectral profile templates of known metabolites (LCModel). Both methods showed good agreement, with coefficients of variance being slightly lower for our approach compared to the related LCModel results. Moreover, the new approach was able to extract information out of the frequency range around the main peaks of aspartate and glutamine where LCModel showed only few usable values for the respective metabolites. RESULTS: MLD spectra clearly differed from controls. The most pronounced differences were found in white matter (much less in grey matter), with larger values corresponding to main peaks of myo-inositol, choline and aspartate, and smaller values associated with NAA and glutamine. Late-infantile patients had more severe changes compared to later-onset patients, especially in intervals corresponding to NAA, aspartate, myo-inositol, choline and glutamine. There was a high correlation of several intervals in the corticospinal tract region with motor function (with the most relevant interval corresponding to NAA peak with a correlation coefficient of -0.75; p < 0.001), while cognitive function, by means of IQ, was found to be most correlating in frontal white matter corresponding to the NAA peak (r = 0.84, p < 0.001). The post-hoc analysis showed that the main NAA peak interval correlated negatively with the NAA in urine (r = -0.584, p < 0.001). CONCLUSION: The applied model and fitting free interval integration approach to analyse MRS data of a semi-LASER sequence at 3T suits well to detect and quantify pathological changes in MLD patients through the different courses of the disease and correlates well with clinical symptoms while showing smaller dimensions of variation compared to the more sophisticated single metabolite analysis using LCModel. NAA seems the most clinically meaningful biomarker to use in this context. Its correlation with urine measurements further underlines its potential as a clinically and biologically useful parameter of disease progression in MLD.

Optically pumped magnetometers detect altered maximal muscle activity in neuromuscular disease.

Optically pumped magnetometers (OPM) are quantum sensors that enable the contactless, non-invasive measurement of biomagnetic muscle signals, i.e., magnetomyography (MMG). Due to the contactless recording, OPM-MMG might be preferable to standard electromyography (EMG) for patients with neuromuscular diseases, particularly when repetitive recordings for diagnostic and therapeutic monitoring are mandatory. OPM-MMG studies have focused on recording physiological muscle activity in healthy individuals, whereas research on neuromuscular patients with pathological altered muscle activity is non-existent. Here, we report a proof-of-principle study on the application of OPM-MMG in patients with neuromuscular diseases. Specifically, we compare the muscular activity during maximal isometric contraction of the left rectus femoris muscle in three neuromuscular patients with severe (Transthyretin Amyloidosis in combination with Pompe's disease), mild (Charcot-Marie-Tooth disease, type 2), and without neurogenic, but myogenic, damage (Myotonia Congenita). Seven healthy young participants served as the control group. As expected, and confirmed by using simultaneous surface electromyography (sEMG), a time-series analysis revealed a dispersed interference pattern during maximal contraction with high amplitudes. Furthermore, both patients with neurogenic damage (ATTR and CMT2) showed a reduced variability of the MMG signal, quantified as the signal standard deviation of the main component of the frequency spectrum, highlighting the reduced possibility of motor unit recruitment due to the loss of motor neurons. Our results show that recording pathologically altered voluntary muscle activity with OPM-MMG is possible, paving the way for the potential use of OPM-MMG in larger studies to explore the potential benefits in clinical neurophysiology.

Probing the Effect of the Density of Active Molecules in Large-Area Molecular Junctions.

The effect of the density of active molecules in molecular junctions (MJs) has been investigated by using a host/guest strategy. Mixed layers consisting of oligothiophene (BTB) encapsulated by ß-cyclodextrin (BTB@ß-CD) were generated. Cyclodextrins were then removed, and the pinholes generated were filled with BTB to obtain BTB@BTB films. MJs based on mixed BTB@ß-CD and BTB@BTB layers, as well as single-component BTB MJs, were compared. The variation of ln J vs thickness is similar for all systems while the Jo of BTB@ß-CD MJs is 20 times lower than that of BTB MJs. After ß-cyclodextrin has been removed, and the pinholes filled, Jo increases and reaches the same value as for the BTB MJs, showing that the conductance scales with the number of active molecules. This strategy provides a unique method for investigating molecular interactions in direct tunneling MJs as well as the possibility of fabricating new functionalized MJs based on mixed layers.

Development of 2-D and 3-D culture platforms derived from decellularized nucleus pulposus.

Bioscaffolds derived from the extracellular matrix (ECM) have shown the capacity to promote regeneration by providing tissue-specific biological instructive cues that can enhance cell survival and direct lineage-specific differentiation. This study focused on the development and characterization of two-dimensional (2-D) and three-dimensional (3-D) cell culture platforms incorporating decellularized nucleus pulposus (DNP). First, a detergent-free protocol was developed for decellularizing bovine nucleus pulposus (NP) tissues that was effective at removing cellular content while preserving key ECM constituents including collagens, glycosaminoglycans, and the cell-adhesive glycoproteins laminin and fibronectin. Next, novel 2-D coatings were generated using the DNP or commercially-sourced bovine collagen type I (COL) as a non-tissue-specific control. In addition, cryo-milled DNP or COL particles were incorporated within methacrylated chondroitin sulphate (MCS) hydrogels as a 3-D cell culture platform for exploring the effects of ECM particle composition. Culture studies showed that the 2-D coatings derived from the DNP could support cell attachment and growth, but did not maintain or rescue the phenotype of primary bovine NP cells, which de-differentiated when serially passaged in monolayer culture. Similarly, while bovine NP cells remained highly viable following encapsulation and 14 days of culture within the hydrogel composites, the incorporation of DNP particles within the MCS hydrogels was insufficient to maintain or rescue changes in NP phenotype associated with extended in vitro culture based on gene expression patterns. Overall, DNP produced with our new decellularization protocol was successfully applied to generate both 2-D and 3-D bioscaffolds; however, further studies are required to assess if these platforms can be combined with additional components of the endogenous NP microenvironment to stimulate regeneration or lineage-specific cell differentiation.

Combined spin filtering actions in hybrid magnetic junctions based on organic chains covalently attached to graphene.

We present a bias-controlled spin-filtering mechanism in spin-valves including a hybrid organic chain/graphene interface. Wet growth conditions of oligomeric molecular chains would usually lead, during standard CMOS-compatible fabrication processes, to the quenching of spintronics properties of metallic spin sources due to oxidation. We demonstrate by X-ray photoelectron spectroscopy that the use of a protective graphene layer fully preserves the metallic character of the ferromagnetic surface and thus its capability to deliver spin polarized currents. We focus here on a small aromatic chain of controllable lengths, formed by nitrobenzene monomers and derived from the commercial 4-nitrobenzene diazonium tetrafluoroborate, covalently attached to the graphene passivated spin sources thanks to electroreduction. A unique bias dependent switch of the spin signal is then observed in complete spin valve devices, from minority to majority spin carriers filtering. First-principles calculations are used to highlight the key role played by the spin-dependent hybridization of electronic states present at the different interfaces. Our work is a first step towards the exploration of spin transport using different functional molecular chains. It opens the perspective of atomic tailoring of magnetic junction devices towards spin and quantum transport control, thanks to the flexibility of ambient electrochemical surface functionalization processes.

Structural network alterations in focal and generalized epilepsy assessed in a worldwide ENIGMA study follow axes of epilepsy risk gene expression.

Epilepsy is associated with genetic risk factors and cortico-subcortical network alterations, but associations between neurobiological mechanisms and macroscale connectomics remain unclear. This multisite ENIGMA-Epilepsy study examined whole-brain structural covariance networks in patients with epilepsy and related findings to postmortem epilepsy risk gene expression patterns. Brain network analysis included 578 adults with temporal lobe epilepsy (TLE), 288 adults with idiopathic generalized epilepsy (IGE), and 1328 healthy controls from 18 centres worldwide. Graph theoretical analysis of structural covariance networks revealed increased clustering and path length in orbitofrontal and temporal regions in TLE, suggesting a shift towards network regularization. Conversely, people with IGE showed decreased clustering and path length in fronto-temporo-parietal cortices, indicating a random network configuration. Syndrome-specific topological alterations reflected expression patterns of risk genes for hippocampal sclerosis in TLE and for generalized epilepsy in IGE. These imaging-transcriptomic signatures could potentially guide diagnosis or tailor therapeutic approaches to specific epilepsy syndromes.

Event-based modeling in temporal lobe epilepsy demonstrates progressive atrophy from cross-sectional data.

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.

Topographic divergence of atypical cortical asymmetry and atrophy patterns in temporal lobe epilepsy.

Temporal lobe epilepsy, a common drug-resistant epilepsy in adults, is primarily a limbic network disorder associated with predominant unilateral hippocampal pathology. Structural MRI has provided an in vivo window into whole-brain grey matter structural alterations in temporal lobe epilepsy relative to controls, by either mapping (i) atypical inter-hemispheric asymmetry; or (ii) regional atrophy. However, similarities and differences of both atypical asymmetry and regional atrophy measures have not been systematically investigated. Here, we addressed this gap using the multisite ENIGMA-Epilepsy dataset comprising MRI brain morphological measures in 732 temporal lobe epilepsy patients and 1418 healthy controls. We compared spatial distributions of grey matter asymmetry and atrophy in temporal lobe epilepsy, contextualized their topographies relative to spatial gradients in cortical microstructure and functional connectivity calculated using 207 healthy controls obtained from Human Connectome Project and an independent dataset containing 23 temporal lobe epilepsy patients and 53 healthy controls and examined clinical associations using machine learning. We identified a marked divergence in the spatial distribution of atypical inter-hemispheric asymmetry and regional atrophy mapping. The former revealed a temporo-limbic disease signature while the latter showed diffuse and bilateral patterns. Our findings were robust across individual sites and patients. Cortical atrophy was significantly correlated with disease duration and age at seizure onset, while degrees of asymmetry did not show a significant relationship to these clinical variables. Our findings highlight that the mapping of atypical inter-hemispheric asymmetry and regional atrophy tap into two complementary aspects of temporal lobe epilepsy-related pathology, with the former revealing primary substrates in ipsilateral limbic circuits and the latter capturing bilateral disease effects. These findings refine our notion of the neuropathology of temporal lobe epilepsy and may inform future discovery and validation of complementary MRI biomarkers in temporal lobe epilepsy.

[Spinal muscular atrophy]. / Spinale Muskelatrophie.

Spinal muscular atrophy (SMA) is an autosomal recessive disease caused by biallelic mutations in the SMN1 (survival motor neuron 1) gene on chromosome 5q13.2, which leads to a progressive degeneration of alpha motor neurons in the spinal cord and in motor nerve nuclei in the caudal brainstem. It is characterized by progressive proximally accentuated muscle weakness with loss of already acquired motor skills, areflexia and, depending on the phenotype, varying degrees of weakness of the respiratory and bulbar muscles, although the facial muscles and eye muscles are not affected. The previously purely symptom-oriented treatment has undergone a significant expansion since 2017 with the approval of three drugs (nusinersen, onasemnogene abeparvovec and risdiplam) that modify the course of the disease at the gene expression level and have led to a change in the natural disease course of SMA. The effect of these new forms of treatment can only be fully assessed in the coming years. New aspects and challenges in this context are discussed in this article.

Flagella-like beating of actin bundles driven by self-organized myosin waves.

Wave-like beating of eukaryotic cilia and flagella-threadlike protrusions found in many cells and microorganisms-is a classic example of spontaneous mechanical oscillations in biology. This type of self-organized active matter raises the question of the coordination mechanism between molecular motor activity and cytoskeletal filament bending. Here we show that in the presence of myosin motors, polymerizing actin filaments self-assemble into polar bundles that exhibit wave-like beating. Importantly, filament beating is associated with myosin density waves initiated at twice the frequency of the actin-bending waves. A theoretical description based on curvature control of motor binding to the filaments and of motor activity explains our observations in a regime of high internal friction. Overall, our results indicate that the binding of myosin to actin depends on the actin bundle shape, providing a feedback mechanism between the myosin activity and filament deformations for the self-organization of large motor filament assemblies.