Brain

There is substantial interest in understanding neurological impact and recovery over time, but there is a dearth of longitudinal assessment extending from minutes to months surrounding neural system impact. We compared rare intraoperative recordings in three patients, obtained immediately before and after anterior temporal lobe (ATL) resection during a semantic prediction task, with longitudinal source-localized electroencephalography (EEG) obtained 2-6 weeks before and 2 and 6-14 months after surgery. Relative to controls (n = 20), task performance showed sustained impairment in the two left-hemisphere patients and delayed impact in the right-hemisphere patient. Consistent with theory on ipsilateral and contralateral hemisphere compensation, all three patients exhibited bilateral EEG alterations in speech responses and effective connectivity that did not recover to pre-operative levels. Direct comparison of the datasets for intrinsic neurophysiological biomarkers associated with timescales of processing ({tau}INT) and excitatory-inhibitory balance (aperiodic slope, {chi}SPEC) showed a striking months-long reduction in rapid timescale processing and gradually increasing aperiodic slope (e.g., putatively increased cortical inhibition) in the ipsilateral hemisphere of all three patients. Amidst these neurophysiological alterations, task performance did not return to pre-operative levels. These rare longitudinal patient data advance a framework to broadly evaluate neurological impact over multiple timeframes.

Status epilepticus (SE) is a neurological emergency with a mortality of up to 39% in population-based studies. Animal studies suggest that, beyond a critical timepoint (t2), SE induces neuronal injury exceeding what can be expected from the underlying aetiology, but in vivo evidence in humans is scarce. Thirty-six prospectively recruited individuals with SE with a mean age of 59 years underwent serial high-resolution T1-weighted brain MRI over a mean follow-up period of 5 months and were compared with 34 individuals with drug-resistant focal epilepsy and 36 propensity-score matched healthy controls, which were retrospectively included. Cortical thickness and volume of subcortical structures were estimated and harmonised for scanner-related effects. Longitudinal change was assessed using linear mixed-effects models correcting for age at baseline and interscan interval and compared between groups. We further investigated the independent effects of SE duration, semiology and level of consciousness after mutual adjustment for each variable as well as aetiology and age at baseline, and investigated longitudinal structural change associated with key locations of peri-ictal MRI abnormalities (PMA). SE was associated with pronounced bilateral hippocampal atrophy in comparison to normal aging and drug-resistant epilepsy, alongside volume increase in several deep grey matter nuclei as well as a trend for cortical thinning of medial brain structures. SE duration was the strongest independent driver of brain change, producing widespread cortical thinning and bilateral hippocampal atrophy. A convulsive semiology was independently associated with accelerated medial temporal cortical thinning and bilateral hippocampal volume loss when compared with non-convulsive (NCSE) and other prominent-motor SE, while reduced consciousness predicted faster thinning of medial frontoparietal cortex. PMA was associated with distinct longitudinal trajectories of subcortical volume, with pulvinar and hippocampus involvement predicting thalamic and hippocampal atrophy patterns. According to our findings, a single episode of SE was associated with a measurable structural imprint in the brain that evolved over months beyond what would be expected for aetiology alone, with atrophy trajectories highlighting a vulnerability of the hippocampus and other limbic structures. A long SE duration, together with, to a lesser extent, convulsive semiology and impaired consciousness, independently amplified this damage. These findings corroborate the timepoint-based (t2) concept of SE and reinforce the clinical imperative of rapid seizure termination to contain long-term structural brain injury.

KCNT1-related disorders represent clinically heterogeneous severe epilepsies associated with profound neurodevelopmental impairment. The full phenotypic spectrum and longitudinal disease trajectory remain incompletely characterized, which is a critical gap limiting the establishment of quantifiable endpoints necessary for future clinical trials. Compounding this challenge, identical pathogenic variants result in phenotypically distinct syndromes, including early infantile developmental and epileptic encephalopathy (EIDEE) and autosomal dominant sleep-related hypermotor epilepsy (ADSHE), underscoring unresolved genotype-phenotype relationships. To address these gaps, we performed a comprehensive analysis of 159 individuals with KCNT1-related disorders, including a longitudinally characterized subgroup of 62 individuals across 390 patient years, systematically defining disease progression, seizure trajectories, developmental outcomes, and treatment response across the full spectrum of the disorder. Seizures were nearly universal, affecting 157 of 159 individuals, with 81% (n=126/156) having seizure onset within the first year of life. Stratification by clinical subgroup revealed divergent seizure onset patterns. Recurrent variants did not significantly differ in age of seizure onset yet exhibited variant-specific clinical fingerprints, such as the preponderance of focal clonic seizures (OR=5.03, 95% CI 1.60-15.7, f=0.47) in those with the p.Gly288Ser variant. Comparison with a broader cohort of 14,893 individuals with neurodevelopmental disorders revealed phenotypic features such as migrating focal seizures (OR=21716, 95% CI 2409-Inf, f=0.42) and hypertonia (OR=26.5, 95% CI 18.2-38.3, f=0.45) to be more common in EIDEE, and nocturnal seizures (OR=29787, 95% CI 3062-Inf, f=0.5) and hyperactivity (OR=13.7, 95% CI 4.70-35.9, f=0.32) to be more common in ADSHE. These findings corroborate and extend those reported in the existing literature. Developmental milestones revealed marked delays across all domains. Analysis of longitudinal medication prescription patterns exposed striking therapeutic variability, reflecting the absence of a consistent treatment framework. Several anti-seizure medications frequently cited as beneficial, quinidine and cannabidiol, were not associated with seizure improvement or sustained seizure freedom in our cohort. In contrast, clobazam (OR=1.39, 95% CI 1.12-1.72, f=0.85), ketogenic diet (OR=1.30, 95% CI 1.07-1.57, f=0.75), and lacosamide (OR=2.03, 95% CI 1.54-2.66, f=0.59) demonstrated positive comparative effectiveness. Quantitative EEG analysis distinguished individuals with KCNT1-related disorders from age-matched controls with high accuracy (AUC=0.906), with key discriminating spectral features, including alpha power in the central and parietal regions, demonstrating significant reduction across childhood and adolescence. Collectively, these findings expand the phenotypic and genotypic landscape of KCNT1-related disorders through large-scale real-world clinical data, establish quantifiable longitudinal clinical endpoints, and provide actionable insights into genotype-phenotype relationships and differential treatment response. Together, these findings will help identify outcome measures and biomarkers to inform future clinical trial design.

Late-onset unexplained epilepsy is a potential harbinger of dementia, likely driven by network hyperexcitability that facilitates amyloid-{beta} release and tau propagation. Dampening this activity with antiseizure medications offers a potential disease modifying strategy, yet whether specific agents differentially alter this neurodegenerative trajectory remains unknown. Here, we emulated a target trial using global real-world federated data on patients with late-onset unexplained epilepsy to compare dementia risk across antiseizure monotherapies. Using data from over 75 million adults aged 55 years or older, we found that sodium channel blockers were associated with a 27% lower hazard of incident all-cause dementia (hazard ratio = 0.73, 95% confidence interval 0.61- 0.88) and 34% lower hazard of Alzheimer's disease (hazard ratio = 0.66, 0.49 -0.88), compared with levetiracetam/brivaracetam. While the class effect was protective, individual agents such as phenytoin, carbamazepine, and lamotrigine showed divergent safety and efficacy profiles. We replicated these findings in both a Down syndrome cohort and the external National Alzheimer's Coordinating Center dataset. Our results suggest that targeting neuronal excitability with sodium channel blockers is associated with lower risk of dementia, prioritizing the repurposing of these agents for dementia prevention trials.

Adapting ongoing gait patterns to environmental challenges is essential for safe navigation through the environment. Impairment of gait adaptation is common in many neurodegenerative disorders, such as Parkinson's disease (PD), where it hampers mobility and limits quality of life. The neural control of gait adaptation remains largely unclear, thereby limiting the development of targeted treatments, such as deep brain stimulation of the subthalamic nucleus (STN-DBS). We integrated clinical, kinematic, brain metabolic imaging, and electrophysiological data, obtained during a fully immersive virtual reality overground walking task, to characterize the neural underpinnings of gait adaptation performance during dynamic obstacle avoidance and its improvement with STN-DBS. Movement kinematics, brain oscillatory activity, and metabolic activation were simultaneously acquired in 12 patients with PD during rest and gait adaptation, under active or paused STN-DBS, using inertial measurement units, electroencephalography, and three separate [18F]fluorodeoxyglucose positron emission tomography scans. Eight age-matched healthy subjects completed the same task for comparative kinematic analyses. All patients showed significant clinical improvement with STN-DBS. During the gait adaptation task with paused stimulation, patients exhibited increased metabolic activity in the cerebellum and sensorimotor cortex. Active STN-DBS selectively enhanced thalamic and superior frontal gyrus (SFG) metabolism, while concomitantly reducing cerebellar uptake. Right-lateralized SFG metabolism correlated with gait adaptation performance, with DBS-driven shifts toward greater right SFG activity predicting the magnitude of gait adaptation improvement. This correlation was independent of baseline asymmetry in clinical impairment, electrode placement, or structural connectivity to the SFG. Of note, STN-DBS amplitude asymmetry emerged as an independent predictor of right-lateralization of SFG metabolism. EEG recordings confirmed this lateralized network modulation, with theta-band asymmetry paralleling PET findings. Our findings identify a lateralized thalamo-cortical network supporting gait adaptation in PD and highlight a distinctive role for the SFG. We further show that effective STN-DBS acts as a lateralized regulator, dynamically rebalancing cortico-thalamic circuits to support context-appropriate gait control. The observed right-hemispheric lateralization may foster novel image-guided programming strategies to enhance the consistency and effectiveness of gait control in PD.

Parkinsons disease is defined clinically by motor dysfunction, but its pathology is not confined to nigral dopaminergic neurons. Prominent non-motor features including cognitive impairment, autonomic failure and sleep disturbance indicate widespread neurodegeneration that remains incompletely characterised. We pre-registered and conducted a multilevel meta-analysis of 166 case-control post-mortem studies published between 1963 and 2025, mapping neuronal loss across 85 brain regions, 38 cell types and 145 region-cell populations. The evidence base behind this map is thin. Only 4 of 145 populations are adequately powered, and 82% of Allen Brain Atlas regions have never been quantified in Parkinsons disease. A further 18 populations would reach adequate power with five or fewer additional studies, identifying an efficient route to closing current gaps. Noradrenergic neurons of the locus coeruleus degenerate to a similar extent as substantia nigra dopaminergic neurons, with both populations losing more than 60% of neurons. Cholinergic neurons of the basal nucleus and pedunculopontine tegmental nucleus and dopaminergic neurons of the ventral tegmental area show significant but less severe loss. These findings establish Parkinsons disease as a multi-system neurodegenerative disorder and expose key gaps and biases in the existing literature.

Gain-of-function variants (GOF) in SCN8A, which encodes the NaV1.6 sodium channel, lead to epilepsy syndromes ranging from drug-responsive self-limited (SeLIE) and intermediate epilepsy to drug-resistant developmental and epileptic encephalopathy (DEE). It is currently unclear why individuals with SCN8A GOF variants show variable responses to sodium channel blockers (SCBs). Here, we compared the clinical characteristics of 173 individuals with 25 different SCN8A GOF variants following the hypothesis that carriers of variants affecting activation gating respond less well to SCBs than those with variants affecting fast inactivation gating, given that use-dependent SCBs preferentially target inactivated channel states. We found that individuals with variants altering channel activation gating were more severely affected than those with variants altering inactivation properties: They had an earlier age at onset (3 vs. 5 months, P < 0.0001), higher prevalence of DEE (75% vs. 39%; P < 0.0001), and poorer response to SCBs (20% vs. 69% seizure free; P < 0.0001). We performed pharmacological studies on representative and recurrent variants from each group: two variants (F846S and M1760I) causing hyperpolarizing shifts of the voltage-dependent activation curves, and two variants (G1475R and N1877S) causing depolarizing shifts of the voltage-dependent fast inactivation curves. Phenytoin failed to suppress neuronal firing in neurons expressing activation-related variants, but showed good suppressing effects in neurons expressing inactivation-related variants. In contrast, PRAX-330, a new SCB, which showed much faster binding rates than phenytoin, was effective for both groups of variants by markedly reducing neuronal firing through rapidly and persistently stabilizing NaV1.6 in the inactivated state. Our findings provide new insights into the mechanism of drug-resistance in SCN8A-DEE and support PRAX-330 and compounds with similar pharmacological properties as a promising preclinical candidate for targeted therapies.

Synapse loss is an early feature of neurodegeneration and may provide sensitive biomarkers for experimental medicine. Positron emission tomography (PET) with the synaptic vesicle glycoprotein 2A radioligand [11C]UCB-J shows widespread signal reduction across dementias. However, it remains unclear which aspects of synaptic integrity [11C]UCB-J PET measures. We developed a histological-imaging pipeline to quantify structurally intact synapses in post-mortem brain tissue. We applied it to six donors with the tauopathy progressive supranuclear palsy (PSP) who had ante-mortem [11C]UCB-J-PET, alongside six controls across 11 brain regions. Synapse loss in PSP was widespread but region-specific across cortical, subcortical, and brainstem regions. Greater synapse loss was associated with higher tau burden and pathology, and cortical synaptic density correlated with ante-mortem cognition. Post-mortem synaptic density correlated with in vivo [11C]UCB-J-PET signal. This study provides validation of SV2A PET as a biomarker of synaptic density and supports integration of imaging with histopathology in neurodegenerative disease research.

Guillain-Barre syndrome is an acute immune-mediated polyradiculoneuropathy with heterogeneous outcomes and limited molecular biomarkers for diagnosis, disease monitoring, and prognosis. To elucidate the circulating proteomic profile of this disorder and identify candidate biomarkers associated with disease activity and recovery, we measured over 6,500 proteins using an aptamer-based proteomic platform. We analysed paired, longitudinal sera from 20 patients at disease onset and one-year follow-up, alongside 15 healthy controls. Unbiased differential protein abundance and gene-set enrichment analyses were performed. Candidate proteins were validated using conventional immunoassays in a cohort including healthy and disease controls. We identified 39 differentially abundant proteins between the acute and recovery phases and 248 proteins altered in acute Guillain-Barre syndrome compared to controls. The acute phase was characterised by a marked enrichment in systemic immune cascades and muscle sarcomere proteins, alongside a significant depletion of axonal adhesion molecules. Serum amyloid A1 (SAA1) emerged as the most strongly increased protein in the acute phase. Validation through independent immunoassays confirmed robust serum amyloid A elevations at disease onset relative to the one-year recovery phase, healthy controls, and relevant post-infectious and neuromuscular disease controls (acute disseminated encephalomyelitis and myasthenia gravis), underscoring a peripheral nerve-specific inflammatory response. Furthermore, unexpected elevations of cardiac troponin T (cTnT) were observed at disease onset. Clinical validation using high-sensitivity assays demonstrated that cTnT exceeded the diagnostic 99th percentile upper reference limit in 25.5% of acute Guillain-Barre syndrome patients. A similarly high frequency of elevation in the myasthenia gravis disease control group (42.1%) suggests these increases predominantly reflect neuromuscular damage rather than myocardial injury. Finally, Mendelian randomisation provided causal genetic evidence linking specific systemic proteins to disease susceptibility, identifying robust roles for SERPING1 (plasma protease C1 inhibitor), CNDP1 (an antioxidant protein), and CRISPLD2 (a lipopolysaccharide-binding protein that regulates endotoxin function). Together, this comprehensive proteomic characterisation reveals distinct, stage-specific molecular signatures in Guillain-Barre syndrome. Importantly, it suggests SAA1 as a robust marker of acute peripheral nerve inflammation and challenges the conventional interpretation of elevated cTnT in severe neuropathies and neuromuscular disorders. Furthermore, this work provides a novel dataset to explore future targeted therapeutic development in Guillain-Barre syndrome.

Young onset Parkinson's disease may be caused by biallelic mutations in PRKN or other autosomal recessive Parkinson's disease genes, but the majority of patients do not carry known monogenic variants. Previous studies have found an increased cumulative burden of common genetic risk variants for Parkinson's disease in young onset patients, but the specific genetic architecture of non-monogenic young onset Parkinson's disease is not well characterized. We conducted a genome-wide association study of 1,528 Parkinson's disease patients with symptom onset between 18 and 40 years and 20,408 controls of European ancestry using data from The Global Parkinson's Genetic Program, the International Parkinson's Disease Genomics Consortium, and the NeuroGenetics Research Consortium. We performed meta-analyses of additive and recessive regression models and investigated associations between age at onset groups and different polygenic risk scores. An additive model meta-analysis identified six independent loci passing a genome-wide significance threshold, including three loci identified in previous genome-wide association studies (near SNCA, GBA1, and HIP1R) and two loci not previously associated with Parkinson's disease (rs74950462, P = 1.24e-8 and rs72848817, P = 4.89e-8). Furthermore, we identified a significant signal at the PRKN locus, prompting a follow-up analysis employing a recessive model. The recessive genome-wide association meta-analysis identified nine loci passing a genome-wide significance threshold, including SNCA, PRKN, and seven novel variants. Patients with onset between 18 and 40 years had significantly higher polygenic risk scores than later onset patients when the score was modelled specifically on genome-wide association statistics from independent young onset Parkinson's disease participants versus healthy controls. This increased polygenic burden was driven in part by loci harbouring mitochondrial pathway genes. Our results indicate that previously unidentified common and low-frequency variants contribute specifically to the young onset subgroup of Parkinson's disease. Association signals detected uniquely with a recessive model suggest that genetic susceptibility to young onset Parkinson's disease may be partially driven by homozygous variation, in line with previous reports of increased runs of homozygosity in this particular group of patients and may be consistent with a loss of function mechanism. The findings support the notion of young onset Parkinson's disease as a partly distinct subphenotype and highlight the mitochondrial pathway. These results may have implications for future precision medicine but should be interpreted with caution pending independent replication.

The temporal coupling between cortical blood-oxygen-level-dependent (BOLD) activity and CSF inflow has recently been proposed as a non-invasive marker of glymphatic function, a brain-wide clearance system closely linked to sleep, neuromodulatory regulation and neurodegeneration. Reduced BOLD-CSF coupling has been previously reported in Parkinsons disease but its characterization in dementia with Lewy bodies, regional specificity and relevance to shared neuropsychiatric symptoms remain unclear. Using resting-state functional MRI, we quantified global and regional BOLD-CSF coupling in 39 participants, including 17 with Parkinsons disease (mean age 61.4 years), 10 with dementia with Lewy bodies (mean age 72.8 years) and 12 healthy controls (mean age 66.2 years), and examined the relationship with clinical and cognitive measures, as well as volumetric measures of the subcortical ascending arousal network. Parkinsons disease and dementia with Lewy bodies patients both demonstrated weaker global BOLD-CSF coupling compared to controls, with no detectable difference between patient groups. Coupling reductions were most pronounced within the unimodal and attentional networks, encompassing regions that are particularly vulnerable in Lewy body disease. Weaker coupling was associated with the severity of hallucinations and cognitive fluctuations, poorer nocturnal sleep quality and impaired attentional working memory, but not overall motor symptom burden. Associations between BOLD-CSF coupling and basal forebrain and brainstem volumes were observed, though partially age-dependent, suggesting a complex interaction between neuromodulatory system degeneration, ageing and brain-fluid dynamics. Our results provide preliminary evidence that disrupted temporal coordination between cerebrovascular activity and CSF inflow may contribute to the fluctuating neuropsychiatric features of Lewy body disease and highlight the utility of BOLD-CSF coupling as a dynamic in vivo proxy of glymphatic function. Replication in larger cohorts incorporating multimodal imaging and biomarkers of pathology will be essential to validate these findings and determine whether brain-fluid dysregulation represents a potentially modifiable therapeutic target.

Mutations in SCN1A, which encodes the voltage-gated sodium channel Nav1.1 (I subunit), are the major cause of Dravet syndrome, a severe developmental and epileptic encephalopathy. Although Nav1.1 haploinsufficiency preferentially impairs inhibitory interneuron function, the region-specific contributions of distributed brain circuits to seizure susceptibility, particularly in subcortical structures that have received less attention than the neocortex and hippocampus, remain unclear. Here, we examined the effects of region-specific Nav1.1 deficiency on hyperthermia-induced seizures by selectively deleting Scn1a in the neocortex, nucleus accumbens (NAc), and dorsal striatum (caudate-putamen, CPu) of adult mice using an adeno-associated virus-mediated Cre-loxP approach. Contrary to expectations based on prior cortical studies, homozygous Scn1a deletion in the neocortex produced only modest effects on seizure generalization. In contrast, homozygous deletion in the NAc and CPu induced generalized seizures to varying degrees. Notably, heterozygous Scn1a deletion in the CPu alone was sufficient to trigger generalized seizures, whereas similar manipulations in the neocortex or NAc were not. Seizure threshold temperatures were largely comparable across regions. These findings identify the dorsal striatum as particularly vulnerable to partial Nav1.1 loss and reveal functional heterogeneity within striatal circuits. Our results underscore a previously underappreciated role of striatal inhibitory networks in hyperthermia-induced seizure susceptibility and provide new insights into the circuit mechanisms underlying Dravet syndrome.

Approximately 30-40% of stroke patients retain aphasia at 12 months. Early forecasting may guide rehabilitation and prognostic enrichment of clinical trials, yet machine learning (ML) prediction of language recovery has typically relied on chronic-phase data unavailable at the acute decision point. Whether acute features predict 12-month outcomes, and whether global severity and connected-speech recovery share substrates in an ML framework, is untested. We studied 73 patients with acute left-hemisphere ischemic stroke and aphasia (mean 2.8 days post-onset). Two 12-month outcomes were defined: aphasia resolution (Western Aphasia Battery-Revised Aphasia Quotient [WAB-AQ] [&ge;]93.8) and discourse normalization (Modern Cookie Theft content units [&ge;]22.1; N=61). Four ML algorithms were trained on four hierarchical feature sets (clinical, volumetric, anatomical, network-disconnection) using nested cross-validation and SHapley Additive exPlanations (SHAP) stability analysis. Acute WAB-AQ dominated (mean |SHAP| = 13.60, ~20x the next feature). For aphasia resolution, random forest achieved F1 = 0.874 (95% CI, 0.800-0.941), Pearson r = 0.827, mean absolute error (MAE) = 7.26 WAB-AQ points; clinical features alone achieved F1 = 0.851. For discourse, support vector regression achieved F1 = 0.725 (95% CI 0.593-0.831), r = 0.617, MAE = 8.96 content units. Three predictors were shared (acute WAB-AQ, lesion volume, left pars triangularis); ventral-stream tracts were linked to aphasia resolution, whereas interhemispheric and prefrontal connectivity were linked to discourse. Both models overpredicted severe chronic outcomes. Acute-phase ML forecasts 12-month aphasia resolution accurately and discourse more modestly. Clinical features carry most predictive variance; acute imaging reveals shared and outcome-specific substrates mapping onto dual-stream architecture, supporting early stratification for rehabilitation and prognostic trial enrichment.

Despite growing evidence for glial involvement in Parkinsons disease, oligodendrocyte dysfunction remains poorly defined. To address this gap, we compared single-cell RNA sequencing from a mouse model of -synuclein aggregation pathology with fresh human brain tissue from deep brain stimulation surgery to build a cross-species framework of disease progression. In total, we profiled over 200,000 cortical transcriptomes, including 55,000 oligodendrocytes. Early disease in mice was characterized by inflammatory activation, while advanced stages in both species converged on metabolic dysfunction, including impaired ribosomal output, chaperone stress responses, ubiquitination deficits, and lysosomal perturbation. In patients, APLP1 was upregulated and correlated with clinical disease progression and increased levodopa demand, linking -synuclein spread in oligodendrocytes to disease severity. APP and CNTN pathways emerged as key signalling axes, with CNTN reflecting weakened reparative communication and reduced resilience. Together, these findings define oligodendrocyte subtype dynamics as shared and clinically relevant features of PD progression.

Objective: To determine whether absolute ictal energy on intracranial EEG identifies brain regions whose epileptogenic involvement is attenuated under existing baseline-normalized, dynamic-systems, and event-based frameworks. Approach: Intracranial EEG from 56 patients (five centers; 21 SEEG, 35 ECoG) was analyzed using the Teager-Kaiser Energy Operator computed as z-scored and raw envelopes; energy-dominant network regions (EDNRs) were defined as electrodes whose raw-energy rank exceeded their z-score rank by at least 2 positions. Hilbert decomposition characterized instantaneous amplitude and frequency. Main results: EDNRs were identified in 51 of 56 patients (91%; mean 3.4). Hilbert decomposition revealed elevated baseline amplitude in EDNRs relative to both non-involved regions (p < 0.001) and potential seizure onset zones (PSOZs, the top-ranked electrodes under both metrics; p = 0.029), with EDNRs participating in seizure-frequency dynamics comparable to PSOZs (mean ictal frequency shift +3.7 versus +4.1 Hz). EDNR detectability correlated directly with electrode count (Spearman r = 0.899, p < 0.001) without plateau. Significance: Absolute ictal energy identifies an epileptogenic network component with elevated baseline amplitude attenuated under baseline-normalized metrics. The dual-metric framework defines a complementary energy-based axis and establishes the second layer of a two-layer approach with seizure onset and propagation mapping as the first layer. EDNR detectability scales with electrode count, directly relevant to SEEG implantation strategy and to network-level inferences from heterogeneously covered cohorts.

Adaptive deep brain stimulation (aDBS) of the subthalamic nucleus (STN) ameliorates motor symptoms in advanced Parkinson's disease (PD) by modulating stimulation in real time using neural signals linked to motor symptoms. Whether these signals also reflect ongoing behavior in naturalistic settings remains unknown. We recorded bilateral STN local field potentials from eight PD patients undergoing aDBS during live-streamed sports viewing and show that low-frequency dynamics encode behavioral engagement across multiple timescales. Engaged viewing increased activity in the stimulation-targeted frequency band relative to control conditions. At a finer timescale, moment-to-moment engagement modulated rapid fluctuations in left STN activity with amplitude maxima and minima time-locked to salient in-match events. These findings reveal that STN activity dynamically reflects real-world behavioral states and establish a foundation for behaviorally informed neuromodulation strategies.

BACKGROUND: Dementia with Lewy bodies shares clinical and pathological features with both Parkinson's disease and Alzheimer's disease, but the local biological factors that render specific cortical regions vulnerable to atrophy remain poorly defined. In particular, it is unclear whether cortical thinning in dementia with Lewy bodies reflects generic neurodegenerative mechanisms, processes shared with Parkinson's disease and Alzheimer's disease, or dementia with Lewy bodies-specific molecular and network susceptibilities. METHODS: A total of 89 patients with dementia with Lewy bodies and 89 matched controls underwent T1-weighted brain MRI. Scans were processed to generate surface-based cortical thickness maps. Regional cortical thickness estimates, after slice-by-slice manual correction, were mapped to gene expression data from healthy postmortem human brains to identify transcriptomic signatures associated with decreased thickness in dementia with Lewy bodies. We assessed whether genes whose expression was increased with regional thinning converged onto established Parkinson's disease- and Alzheimer's disease-related pathways and isolated genes uniquely implicated in dementia with Lewy bodies. Spatial annotation mapping was then used to test whether patterns of cortical thinning overlapped with in vivo neurotransmitter system distributions and whether the observed thickness pattern was constrained by large-scale structural connectivity, consistent with a network-based propagation process. RESULTS: Cortical thinning predominated in regions that, in the healthy brain, show higher expression of genes involved in mitochondrial function and synaptic transmission. The transcriptomic profile associated with thinning significantly overlapped with genes belonging to Parkinson's disease and Alzheimer's disease pathways, supporting shared pathogenic mechanisms across Lewy body and Alzheimer-type neurodegeneration. However, 90 genes associated with cortical thinning did not overlap with Parkinson's disease or Alzheimer's disease pathways and were enriched for GABAergic signalling. Spatial mapping analyses showed that regions with greatest thickness reductions colocalized with GABAA, serotoninergic 5-HT1A, 5-HT1B, 5-HT4, and dopaminergic D2 receptor distributions, and that the thickness pattern followed structural connectivity. CONCLUSIONS: MRI-derived cortical thickness changes in dementia with Lewy bodies reflect selective molecular and network vulnerabilities rather than a non-specific degenerative process. Mitochondrial and synaptic genes, together with a distinct GABAergic association and connectivity constraints, delineate mechanisms explaining why some cortical territories are more affected in dementia with Lewy bodies.

Wolfram syndrome (WFS) is characterized by youth-onset insulin-dependent diabetes and neurological deficits. Brain white matter deficiency has been reported, but its trajectory remains unclear. Applying diffusion basis spectrum imaging models longitudinally in 29 individuals with WFS (baseline ages, 5.2 to 25.8 years; maximum 7 visits) and 52 matched controls, we found that WFS is associated with microstructural alterations suggesting diminished axonal integrity, myelin content, and cellularity. These changes were present and stable early in the disease progression in visual and auditory-related regions, whereas abnormalities in the corpus callosum appeared later in adolescence and adulthood. Our results support developmental hypomyelination as a neurophenotype of WFS.

The mechanisms that drive myelin damage as seen in demyelinating disorders such as multiple sclerosis remain incompletely understood. Much of our current knowledge is derived from animal models, but interspecies differences limit their relevance in the context of human pathology and could explain why various promising preclinical therapies failed during clinical translation. Human post-mortem organotypic brain slice cultures provide a unique platform to study human myelin biology, as they preserve genetic, cytoarchitectural, pathological and species-specific context. Here, we evaluated myelin integrity in a human post-mortem brain organotypic slice culture model and experimentally induce focal myelin damage. Human post-mortem organotypic slices cultures retain key features throughout the culturing period, but exhibit gradual cellular and myelin loss over time. Myelin fibres within the white matter remain detectable and present preserved structural and chemical integrity up to 13 days in vitro, indicated by the conserved paranodal and nodal organization and stable myelin spectroscopic signature. Delivery of lysophosphatidylcholine using cryogel scaffolds enables focal drug administration throughout the full depth of the slice with minimal diffusion into surrounding tissue and induces localized demyelination after lysophosphatidylcholine application. Similar focal application of the selective Nav1.6 stimulator {beta}-mammal scorpion toxin Cn2 induces subtle myelin destabilization. Overall, our results demonstrate the suitability of a human post-mortem brain organotypic slice culture model as an adequate platform for studying myelin damage in a human disease context.

-Synuclein nitration is a prominent post-translational modification in Parkinsons disease, but whether nitrated -synuclein merely reflects oxidative stress or actively contributes to pathology remains unclear. Here, we generated and characterized 6G6, an antibody selective for Tyr39-nitrated -synuclein, and tested whether targeting this modified -synuclein species affected pathology in different mouse models of -synuclein aggregation and spread. In two models of -synuclein overexpression targeting medullary vagal neurons, oxidative stress was induced by either exposure to the herbicide paraquat or transgenic heterozygous expression of the Gba1-L444P mutation. Both conditions were characterized by robust -synuclein spreading that was markedly counteracted by 6G6 administration. A third model consisted of an injection of -synuclein fibrils into the striatum of -synuclein-overexpressing mice. In this model, treatment with 6G6 protected against fibril-induced aggregate pathology and ensuing degeneration of nigral dopaminergic neurons. In a pilot human study, CSF levels of Tyr39-nitrated -synuclein were measured and found increased in Parkinson patients as compared to controls. These findings identify Tyr39-nitrated -synuclein as a pathogenic, therapeutically targetable -synuclein species linking oxidative/nitrative stress to PD pathological processes.