Brain

Somatic mosaicism in a fraction of brain cells causes neurodevelopmental disorders, including childhood intractable epilepsy. However, the threshold for somatic mosaicism leading to brain dysfunction is unknown. In this study, we induced various mosaic burdens in mice of focal cortical dysplasia type II (FCD II), featuring mTOR somatic mosaicism and spontaneous behavioral seizures. Mosaic burdens ranged from approximately 1,000 to 40,000 neurons expressing the mTOR mutant in the somatosensory (SSC) or medial prefrontal (PFC) cortex. Surprisingly, just [~]8,000-9,000 neurons expressing the MTOR mutant were sufficient to trigger epileptic seizures. Mutational burden correlated with seizure frequency and onset, with a higher tendency for electrographic inter-ictal spikes and beta- and gamma-frequency oscillations in FCD II mice exceeding the threshold. Moreover, mutation-negative FCD II patients in deep sequencing of their bulky brain tissues revealed somatic mosaicism of mTOR pathway genes as low as 0.07% in resected brain tissues through ultra-deep targeted sequencing (up to 20 million reads). Thus, our study suggests that extremely low levels of somatic mosaicism can contribute to brain dysfunction.

ObjectivePeriventricular Nodular Heterotopia (PVNH) is the most common neuronal heterotopia, frequently resulting in pharmaco-resistant epilepsy. PVNH has a deep location which renders localization of seizure onsets and traditional surgical therapy challenging and of limited success. Here we characterize variables that predict good epilepsy outcomes following surgical intervention using SEEG-informed MRgLITT. MethodsA prospectively compiled surgical epilepsy database from a single high-volume epilepsy referral center was used to identify patients who underwent SEEG evaluation for PVNH and characterize the intervention on outcomes. ResultsThirty-nine patients underwent SEEG-informed MRgLITT. Associated imaging abnormalities-- mesial temporal sclerosis (MTS) or polymicrogyria (PMG) were treated based on SEEG. SEEG-guided MRgLITT of the seizure onset zone (SoZ) in PVNH and associated epileptic tissue was carried out. PVNH and PMG were densely sampled--mean 16.5(SD=2)/209.4(SD=36.9) SEEG probes/recording contacts. A single trajectory was used in 18, two in 13, and three or more in eight patients. Volumetric analyses revealed a high percentage of PVNH SoZ ablation (96.6%, SD=5.3%) in unilateral and bilateral (92.9%, SD=7.2%) cases. Mean follow-up duration was 31.4 months (SD=20.9). Seizure freedom was excellent overall: unilateral PVNH without other imaging abnormalities--80%; PVNH with MTS or PMG--63%; Bilateral PVNH--50%. SoZ ablation percentage significantly impacted surgical outcomes (p<0.001). InterpretationPVNH plays a central role in seizure genesis. MRgLITT represents a transformative technological advance in PVNH-associated epilepsy with seizure control outcomes consistent with those seen in focal lesional epilepsies. In localized unilateral cases and otherwise normal imaging, performing PVNH ablation without invasive recordings may be reasonable.

Essential tremor (ET), the most common movement disorder in adults, presents with involuntary shaking of the arms during postural hold and kinetic tasks linked to dysfunction in the cerebello-thalamo-cortical (CTC) network. Recently, transcutaneous afferent patterned stimulation (TAPS), applied through a wrist-worn device, has emerged as a non-invasive therapy for medication refractory ET. However, its mechanism remains unclear. We hypothesize that TAPS reduces tremor through modulation of the VIM thalamus in the CTC network. Employing refractory ET patients seeking VIM deep brain stimulation (DBS), we quantified clinical tremor improvement following TAPS treatment in a pre-operative setting, followed by intra-operative, microelectrode recording of the contralateral thalamus with concurrent TAPS treatment on and off. After one preoperative session, TAPS significantly reduces upper limb tremor, with asymmetric effect favoring the treated limb and greatest improvement tending to kinetic tremor. The magnitude of TAPS-related tremor reduction demonstrates a positive correlation with the modulation of alpha and beta band LFPs in the VIM. TAPS also modulated spiking activity in the VIM, though it was uncorrelated with the degree of tremor reduction. Of note, TAPS related modulation of LFPs and spiking activity was greatest near the optimal placement location for DBS lead in treating ET. In sum, TAPS likely reduces tremor in ET by modulating the VIM and connected nodes in the cerebello-thalamo-cortical pathway.

Artificial intelligence (AI)-based tools are widely employed, but their use for diagnosis and prognosis of neurological disorders is still evolving. We capitalise on a large-scale, cross-sectional structural MRI dataset of 814 people with epilepsy. We use a recently developed machine-learning algorithm, Subtype and Stage Inference (SuStaIn), to develop a novel data-driven disease taxonomy based on distinct patterns of spatiotemporal progression of brain atrophy. We identify two subtypes common to focal and idiopathic generalised epilepsies, characterised by neocortical-driven or basal ganglia-driven progression, and a third subtype, only detected in focal epilepsies, characterised by hippocampus-driven progression. We corroborate external validity via an independent cohort of 254 people and decode associations between progression subtypes and clinical measures of epilepsy severity. Our findings suggest fundamental processes underlying the progression of epilepsy-related brain atrophy. We deliver a novel MRI- and AI-guided epilepsy taxonomy, which could be used for individualised prognostics and targeted therapeutics.

Focal Cortical Dysplasia Type II (FCDII) is a subtype of cortical malfunction and is the primary cause of drug-resistant epilepsy in children. Although somatic mosaicism and clonal expansion of brain cells have been identified as crucial factors in FCD cases, the overall genetic landscape and clinical implications of FCDII remain largely unclear due to a significant gap in translating genetic data to inform surgical approaches and prognostic evaluations of individual cases. We carried out deep exome sequencing and deep amplicon validation of surgical biopsies and matched blood samples from 14 FCDII patients with confirmed neuropathology. We further performed multiscale pathogenic validations and took advantage of existing single-nucleus RNA sequencing and spatial maps from developing human cortices to explore the functionality of potential pathogenic somatic variants. We identified novel somatic variants in several functional categories, like neurotransmission (TAAR2, GRM6, ZACN), structural regulation (TUBB2A, PLEC, COL18A1), cellular maintenance (IDO2, PARP4, P2RX5), and RNA processing (RBMX), mapping the expression of these genes back to the developing human brain demonstrated significant enrichment in neuronal cell types, especially excitatory neurons, further confirming their contributions in early brain development and phenotypic functions in dysmorphic neurons. Combining these genetic findings with clinical phenotypes, we found brain-specific mosaic variants with very high mosaic fractions (fraction of mosaic cells, MF, up to 99.5% on P2RX5) associated with different clinical phenotypes. FCDIIB, a more severe subtype that contains balloon cells, had higher MFs (>40%) for variants within resectable cortical layers (excitatory neurons in Layers 5 and 6). This allows potentially targeted resection and achieves better clinical outcome (87.5 % with Engel score I). FCDIIA subtype, on the other hand, displayed lower MFs (<5%) with diffuse distribution, and required hemispherectomy, with poor surgical outcomes (Engel score II/III). Our results suggest MF thresholds are high-definition biomarkers of surgical outcome estimate, with MF > 40% predicting viable focal resection and MF < 5% indicating network dysfunction that necessitates broad-spectrum resection. Combining genetic mapping with cellular localization thus offers a coherent solution to precision surgery in FCDII, translating molecular diagnosis to clinical practice.

AO_SCPLOWBSTRACTC_SCPLOWTemporal lobe epilepsy (TLE) is the most common drug-resistant epilepsy in adults. While commonly related to hippocampal pathology, increasing evidence suggests structural changes beyond the mesiotemporal lobe. Functional anomalies and their link to underlying structural alterations, however, remain incompletely understood. We studied 30 drug-resistant TLE patients and 57 healthy controls using multimodal magnetic resonance imaging analyses. We developed a novel framework that parameterizes functional connectivity distance, consolidating functional and geometric properties of macroscale networks. Compared to controls, TLE showed connectivity distance reductions in temporo-insular and prefrontal networks, suggesting topological segregation of functional networks. Our novel approach furthermore allowed for the testing of morphological and microstructural associations, and revealed that functional connectivity contractions occurred independently from TLE-related cortical atrophy but were mediated by microstructural changes in the underlying white matter. All patients underwent a comparable resective surgery after our study and a regularized supervised machine learning paradigm with 5-fold cross-validation demonstrated that patient-specific functional anomalies predicted post-surgical seizure outcome with 74{+/-}8% accuracy, outperforming classifiers operating on clinical and structural imaging features. Our findings suggest connectivity distance contractions as a clinically relevant pathoconnectomic substrate of TLE. Functional topological isolation may represent a microstructurally mediated network mechanism that tilts the balance towards epileptogenesis.

Status epilepticus (SE) has long been linked to neuronal damage in experimental and animal studies, yet direct human evidence remains scarce. The risk of seizure-induced brain injury is central to the definition, urgency, treatment, and prognosis of SE. We studied 2,055 longitudinal MRI scans from 559 individuals, including 33 patients with new-onset refractory SE (NORSE) across multiple centres, to quantify grey matter volume changes during and after SE. We demonstrate a rapid, widespread, and irreversible decline in grey matter volume during NORSE, exceeding normal aging by 80-fold and Alzheimers disease by 20-fold. Fluid biomarkers confirmed marked neurodegeneration during NORSE, correlated with grey matter volume reduction, and returned to low levels after SE. Accelerated atrophy was linked to longer SE duration, poorer long-term outcome, and cryptogenic aetiology. These findings underscore the urgency of treating SE to limit brain damage and provide a framework for evaluating potentially neuroprotective interventions in humans.

Progressive supranuclear palsy (PSP) is a heterogeneous neurodegenerative disease characterised by the accumulation of misfolded 4-repeat tau within neurones and glial cells. There is limited longitudinal data on pathologically confirmed PSP patients with phenotypes other than classical Richardsons syndrome (RS), and the pathomechanisms responsible for the broad variability in clinical phenotype and progression are not well understood. An unresolved question in this context is whether distinct spatiotemporal patterns of tau pathology propagation exist within the clinicopathological spectrum of PSP. We identified 241 consecutive, pathologically confirmed patients with PSP from the Queen Square Brain Bank for Neurological Disorders (2010-2022). Phenotyping was performed based on clinical features present within the first 3 years from symptom onset according to the Movement Disorder Society (MDS) criteria, and specific clinical features and disease milestones were recorded. Genotyping was performed using Illumina NeuroBooster and NeuroChip arrays and MAPT haplotype, APOE genotype, TRIM11 rs564309, and SLC2A13 rs2242367 single nucleotide polymorphism status were collated from imputed data. Tissue sections from eight brain regions, mounted on glass slides, were immunostained for hyperphosphorylated tau and digitised using whole-slide scanning. Forty-one anatomical regions of interest were manually segmented, and total tau pathology burden was quantified using an automated, machine learning-based algorithm. The associations between survival and both clinicogenetic features and regional tau pathology burden were modelled using Cox regression and generalised linear models, respectively, and the Subtype and Stage Inference (SuStaIn) algorithm was used to identify subgroups with distinct progression patterns. We have identified: 1) several clinical predictors of survival in PSP and the relationship between regional tau pathology burden and survival; 2) novel anatomical reference standards for the expected distribution of tau pathology across MDS-defined PSP phenotypes, emphasising region-specific white matter involvement in patients with corticobasal syndrome and speech/language variants; 3) associations linking biological sex, MAPT haplotype, and TDP-43 co-pathology to clinical phenotype and regional tau pathology burden; 4) patterns of covariance in regional tau pathology implicating inter-regional connectivity in tau spreading; and 5) three distinct spatiotemporal patterns of tau pathology progression: one characterised by initial involvement of subcortical grey matter followed by rostral spread to frontal white matter and other cortical regions, and two characterised by early, simultaneous involvement of subcortical grey matter and frontal white matter. Taken together, these results indicate that PSP clinicopathological heterogeneity is mediated by propagation of tau pathology along anatomically connected networks, and via cell- autonomous mechanisms influenced by sex, genetic factors and possibly co-pathology.

ObjectiveWe assessed pre-operative structural brain networks and clinical characteristics of patients with drug resistant temporal lobe epilepsy (TLE) to identify correlates of post-surgical seizure outcome at 1 year and seizure relapses up to 5 years.\n\nMethodsWe retrospectively examined data from 51 TLE patients who underwent anterior temporal lobe resection (ATLR) and 29 healthy controls. For each patient, using the pre-operative structural, diffusion, and post-operative structural MRI, we generated two networks: pre-surgery network and surgically-spared network. The pre-surgery network is the whole-brain network before surgery and the surgically-spared network is a subnetwork of the pre-surgery network which is expected to remain unaffected by surgery and hence present post-operatively. Standardising these networks with respect to controls, we determined the number of abnormal nodes before surgery and expected to remain after surgery. We incorporated these 2 abnormality measures and 13 commonly acquired clinical data from each patient in a robust machine learning framework to estimate patient-specific chances of seizures persisting after surgery.\n\nResultsPatients with more abnormal nodes had lower chance of seizure freedom at 1 year and even if seizure free at 1 year, were more likely to relapse within five years. In the surgically-spared networks of poor outcome patients, the number of abnormal nodes was greater and their locations more widespread than in good outcome patients. We achieved 0.84 {+/-} 0.06 AUC and 0.89 {+/-} 0.09 specificity in detecting unsuccessful seizure outcomes at 1-year. Moreover, the model-predicted likelihood of seizure relapse was significantly correlated with the grade of surgical outcome at year-one and associated with relapses up-to five years post-surgery.\n\nConclusionNode abnormality offers a personalised non-invasive marker, that can be combined with clinical data, to better estimate the chances of seizure freedom at 1 year, and subsequent relapse up to 5 years after ATLR.

ImportanceMesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy subtype and is often refractory to anti-seizure medications. While most MTLE patients do not have pathogenic germline genetic variants, the contribution of post-zygotic (i.e., somatic) variants in the brain is unknown. ObjectiveTo test the association between pathogenic somatic variants in the hippocampus and MTLE. DesignThis case-control genetic association study analyzed the DNA derived from hippocampal tissue of neurosurgically-treated patients with MTLE and age- and sex-matched neurotypical controls. Participants were enrolled from 1988 through 2019 and clinical data was collected retrospectively. Whole-exome and gene-panel sequencing (depth>500X) were used to identify candidate pathogenic somatic variants. A subset of novel variants were functionally evaluated using cellular and molecular assays. SettingLevel 4 epilepsy centers, multi-center study. ParticipantsNon-lesional and lesional (mesial temporal sclerosis, focal cortical dysplasia, and low-grade epilepsy-associated tumors) drug-resistant MTLE patients who underwent anterior medial temporal lobectomy. All patients with available frozen tissue and appropriate consents were included. Control brain tissue was obtained from neurotypical donors at brain banks. ExposuresDrug-resistant MTLE. Main Outcomes and MeasuresPresence and abundance of pathogenic somatic variants in the hippocampus versus the unaffected temporal neocortex. ResultsSamples were obtained from 105 MTLE patients (52 male, 53 female; age: MED [IQR], 32 [26-44]) and 30 neurotypical controls (19 male, 11 female; age: MED [IQR], 37 [18-53]). Eleven pathogenic somatic variants, enriched in the hippocampus relative to the unaffected temporal neocortex (MED [IQR], 1.92 [1.5-2.7] vs 0.3 [0-0.9], p<0.05), were detected in MTLE patients but not in the controls. Ten of these variants were in PTPN11, SOS1, KRAS, BRAF, and NF1, all predicted to constitutively activate Ras/Raf/MAPK signaling. Immunohistochemical studies of variant-positive hippocampal tissue demonstrated increased Erk1/2 phosphorylation, indicative of Ras/Raf/MAPK activation, predominantly in glial cells. Molecular assays showed abnormal liquid-liquid phase separation for the PTPN11 variants as a possible dominant gain-of-function mechanism. Conclusions and RelevanceHippocampal somatic variants, particularly those activating Ras/Raf/MAPK signaling, may contribute to the pathogenesis of sporadic, drug-resistant MTLE. These findings may provide a novel genetic mechanism and highlight new therapeutic targets for this common indication for epilepsy surgery.

ObjectiveThe cognitive profile of juvenile absence epilepsy (JAE) remains uncharacterized. This study aimed to: (i) elucidate the neuropsychological profile of JAE; (ii) identify familial cognitive traits, by investigating unaffected JAE siblings; (iii) determine whether cognitive traits across the idiopathic generalized epilepsy (IGE) spectrum are shared or syndrome-specific, by comparing JAE to JME; and (iv) identify associations between cognitive abilities and clinical characteristics. MethodsWe investigated 123 participants: 23 patients with JAE, 16 unaffected siblings of JAE patients, 45 healthy controls, and 39 patients with JME, who underwent a comprehensive neuropsychological test battery including measures within four cognitive domains: attention/psychomotor speed, language, learning, and executive function. We also correlated clinical measures with cognitive performance data to decode effects of age at onset and duration of epilepsy. ResultsPatients with JAE performed worse than controls across tests of psychomotor speed, language, learning and executive function. Patients and siblings were similarly impaired on language measures of verbal comprehension, phonemic fluency, and semantic fluency compared to controls. Receiver operating characteristic curves indicated successful discrimination of patients with JAE and siblings from controls via linguistic measures. Individuals with JME also presented with multidomain cognitive impairment and had worse response inhibition than those with JAE. Across all patients, those with older age at onset had better performance on psychomotor speed and executive function tests. SignificanceJAE is associated with wide-ranging cognitive difficulties that encompass domains reliant on frontal lobe processing, including language, attention, and executive function. JAE siblings demonstrate shared impairment with patients on linguistic measures, indicative of a familial trait. Executive function subdomains may be differentially affected across the IGE spectrum. Cognitive abilities are detrimentally modulated by an early age at seizure onset. KEY POINTSO_LIJAE presents with multidomain cognitive impairment involving language, attention/ psychomotor speed, executive function, and learning. C_LIO_LIImpaired language is common to people with JAE and their unaffected siblings, suggestive of a familial trait (endophenotype). C_LIO_LIResponse inhibition is worse in JME than JAE, indicating distinct cognitive profiles across the IGE spectrum. C_LIO_LIEarly age at epilepsy onset is associated with worse cognitive performance in JAE and JME. C_LI

Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) is a recently discovered histopathological lesion entity. Approximately half of affected individuals carry a pathogenic brain mosaicism in the X-linked SLC35A2 gene, and all suffer from epilepsy. In this work, we extended the search for genetic alterations of MOGHE by investigating sex chromosome copy number alterations in 29 brain tissue samples from 19 males and 10 females with histopathologically confirmed MOGHE. Twenty individuals carried pathogenic SLC35A2 variants, while no genetic alteration was identified in nine individuals using targeted deep panel sequencing. Interestingly, DNA methylation-derived copy number variation (CNV) plots revealed significant gains of the Y chromosome in 16/19 males (84.2%) and in 5/10 females (50%). These findings were validated by chromogenic and fluorescent in situ hybridisation (ISH), PCR amplification of Y-specific sequences, and microscopic localisation of cells with Y-chromosomal gain in clusters of oligodendroglial hyperplasia. PCR and ISH demonstrated lesion-restricted Y-chromosome gains, absent in the overlying non-lesional neocortex. Together with pathogenic variants in the X-chromosomal SLC35A2 gene, Y-chromosomal sequences detected in phenotypic females and mosaic Y chromosome gains in males provide a genomic correlate for all cases of MOGHE. Based on SLC35A2 mutational status and Y-chromosome copy number changes, we stratified the cohort into three subgroups: SLC35A2-mutant without Y gain (SLC+/Y-, n = 8), SLC35A2-mutant with Y gain (SLC+/Y+, n = 12), and SLC35A2-wild type with Y gain (SLC-/Y+, n = 9). These genetically defined subgroups also differed in their clinical presentation, with individuals from group 2 having the earliest disease onset and the largest lesion volume on MRI. These findings expand the genetic spectrum of epileptogenic cortical malformations and highlight a potentially overlooked role of sex chromosome biology in this focal epilepsy.

When learning to find the most beneficial course of action, the prefrontal cortex guides decisions by comparing estimates of the relative value of the options available. Basic neuroscience studies in animals support the view that the thalamus can regulate this activity within and across the prefrontal cortex. We studied a group of patients (n=37) undergoing unilateral MR guided focused ultrasound for essential tremor, performing the restless bandit, a reward reinforcement learning task, immediately before and after thalamotomy. Thalamotomy significantly impaired the proportion of switch choices during the task without affecting overall performance. This effect was observed when the task was delivered to co-incide with maximal vasogenic thalamic oedema but not in a control group tested on the same day of their treatment. A reinforcement learning model fitted to the patients choices replicated the effect of thalamotomy when the model increased exploitation of the bandits learnt value estimate. This shift in the explore-exploit trade-off, manifesting as reduced choice flexibility, co-varied with the pattern of post-operative oedema extension into mediodorsal nucleus. These findings confirm a causal role of the thalamus and specifically the mediodorsal nucleus, in regulating the extent to which value estimates are used to guide decisions and learning from reward.

Focal cortical dysplasias (FCDs) are malformations of cortical development associated with drug-resistant focal epilepsy. We analysed surgical tissue from 28 consecutive cases recruited from adult and pediatric epilepsy surgery programs. We performed high-depth sequencing of lesional tissue, validated somatic variants using droplet digital PCR, and investigated genotype-phenotype correlations. A pathogenic or likely pathogenic variant was detected in 71% (n=20/28) of cases. Of these, six cases with FCDIIa or FCDIIb had germline variants in NPRL3 (n=4) or DEPDC5 (n=2). Somatic variants were identified in 50% (n=14/28) of cases. The genetic yield for FCDIIb was 85% of cases having a pathogenic mTOR pathway variant detected (n=12/14), and for FCDIIa 66% (n=6/9). This was achieved through high depth sequencing approaches that allowed detection of somatic variants with very low (down to 0.4%) variant allele fractions (VAFs). No pathogenic variants were detected in 3 cases with FCDI. 70% (n=18/26) of the cases with [&ge;]12 months follow up experienced a favourable seizure outcome (Engel 1-2) following surgery. Of note, n=10 patients required repeat surgery to resect residual dysplasia. Determining a genetic diagnosis reveals aetiology and paves the way to precision therapies that may benefit those with FCD who do not respond to current treaments.

Essential tremor is a disabling and highly prevalent movement disorder. Deep brain stimulation of the ventral intermediate nucleus provides substantial symptom relief; however, many patients experience diminishing benefit over time. The underlying causes range from natural disease progression and worsening ataxia to, less commonly, habituation or tolerance. We performed a retrospective longitudinal analysis of 86 individuals with essential tremor who underwent unilateral ventral intermediate nucleus deep brain stimulation and had three or more follow-up visits (mean follow-up duration 5.2 years; maximum 15.4 years; >470 total visits). This approach provided a unique opportunity to assess contralateral limbs in addition to long term effects of stimulation. Tremor severity was quantified using the Fahn-Tolosa-Marin Tremor Rating Scale total score and subscores, with particular focus on contralateral and ipsilateral upper-extremity tremor. Longitudinal trajectories were assessed across limbs and stimulation states at both the population and individual levels. Comparison of tremor between the non-stimulated side and the stimulated side were conducted in the stimulation off condition and served as an intrinsic control to disentangle natural disease progression from tolerance to deep brain stimulation. Contralateral and ipsilateral upper-extremity tremor assessed with stimulation off showed slow, bilateral progression over time. Tremor in the ipsilateral limb followed the same trajectory as the unstimulated contralateral limb, consistent with natural disease progression. Stimulation exerted no measurable cross-hemispheric influence, as ipsilateral tremor progressed similarly with stimulation on and off. During chronic stimulation, tremor progression in the stimulated limb closely tracked that of the ipsilateral limb, with most patients showing no meaningful difference between sides. Progression in the stimulated limb was also similar during stimulation on and off conditions, suggesting that habituation, stimulation-induced maladaptation, or deep brain stimulation-accelerated decline was not observed in this cohort. Long-term symptoms of worsening tremor in essential tremor patients with unilateral ventral intermediate nucleus deep brain stimulation were primarily driven by natural disease progression, not by deep brain stimulation-related causes. While tolerance may rarely emerge, the dominant effect of worsening is disease progression. In this cohort, the stimulation programming parameters were individually optimised over time, likely minimizing the influence of suboptimal programming or stimulation-related decline. These findings underscore the importance of extended comprehensive outcome assessment in essential tremor, incorporating objective measures to distinguish disease progression from treatment-related effects. Follow-up studies are needed to better characterise the relative contributions of tremor and ataxia to long-term disability.

Although the thalamus is supposed to be involved in reinforcement-based decision-making, there is no direct evidence regarding the involvement of this subcortical structure in humans. To fill this gap, we leveraged rare intra-thalamic electrophysiological recordings in patients and found that temporally structured thalamic oscillations encode key learning signals. Our findings also provide neural insight into the computational mechanisms of action inhibition in punishment avoidance learning.

The central pathology causing idiopathic focal dystonia remains unclear, limiting effective treatment targets. The recently identified somato-cognitive action network (SCAN) with its role in coordinating physiologic processes and coarse movements has been implicated in dystonia dysfunction. SCAN is thought to interface between the phylogenetically newer primary motor regions that control fine movements and the cingulo-opercular network (CON) that putatively conveys cognitive intentions for action. We hypothesized that the effector-agnostic nature of SCAN may constitute a central pathology shared across focal dystonia subtypes affecting different body parts. Additionally, the effector-specific areas in the primary sensorimotor cortex may show distinct functional changes depending on the dystonic body region. We collected functional MRI from patients with either of two subtypes of focal dystonia (laryngeal dystonia or LD, N=24, and focal hand dystonia or FHD, N=18) and healthy control participants (N=21). Regions of interest were selected based on prior work that suggested dystonia-related abnormality within the basal-ganglia-thalamo-cortical and cerebello-thalamo-cortical sensorimotor circuitries. We investigated if focal dystonia is associated with resting-state functional connectivity changes 1) between SCAN and other cortical regions (effector-specific areas and CON), 2) between cortical and non-cortical regions, or 3) between non-cortical (subcortical and cerebellar) regions. Cortical regions were individualized based on resting-state data. Separately, individualized hand and mouth/larynx regions were also generated from task-based MRI (finger-tapping and phonation, respectively) for comparison. There was a shared interaction effect in both focal dystonia subtypes (p=0.048 for LD, p=0.017 for FHD) compared to controls, which was driven by SCANs higher functional connectivity to task-derived mouth/larynx region and concomitantly lower connectivity to CON. This dystonia-dependent interaction was not observed with the resting-state mouth/larynx region. No significant resting-state functional changes were observed involving subcortical and cerebellar regions when LD and FHD were modeled as independent groups. However, exploratory analysis combining LD and FHD suggested a dystonia-dependent asynchronization between SCAN and sensorimotor cerebellum (p=0.010) that may indicate a pathological rather than compensatory process. For the first time, our study systematically tested circuitry-based functional connectivity changes in two focal dystonias. Our results show that SCAN is uniquely associated with dystonia dysfunction beyond the dystonic effector regions, potentially offering insights on pathophysiology and treatments.

AO_SCPLOWBSTRACTC_SCPLOWTemporal lobe epilepsy is the most common drug-resistant epilepsy, with surgical resection offering the primary path to seizure freedom. Despite standardized approaches, a substantial proportion of patients experience seizure recurrence, and the neurobiological substrates underlying these divergent outcomes remain unclear. We applied an individualized normative modeling framework to multimodal preoperative MRI data in a group that subsequently underwent surgical resection, to characterize patient-specific structural deviations and identify disease epicenters. Patients who became seizure-free exhibited spatially coherent abnormalities localized to the hippocampus and ipsilateral association regions, anchored in agranular limbic territories and enriched for genes linked to calcium-dependent signaling. Non-seizure-free patients, on the other hand, showed a more heterogeneous and distributed pattern of deviations, consistent with a "temporal-plus" network organization, and broader neuromodulatory dysregulation. Crucially, overlap between resected tissue and network-defined epicenters was closely associated with seizure freedom, independent of total resection volume. These findings provide a multiscale framework for precision surgical planning, shifting the focus from standardized tissue removal to targeted disconnection of patient-specific pathological hubs.

Brain inflammation is a key feature of frontotemporal dementia (FTD). TSPO PET is widely used as an in vivo proxy for neuroinflammation, but whether the elevated signal reflects microglial, astrocytic, or vascular pathology is controversial. We paired ante mortem [11C]PK11195 TSPO PET with post mortem neuropathology in 10 individuals with FTD (5 FTLD-tau, 5 FTLD-TDP) and 5 controls, combining CD68 immunohistochemistry across 17 regions, multiplex immunofluorescence pairing TSPO with microglial/macrophagic (IBA1, CD68), astrocytic (GFAP) and endothelial (CD31) markers, and three-dimensional single-cell reconstruction. CD68 burden was elevated in FTD, concentrated in white matter, and correlated with regional TSPO PET binding across pathologies ({beta} = 8.40, P < 0.001). Only the CD68-TSPO co-localised fraction tracked the PET signal, with no TSPO upregulation per-cell. The elevated TSPO PET signal in FTD likely reflects an increased burden of lysosome-enriched CD68+ microglia, supporting TSPO PET as a microglial-burden biomarker in both FTLD-tau and FTLD-TDP.

Structured AbstractO_ST_ABSImportanceC_ST_ABSDespite immunotherapy, most patients with anti-leucine-rich, glioma-inactivated 1 encephalitis (LGI1-E) develop long-term cognitive deficits that persist for years after peak illness. However, the structural brain changes that underlie these deficits remain poorly understood. ObjectiveTo study the relationship between cognitive outcomes and white matter (WM) networks in LGI1-E. DesignCross-sectional study. SettingGerman university center (Charite - Universitatsmedizin Berlin). Participants25 patients with LGI1-E (19/25 male [76%], mean age: 63 {+/-} 12 years) and 25 age- and sex-matched healthy controls (HC), recruited between January 2013 and April 2019. Main Outcomes and MeasuresClinical assessments including the modified Rankin Scale (mRS) and Clinical Assessment Scale in Autoimmune Encephalitis (CASE); comprehensive cognitive testing; WM tractography using diffusion-weighted MRI. ResultsAll patients had received first-line immunotherapy, and two-thirds underwent second-line immunotherapy. Patients showed a significant reduction in mRS scores from peak illness to post-acute follow-up (z = -3.8, p < 0.001, n = 20), with 85% presenting "good" functional outcomes (post-acute mRS [&le;] 2), paralleled by a significant reduction in CASE scores (z = -3.5, p < 0.001, n = 20). Despite this overall improvement, however, cognitive symptoms were highly prevalent at peak illness (95% of patients affected) and strongly persisted into the post-acute disease stage (85% affected). Neuroimaging at post-acute follow-up (median: 12 months from onset) revealed that LGI1-E is characterized by (i) significantly reduced whole-brain structural connectivity (t = -2.16, p = 0.036, d = -0.61), (ii) a cortico-subcortical hypoconnectivity cluster that strongly affects the hippocampus but also severely impacts extra-limbic brain systems, (iii) systematic limbic and extra-limbic decreases in node degree -- a graph-theoretical measure of overall connectedness, and (iv) a "topological reorganization" of structural brain networks, marked by a bidirectional shift in the relative importance of individual brain regions in the network. Importantly, the extent of this network reorganization was significantly related to persistent cognitive deficits in the domains of verbal memory (r = -0.57, p = 0.007, n = 21), attention (r = -0.47, p = 0.030, n = 21), and executive functions (r = -0.60, p = 0.010, n = 17). Conclusion and RelevanceThis study characterizes LGI1-E as a network disease that affects both limbic and extra-limbic brain systems and shows that a reorganization of WM networks is linked to multi-domain cognitive deficits in the post-acute disease stage - despite immunotherapy and good overall recovery. These findings highlight the need for extended treatment strategies to improve long-term cognitive outcomes and propose a sensitive new neuroimaging marker to include in prospective clinical trials. Key PointsO_ST_ABSQuestionC_ST_ABSWhat structural brain changes underlie the persistent cognitive deficits observed in patients with anti-leucine-rich, glioma-inactivated 1 encephalitis (LGI1-E)? FindingsThis cross-sectional study shows that LGI1-E is characterized by a structural reorganization of white matter networks that affects both limbic and extra-limbic brain systems and correlates with persistent deficits in verbal memory, attention, and executive functions at post-acute follow-up - despite immunotherapy and good overall clinical recovery. MeaningThis study characterizes LGI1-E as a network disease -beyond focal damage to the limbic system- and shows that persistent cognitive deficits relate to immunotherapy-resistant changes in structural brain networks, highlighting the need for extended treatment strategies to improve long-term cognitive outcomes.