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Disorders of consciousness (DoC) following severe brain injury represent a formidable clinical challenge, with limited therapeutic options for patients in prolonged unresponsive or minimally conscious states. Deep brain stimulation (DBS) of the central thalamus has re-emerged as a pivotal strategy to restore arousal and functional communication. In this review, we integrate systems neuroscience with clinical evidence to delineate the transition of DBS from an experimental intervention toward circuit-guided precision medicine. We first articulate the mesocircuit hypothesis, positing that DBS acts not by local excitation alone, but by reversing a circuit-level collapse driven by striatal deafferentation and excessive pallidal inhibition. Synthesizing recent clinical data, we highlight an emerging reinterpretation of targeting, in which efficacy may depend less on named anatomical nuclei than on the recruitment of preserved arousal conduits and fronto-striatal projections-a hypothesis supported by connectomic analyses but awaiting direct causal validation. Furthermore, we discuss the redefinition of patient selection through Cognitive Motor Dissociation (CMD) and the evolution of stimulation paradigms toward biomimetic, adaptive control policies (e.g., 40-60 Hz state-dependent modulation). Finally, we address the ethical framework of "consent under uncertainty" essential for responsible translation. We conclude that while heterogeneity remains a hurdle, combining connectome-based targeting with sensing-enabled technologies offers a viable roadmap to validate DBS as a standard of care for carefully selected patients.

Adult-onset Alexander disease (AOAD) is a genetic neurodegenerative disease due to mutations in GFAP, often causing medullary degeneration. (i) In a kindred of three siblings with AOAD to compare and correlate clinical progression with MRI quantified medullary atrophic changes. (ii) To demonstrate how AOAD risks under-diagnosis in an older patient population. We retrospectively compared three siblings in their fifth and sixth decade from a family of Irish heritage with AOAD with respect to clinical phenotype, radiological measurements and delay to diagnosis. Three siblings (∼60 years of age) harboring a relatively rare GFAP variant p.Ser385Cys presented insidiously with variable degree of motor, cerebellar and autonomic dysfunction. MR imaging demonstrated differences in volume and AP diameter of the medulla oblongata among the siblings, approximately correlating with severity of symptom presentation and showing progression over time. Insidious onset of symptoms led to delay in diagnosis. Serial and detailed MRI surveillance of lower brainstem and upper cervical spine is a valuable biomarker, that can correlate with symptom severity and progression.

Arousal is essential for survival, and maladaptive arousal processing leads to an inability to focus, anxiety-like behavior, and dysregulated affective states. Norepinephrine (NE) is known to regulate anxiety, arousal, and learning through locus coeruleus (LC) projections throughout the brain. Evidence for co-release of the NE precursor and neurotransmitter dopamine (DA) from LC neurons has been accumulating for years, yet definitive measures of DA release across regions, stimulus paradigms, and behaviors associated with the LC-NE system remain controversial. Here, we identified the physiological and behavioral properties that evoke DA release from LC axon terminals. Using concomitant approaches, we inhibited the LC and ventral tegmental area (VTA) to selectively isolate the contributions of LC-derived DA release. Together these findings establish the constraints by which LC neurons release DA in a modality-dependent manner.

To examine the impact of the operated brain region and clinical-surgical variables on intellectual performance in children and adolescents undergoing neurosurgery for pharmacoresistant epilepsy. Fifty-one participants were classified according to surgical site: temporal lobe (TL; n = 23), frontal lobe (FL; n = 9), posterior cortex (PC; n = 9), and hemispherotomy (H; n = 10). Neuropsychological assessment was performed using age-appropriate versions of the Wechsler Intelligence Scales (Wechsler Intelligence Scale for Children/Wechsler Adult Intelligence Scale [WISC/WAIS]). Bayesian linear mixed models compared intelligence quotients and scale indices across three time points: preoperative (T0), 6-month postoperative (T1), and 24-month postoperative (T2). For each outcome, two models were fitted: a simple model and a multiple model adjusted for seizure frequency and epilepsy duration. Estimates were derived from posterior distributions with 95% credibility intervals. Analyses were conducted in R using MCMC sampling, with convergence assessed by trace plots and the Gelman-Rubin diagnostic. A change of ≥10 points was considered a clinically relevant improvement, whereas a decrease of ≥5 points indicated a relevant decline in longitudinal within-group comparisons. Results reflect group-level trajectories rather than individual outcomes. At T1, the H group showed declines in Full-Scale Intelligence Quotient (FSIQ), Verbal Comprehension Index (VCI), Perceptual Organization Index (POI), Working Memory Index (WMI), and Processing Speed Index (PSI). At T2, the FSIQ, POI, and WMI returned to near baseline, whereas VCI and PSI remained reduced. The TL group showed declines in VCI, WMI, and PSI at T1, with a persistent reduction in VCI at T2. FL and PC groups maintained intelligence indices close to baseline at both postoperative assessments. Epilepsy surgery preserved intellectual functioning, particularly in FL and PC procedures. However, persistent VCI decline in H and TL groups suggests effects on verbal abilities associated with temporal lobe involvement. Sustained PSI reduction after hemispherotomy may indicate decreased cognitive efficiency and slower information processing.

Over-generalization of negative memory is common in psychiatric disorders, including depression and anxiety. Here, we present a protocol to dissociate memory generalization from memory strengthening and induce lasting stress-related behavioral alterations using contextual fear conditioning in adult mice. We describe the steps for repeated conditioning in identical or distinct contexts, followed by memory testing and behavioral assays of stress-related phenotypes. This protocol enables the investigation of the behavioral and biological mechanisms underlying pathological memory generalization and its consequences. For complete details on the use and execution of this protocol, please refer to Cheng et al.1.

The COVID-19 pandemic disproportionately impacted historically marginalized populations, especially low-income Latinx and Indigenous Mexican immigrant communities in the United States. These groups face persistent structural and social obstacles to health, such as limited healthcare access, language barriers, and concern regarding immigration status, that contribute to institutional mistrust, health misinformation, and reduced COVID-19 vaccine uptake, deepening existing public health disparities. This mixed-methods study utilized a community-based participatory research (CBPR) approach to address vaccine hesitancy among Latinx and Indigenous Mexican farmworkers in the Eastern Coachella Valley, a rural desert region in Inland Southern California. A toolkit, featuring a mural, mini-documentary, and community talks, was developed and implemented to promote COVID-19 vaccination. Pretest and posttest surveys were conducted with 94 community members and three focus groups with 39 total participants provided qualitative feedback on the intervention. The intervention reduced belief in COVID-19 misinformation and increased trust in institutions (p&#x2009;<&#x2009;0.001, p&#x2009;<&#x2009;0.001). However, no significant improvements were found in reducing fear and insecurity surrounding vaccination or English-language confidence (p&#x2009;=&#x2009;0.557, p&#x2009;=&#x2009;0.292). Focus group feedback highlighted structural inequalities as contributors to mistrust in healthcare and vaccine hesitancy. Community-based interventions tailored to cultural and linguistic contexts show promise in reducing misinformation and improving institutional trust in marginalized communities. However, deeper structural inequities, such as racism and economic instability, must be addressed to reduce vaccine hesitancy in vulnerable and marginalized communities.

Cladribine tablets are an oral immune reconstitution therapy with demonstrated efficacy and durable disease control in relapsing-remitting multiple sclerosis (RRMS). While global evidence supports their use, region-specific guidance adapted to healthcare variability, access constraints, and real-world practice in North-West Africa (NWA) remains limited. To develop expert-based, region-specific consensus recommendations on the optimal use of cladribine tablets in RRMS in the NWA region. A modified Delphi methodology was conducted during a face-to-face advisory board meeting in May 2025 in Tunisia. Senior neurologists with expertise in multiple sclerosis from across NWA reviewed available evidence, discussed key clinical questions, and voted on consensus statements addressing treatment positioning, early use, switching strategies, long-term management, safety, and special populations. Consensus was predefined as agreement by &#x2265;75% of voting experts. All consensus statements met the predefined threshold after discussion and refinement, achieving high to unanimous agreement. Experts endorsed cladribine tablets as a high-efficacy option for treatment-na&#xef;ve patients with moderate-to-high disease activity and as a switch option following suboptimal response to platform therapies and in selected patients previously treated with high-efficacy therapies. Benefits include early initiation, durable disease control without continuous immunosuppression, and suitability for patients with limited access to hospital-based care. Expert consensus recommendations also addressed long-term management beyond Year 4, retreatment strategies, safety monitoring, pregnancy planning, and use in older patients, recognizing that some areas are supported mainly by emerging real-world evidence and expert clinical experience. This Delphi consensus provides practical, region-specific guidance to optimize the use of cladribine tablets in RRMS across NWA, aiming to harmonize treatment practices and improve long-term outcomes.

GNE myopathy (GNEM) is a rare neuromuscular disorder caused by pathogenic variants in the GNE gene and traditionally associated with impaired sialic acid biosynthesis. In a previous untargeted lipidomic study, we identified a lipid feature significantly enriched in the serum of patients with GNE myopathy compared with healthy controls. In the present work, we aimed to determine the structural identity of this disease-associated feature and to establish a robust analytical strategy for its quantitative assessment. Analysis of the mass spectrometric data pointed to bis(monoacylglycero)phosphate 18:1_18:1 or BMP (18:1_18:1) as a plausible candidate, based on the consistency of the nominal mass and fragmentation pattern with this lipid class. In the present work, we therefore aimed to determine the structural identity of this disease-associated feature and to establish a robust analytical strategy for quantitative assessment. We therefore performed the chemical synthesis of BMP (18:1_18:1) and, based on its MS/MS fragmentation pattern, developed a selective tandem mass spectrometry method for its quantification. Levels of BMP (18:1_18:1) were measured in serum samples from patients with GNE myopathy, healthy controls, and patients with myotonic dystrophy type 2 (DM2) as a disease comparison cohort. BMP levels were significantly increased in the serum of patients with GNE myopathy compared with both healthy controls and DM2 patients. Together, these findings define a previously unrecognized circulating lipid alteration in GNE myopathy and provide new insight into disease-associated lipid dysregulation.

Non-small cell lung cancer (NSCLC) is one of the deadliest malignancies, which is mostly caused by activating mutations in the epidermal growth factor receptor (EGFR). While EGFR tyrosine kinase inhibitors (TKIs) of the first, second, and third generations have improved patient outcomes, long-term efficacy is often compromised by acquired resistance caused by mutations like T790&#x202f;M and C797S. The discovery and promise of small-molecule allosteric modulators, including both reversible allosteric, ATP dual targeting inhibitors and targeted protein degraders (PROTACs) that employ allosteric binding for mutant-selective EGFR degradation that target mutant EGFR in NSCLC treatment are thoroughly evaluated in this study. We detail advances in design strategies and structure-activity relationship (SAR) studies of various compounds, including marine-derived Clathrin analogues, and a spectrum of heterocyclic derivatives catalogued as C1-C19. The integration of in silico docking, molecular dynamics simulations, and in vitro/in vivo evaluations reveals that modifications to functional groups, heterocyclic scaffolds, and linker structures are critical for enhancing binding affinity and selectivity toward the allosteric site, while acknowledging that the proposed SAR trends and pharmacophore model require further experimental validation through co-crystallization and systematic analogue studies across different chemotypes. Notably, compounds C7, C8, C10, and C14 exhibit excellent superimposition with the benchmark allosteric inhibitor JBJ-09-063, underscoring their robust activity profiles and potential to overcome ATP-site mediated resistance. By bridging both the ATP and allosteric sites, these molecules offer a novel dual-targeting approach to counteract the heterogeneity of resistance mechanisms. Overall, the gathered data support the promise of allosteric modulators as a next-generation therapeutic strategy in EGFR-mutant NSCLC, and a 3-Point pharmacophoric framework is presented to guide future drug design aimed at maximising potency while limiting toxicity.

Both clinical and experimental evidence support the notion that traumatic brain injury (TBI) through the top-down dysregulation of gut-microbiota-brain axis (GMBA) profoundly affects the function and structural integrity of the gut, and that this GMBA dysregulation, in turn may contribute to certain chronic sequelae of TBI, possibly including epilepsy. It is therefore plausible that early post-TBI GMBA perturbations may serve as a source of susceptibility/risk PTE biomarkers derived from TBI-induced intestinal epithelial injury, disruption of intestinal barrier and altered composition and function of gut microbiome. The review particularly focuses on disentangling general biomarkers of TBI-induced intestinal dysfunction from those specifically associated with PTE risk. Although the subject in question is still in its nascent stage, several biomarkers appear promising, such as plasma intestinal fatty acid binding protein, plasma lipopolysaccharide and fecal profiles of gut microbes and their metabolic products, short chain fatty acids. It is concluded that while GMBA-derived biomarkers may not be able alone to stratify PTE risk with high certainty, they may enhance the performance of multimodal predictive models when integrated with other biomarkers in development.

Cerebral ischemia-reperfusion (IR) injury is a major cause of brain damage following stroke, in which excessive reactive oxygen species play a critical role. Therefore, the development of novel therapeutic agents targeting oxidative stress is highly desirable. We investigated the protective effects of an orally administered silicon (Si)-based agent that continuously generates hydrogen in the intestinal tract, thereby acting as a selective antioxidant, in a rat model of middle cerebral artery occlusion and reperfusion. Rats fed an Si-based agent-containing diet showed trends toward improved neurological symptom scores, reduced asymmetric behavior in the elevated body swing test, and a higher survival rate compared with control rats. Furthermore, infarct size was significantly reduced in the Si group. Analysis of plasma derivatives of reactive oxygen metabolites revealed a significant reduction in systemic oxidative stress in the Si group. These results suggest that the Si-based agent exerts protective effects against cerebral IR injury, at least in part through its antioxidant effects, warranting further preclinical investigation.

Intracerebral hemorrhage (ICH) causes high morbidity and mortality, with neurotoxic inflammation driven by infiltrating monocytes. This study is an in-depth longitudinal examination of the immune response during the first week of ICH in the presence and absence of the immunomodulatory drug BAF312 (Siponimod). We performed single-cell RNA sequencing on peripheral blood samples taken 1, 3, and 7&#x2009;days post-ICH in patients treated with BAF312 (5 patients) or placebo (2 patients). The correlation of gene expression with time, drug treatment, measures of ICH severity, and clinical outcome was examined. Results were validated by comparison with previous studies and measurement of plasma cytokine concentration. A broad peripheral inflammatory response involving both lymphoid and myeloid cells peaked at day 3 post ICH. BAF312 markedly reduced peripheral blood T and B lymphocyte numbers by day 3. BAF312 also impacted the myeloid response, suppressing TNF signaling in classical and nonclassical monocytes. Multiple cytokine signaling pathways were decreased, though BAF312 did not impact plasma cytokine or chemokine concentrations. Surprisingly, increased monocyte TNF signaling was associated with better 90-day clinical outcome. These findings demonstrate broad peripheral leukocyte activation after ICH and suggest that during ICH, BAF312 suppresses both lymphoid and myeloid responses. The positive association of monocyte TNF signaling with better outcome points to the positive role of monocytes during the subacute stage of ICH and supports a complex role of monocytes in this disease. Larger studies will determine the extent to which these findings apply beyond the small cohort examined here.

Whether arithmetic and language rely on shared or distinct processing mechanisms remains unresolved, particularly at the level of semantic and structural anomaly processing. The present EEG study addressed this question by comparing three written expression types: symbolic arithmetic, verbal arithmetic in Russian, and factual statements in Russian. Thirty-nine native Russian-speaking adults read segmented expressions and made explicit judgments about semantic correctness, while structural violations remained task-irrelevant. Semantic and structural correctness were manipulated orthogonally, and event-related potentials were analyzed with a priori focus on the N400, LAN, and P600. Semantic anomalies elicited a robust N400-like response across all three expression types, indicating broadly comparable meaning-related anomaly processing. Structural effects, however, were more dependent on representational format and processing stage. In earlier time windows, the clearest 300-500&#x202f;ms structural effect was observed in symbolic arithmetic under the present local anomaly manipulations, although this early difference may partly reflect greater transparency of the symbolic structural violation. In the later P600 range, both symbolic arithmetic and factual statements showed significant structural-anomaly positivities, whereas no reliable comparable effect was detected for verbal arithmetic. These findings argue against both a fully shared and a fully segregated account of arithmetic- and language-related processing. Instead, they suggest a stage-dependent pattern of partial convergence and divergence. Semantic anomaly processing was broadly similar across expression types, whereas structural anomaly processing was more format-sensitive. Verbal arithmetic did not show a stable intermediate ERP profile across components under the present task and materials, suggesting that verbalized arithmetic should not be treated simply as symbolic arithmetic in words or as ordinary language with numerical content.

The microbiota-gut-brain axis (MGBA) is a bidirectional signaling pathway regulated by the gut microbiome and the central nervous system (CNS). Moreover, MGBA is crucial for normal growth, development, and physiology of the brain and gut of the host; dysfunction in MGBA has been closely linked with the development of neurological disorders. Gut dysbiosis and its metabolites modulate barrier permeability and cause gastrointestinal tract (GIT) inflammation, which is followed by an increase in pro-inflammatory cytokines, immune cell infiltration into the brain, and vagus nerve dysfunction, resulting in neuroinflammation and neuronal defects in the brain, as well as some other behavioral defects. In this review, we will discuss the molecular and neurobehavioral properties of Zebrafish as a research model to study MGBA, as well as current discoveries in humans, highlighting the vital role of MGBA in neuropathological conditions. Using Zebrafish as a genetic model in combination with in vivo imaging technology may suggest some novel mechanisms for the interaction between gut microbiota and CNS, particularly in the case of neurological disorders including Alzheimer's disease (AD), Parkinson's disease (PD) and autism spectrum disorder (ASD). A comprehensive literature search was conducted using electronic databases including PubMed, Scopus, Web of Science, and Google Scholar.

The Brief Assessment of Cognition in Schizophrenia (BACS) and Schizophrenia Cognition Rating Scale (SCoRS) tests help to assess cognition in schizophrenia; however, anchor-based determinations of meaningful change are needed. This analysis derived minimal clinically important difference (MCID) estimates using data from INTERACT, a phase 2 randomized study of luvadaxistat as treatment of negative symptoms of schizophrenia. Blinded retrospective analysis of a subsample selected for cognitive impairment (baseline BACS composite score: 10-40). MCID ranges were estimated via anchor-based analyses using the SCoRS interviewer change rating (overall impression of global cognitive change) to group the subsample (n&#xa0;=&#xa0;140) into observable interviewer-rated improvement (n&#xa0;=&#xa0;81) and no observable interviewer-rated change (n&#xa0;=&#xa0;59). Distribution analyses evaluated effect-size cutoffs. MCID thresholds were tested for treatment sensitivity across INTERACT arms. Baseline BACS composite score and SCoRS interviewer total score were comparable between subgroups. At end of treatment, the difference between subgroups in change from baseline in BACS composite score and SCoRS interviewer total score was 2.08 (P&#xa0;=&#xa0;0.060) and 3.16 (P&#xa0;<&#xa0;0.001), respectively, both directionally toward the improvement subgroup. Distribution analyses using a moderate effect-size cutoff (standard deviation: 0.5) indicated 3.98-point and 5.21-point subgroup differences for BACS and SCoRS, respectively, to be potentially significant. A 4-point MCID threshold was considered most sensitive to study treatment. Results suggest that a 2- to 4-point difference in BACS composite score and a 3- to 5-point difference in SCoRS interviewer total score may be clinically meaningful in cognitive impairment in schizophrenia.

Lafora disease (LD) and Unverricht-Lundborg disease (EPM1A) are the most common forms of progressive myoclonic epilepsy and are frequently associated with photosensitivity and photic reflex myoclonus (PRM). This study aimed to characterize the photoparoxysmal response (PPR), evaluate the effect of blue lenses, and explore the neural networks underlying PPR and PRM in both conditions. Twenty-six patients with LD and 51 with EPM1A were included. PPR was assessed on the first available electroencephalogram (EEG), including background activity and the presence and distribution of interictal epileptiform discharges, which were compared between groups. A subset of patients underwent back-averaging analysis using 1-Hz flash stimuli as triggers, allowing identification of the principal components of flash-evoked responses. PPR was detected in 85% of LD patients and 33% of EPM1A patients (p&#x2009;<&#x2009;.001). Compared with EPM1A, LD patients more often showed focal seizures with visual symptoms, slower EEG background activity, and a higher presence of focal epileptiform abnormalities over the posterior regions. In both groups, PPR was mainly Waltz type 4 at 14-15&#x2009;Hz and was associated with PRM in approximately half of the cases. However, in LD, the PPR latency from stimulus onset was shorter, and sensitivity to blue lenses was significantly lower. Compared with healthy controls, both patient groups exhibited increased amplitude and prolonged latency of the flash-evoked responses. Photosensitivity is more frequent and severe in LD than in EPM1A and is associated with electrophysiological markers of occipital cortex hyperexcitability. The shorter PPR latency in LD suggests an intrinsic predisposition to generate PPR immediately after visual input, possibly related to a lack of inhibitory mechanisms. The frequent occurrence of PRM in both conditions reflects aberrant large-scale network dynamics involving cortical and subcortical structures rather than pure occipital cortex dysfunction.

Neuronal morphology shapes circuit organization, yet its multiscale complexity has hindered systematic brain-wide analysis. Here, we introduce multiscale morpho-barcoding (MMB), a framework that encodes whole-brain neuronal morphology into symbolic barcodes spanning cellular geometry, axonal tract routing, arbor organization, and predicted presynaptic distributions. Applying MMB to 1,876 fully reconstructed mouse neurons, comprising 3,776 arbors, and 2.63 million predicted presynaptic sites, we identified distinct multiscale morpho-patterns that help reveal two organizational principles. First, neuronal morphology is region specific: regional identity arises from distinct combinations of shared and region-biased morpho-motifs. Second, organization is scale dependent: different morphological scales contribute differentially to the neuronal classification and circuit architecture. Within this mouse dataset, MMB discriminates major anatomical divisions and resolves canonical thalamic circuit classes, exceeding the resolution of projection strength-based representations. MMB provides an interpretable and scalable framework for integrating morphology with connectivity and function. This framework could further be applicable to analyze disease-oriented structural phenotypes.

Men possess a greater density of cortical synapses in the adult brain relative to women, but the underlying mechanism and functional significance of this sex difference is unclear. Here, we identify a greater density of excitatory synapses in the male mouse somatosensory cortex (S1) which emerges during development and persists into the adult brain. We show that increased phagocytic activity in microglia of female mice causes a greater engulfment of astrocytes in the female S1 in a MERTK-dependent manner during a discrete developmental window, regulated at least in part by estrogen signaling. The resulting greater astrocyte density in males corresponds with an increase in astrocyte-derived synaptogenic factors, hevin and thrombospondin-2, which we propose leads to the observed sex difference in S1 synapse density. Moreover, we demonstrate that this sex difference in synapse density correlates with an increase in neuronal activity in the male S1 both in development and adulthood.

Neural circuit assembly requires precise coordinated interactions between developing neurons and the vasculature; yet, the instructive signals provided by endothelial cells remain largely unknown. Here, we find a vascular-to-neural signaling axis that orchestrates postnatal cerebellar development. Endothelial-specific deletion of the adapter protein Dab1 (Dab1i&#x394;EC) in mice disrupts vascular patterning and uncouples the growth of major cerebellar neuronal populations. We show that endothelial Dab1 in the cerebellum drives secretion of the morphogen Wnt5a, which acts through Frizzled-2 to restrain granule-cell progenitor proliferation and promotes Purkinje cell dendritic maturation. Endothelial Wnt5a deletion phenocopies Dab1i&#x394;EC defects, whereas exogenous Wnt5a restores normal progenitor dynamics in Dab1i&#x394;EC cerebellar slices, demonstrating pathway sufficiency. Functionally, loss of this vascular signal impairs Purkinje cell firing, diminishes parallel-fiber input, reduces synapse formation from both parallel and climbing fibers, and disrupts long-term plasticity. These findings indicate a key instructive role for blood vessels in shaping cerebellar architecture and establishing functional circuit connectivity.