Aims: The causes of distinct patterns of reduced cortical thickness in the common human epilepsies, detectable on neuroimaging and with important clinical consequences, are unknown. We investigated the underlying mechanisms of cortical thinning using a systems‐level analysis.Methods: Imaging‐based cortical structural maps from a large‐scale epilepsy neuroimaging study were overlaid with highly spatially resolved human brain gene expression data from the Allen Human Brain Atlas. Cell‐type deconvolution, differential expression analysis and cell‐type enrichment analyses were used to identify differences in cell‐type distribution. These differences were followed up in post‐mortem brain tissue from humans with epilepsy using Iba1 immunolabelling. Furthermore, to investigate a causal effect in cortical thinning, cell‐type‐specific depletion was used in a murine model of acquired epilepsy.Results: We identified elevated fractions of microglia and endothelial cells in regions of reduced cortical thickness. Differentially expressed genes showed enrichment for microglial markers and, in particular, activated microglial states. Analysis of post‐mortem brain tissue from humans with epilepsy confirmed excess activated microglia. In the murine model, transient depletion of activated microglia during the early phase of the disease development prevented cortical thinning and neuronal cell loss in the temporal cortex. Although the development of chronic seizures was unaffected, the epileptic mice with early depletion of activated microglia did not develop deficits in a non‐spatial memory test seen in epileptic mice not depleted of microglia.Conclusions: These convergent data strongly implicate activated microglia in cortical thinning, representing a new dimension for concern and disease modification in the epilepsies, potentially distinct from seizure control.

Post-traumatic epilepsy (PTE) accounts for 5% of all epilepsies and 10–20% of the acquired forms. The latency between traumatic brain injury (TBI) and epilepsy onset in high-risk patients offers a therapeutic window for intervention to prevent or improve the disease course. However, progress towards effective treatments has been hampered by the lack of sensitive prognostic biomarkers of PTE, and of therapeutic targets. There is therefore a pressing clinical need for preclinical PTE models suitable for biomarker discovery and drug testing. We characterized in-depth a model of severe TBI induced by controlled cortical impact evolving into PTE in CD1 adult male mice. To identify sensitive measures predictive of PTE development and severity, TBI mice were longitudinally monitored by video-electrocorticography (ECoG), examined by MRI, and tested for sensorimotor and cognitive deficits and locomotor activity. At the end of the video-ECoG recording mice were killed for brain histological analysis. PTE occurred in 58% of mice with frequent motor seizures (one seizure every other day), as determined up to 5 months post-TBI. The weight loss of PTE mice in 1 week after TBI correlated with the number of spontaneous seizures at 5 months. Moreover, the recovery rate of the sensorimotor deficit detected by the SNAP test before the predicted time of epilepsy onset was significantly lower in PTE mice than in those without epilepsy. Neuroscore, beam walk and cognitive deficit were similar in all TBI mice. The increase in the contusion volume, the volume of forebrain regions contralateral to the lesioned hemisphere and white matter changes over time assessed by MRI were similar in PTE and no-PTE mice. However, brain histology showed a more pronounced neuronal cell loss in the cortex and hippocampus contralateral to the injured hemisphere in PTE than in no-PTE mice. The extensive functional and neuropathological characterization of this TBI model, provides a tool to identify sensitive measures of epilepsy development and severity clinically useful for increasing PTE prediction in high-risk TBI patients. The high PTE incidence and spontaneous seizures frequency in mice provide an ideal model for biomarker discovery and for testing new drugs.

Traumatic brain injury (TBI) disrupts thalamic and cortical integrity. The effect of post-injury reorganization and plasticity in thalamocortical pathways on the functional outcome remains unclear. We evaluated whether TBI causes structural changes in the thalamocortical axonal projection terminals in the primary somatosensory cortex (S1) that lead to hyperexcitability. TBI was induced in adult male Sprague Dawley rats with lateral fluid-percussion injury. A virus carrying the fluorescent-tagged opsin channel rhodopsin 2 transgene was injected into the ventroposterior thalamus. We then traced the thalamocortical pathways and analyzed the reorganization of their axonal terminals in S1. Next, we optogenetically stimulated the thalamocortical relays from the ventral posterior lateral and medial nuclei to assess the post-TBI functionality of the pathway. Immunohistochemical analysis revealed that TBI did not alter the spatial distribution or lamina-specific targeting of projection terminals in S1. TBI reduced the axon terminal density in the motor cortex by 44% and in S1 by 30%. A nematic tensor-based analysis revealed that in control rats, the axon terminals in layer V were orientated perpendicular to the pial surface (60.3°). In TBI rats their orientation was more parallel to the pial surface (5.43°, difference between the groups p < 0.05). Moreover, the level of anisotropy of the axon terminals was high in controls (0.063) compared with TBI rats (0.045, p < 0.05). Optical stimulation of the sensory thalamus increased alpha activity in electroencephalography by 312% in controls (p > 0.05) and 237% (p > 0.05) in TBI rats compared with the baseline. However, only TBI rats showed increased beta activity (33%) with harmonics at 5 Hz. Our findings indicate that TBI induces reorganization of thalamocortical axonal terminals in the perilesional cortex, which alters responses to thalamic stimulation.

Objective: Drug‐resistant epilepsy (DRE) remains a clinical challenge, as therapies modifying disease trajectory are lacking. Increasing evidence implicates gut microbiota dysbiosis in epilepsy pathophysiology, with short‐chain fatty acids (SCFAs) emerging as key microbial metabolites with neuroprotective and anti‐inflammatory properties. Clinical studies show that people with DRE exhibit gut microbiota alterations that may impair fecal SCFAs production. Here, we investigated whether supplementation of SCFAs confers disease‐modifying effects in a preclinical model of DRE. Methods: Adult male mice were subjected to status epilepticus (SE) and subsequently treated with a balanced mixture of acetate, propionate, and butyrate, or vehicle. Seizure frequency and temporal progression were monitored for 70 days by electroencephalography (EEG). At the study end point, cognitive performance, brain and gut histopathology, and neuroinflammation were assessed, together with metabolomic profiling of feces and blood. Brain SCFA levels and receptor expression were also analyzed in mice and in brain tissue from individuals with DRE. Results: SCFA supplementation reduced the proportion of mice exhibiting a progressive phenotype and decreased the overall progression index (PI) 3‐fold, without significantly altering overall daily seizure frequency. Treatment reduced seizure clustering, improved cognitive deficits, restored hippocampal and intestinal alterations, and partially normalized cerebral SCFAs levels. Metabolomic profiling in epileptic mice and analysis of human epilepsy brain tissue support a mechanistic contribution of gut‐brain axis dysfunction to disease progression. Interpretation: These findings identify SCFAs supplementation as a therapeutic strategy capable of modifying disease trajectory in experimental DRE, with clear translational relevance. ANN NEUROL 2026

Epilepsy is increasingly recognized as a systemic disorder involving complex interactions between the brain and peripheral systems. Among these, the gut microbiota has emerged as a key regulator of host metabolism and immune homeostasis through the production of bioactive metabolites that mediate the communication between gut and brain. In recent years, growing evidence has linked gut dysbiosis to epilepsy, particularly in drug-resistant forms, and interventional studies targeting the gut microbiota in animal models suggest that microbiota-driven metabolic alterations may contribute to seizure generation and recurrence, as well as the associated neuropathology and cognitive deficits. In this review, we summarize current knowledge on the role of the gut microbiota–metabolome axis in acquired epilepsy, with a particular focus on short-chain fatty acids (SCFAs) and tryptophan-derived pathways. SCFAs represent major microbial products involved in energy metabolism, inflammation, blood–brain barrier integrity, neurotransmission and epigenetic mechanisms. In parallel, microbiota-dependent tryptophan metabolism represents a central hub linking intestinal microbial activity to brain function through serotonin, kynurenine, and indole pathways. Dysregulation of these pathways may influence neuronal excitability and contribute to seizures. Converging evidence supports the concept that epilepsy is associated with a coordinated alteration of gut microbial composition and host–microbiota metabolic interactions. However, further research is needed to elucidate the mutual communication between the gut and its microbiota and the metabolic flux, and their influence on brain function in neurological conditions. A better understanding of the underlying pathways and mechanisms may highlight novel therapeutic strategies and discover novel biomarkers of disease trajectory.

Objective: Elevated body temperature may increase seizure risk, yet the relationship between thermoregulation and seizures, as well as the underlying mechanisms, remains poorly understood. We investigated whether thermoregulatory control is altered in experimental temporal lobe epilepsy (TLE), as such impairment could reduce the ability of affected individuals to adapt to environmental temperature changes. Methods: Using an adult mouse model of temporal lobe epilepsy (TLE), we longitudinally measured brain temperature before and after epilepsy onset using 7 T ¹ H‐magnetic resonance spectroscopy thermometry. The temporal relationship between spontaneous seizures and body temperature fluctuations was assessed using electroencephalographic recordings combined with implanted temperature probes under controlled environmental conditions. Neuronal density, glial reactivity, and transcriptomic profiles were examined in hypothalamic temperature‐sensing regions (ventromedial preoptic nucleus [VMPO] and dorsomedial nucleus [DMD]) in epileptic mice and sham mice. Hypothalamic volume was assessed by magnetic resonance imaging (MRI) in both mice and people with epilepsy (PWE). Serum thyroid‐stimulating hormone (TSH), T3, and T4 concentrations were measured as indices of hypothalamic–pituitary–thyroid (HPT) axis activity and metabolic thermogenesis. Results: Hippocampal temperature increased by ~.5–1.5°C prior to epilepsy onset (3 days postkainate) and remained elevated during chronic epilepsy (1.5 months postkainate). Acutely, body temperature rose from 15 min before to 15 min after spontaneous seizures. Serum T3 and T4 levels were reduced by ~50% without compensatory TSH elevation, indicating HPT axis dysregulation in epileptic mice. Neuronal density in VMPO and DMD decreased by ~20% in chronic epileptic mice versus sham mice ( p < .05), accompanied by induction of FosB, immune/inflammatory pathways, and glia reactivity. MRI revealed reduced hypothalamic volume in epileptic mice ( p < .05), paralleling findings in PWE. Significance: Thermoregulatory control is impaired in experimental TLE and is associated with neuronal loss and inflammation in hypothalamic temperature‐sensing regions. These findings reveal a link between thermoregulatory dysfunction and epilepsy and highlight that alterations in temperature homeostasis may interact with mechanisms underlying seizure generation.