Reactive microglia fail to respond to environmental damage signals in a viral-induced mouse model of temporal lobe epilepsy.

Microglia are highly adaptable innate immune cells that rapidly respond to damage signals in the brain through adoption of a reactive phenotype and production of defensive inflammatory cytokines. Microglia express a distinct transcriptome, encoding receptors that allow them to dynamically respond to pathogens, damage signals, and cellular debris. Expression of one such receptor, the microglia-specific purinergic receptor P2ry12, is known to be downregulated in reactive microglia. Here, we explore the microglial response to purinergic damage signals in reactive microglia in the TMEV mouse model of viral brain infection and temporal lobe epilepsy. Using two-photon calcium imaging in acute hippocampal brain slices, we found that the ability of microglia to detect damage signals, engage calcium signaling pathways, and chemoattract towards laser-induced tissue damage was dramatically reduced during the peak period of seizures, cytokine production, and infection. Using combined RNAscope in situ hybridization and immunohistochemistry, we found that during this same stage of heightened infection and seizures, microglial P2ry12 expression was reduced, while the pro-inflammatory cytokine TNF-a expression was upregulated in microglia, suggesting that the depressed ability of microglia to respond to new damage signals via P2ry12 occurs during the time when local elevated cytokine production contributes to seizure generation following infection. Therefore, changes in microglial purinergic receptors during infection likely limit the ability of reactive microglia to respond to new threats in the CNS and locally contain the scale of the innate immune response in the brain.

Reproducibility of arterial spin labeling cerebral blood flow image processing: A report of the ISMRM open science initiative for perfusion imaging (OSIPI)_and the ASL MRI challenge.

PURPOSE: Arterial spin labeling (ASL) is a widely used contrast-free MRI method for assessing cerebral blood flow (CBF). Despite the generally adopted ASL acquisition guidelines, there is still wide variability in ASL analysis. We explored this variability through the ISMRM-OSIPI ASL-MRI Challenge, aiming to establish best practices for more reproducible ASL analysis. METHODS: Eight teams analyzed the challenge data, which included a high-resolution T1-weighted anatomical image and 10 pseudo-continuous ASL datasets simulated using a digital reference object to generate ground-truth CBF values in normal and pathological states. We compared the accuracy of CBF quantification from each team's analysis to the ground truth across all voxels and within predefined brain regions. Reproducibility of CBF across analysis pipelines was assessed using the intra-class correlation coefficient (ICC), limits of agreement (LOA), and replicability of generating similar CBF estimates from different processing approaches. RESULTS: Absolute errors in CBF estimates compared to ground-truth synthetic data ranged from 18.36 to 48.12 mL/100 g/min. Realistic motion incorporated into three datasets produced the largest absolute error and variability between teams, with the least agreement (ICC and LOA) with ground-truth results. Fifty percent of the submissions were replicated, and one produced three times larger CBF errors (46.59 mL/100 g/min) compared to submitted results. CONCLUSIONS: Variability in CBF measurements, influenced by differences in image processing, especially to compensate for motion, highlights the significance of standardizing ASL analysis workflows. We provide a recommendation for ASL processing based on top-performing approaches as a step toward ASL standardization.

Refinement in Post-Operative Care for Orthopaedic Models: Implementing a Sheep Walking Cast (SWC) for Effective Tibial Fracture Management.

In the healthcare system, lower leg fractures remain relevant, incurring costs related to surgical treatment, hospitalization, and rehabilitation. The duration of treatment may vary depending on the individual case and its severity. Casting as a post-surgical fracture treatment is a common method in human and experimental veterinary medicine. Despite the high importance of sheep in preclinical testing materials for osteosynthesis, there is no standardised cast system ensuring proper stabilisation and functionality of hind limbs during the healing of tibia fractures or defects. Existing treatment approaches for tibial osteosynthesis in laboratory animal science include sling hanging, external fixators, or former Achilles tendon incision. These methods restrict animal movement for 4-6 weeks, limit species-typical behaviour, and impact social interactions. Our pilot study introduces a Standardised Walking Cast (SWC) for sheep, enabling immediate physiological movement post surgery. Seven Rhone sheep (female, 63.5 kg ± 6.45 kg) each with a single tibia defect (6 mm mechanical drilled defect) underwent SWC application for 4 weeks after plate osteosynthesis. The animals bore weight on their operated leg from day one, exhibiting slight lameness (grade 1-2 out of 5). Individual step lengths showed good uniformity (average deviation: 0.89 cm). Group housing successfully started on day three after surgery. Weekly X-rays and cast changes ensured proper placement, depicting the healing process. This study demonstrates the feasibility of using an SWC for up to 72 kg of body weight without sling hanging via ceiling mounting or external fixation techniques. Allowing species-typical movement and social behaviour can significantly improve the physiological behaviour of sheep in experiments, contributing to refinement.

Contrast-agent-based perfusion MRI code repository and testing framework: ISMRM Open Science Initiative for Perfusion Imaging (OSIPI).

PURPOSE: Software has a substantial impact on quantitative perfusion MRI values. The lack of generally accepted implementations, code sharing and transparent testing reduces reproducibility, hindering the use of perfusion MRI in clinical trials. To address these issues, the ISMRM Open Science Initiative for Perfusion Imaging (OSIPI) aimed to establish a community-led, centralized repository for sharing open-source code for processing contrast-based perfusion imaging, incorporating an open-source testing framework. METHODS: A repository was established on the OSIPI GitHub website. Python was chosen as the target software language. Calls for code contributions were made to OSIPI members, the ISMRM Perfusion Study Group, and publicly via OSIPI websites. An automated unit-testing framework was implemented to evaluate the output of code contributions, including visual representation of the results. RESULTS: The repository hosts 86 implementations of perfusion processing steps contributed by 12 individuals or teams. These cover all core aspects of DCE- and DSC-MRI processing, including multiple implementations of the same functionality. Tests were developed for 52 implementations, covering five analysis steps. For T1 mapping, signal-to-concentration conversion and population AIF functions, different implementations resulted in near-identical output values. For the five pharmacokinetic models tested (Tofts, extended Tofts-Kety, Patlak, two-compartment exchange, and two-compartment uptake), differences in output parameters were observed between contributions. CONCLUSIONS: The OSIPI DCE-DSC code repository represents a novel community-led model for code sharing and testing. The repository facilitates the re-use of existing code and the benchmarking of new code, promoting enhanced reproducibility in quantitative perfusion imaging.

A community-endorsed open-source lexicon for contrast agent-based perfusion MRI: A consensus guidelines report from the ISMRM Open Science Initiative for Perfusion Imaging (OSIPI).

This manuscript describes the ISMRM OSIPI (Open Science Initiative for Perfusion Imaging) lexicon for dynamic contrast-enhanced and dynamic susceptibility-contrast MRI. The lexicon was developed by Taskforce 4.2 of OSIPI to provide standardized definitions of commonly used quantities, models, and analysis processes with the aim of reducing reporting variability. The taskforce was established in February 2020 and consists of medical physicists, engineers, clinicians, data and computer scientists, and DICOM (Digital Imaging and Communications in Medicine) standard experts. Members of the taskforce collaborated via a slack channel and quarterly virtual meetings. Members participated by defining lexicon items and reporting formats that were reviewed by at least two other members of the taskforce. Version 1.0.0 of the lexicon was subject to open review from the wider perfusion imaging community between January and March 2022, and endorsed by the Perfusion Study Group of the ISMRM in the summer of 2022. The initial scope of the lexicon was set by the taskforce and defined such that it contained a basic set of quantities, processes, and models to enable users to report an end-to-end analysis pipeline including kinetic model fitting. We also provide guidance on how to easily incorporate lexicon items and definitions into free-text descriptions (e.g., in manuscripts and other documentation) and introduce an XML-based pipeline encoding format to encode analyses using lexicon definitions in standardized and extensible machine-readable code. The lexicon is designed to be open-source and extendable, enabling ongoing expansion of its content. We hope that widespread adoption of lexicon terminology and reporting formats described herein will increase reproducibility within the field.

APOE4 expression confers a mild, persistent reduction in neurovascular function in the visual cortex and hippocampus of awake mice.

Vascular factors are known to be early and important players in Alzheimer's disease (AD) development, however the role of the ε4 allele of the Apolipoprotein (APOE) gene (a risk factor for developing AD) remains unclear. APOE4 genotype is associated with early and severe neocortical vascular deficits in anaesthetised mice, but in humans, vascular and cognitive dysfunction are focused on the hippocampal formation and appear later. How APOE4 might interact with the vasculature to confer AD risk during the preclinical phase represents a gap in existing knowledge. To avoid potential confounds of anaesthesia and to explore regions most relevant for human disease, we studied the visual cortex and hippocampus of awake APOE3 and APOE4-TR mice using 2-photon microscopy of neurons and blood vessels. We found mild vascular deficits: vascular density and functional hyperaemia were unaffected in APOE4 mice, and neuronal or vascular function did not decrease up to late middle-age. Instead, vascular responsiveness was lower, arteriole vasomotion was reduced and neuronal calcium signals during visual stimulation were increased. This suggests that, alone, APOE4 expression is not catastrophic but stably alters neurovascular physiology. We suggest this state makes APOE4 carriers more sensitive to subsequent insults such as injury or beta amyloid accumulation.

[Developing Knowledge Together: Participatory Methods in Psychological and Neuroscientific Research with Children and Adolescents]. / Wissen gemeinsam erarbeiten: Partizipative Methoden in der psychologischen und neurowissenschaftlichen Forschung mit Kindern und Jugendlichen.

Developing Knowledge Together: Participatory Methods in Psychological and Neuroscientific Research with Children and Adolescents Abstract: Participatory action research understands the implementation of research as a cooperation or coproduction of researchers with nonscientific individuals. However, the general knowledge about the participatory approach as well as participatory methods and their implementation is still limited. Especially the active involvement and empowerment of children and adolescents require special measures and a creative and flexible application of various methods. In addition, the use of participatory methods in neurodevelopmental research first demands prior explanation of complex techniques to successfully implement the cooperation and coproduction between researchers and children and adolescents. In this contribution, we emphasize the relevance of the participatory approach for scientific work, present different methods that allow an introduction of complex techniques in neurodevelopmental research, and illustrate how to systematically apply this approach to research in children and adolescents.

Identification of single-dose, dual-echo based CBV threshold for fractional tumor burden mapping in recurrent glioblastoma.

Background: Relative cerebral blood volume (rCBV) obtained from dynamic susceptibility contrast (DSC) MRI is widely used to distinguish high grade glioma recurrence from post treatment radiation effects (PTRE). Application of rCBV thresholds yield maps to distinguish between regional tumor burden and PTRE, a biomarker termed the fractional tumor burden (FTB). FTB is generally measured using conventional double-dose, single-echo DSC-MRI protocols; recently, a single-dose, dual-echo DSC-MRI protocol was clinically validated by direct comparison to the conventional double-dose, single-echo protocol. As the single-dose, dual-echo acquisition enables reduction in the contrast agent dose and provides greater pulse sequence parameter flexibility, there is a compelling need to establish dual-echo DSC-MRI based FTB mapping. In this study, we determine the optimum standardized rCBV threshold for the single-dose, dual-echo protocol to generate FTB maps that best match those derived from the reference standard, double-dose, single-echo protocol. Methods: The study consisted of 23 high grade glioma patients undergoing perfusion scans to confirm suspected tumor recurrence. We sequentially acquired single dose, dual-echo and double dose, single-echo DSC-MRI data. For both protocols, we generated leakage-corrected standardized rCBV maps. Standardized rCBV (sRCBV) thresholds of 1.0 and 1.75 were used to compute single-echo FTB maps as the reference for delineating PTRE (sRCBV < 1.0), tumor with moderate angiogenesis (1.0 < sRCBV < 1.75), and tumor with high angiogenesis (sRCBV > 1.75) regions. To assess the sRCBV agreement between acquisition protocols, the concordance correlation coefficient (CCC) was computed between the mean tumor sRCBV values across the patients. A receiver operating characteristics (ROC) analysis was performed to determine the optimum dual-echo sRCBV threshold. The sensitivity, specificity, and accuracy were compared between the obtained optimized threshold (1.64) and the standard reference threshold (1.75) for the dual-echo sRCBV threshold. Results: The mean tumor sRCBV values across the patients showed a strong correlation (CCC = 0.96) between the two protocols. The ROC analysis showed maximum accuracy at thresholds of 1.0 (delineate PTRE from tumor) and 1.64 (differentiate aggressive tumors). The reference threshold (1.75) and the obtained optimized threshold (1.64) yielded similar accuracy, with slight differences in sensitivity and specificity which were not statistically significant (1.75 threshold: Sensitivity = 81.94%; Specificity: 87.23%; Accuracy: 84.58% and 1.64 threshold: Sensitivity = 84.48%; Specificity: 84.97%; Accuracy: 84.73%). Conclusions: The optimal sRCBV threshold for single-dose, dual-echo protocol was found to be 1.0 and 1.64 for distinguishing tumor recurrence from PTRE; however, minimal differences were observed when using the standard threshold (1.75) as the upper threshold, suggesting that the standard threshold could be used for both protocols. While the prior study validated the agreement of the mean sRCBV values between the protocols, this study confirmed that their voxel-wise agreement is suitable for reliable FTB mapping. Dual-echo DSC-MRI acquisitions enable robust single-dose sRCBV and FTB mapping, provide pulse sequence parameter flexibility and should improve reproducibility by mitigating variations in preload dose and incubation time.

Revealing the neurobiology underlying interpersonal neural synchronization with multimodal data fusion.

Humans synchronize with one another to foster successful interactions. Here, we use a multimodal data fusion approach with the aim of elucidating the neurobiological mechanisms by which interpersonal neural synchronization (INS) occurs. Our meta-analysis of 22 functional magnetic resonance imaging and 69 near-infrared spectroscopy hyperscanning experiments (740 and 3721 subjects) revealed robust brain regional correlates of INS in the right temporoparietal junction and left ventral prefrontal cortex. Integrating this meta-analytic information with public databases, biobehavioral and brain-functional association analyses suggested that INS involves sensory-integrative hubs with functional connections to mentalizing and attention networks. On the molecular and genetic levels, we found INS to be associated with GABAergic neurotransmission and layer IV/V neuronal circuits, protracted developmental gene expression patterns, and disorders of neurodevelopment. Although limited by the indirect nature of phenotypic-molecular association analyses, our findings generate new testable hypotheses on the neurobiological basis of INS.

Virtual Reality in Biomedical Education in the sense of the 3Rs.

Article 23(2) of EU Directive 2010/63 on the protection of animals used for scientific purposes requires staff involved in the care and use of animals to be adequately educated and trained before carrying out procedures. Therefore, the 3Rs (refinement, reduction, and replacement) and knowledge of alternative methods should be part of the education and training itself. For this purpose, the digital learning concept "Virtual Reality (VR) in Biomedical Education" evolved, which successfully combines VR components with classical learning content. Procedures, such as anesthesia induction, substance application, and blood sampling in rats, as well as aspects of the laboratory environment were recorded in 360° videos. The generated VR teaching/learning modules (VR modules) were used to better prepare participants for hands-on training (refinement) or as a complete replacement for a live demonstration; thus, reducing the number of animals used for hands-on skills training (reduction). The current study evaluated users' experience of the VR modules. Despite little previous VR experience, participants strongly appreciated the VR modules and indicated that they believed VR has the potential to enhance delivery of procedures and demonstrations. Interestingly, participants with previous experience of laboratory animal science were more convinced about VR's potential to support the 3Rs principle, and endorsed its use for further educational purposes. In conclusion, VR appeared to be highly accepted as a learning/teaching method, indicating its great potential to further replace and reduce the use of animals in experimental animal courses.

A Model for Epilepsy of Infectious Etiology using Theiler's Murine Encephalomyelitis Virus.

One of the main causes of epilepsy is an infection of the central nervous system (CNS); approximately 8% of patients who survive such an infection develop epilepsy as a consequence, with rates being significantly higher in less economically developed countries. This work provides an overview of modeling epilepsy of infectious etiology and using it as a platform for novel antiseizure compound testing. A protocol of epilepsy induction by non-stereotactic intracerebral injection of Theiler's murine encephalomyelitis virus (TMEV) in C57BL/6 mice is presented, which replicates many of the early and chronic clinical symptoms of viral encephalitis and subsequent epilepsy in human patients. The clinical evaluation of mice during encephalitis to monitor seizure activity and detect the potential antiseizure effects of novel compounds is described. Furthermore, histopathological consequences of viral encephalitis and seizures such as hippocampal damage and neuroinflammation are shown, as well as long-term consequences such as spontaneous epileptic seizures. The TMEV model is one of the first translational, infection-driven, experimental platforms to allow for the investigation of the mechanisms of epilepsy development as a consequence of CNS infection. Thus, it also serves to identify potential therapeutic targets and compounds for patients at risk of developing epilepsy following a CNS infection.

Chronic Cognitive and Cerebrovascular Function after Mild Traumatic Brain Injury in Rats.

Severe traumatic brain injury (TBI) results in cognitive dysfunction in part due to vascular perturbations. In contrast, the long-term vasculo-cognitive pathophysiology of mild TBI (mTBI) remains unknown. We evaluated mTBI effects on chronic cognitive and cerebrovascular function and assessed their interrelationships. Sprague-Dawley rats received midline fluid percussion injury (n = 20) or sham (n = 21). Cognitive function was assessed (3- and 6-month novel object recognition [NOR], novel object location [NOL], and temporal order object recognition [TOR]). Six-month cerebral blood flow (CBF) and cerebral blood volume (CBV) using contrast magnetic resonance imaging (MRI) and ex vivo circle of Willis artery endothelial and smooth muscle-dependent function were measured. mTBI rats showed significantly impaired NOR, with similar trends (non-significant) in NOL/TOR. Regional CBF and CBV were similar in sham and mTBI. NOR correlated with CBF in lateral hippocampus, medial hippocampus, and primary somatosensory barrel cortex, whereas it inversely correlated with arterial smooth muscle-dependent dilation. Six-month baseline endothelial and smooth muscle-dependent arterial function were similar among mTBI and sham, but post-angiotensin 2 stimulation, mTBI showed no change in smooth muscle-dependent dilation from baseline response, unlike the reduction in sham. mTBI led to chronic cognitive dysfunction and altered angiotensin 2-stimulated smooth muscle-dependent vasoreactivity. The findings of persistent pathophysiological consequences of mTBI in this animal model add to the broader understanding of chronic pathophysiological sequelae in human mild TBI.

Teaching of Nuclear Cardiology in Times of Pandemic: Transfer of a Case-based Interactive Course from Classroom to Distance Learning.

AIM: While methods of independent study, such as problem-based learning, have been shown beneficial to students' learning outcome and motivation to self-educate, these concepts are currently challenged by the pandemic. The aim of the current study was the evaluation of the transfer of an interactive nuclear cardiology teaching module to an online, distance learning setting. METHODS: Two-hundred-forty medical students completed and evaluated the teaching module in a classroom and 127 students in the distance learning setting. RESULTS: The interactive, problem-based teaching module was transferred well into the distance learning setting during the pandemic. However, while the presented results suggest that distance learning is a good substitute for classroom teaching when in-person teaching is not possible, the distance teaching module was perceived less efficient in its course didactics, demands as well as applicability than the same module in a classroom setting. CONCLUSION: Although distance learning thus cannot entirely replace classroom education, it does provide a well-suited alternative method to teach particularly nuclear medicine and medicine in general. Future applications should offer introductory sessions, provide learning materials in advance and slow down the teaching pace to facilitate online, distance learning.

Longitudinal evaluation of myofiber microstructural changes in a preclinical ALS model using the transverse relaxivity at tracer equilibrium (TRATE): A preliminary study.

T2⁎ relaxivity contrast imaging may serve as a potential imaging biomarker for amyotrophic lateral sclerosis (ALS) by noninvasively quantifying the tissue microstructure. In this preliminary longitudinal study, we investigated the Transverse Relaxivity at Tracer Equilibrium (TRATE) in three muscle groups between SOD1-G93A (ALS model) rat and a control population at two different timepoints. The control group was time matched to the ALS group such that the second timepoint was the onset of disease. We observed a statistically significant decrease in TRATE over time in the gastrocnemius, tibialis, and digital flexor muscles in the SOD1-G93A model (p-value = 0.003, 0.008, 0.005; respectively), whereas TRATE did not change over time in the control group (p-value = 0.4777, 0.6837, 0.9682; respectively). Immunofluorescent staining revealed a decrease in minimum fiber area and cell density in the SOD1-G93A model when compared to the control group (p-value = 6.043E-10 and 2.265E-10, respectively). These microstructural changes observed from histology align with the theorized biophysical properties of TRATE. We demonstrate that TRATE can longitudinally differentiate disease associated atrophy from healthy muscle and has potential to serve as a biomarker for disease progression and ultimately therapy response in patients with ALS.

Comparing helpful and hindering processes in good and poor outcome cases: A qualitative metasynthesis of eight Hermeneutic Single Case Efficacy Design studies.

Objective: We tested qualitative metasynthesis of a series of Hermeneutic Single Case Efficacy Design (HSCED) studies as a method for comparing within-session processes that may explain good and poor therapeutic outcome. Method: We selected eight HSCED studies according to change in clients' scores on the Strathclyde Inventory (SI), a brief self-report instrument used to measure outcome in person-centered psychotherapy. Four of the case studies investigated the experience of clients whose pre-post change in SI scores showed improvement by the end of therapy, and the other four focused on clients whose change in SI scores indicated deterioration. We conducted a qualitative metasynthesis, adopting a generic descriptive-interpretive approach to analyze and compare the data generated by the HSCED studies. Results: In contrast to improvers, deteriorators appeared to be less ready to engage in therapeutic work at the beginning of therapy, and found the process more difficult; their therapists were less able to respond to these difficulties in a responsive, empathic manner; deteriorators were less able to cope successfully with changes of therapist and, eventually, gave up on therapy. Conclusion: We found that our qualitative metasynthesis of a series of HSCED studies produced a plausible explanation for the contrasting outcomes that occurred.

Multi-Site Concordance of Diffusion-Weighted Imaging Quantification for Assessing Prostate Cancer Aggressiveness.

BACKGROUND: Diffusion-weighted imaging (DWI) is commonly used to detect prostate cancer, and a major clinical challenge is differentiating aggressive from indolent disease. PURPOSE: To compare 14 site-specific parametric fitting implementations applied to the same dataset of whole-mount pathologically validated DWI to test the hypothesis that cancer differentiation varies with different fitting algorithms. STUDY TYPE: Prospective. POPULATION: Thirty-three patients prospectively imaged prior to prostatectomy. FIELD STRENGTH/SEQUENCE: 3 T, field-of-view optimized and constrained undistorted single-shot DWI sequence. ASSESSMENT: Datasets, including a noise-free digital reference object (DRO), were distributed to the 14 teams, where locally implemented DWI parameter maps were calculated, including mono-exponential apparent diffusion coefficient (MEADC), kurtosis (K), diffusion kurtosis (DK), bi-exponential diffusion (BID), pseudo-diffusion (BID*), and perfusion fraction (F). The resulting parametric maps were centrally analyzed, where differentiation of benign from cancerous tissue was compared between DWI parameters and the fitting algorithms with a receiver operating characteristic area under the curve (ROC AUC). STATISTICAL TEST: Levene's test, P < 0.05 corrected for multiple comparisons was considered statistically significant. RESULTS: The DRO results indicated minimal discordance between sites. Comparison across sites indicated that K, DK, and MEADC had significantly higher prostate cancer detection capability (AUC range = 0.72-0.76, 0.76-0.81, and 0.76-0.80 respectively) as compared to bi-exponential parameters (BID, BID*, F) which had lower AUC and greater between site variation (AUC range = 0.53-0.80, 0.51-0.81, and 0.52-0.80 respectively). Post-processing parameters also affected the resulting AUC, moving from, for example, 0.75 to 0.87 for MEADC varying cluster size. DATA CONCLUSION: We found that conventional diffusion models had consistent performance at differentiating prostate cancer from benign tissue. Our results also indicated that post-processing decisions on DWI data can affect sensitivity and specificity when applied to radiological-pathological studies in prostate cancer. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 3.

Inflammation Unleashed in Viral-Induced Epileptogenesis.

Viral infection of the central nervous system increasingly places people at risk of developing life-threatening and treatment-resistant acute and chronic seizures (epilepsy). The emergence of new human viruses due to ongoing social, political, and ecological changes places people at risk more than ever before. The development of new preventative or curative strategies is critical to address this burden. However, our understanding of the complex relationship between viruses and the brain has been hindered by the lack of animal models that survive the initial infection and are amenable for long-term mechanistic, behavioral, and pharmacological studies in the process of viral-induced epileptogenesis. In this review, we focus on the Theiler's murine encephalomyelitis virus (TMEV) mouse model of viral infection-induced epilepsy. The TMEV model has a number of important advantages to address the quintessential processes underlying the development of epilepsy following a viral infection, as well as fuel new therapeutic development. In this review, we highlight the contributions of the TMEV model to our current understanding of the relationship between viral infection, inflammation, and seizures.