The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus.

The choroid plexus (ChP) is the blood-cerebrospinal fluid (CSF) barrier and the primary source of CSF. Acquired hydrocephalus, caused by brain infection or hemorrhage, lacks drug treatments due to obscure pathobiology. Our integrated, multi-omic investigation of post-infectious hydrocephalus (PIH) and post-hemorrhagic hydrocephalus (PHH) models revealed that lipopolysaccharide and blood breakdown products trigger highly similar TLR4-dependent immune responses at the ChP-CSF interface. The resulting CSF "cytokine storm", elicited from peripherally derived and border-associated ChP macrophages, causes increased CSF production from ChP epithelial cells via phospho-activation of the TNF-receptor-associated kinase SPAK, which serves as a regulatory scaffold of a multi-ion transporter protein complex. Genetic or pharmacological immunomodulation prevents PIH and PHH by antagonizing SPAK-dependent CSF hypersecretion. These results reveal the ChP as a dynamic, cellularly heterogeneous tissue with highly regulated immune-secretory capacity, expand our understanding of ChP immune-epithelial cell cross talk, and reframe PIH and PHH as related neuroimmune disorders vulnerable to small molecule pharmacotherapy.

mbQTL: an R/Bioconductor package for microbial quantitative trait loci (QTL) estimation.

MOTIVATION: In recent years, significant strides have been made in the field of genomics, with the commencement of large-scale studies aimed at collecting host mutational profiles and microbiome data. The amalgamation of host gene mutational profiles in both healthy and diseased subjects with microbial abundance data holds immense promise in providing insights into several crucial research questions, including the development and progression of diseases, as well as individual responses to therapeutic interventions. With the advent of sequencing methods such as 16s ribosomal RNA (rRNA) sequencing and whole genome sequencing, there is increasing evidence of interplay of human genetics and microbial communities. Quantitative trait loci associated with microbial abundance (mbQTLs), are genetic variants that influence the abundance of microbial populations within the host. RESULTS: Here, we introduce mbQTL, the first R package integrating 16S ribosomal RNA (rRNA) sequencing and single-nucleotide variation (SNV) and single-nucleotide polymorphism (SNP) data. We describe various statistical methods implemented for the identification of microbe-SNV pairs, relevant statistical measures, and plot functionality for interpretation. AVAILABILITY AND IMPLEMENTATION: mbQTL is available on bioconductor at https://bioconductor.org/packages/mbQTL/.

Pan-African evolution of within- and between-country COVID-19 dynamics.

The coronavirus disease 2019 (COVID-19) pandemic is heterogeneous throughout Africa and threatening millions of lives. Surveillance and short-term modeling forecasts are critical to provide timely information for decisions on control strategies. We created a strategy that helps predict the country-level case occurrences based on cases within or external to a country throughout the entire African continent, parameterized by socioeconomic and geoeconomic variations and the lagged effects of social policy and meteorological history. We observed the effect of the Human Development Index, containment policies, testing capacity, specific humidity, temperature, and landlocked status of countries on the local within-country and external between-country transmission. One-week forecasts of case numbers from the model were driven by the quality of the reported data. Seeking equitable behavioral and social interventions, balanced with coordinated country-specific strategies in infection suppression, should be a continental priority to control the COVID-19 pandemic in Africa.

Detection of Intracerebral Hemorrhage Using Low-Field, Portable Magnetic Resonance Imaging in Patients With Stroke.

BACKGROUND: Neuroimaging is essential for detecting spontaneous, nontraumatic intracerebral hemorrhage (ICH). Recent data suggest ICH can be characterized using low-field magnetic resonance imaging (MRI). Our primary objective was to investigate the sensitivity and specificity of ICH on a 0.064T portable MRI (pMRI) scanner using a methodology that provided clinical information to inform rater interpretations. As a secondary aim, we investigated whether the incorporation of a deep learning (DL) reconstruction algorithm affected ICH detection. METHODS: The pMRI device was deployed at Yale New Haven Hospital to examine patients presenting with stroke symptoms from October 26, 2020 to February 21, 2022. Three raters independently evaluated pMRI examinations. Raters were provided the images alongside the patient's clinical information to simulate real-world context of use. Ground truth was the closest conventional computed tomography or 1.5/3T MRI. Sensitivity and specificity results were grouped by DL and non-DL software to investigate the effects of software advances. RESULTS: A total of 189 exams (38 ICH, 89 acute ischemic stroke, 8 subarachnoid hemorrhage, 3 primary intraventricular hemorrhage, 51 no intracranial abnormality) were evaluated. Exams were correctly classified as positive or negative for ICH in 185 of 189 cases (97.9% overall accuracy). ICH was correctly detected in 35 of 38 cases (92.1% sensitivity). Ischemic stroke and no intracranial abnormality cases were correctly identified as blood-negative in 139 of 140 cases (99.3% specificity). Non-DL scans had a sensitivity and specificity for ICH of 77.8% and 97.1%, respectively. DL scans had a sensitivity and specificity for ICH of 96.6% and 99.3%, respectively. CONCLUSIONS: These results demonstrate improvements in ICH detection accuracy on pMRI that may be attributed to the integration of clinical information in rater review and the incorporation of a DL-based algorithm. The use of pMRI holds promise in providing diagnostic neuroimaging for patients with ICH.

Neonatal Paenibacilliosis: Paenibacillus Infection as a Novel Cause of Sepsis in Term Neonates With High Risk of Sequelae in Uganda.

BACKGROUND: Paenibacillus thiaminolyticus may be an underdiagnosed cause of neonatal sepsis. METHODS: We prospectively enrolled a cohort of 800 full-term neonates presenting with a clinical diagnosis of sepsis at 2 Ugandan hospitals. Quantitative polymerase chain reaction specific to P. thiaminolyticus and to the Paenibacillus genus were performed on the blood and cerebrospinal fluid (CSF) of 631 neonates who had both specimen types available. Neonates with Paenibacillus genus or species detected in either specimen type were considered to potentially have paenibacilliosis, (37/631, 6%). We described antenatal, perinatal, and neonatal characteristics, presenting signs, and 12-month developmental outcomes for neonates with paenibacilliosis versus clinical sepsis due to other causes. RESULTS: Median age at presentation was 3 days (interquartile range 1, 7). Fever (92%), irritability (84%), and clinical signs of seizures (51%) were common. Eleven (30%) had an adverse outcome: 5 (14%) neonates died during the first year of life; 5 of 32 (16%) survivors developed postinfectious hydrocephalus (PIH) and 1 (3%) additional survivor had neurodevelopmental impairment without hydrocephalus. CONCLUSIONS: Paenibacillus species was identified in 6% of neonates with signs of sepsis who presented to 2 Ugandan referral hospitals; 70% were P. thiaminolyticus. Improved diagnostics for neonatal sepsis are urgently needed. Optimal antibiotic treatment for this infection is unknown but ampicillin and vancomycin will be ineffective in many cases. These results highlight the need to consider local pathogen prevalence and the possibility of unusual pathogens when determining antibiotic choice for neonatal sepsis.

Deep Learning Applications for Acute Stroke Management.

Brain imaging is essential to the clinical care of patients with stroke, a leading cause of disability and death worldwide. Whereas advanced neuroimaging techniques offer opportunities for aiding acute stroke management, several factors, including time delays, inter-clinician variability, and lack of systemic conglomeration of clinical information, hinder their maximal utility. Recent advances in deep machine learning (DL) offer new strategies for harnessing computational medical image analysis to inform decision making in acute stroke. We examine the current state of the field for DL models in stroke triage. First, we provide a brief, clinical practice-focused primer on DL. Next, we examine real-world examples of DL applications in pixel-wise labeling, volumetric lesion segmentation, stroke detection, and prediction of tissue fate postintervention. We evaluate recent deployments of deep neural networks and their ability to automatically select relevant clinical features for acute decision making, reduce inter-rater variability, and boost reliability in rapid neuroimaging assessments, and integrate neuroimaging with electronic medical record (EMR) data in order to support clinicians in routine and triage stroke management. Ultimately, we aim to provide a framework for critically evaluating existing automated approaches, thus equipping clinicians with the ability to understand and potentially apply DL approaches in order to address challenges in clinical practice. ANN NEUROL 2022;92:574-587.

On-site construction of a point-of-care low-field MRI system in Africa.

PURPOSE: To describe the construction and testing of a portable point-of-care low-field MRI system on site in Africa. METHODS: All of the components to assemble a 50 mT Halbach magnet-based system, together with the necessary tools, were air-freighted from the Netherlands to Uganda. The construction steps included individual magnet sorting, filling of each ring of the magnet assembly, fine-tuning the inter-ring separations of the 23-ring magnet assembly, gradient coil construction, integration of gradient coils and magnet assembly, construction of the portable aluminum trolley and finally testing of the entire system with an open source MR spectrometer. RESULTS: With four instructors and six untrained personnel, the complete project from delivery to first image took approximately 11 days. CONCLUSIONS: An important step in translating scientific developments in the western world from high-income industrialized countries to low- and middle-income countries (LMICs) is to produce technology that can be assembled and ultimately constructed locally. Local assembly and construction are associated with skill development, low costs and jobs. Point-of-care systems have a large potential to increase the accessibility and sustainability of MRI in LMICs, and this work demonstrates that technology and knowledge transfer can be performed relatively seamlessly.

mirTarRnaSeq: An R/Bioconductor Statistical Package for miRNA-mRNA Target Identification and Interaction Analysis.

We introduce mirTarRnaSeq, an R/Bioconductor package for quantitative assessment of miRNA-mRNA relationships within sample cohorts. mirTarRnaSeq is a statistical package to explore predicted or pre-hypothesized miRNA-mRNA relationships following target prediction.We present two use cases applying mirTarRnaSeq. First, to identify miRNA targets, we examined EBV miRNAs for interaction with human and virus transcriptomes of stomach adenocarcinoma. This revealed enrichment of mRNA targets highly expressed in CD105+ endothelial cells, monocytes, CD4+ T cells, NK cells, CD19+ B cells, and CD34 cells. Next, to investigate miRNA-mRNA relationships in SARS-CoV-2 (COVID-19) infection across time, we used paired miRNA and RNA sequenced datasets of SARS-CoV-2 infected lung epithelial cells across three time points (4, 12, and 24 hours post-infection). mirTarRnaSeq identified evidence for human miRNAs targeting cytokine signaling and neutrophil regulation immune pathways from 4 to 24 hours after SARS-CoV-2 infection. Confirming the clinical relevance of these predictions, three of the immune specific mRNA-miRNA relationships identified in human lung epithelial cells after SARS-CoV-2 infection were also observed to be differentially expressed in blood from patients with COVID-19. Overall, mirTarRnaSeq is a robust tool that can address a wide-range of biological questions providing improved prediction of miRNA-mRNA interactions.

IDENTIFIABILITY OF INFECTION MODEL PARAMETERS EARLY IN AN EPIDEMIC.

It is known that the parameters in the deterministic and stochastic SEIR epidemic models are structurally identifiable. For example, from knowledge of the infected population time series I(t) during the entire epidemic, the parameters can be successfully estimated. In this article we observe that estimation will fail in practice if only infected case data during the early part of the epidemic (prepeak) is available. This fact can be explained using a well-known phenomenon called dynamical compensation. We use this concept to derive an unidentifiability manifold in the parameter space of SEIR that consists of parameters indistinguishable from I(t) early in the epidemic. Thus, identifiability depends on the extent of the system trajectory that is available for observation. Although the existence of the unidentifiability manifold obstructs the ability to exactly determine the parameters, we suggest that it may be useful for uncertainty quantification purposes. A variant of SEIR recently proposed for COVID-19 modeling is also analyzed, and an analogous unidentifiability surface is derived.

The Problem of Microbial Dark Matter in Neonatal Sepsis.

Neonatal sepsis (NS) kills 750,000 infants every year. Effectively treating NS requires timely diagnosis and antimicrobial therapy matched to the causative pathogens, but most blood cultures for suspected NS do not recover a causative pathogen. We refer to these suspected but unidentified pathogens as microbial dark matter. Given these low culture recovery rates, many non-culture-based technologies are being explored to diagnose NS, including PCR, 16S amplicon sequencing, and whole metagenomic sequencing. However, few of these newer technologies are scalable or sustainable globally. To reduce worldwide deaths from NS, one possibility may be performing population-wide pathogen discovery. Because pathogen transmission patterns can vary across space and time, computational models can be built to predict the pathogens responsible for NS by region and season. This approach could help to optimally treat patients, decreasing deaths from NS and increasing antimicrobial stewardship until effective diagnostics that are scalable become available globally.

Endoscopic Treatment versus Shunting for Infant Hydrocephalus in Uganda.

BACKGROUND: Postinfectious hydrocephalus in infants is a major health problem in sub-Saharan Africa. The conventional treatment is ventriculoperitoneal shunting, but surgeons are usually not immediately available to revise shunts when they fail. Endoscopic third ventriculostomy with choroid plexus cauterization (ETV-CPC) is an alternative treatment that is less subject to late failure but is also less likely than shunting to result in a reduction in ventricular size that might facilitate better brain growth and cognitive outcomes. METHODS: We conducted a randomized trial to evaluate cognitive outcomes after ETV-CPC versus ventriculoperitoneal shunting in Ugandan infants with postinfectious hydrocephalus. The primary outcome was the Bayley Scales of Infant Development, Third Edition (BSID-3), cognitive scaled score 12 months after surgery (scores range from 1 to 19, with higher scores indicating better performance). The secondary outcomes were BSID-3 motor and language scores, treatment failure (defined as treatment-related death or the need for repeat surgery), and brain volume measured on computed tomography. RESULTS: A total of 100 infants were enrolled; 51 were randomly assigned to undergo ETV-CPC, and 49 were assigned to undergo ventriculoperitoneal shunting. The median BSID-3 cognitive scores at 12 months did not differ significantly between the treatment groups (a score of 4 for ETV-CPC and 2 for ventriculoperitoneal shunting; Hodges-Lehmann estimated difference, 0; 95% confidence interval [CI], -2 to 0; P=0.35). There was no significant difference between the ETV-CPC group and the ventriculoperitoneal-shunt group in BSID-3 motor or language scores, rates of treatment failure (35% and 24%, respectively; hazard ratio, 0.7; 95% CI, 0.3 to 1.5; P=0.24), or brain volume (z score, -2.4 and -2.1, respectively; estimated difference, 0.3; 95% CI, -0.3 to 1.0; P=0.12). CONCLUSIONS: This single-center study involving Ugandan infants with postinfectious hydrocephalus showed no significant difference between endoscopic ETV-CPC and ventriculoperitoneal shunting with regard to cognitive outcomes at 12 months. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01936272 .).

A Brain-Heart Biomarker for Epileptogenesis.

Postinjury epilepsy is an potentially preventable sequela in as many as 20% of patients with brain insults. For these cases biomarkers of epileptogenesis are critical to facilitate identification of patients at high-risk of developing epilepsy and to introduce effective anti-epileptogenic interventions. Here, we demonstrate that delayed brain-heart coincidences serve as a reliable biomarker. In a murine model of post-infection acquired epilepsy, we used long-term simultaneous measurements of the brain activity via electroencephalography and autonomic cardiac activity via electrocardiography, in male mice, to quantitatively track brain-heart interactions during epileptogenesis. We find that abnormal cortical discharges precede abnormal fluctuations in the cardiac rhythm at the resolution of single beat-to-beat intervals. The delayed brain-heart coincidence is detectable as early as the onset of chronic measurements, 2-14 weeks before the first seizure, only in animals that become epileptic, and increases during epileptogenesis. Therefore, delayed brain-heart coincidence serves as a biomarker of epileptogenesis and could be used for phenotyping, diagnostic, and therapeutic purposes.SIGNIFICANCE STATEMENT No biomarker that readily predicts and tracks epileptogenesis currently exists for the wide range of human acquired epilepsies. Here, we used long-term measurements of brain and heart activity in a mouse model of post-infection acquired epilepsy to investigate the potential of brain-heart interaction as a biomarker of epileptogenesis. We found that delayed coincidences from brain to heart can clearly separate the mice that became epileptic from those that did not weeks before development of epilepsy. Our findings allow for phenotyping and tracking of epileptogenesis in this and likely other models of acquired epilepsy. Such capability is critical for efficient adjunctive treatment development and for tracking the efficacy of such treatments.

Design of a sustainable prepolarizing magnetic resonance imaging system for infant hydrocephalus.

OBJECTIVES: The need for affordable and appropriate medical technologies for developing countries continues to rise as challenges such as inadequate energy supply, limited technical expertise, and poor infrastructure persist. Low-field magnetic resonance imaging (LF MRI) is a technology that can be tailored to meet specific imaging needs within such countries. Its low power requirements and the possibility of operating in minimally shielded or unshielded environments make it especially attractive. Although the technology has been widely demonstrated over several decades, it is yet to be shown that it can be diagnostic and improve patient outcomes in clinical applications. We here demonstrate the robustness of prepolarizing MRI (PMRI) technology for assembly and deployment in developing countries for the specific application to infant hydrocephalus. Hydrocephalus treatment planning and management requires only modest spatial resolution, such that the brain can be distinguished from fluid-tissue contrast detail within the brain parenchyma is not essential. MATERIALS AND METHODS: We constructed an internally shielded PMRI system based on the Lee-Whiting coil system with a 22-cm diameter of spherical volume. RESULTS: In an unshielded room, projection phantom images were acquired at 113 kHz with in-plane resolution of 3 mm × 3 mm, by introducing gradient fields of sufficient magnitude to dominate the 5000 ppm inhomogeneity of the readout field. DISCUSSION: The low cost, straightforward assembly, deployment potential, and maintenance requirements demonstrate the suitability of our PMRI system for developing countries. Further improvement in image spatial resolution and contrast of LF MRI will broaden its potential clinical utility beyond hydrocephalus.

Prevalence and correlates of MRSA and MSSA nasal carriage at a Ugandan regional referral hospital.

Background: Despite increasing antimicrobial resistance globally, data are lacking on prevalence and factors associated with Staphylococcus aureus (SA) and MRSA carriage in resource-limited settings. Objectives: To determine the prevalence of SA and MRSA nasal carriage and factors associated with carriage among Ugandan regional referral hospital patients. Methods: We enrolled a cross-section of 500 adults, sampling anterior nares for SA and MRSA carriage using Cepheid Xpert SA Nasal Complete. Results: Mean age was 37 years; 321 (64%) were female and 166 (33%) were HIV infected. Overall, 316 (63%) reported risk factors for invasive SA infection; 368 (74%) reported current antibiotic use. SA was detected in 29% and MRSA in 2.8%. MRSA and MSSA carriers were less likely than SA non-carriers to be female (50% and 56% versus 68%, P = 0.03) or to have recently used ß-lactam antibiotics (43% and 65% versus 73%, P = 0.01). MRSA carriers were more likely to have open wounds than MSSA carriers and SA non-carriers (71% versus 27% and 40%, P = 0.001) and contact with pigs (21% versus 2% and 6%, P = 0.008). MRSA carriage ranged from 0% of HIV clinic participants to 8% of inpatient surgical ward participants ( P = 0.01). In multivariable logistic regression analysis, male sex was independently associated with SA carriage (OR 1.68, 95% CI 1.12-2.53, P = 0.01) and recent ß-lactam antibiotic use was associated with reduced odds of SA carriage (OR 0.61, 95% CI 0.38-0.97, P = 0.04). Conclusions: MRSA nasal carriage prevalence was low and associated with pig contact, open wounds and surgical ward admission, but not with HIV infection.

The Role of Cell Volume in the Dynamics of Seizure, Spreading Depression, and Anoxic Depolarization.

Cell volume changes are ubiquitous in normal and pathological activity of the brain. Nevertheless, we know little of how cell volume affects neuronal dynamics. We here performed the first detailed study of the effects of cell volume on neuronal dynamics. By incorporating cell swelling together with dynamic ion concentrations and oxygen supply into Hodgkin-Huxley type spiking dynamics, we demonstrate the spontaneous transition between epileptic seizure and spreading depression states as the cell swells and contracts in response to changes in osmotic pressure. Our use of volume as an order parameter further revealed a dynamical definition for the experimentally described physiological ceiling that separates seizure from spreading depression, as well as predicted a second ceiling that demarcates spreading depression from anoxic depolarization. Our model highlights the neuroprotective role of glial K buffering against seizures and spreading depression, and provides novel insights into anoxic depolarization and the relevant cell swelling during ischemia. We argue that the dynamics of seizures, spreading depression, and anoxic depolarization lie along a continuum of the repertoire of the neuron membrane that can be understood only when the dynamic ion concentrations, oxygen homeostasis,and cell swelling in response to osmotic pressure are taken into consideration. Our results demonstrate the feasibility of a unified framework for a wide range of neuronal behaviors that may be of substantial importance in the understanding of and potentially developing universal intervention strategies for these pathological states.

Design of a mobile, homogeneous, and efficient electromagnet with a large field of view for neonatal low-field MRI.

OBJECTIVE: In this work, a prototype of an effective electromagnet with a field-of-view (FoV) of 140 mm for neonatal head imaging is presented. The efficient implementation succeeded by exploiting the use of steel plates as a housing system. We achieved a compromise between large sample volumes, high homogeneity, high B0 field, low power consumption, light weight, simple fabrication, and conserved mobility without the necessity of a dedicated water cooling system. MATERIALS AND METHODS: The entire magnetic resonance imaging (MRI) system (electromagnet, gradient system, transmit/receive coil, control system) is introduced and its unique features discussed. Furthermore, simulations using a numerical optimization algorithm for magnet and gradient system are presented. RESULTS: Functionality and quality of this low-field scanner operating at 23 mT (generated with 500 W) is illustrated using spin-echo imaging (in-plane resolution 1.6 mm × 1.6 mm, slice thickness 5 mm, and signal-to-noise ratio (SNR) of 23 with a acquisition time of 29 min). B0 field-mapping measurements are presented to characterize the homogeneity of the magnet, and the B0 field limitations of 80 mT of the system are fully discussed. CONCLUSION: The cryogen-free system presented here demonstrates that this electromagnet with a ferromagnetic housing can be optimized for MRI with an enhanced and homogeneous magnetic field. It offers an alternative to prepolarized MRI designs in both readout field strength and power use. There are multiple indications for the clinical medical application of such low-field devices.

Unification of neuronal spikes, seizures, and spreading depression.

The pathological phenomena of seizures and spreading depression have long been considered separate physiological events in the brain. By incorporating conservation of particles and charge, and accounting for the energy required to restore ionic gradients, we extend the classic Hodgkin-Huxley formalism to uncover a unification of neuronal membrane dynamics. By examining the dynamics as a function of potassium and oxygen, we now account for a wide range of neuronal activities, from spikes to seizures, spreading depression (whether high potassium or hypoxia induced), mixed seizure and spreading depression states, and the terminal anoxic "wave of death." Such a unified framework demonstrates that all of these dynamics lie along a continuum of the repertoire of the neuron membrane. Our results demonstrate that unified frameworks for neuronal dynamics are feasible, can be achieved using existing biological structures and universal physical conservation principles, and may be of substantial importance in enabling our understanding of brain activity and in the control of pathological states.

Rapid eye movement sleep and hippocampal theta oscillations precede seizure onset in the tetanus toxin model of temporal lobe epilepsy.

Improved understanding of the interaction between state of vigilance (SOV) and seizure onset has therapeutic potential. Six rats received injections of tetanus toxin (TeTX) in the ventral hippocampus that resulted in chronic spontaneous seizures. The distribution of SOV before 486 seizures was analyzed for a total of 19 d of recording. Rapid eye movement sleep (REM) and exploratory wake, both of which express prominent hippocampal theta rhythm, preceded 47 and 34%, for a total of 81%, of all seizures. Nonrapid eye movement sleep (NREM) and nonexploratory wake, neither of which expresses prominent theta, preceded 6.8 and 13% of seizures. We demonstrate that identification of SOV yields significant differentiation of seizure susceptibilities, with the instantaneous seizure rate during REM nearly 10 times higher than baseline and the rate for NREM less than half of baseline. Survival analysis indicated a shorter duration of preseizure REM bouts, with a maximum transition to seizure at ∼90 s after the onset of REM. This study provides the first analysis of a correlation between SOV and seizure onset in the TeTX model of temporal lobe epilepsy, as well as the first demonstration that hippocampal theta rhythms associated with natural behavioral states can serve a seizure-promoting role. Our findings are in contrast with previous studies suggesting that the correlations between SOV and seizures are primarily governed by circadian oscillations and the notion that hippocampal theta rhythms inhibit seizures. The documentation of significant SOV-dependent seizure susceptibilities indicates the potential utility of SOV and its time course in seizure prediction and control.

Oxygen and seizure dynamics: II. Computational modeling.

Electrophysiological recordings show intense neuronal firing during epileptic seizures leading to enhanced energy consumption. However, the relationship between oxygen metabolism and seizure patterns has not been well studied. Recent studies have developed fast and quantitative techniques to measure oxygen microdomain concentration during seizure events. In this article, we develop a biophysical model that accounts for these experimental observations. The model is an extension of the Hodgkin-Huxley formalism and includes the neuronal microenvironment dynamics of sodium, potassium, and oxygen concentrations. Our model accounts for metabolic energy consumption during and following seizure events. We can further account for the experimental observation that hypoxia can induce seizures, with seizures occurring only within a narrow range of tissue oxygen pressure. We also reproduce the interplay between excitatory and inhibitory neurons seen in experiments, accounting for the different oxygen levels observed during seizures in excitatory vs. inhibitory cell layers. Our findings offer a more comprehensive understanding of the complex interrelationship among seizures, ion dynamics, and energy metabolism.

Frequency dependence of behavioral modulation by hippocampal electrical stimulation.

Electrical stimulation offers the potential to develop novel strategies for the treatment of refractory medial temporal lobe epilepsy. In particular, direct electrical stimulation of the hippocampus presents the opportunity to modulate pathological dynamics at the ictal focus, although the neuroanatomical substrate of this region renders it susceptible to altering cognition and affective processing as a side effect. We investigated the effects of three electrical stimulation paradigms on separate groups of freely moving rats (sham, 8-Hz and 40-Hz sine-wave stimulation of the ventral/intermediate hippocampus, where 8- and 40-Hz stimulation were chosen to mimic naturally occurring hippocampal oscillations). Animals exhibited attenuated locomotor and exploratory activity upon stimulation at 40 Hz, but not at sham or 8-Hz stimulation. Such behavioral modifications were characterized by a significant reduction in rearing frequency, together with increased freezing behavior. Logistic regression analysis linked the observed changes in animal locomotion to 40-Hz electrical stimulation independently of time-related variables occurring during testing. Spectral analysis, conducted to monitor the electrophysiological profile in the CA1 area of the dorsal hippocampus, showed a significant reduction in peak theta frequency, together with reduced theta power in the 40-Hz vs. the sham stimulation animal group, independent of locomotion speed (theta range: 4-12 Hz). These findings contribute to the development of novel and safe medical protocols by indicating a strategy to constrain or optimize parameters in direct hippocampal electrical stimulation.