Biology subjects

Costine-Bartell, B. A.

Publications and source records attributed to Costine-Bartell, B. A..

5 recordsLinked to original sources

bioRxiv2026

Individualized and stereotypical seizure semiology in a porcine model of post-traumatic epilepsy.

Large-animal models of traumatic brain injury may yield translatable data on epileptogenesis, given their similarities in anatomy, brain size, and immune systems to humans. Adult male and female swine received bilateral cortical impact (N=16) or sham surgery (N=6) and were screened for convulsions via video-EEG for up to one year. Post-traumatic epilepsy (PTE) was defined as 2 seizures after 1-week post-injury. Nine out of sixteen pigs (56%) receiving bilateral cortical impact developed PTE, with an average 4.6 months ({+/-}3.4,SD) latent period. Seizures (N = 199) began focally, sometimes with motor onset including automatisms, before becoming generalized, with tonic-clonic or tonic convulsions. We defined a library differentiating peri-ictal behaviors (N = 31) from rhythmic/odd behaviors typical in healthy pigs (N = 12). Seizures had an average of 7.3 behaviors per seizure (max 26) lasting an average of 1.8 minutes (max 7.9). For seizures comprised of multiple convulsive episodes, the first convulsion had a greater number of peri-ictal behaviors than subsequent convulsions (P < 0.001). The array of peri-ictal behaviors displayed was pig-specific, with many behaviors consistently observed across seizures. The seizure frequency detected was 0.38/day. This large-brain model of PTE exhibits a variable period of epileptogenesis, a substantial rate of PTE, and an expansive repertoire of ictal behaviors. This first description of semiology in this species will serve as a guide for other porcine epilepsy models. Biofidelic models of PTE are expected to increase our understanding of the pathophysiology, enabling the identification and testing of therapeutics that translate into human patients. HighlightsO_LIThe average time from bilateral cortical impact to post-traumatic epilepsy in swine is 6 months, and is highly variable, ranging from 2 to 47 weeks post-TBI. C_LIO_LISwine with post-traumatic epilepsy display an array of specific behaviors around convulsions, distinct from pigs without post-traumatic epilepsy. C_LIO_LIThough the duration of convulsion was typically a few seconds, the entire seizure, with the associated peri-ictal behaviors, lasts up to 7.9 minutes. C_LIO_LIThe complexity of behaviors around convulsions tended to increase from early traumatic seizures to post-traumatic seizures. C_LIO_LIPeri-ictal behaviors observed around convulsions in an individual were often displayed prior to the first convulsion. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=115 SRC="FIGDIR/small/708000v2_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@9523aborg.highwire.dtl.DTLVardef@158cfa6org.highwire.dtl.DTLVardef@1a8b499org.highwire.dtl.DTLVardef@e8c86f_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Acute temporal, regional, and cell-type specific NKCC1 disruption following severe TBI in the developing gyrencephalic brain.

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in infants and toddlers, with limited treatment options and persistent neurological sequelae. We developed a multi-pathoanatomic lesion multi-insult (MuLMI) severe TBI model in piglets that replicates age-dependent damage patterns to the cortical ribbon observed in human patients with less injury in postnatal day (PND) 7 "infant" piglets and more extensive tissue damage in PND30 "toddler" piglets. Given that neuronal chloride homeostasis influences excitability, seizure susceptibility, and edema, we examined the developmental and injury-induced regulation of key cation-chloride cotransporters and modulators: NKCC1 (sodium-potassium-2-chloride cotransporter), KCC2 (potassium-chloride cotransporter), and the regulatory kinase SPAK, which are biomarkers of neuronal chloride concentrations. This study is the first to define the spatiotemporal expression and phosphorylation profiles of these proteins in the developing piglet brain. We found a perinatal shift in the ratio of KCC2:NKCC1 across the brain, driven primarily by protein abundance, rather than transcriptional levels. We hypothesized that toddler piglets would exhibit an increase in cortical NKCC1 and SPAK causing hyperexcitability and perhaps explaining their more severe, unilateral cortical damage. Severe TBI induced a transcriptional increase in Slc12a2 and Stk39, and a decrease in Slc12a5 in toddler piglets, but not infant piglets. We further found that infant piglets, not toddler piglets, upregulated SPAK and Tyrosine Receptor Kinase B (TRKB) protein in cortex after TBI, with minimal changes in NKCC1 and KCC2. However, phosphorylated NKCC1 (pNKCC1) was significantly upregulated in surviving cortical neurons after TBI in infant piglets and was unchanged in toddlers, despite more severe injury. These findings suggest that cortical neuronal NKCC1 activation may play a role in post-traumatic excitability or resilience in the immature brain and identify NKCC1 and/or SPAK as a potential therapeutic target. In human tissue, the KCC2:NKCC1 ratio also increased postnatally, and TBI caused region and cell-type specific dysregulation of pNKCC1. Our results establish piglets as a valuable model for investigating age-specific mechanisms of pediatric TBI and for testing targeted interventions, particularly for infant populations where seizure control remains a major clinical challenge.

neuroscience↗

bioRxiv2023

Brief Apnea and Hypoventilation Reduces Seizure Duration and Shifts Seizure Location for Several Hours in a Model of Severe Traumatic Brain Injury.

ObjectiveSeizures are difficult to control in infants and toddlers. Seizures with periods of apnea and hypoventilation are common following severe traumatic brain injury (TBI). In our multifactorial, severe TBI model (cortical impact, mass effect, subdural hematoma, subarachnoid hemorrhage, seizures induced with kainic acid, and brief apnea and hypoventilation), we observed that brief apnea with hypoventilation (A&H) after induced seizure acutely interrupted seizures, leading us to hypothesize that brief A&H might reduce seizure duration beyond the brief hypoxia and hypercapnia for several hours thereafter. The effects of the timing of A&H on seizure duration and location might inform the pathophysiology of this hypoxic-ischemic injury as well as potential treatments. MethodsPiglets (1 week or 1 month old) received multi-factorial injuries. Apnea and hypoventilation (1 min apnea, 10 min hypoventilation; A&H) was induced either before or after seizure induction, or as a control piglets received subdural/subarachnoid hematoma and seizure without A&H. In an intensive care unit, piglets were sedated, intubated, mechanically ventilated, and epidural EEG was recorded for an average of 18 hours after seizure induction. ResultsIn our severe TBI model, A&H after seizure reduced ipsilateral seizure burden by 80% compared to the same injuries without A&H. In the A&H before seizure induction group, more piglets had exclusively contralateral seizures though most piglets in all groups had seizures that shifted location throughout the several hours of seizure. After 8-10 hours, seizures transitioned to interictal epileptiform discharges regardless of timing of A&H. SignificanceEven brief A&H may alter traumatic seizures We will address the possibility of induced spreading depolarization prior to preclinical investigations of hypercapnia with normoxia, with controlled intracranial pressure, as a therapeutic option for children with status epilepticus after hemorrhagic TBI.

neuroscience↗

bioRxiv2023

2-photon imaging of fluorescent proteins in living swine

A common point of failure in translation of preclinical neurological research to successful clinical trials comes in the giant leap from rodent models to humans. Non-human primates are phylogenetically close to humans, but cost and ethical considerations prohibit their widespread usage in preclinical trials. Swine have large, gyrencencephalic brains, which are biofidelic to human brains. Their classification as livestock makes them a readily accessible model organism. However, their size has precluded experiments involving intravital imaging with cellular resolution. Here, we present a suite of techniques and tools for in vivo imaging of porcine brains with subcellular resolution. Specifically, we describe surgical techniques for implanting a synthetic, flexible, transparent dural window for chronic optical access to the neocortex. We detail optimized parameters and methods for injecting adeno-associated virus vectors through the cranial imaging window to express fluorescent proteins. We introduce a large-animal 2-photon microscope that was constructed with off-the shelf components, has a gantry design capable of accommodating animals > 80 kg, and is equipped with a high-speed digitizer for digital fluorescence lifetime imaging. Finally, we delineate strategies developed to mitigate the substantial motion artifact that complicates high resolution imaging in large animals, including heartbeat-triggered high-speed image stack acquisition. The effectiveness of this approach is demonstrated in sample images acquired from pigs transduced with the chloride-sensitive fluorescent protein SuperClomeleon.

neuroscience↗

bioRxiv2022

Robust, long-term video EEG monitoring in a porcine model of post-traumatic epilepsy.

To date, post-traumatic epilepsy (PTE) research in large animal models has been limited. Recent advances in neocortical microscopy have made possible new insights into neocortical PTE. However, it is very difficult to engender convincing neocortical PTE in rodents. Thus, large animal models that develop neocortical PTE may provide useful insights that also can be more comparable to human patients. Because gyrencephalic species have prolonged latent periods, long-term video EEG recording is required. Here, we report a fully subcutaneous EEG implant with synchronized video in freely ambulatory swine for up to 14 months during epileptogenesis following bilateral cortical impact injuries or sham surgery The advantages of this system include the availability of a commercially available system that is simple to install, a low failure rate after surgery for EEG implantation, radiotelemetry that enables continuous monitoring of freely ambulating animals, excellent synchronization to video to EEG, and a robust signal to noise ratio. The disadvantages of this system in this species and age are the accretion of skull bone which entirely embedded a subset of skull screws and EEG electrodes, and the inability to rearrange the EEG electrode array. These disadvantages may be overcome by splicing a subdural electrode strip to the electrode leads so that skull growth is less likely to interfere with long-term signal capture and by placing two implants for a more extensive montage. This commercially available system in this bilateral cortical impact swine model may be useful to a wide range of investigators studying epileptogenesis in PTE. SignificancePost-traumatic epilepsy (PTE) is a cause of significant morbidity after traumatic brain injury (TBI) and is often drug-resistant. Robust, informative animal models would greatly facilitate PTE research. Ideally, this biofidelic model of PTE would utilize a species that approximates human brain anatomy, brain size, glial populations, and inflammatory pathways. An ideal model would also incorporate feasible methods for long-term video EEG recording required to quantify seizure activity. Here, we describe the first model of PTE in swine and describe a method for robust long-term video EEG monitoring for up to 14 months post-TBI. The relatively easy "out-of-the-box" radiotelemetry system and surgical techniques described here will be adaptable by a wide array of investigators studying the pathogenesis and treatment of PTE.

neuroscience↗