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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 19 records
All sourcesNASA NTRSDOE OSTI
NASA NTRS2000

Oxygen desaturations triggered by partial seizures: implications for cardiopulmonary instability in epilepsy

PURPOSE: The occurrence of hypoxemia in adults with partial seizures has not been systematically explored. Our aim was to study in detail the temporal dynamics of this specific type of ictal-associated hypoxemia. METHODS: During long-term video/EEG monitoring (LTM), patients underwent monitoring of oxygen saturation using a digital Spo2 (pulse oximeter) transducer. Six patients (nine seizures) were identified with oxygen desaturations after the onset of partial seizure activity. RESULTS: Complex partial seizures originated from both left and right temporal lobes. Mean seizure duration (+/-SD) was 73 +/- 18 s. Mean Spo2 desaturation duration was 76 +/- 19 s. The onset of oxygen desaturation followed seizure onset with a mean delay of 43 +/- 16 s. Mean (+/-SD) Spo2 nadir was 83 +/- 5% (range, 77-91%), occurring an average of 35 +/- 12 s after the onset of the desaturation. One seizure was associated with prolonged and recurrent Spo2 desaturations. CONCLUSIONS: Partial seizures may be associated with prominent oxygen desaturations. The comparable duration of each seizure and its subsequent desaturation suggests a close mechanistic (possibly causal) relation. Spo2 monitoring provides an added means for seizure detection that may increase LTM yield. These observations also raise the possibility that ictal ventilatory dysfunction could play a role in certain cases of sudden unexpected death in epilepsy in adults with partial seizures.

NASA Program Biomedical Research and Countermeasur↗
DOE OSTI2023

Drug-Inducible Gene Therapy Effectively Reduces Spontaneous Seizures in Kindled Rats but Creates Off-Target Side Effects in Inhibitory Neurons

Over a third of patients with temporal lobe epilepsy (TLE) are not effectively treated with current anti-seizure drugs, spurring the development of gene therapies. The injection of adeno-associated viral vectors (AAV) into the brain has been shown to be a safe and viable approach. However, to date, AAV expression of therapeutic genes has not been regulated. Moreover, a common property of antiepileptic drugs is a narrow therapeutic window between seizure control and side effects. Therefore, a long-term goal is to develop drug-inducible gene therapies that can be regulated by clinically relevant drugs. In this study, a first-generation doxycycline-regulated gene therapy that delivered an engineered version of the leak potassium channel Kcnk2 (TREK-M) was injected into the hippocampus of male rats. Rats were electrically stimulated until kindled. EEG was monitored 24/7. Electrical kindling revealed an important side effect, as even low expression of TREK M in the absence of doxycycline was sufficient to cause rats to develop spontaneous recurring seizures. Treating the epileptic rats with doxycycline successfully reduced spontaneous seizures. Localization studies of infected neurons suggest seizures were caused by expression in GABAergic inhibitory neurons. In contrast, doxycycline increased the expression of TREK-M in excitatory neurons, thereby reducing seizures through net inhibition of firing. These studies demonstrate that drug-inducible gene therapies are effective in reducing spontaneous seizures and highlight the importance of testing for side effects with pro-epileptic stressors such as electrical kindling. These studies also show the importance of evaluating the location and spread of AAV-based gene therapies in preclinical studies.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Astrocyte FABP7 Modulates Seizure Activity-Dependent Protein Expression in Mouse Brain

Background/Objectives: Patients with epilepsy commonly experience patterns of seizures that change with sleep/wake behavior or diurnal rhythms. The cellular and molecular mechanisms that underlie these patterns in seizure activity are not well understood but may involve non-neuronal cells, such as astrocytes. Our previous studies show the critical importance of one specific astrocyte factor, the brain-type fatty acid binding protein Fabp7, in the regulation of time-of-day-dependent electroshock seizure threshold and neural activity-dependent gene expression in mice. Here, we examined whether Fabp7 influences differential seizure activity-dependent protein expression, by comparing Fabp7 knockout (KO) to wild-type (WT) mice under control conditions and after reaching the maximal electroshock seizure threshold (MEST). Methods: We analyzed the proteome in cortical–hippocampal extracts from MEST and SHAM groups of WT and KO mice using mass spectrometry (MS), followed by Gene Ontology (GO) and pathway analyses. GO and pathway analyses of all groups revealed a diverse set of up- and downregulated differentially expressed proteins (DEPs). Results: We identified 65 significant DEPs in the comparison of KO SHAM versus WT SHAM; 33 proteins were upregulated and 32 were downregulated. We found downregulation in mitochondrial-associated proteins in WT MEST compared to WT SHAM controls, including Slc1a4, Slc25a27, Cox7a2, Cox8a, Micos10, and Atp5mk. Several upregulated DEPs in the KO SHAM versus WT SHAM comparison were associated with the 20S proteasomal subunit, suggesting proteasomal activity is elevated in the absence of Fabp7 expression. We also observed 92 DEPs significantly altered in the KO MEST versus WT MEST, with 49 proteins upregulated and 43 downregulated. Conclusions: Together, these data suggest that the astrocyte Fabp7 regulation of time-of-day-mediated neural excitability is modulated by multiple cellular mechanisms, which include proteasomal pathways, independent of its role in activity-dependent gene expression.

Neural Excitability↗
NASA NTRS1972

Effect of sleep-wake reversal and sleep deprivation on the circadian rhythm of oxygen toxicity seizure susceptibility.

Albino Sprague-Dawley rats were exposed in a previously O2 flushed, CO2 free chamber. The exposure began with attainment of 60 psi (gauge) and the end point was the first generalized oxygen toxicity seizure. Animals were exposed to reversal diurnal conditions since weanlings until their sleep-wake cycles had completely reversed, and then divided into four groups of 20 based on the time of day exposed. The time of exposure to oxygen at high pressure prior to seizure was now significantly longer in the group exposed from 1900 to 2000 hr and a reversal of the circadian rhythm of oxygen toxicity seizure susceptibility was noted. Animals maintained on normal diurnal conditions were deprived of sleep on the day of exposure for the 12 hours prior to exposure at 1900 hr, while controls were allowed to sleep. There was no significant differences in the time prior to seizure between the deprived animals and the controls with an n = 40. Thus the inherent threshold in susceptibility to high-pressure oxygen seizures seems not to be a function of sleep itself, but of some biochemical/physiologic event which manifests a circadian rhythm.

Dexter, J. D.↗
NASA NTRS1993

Automatic Detection of Seizures with Applications

There are an estimated two million people with epilepsy in the United States. Many of these people do not respond to anti-epileptic drug therapy. Two devices can be developed to assist in the treatment of epilepsy. The first is a microcomputer-based system designed to process massive amounts of electroencephalogram (EEG) data collected during long-term monitoring of patients for the purpose of diagnosing seizures, assessing the effectiveness of medical therapy, or selecting patients for epilepsy surgery. Such a device would select and display important EEG events. Currently many such events are missed. A second device could be implanted and would detect seizures and initiate therapy. Both of these devices require a reliable seizure detection algorithm. A new algorithm is described. It is believed to represent an improvement over existing seizure detection algorithms because better signal features were selected and better standardization methods were used.

Olsen, Dale E.↗
DOE OSTI2023

Seizure detection device

A method of detecting a seizure includes collecting volatile organic compounds with a collector material of a collector; separating a mixture of the volatile organic compounds into its constituent chemicals with a gas chromatography column; ionizing the constituent chemicals to create ionized chemicals and detecting the ionized chemicals; and analyzing the ionized chemicals to identify seizure-indicative volatile organic compounds.

Arnold, Gary Stephen↗
NASA NTRS1978

The control and prevention of seizures in children, a developmental and environmental approach

The clinical effectiveness of neurophysiological and developmental factors in controlling and preventing seizure mechanisms is detailed. It is shown that as cortical control advances with maturation, it requires increasingly severe environmental adversity to release this residual defensive reflex mechanism. Administration of anticonvulsant drugs is discouraged because of possible undesirable neuronal effects on the very young brain.

Lewinn, E. B.↗
NASA NTRS1994

Monitor for status epilepticus seizures

This paper describes the sensor technology and associated electronics of a monitor designed to detect the onset of a seizure disorder called status epilepticus. It is a condition that affects approximately 3-5 percent of those individuals suffering from epilepsy. This form of epilepsy does not follow the typical cycle of start-peak-end. The convulsions continue until medically interrupted and are life threatening. The mortality rate is high without prompt medical treatment at a suitable facility. The paper describes the details of a monitor design that provides an inexpensive solution to the needs of those responsible for the care of individuals afflicted with this disorder. The monitor has been designed as a cooperative research and development effort involving the United States Army Armament Research, Development, and Engineering Center's Benet Laboratories (Benet) and the Cerebral Palsy Center for the Disabled (Center), in association with the Department of Neurology at Albany Medical College (AMC). Benet has delivered a working prototype of the device for field testing, in collaboration with Albany Medical College. The Center has identified several children in need of special monitoring and has agreed to pursue commercialization of the device.

Johnson, Mark↗
NASA NTRS2001

Screening EEG in Aircrew Selection: Clinical Aerospace Neurology Perspective

As clinical aerospace neurologists we do not favor using screening EEG in pilot selection on unselected and otherwise asymptomatic individuals. The role of EEG in aviation screening should be as an adjunct to diagnosis, and the decision to disqualify a pilot should never be based solely on the EEG. Although a policy of using a screening EEG in an unselected population might detect an individual with a potentially increased relative risk, it would needlessly exclude many applicants who would probably never have a seizure. A diagnostic test performed on an asymptomatic individual without clinical indications, in a population with a low prevalence of disease (seizure) may be of limited or possibly detrimental value. We feel that rather than do EEGs on all candidates, a better approach would be to perform an EEG for a specific indication, such as family history of seizure, single convulsion (seizure) , history of unexplained loss of consciousness or head injury. Routine screening EEGs in unselected aviation applications are not done without clinical indication in the U.S. Air Force, Navy, or NASA. The USAF discontinued routine screening EEGs for selection in 1978, the U.S. Navy discontinued it in 1981 , and NASA discontinued it in 1995. EEG as an aeromedical screening tool in the US Navy dates back to 1939. The US Navy routinely used EEGs to screen all aeromedical personnel from 1961 to 1981. The incidence of epileptiform activity on EEG in asymptomatic flight candidates ranges from 0.11 to 2.5%. In 3 studies of asymptomatic flight candidates with epileptiform activity on EEG followed for 2 to 15 years, 1 of 31 (3.2%), 1 of 30 (3.3%), and 0 of 14 (0%) developed a seizure, for a cumulative risk of an individual with an epileptiform EEG developing a seizure of 2.67% (2 in 75). Of 28,658 student naval aviation personnel screened 31 had spikes and/or slow waves on EEG, and only 1 later developed a seizure. Of the 28,627 who had a normal EEG, 4 later developed seizures, or .0139% (4/28627). After review of the value of the EEG as a screening tool, the US Navy now uses EEG only for certain clinical indications (head injury, unexplained loss of consciousness, family history of epilepsy, and abnormal neurological exam). Currently the US Navy does not use EEG for screening for any flight applicant without a neurologic indication. In the US Navy, an electroencephalographic pattern is determined to be epileptiform by a neurologist.

Clark, Jonathan B.↗
DOE OSTI2023

Treatment of cholinergic‐induced status epilepticus with polytherapy targeting GABA and glutamate receptors

Abstract Despite new antiseizure medications, the development of cholinergic‐induced refractory status epilepticus (RSE) continues to be a therapeutic challenge as pharmacoresistance to benzodiazepines and other antiseizure medications quickly develops. Studies conducted by Epilepsia . 2005;46:142 demonstrated that the initiation and maintenance of cholinergic‐induced RSE are associated with trafficking and inactivation of gamma‐aminobutyric acid A receptors (GABA A R) thought to contribute to the development of benzodiazepine pharmacoresistance. In addition, Dr. Wasterlain's laboratory reported that increased N‐methyl‐ d ‐aspartate receptors (NMDAR) and alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptors (AMPAR) contribute to enhanced glutamatergic excitation ( Neurobiol Dis . 2013;54:225; Epilepsia . 2013;54:78). Thus, Dr. Wasterlain postulated that targeting both maladaptive responses of reduced inhibition and increased excitation that is associated with cholinergic‐induced RSE should improve therapeutic outcome. We currently review studies in several animal models of cholinergic‐induced RSE that demonstrate that benzodiazepine monotherapy has reduced efficacy when treatment is delayed and that polytherapy with drugs that include a benzodiazepine (eg midazolam and diazepam) to counter loss of inhibition, concurrent with an NMDA antagonist (eg ketamine) to reduce excitation provide improved efficacy. Improved efficacy with polytherapy against cholinergic‐induced seizure is demonstrated by reduction in (1) seizure severity, (2) epileptogenesis, and (3) neurodegeneration compared with monotherapy. Animal models reviewed include pilocarpine‐induced seizure in rats, organophosphorus nerve agent (OPNA)‐induced seizure in rats, and OPNA‐induced seizure in two mouse models: (1) carboxylesterase knockout (Es1 −/− ) mice which, similarly to humans, lack plasma carboxylesterase and (2) human acetylcholinesterase knock‐in carboxylesterase knockout (KIKO) mice. We also review studies showing that supplementing midazolam and ketamine with a third antiseizure medication (valproate or phenobarbital) that targets a nonbenzodiazepine site rapidly terminates RSE and provides further protection against cholinergic‐induced SE. Finally, we review studies on the benefits of simultaneous compared with sequential drug treatments and the clinical implications that lead us to predict improved efficacy of early combination drug therapies. The data generated from seminal rodent studies of efficacious treatment of cholinergic‐induced RSE conducted under Dr. Wasterlain's guidance suggest that future clinical trials should treat the inadequate inhibition and temper the excess excitation that characterize RSE and that early combination therapies may provide improved outcome over benzodiazepine monotherapy.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Allopregnanolone as an Adjunct Therapy to Midazolam is More Effective Than Midazolam Alone in Suppressing Soman‐Induced Status Epilepticus in Male Rats

ABSTRACT Aims Humans and animals acutely intoxicated with the organophosphate soman can develop sustained status epilepticus (SE) that rapidly becomes refractory to benzodiazepines. We compared the antiseizure efficacy of midazolam, a current standard of care treatment for OP‐induced SE, versus combined therapy with midazolam and allopregnanolone (ALLO) in a rat model of soman‐induced SE. Methods Soman‐intoxicated male rats with robust seizure behavior and high‐amplitude electroencephalographic (EEG) activity were administered midazolam (0.65 mg, i.m.) 20 min after seizure initiation and 10 min later either a second dose of midazolam or ALLO (12 or 24 mg/kg, i.m.). Seizure behavior and EEG were monitored for 4 h after treatment. Brains were collected at the end of the monitoring period for histological analyses. Results Animals receiving 2 doses of midazolam exhibited persistent SE. Sequential dosing with midazolam followed by ALLO suppressed electrographic seizure activity. The combination therapy also significantly reduced soman‐induced neurodegeneration and neuroinflammation compared to 2 doses of midazolam. High but not low dose ALLO was associated with transitory and reversible respiratory compromise during the 1 h period after dosing. Conclusions Treatment with midazolam followed by ALLO was more effective than 2 doses of midazolam in suppressing benzodiazepine‐refractory, soman‐induced SE, and in mitigating its acute neuropathological consequences.

Andrew, Peter M. [Department of Molecular Bioscien↗
NASA NTRS1971

Effect of circadian rhythm on CNS oxygen toxicity.

The circadian rhythm in susceptibility to oxygen toxicity seizures was investigated by using six groups of 20 male Sprague-Dawley rats (101-196 gm.). The animals were given standard chow, exposed to standard diurnal conditions of light (0700-1900 hr) and dark (1900-0700 hr), and fasted for 15-16 hr prior to exposure to hyperbaric oxygen. The animals were placed in a previously oxygen flushed chamber and raised to 60 psi (gauge) oxygen at a rate of 3 psi/min. Time of exposure started with attainment of 60 psi. End point was first convulsion. The animals' weights were equally distributed within the groups, and the groups were defined by hour of exposure. Time of exposure in minutes prior to seizure was significantly longer in those exposed at 0700-0800 hr and 1000-1100 hr than in four other groups. There was no relationship between animals' weights and time of exposure to seizures. All R values were negative, and the highest R value was -035. These data suggest a definite circadian rhythm in susceptibility to oxygen toxicity seizures.

Hof, D. G.↗
NASA NTRS1979

Portable device for detection of petit mal epilepsy

A portable device that analyzes the electroencephalogram to determine if petit mal epilepsy waveforms are present is developed and tested. Clinicians should find it useful in diagnosing seizure activity of their patients. The micropower, battery-operated, portable device indicates a seizure has occurred if three criteria are satisfied: (1) frequencies of 2.5-7 Hz, (2) large-amplitude waves, and (3) minimum number of waves per second. Levels and counts are adjustable, thus insuring high reliability against noise artifacts and permitting each subject to be individually fitted. The device has shown promise in giving the patient a possible mechanism of seizure control or suppression.

Smith, R. G.↗
NASA NTRS1991

Measurement and modification of the EEG and related behavior

Electrophysiological changes in the sensorimotor pathways were found to accompany the effect of rhythmic EEG patterns in the sensorimotor cortex. Additionally, several striking behavioral changes were seen, including in particular an enhancement of sleep and an elevation of seizure threshold to epileptogenic agents. This raised the possibility that human seizure disorders might be influenced therapeutically by similar training. Our objective in human EEG feedback training became not only the facilitation of normal rhythmic patterns, but also the suppression of abnormal activity, thus requiring complex contingencies directed to the normalization of the sensorimotor EEG. To achieve this, a multicomponent frequency analysis was developed to extract and separate normal and abnormal elements of the EEG signal. Each of these elements was transduced to a specific component of a visual display system, and these were combined through logic circuits to present the subject with a symbolic display. Variable criteria provided for the gradual shaping of EEG elements towards the desired normal pattern. Some 50-70% of patients with poorly controlled seizure disorders experienced therapeutic benefits from this approach in our laboratory, and subsequently in many others. A more recent application of this approach to the modification of human brain function in our lab has been directed to the dichotomous problems of task overload and underload in the contemporary aviation environment. At least 70% of all aviation accidents have been attributed to the impact of these kinds of problems on crew performance. The use of EEG in this context has required many technical innovations and the application of the latest advances in EEG signal analysis. Our first goal has been the identification of relevant EEG characteristics. Additionally, we have developed a portable recording and analysis system for application in this context. Findings from laboratory and in-flight studies suggest that we will be able to detect appropriate changes in brain function, and feed this information to on-board computers for modification of mission requirements and/or crew status.

Sterman, M. B.↗
DOE OSTI2023

Tigers at a crossroads: Shedding light on the role of Bangladesh in the illegal trade of this iconic big cat

Abstract Unsustainable wildlife trade is a major threat to many species, but quantifying trade remains challenging, as seizure data provides an incomplete understanding. For this reason, integrating multiple types of information, including interviews with actors involved in trade, is crucial if we are to understand the problem better. Hence, in this study, we digitized Bangladesh Forest Department tiger seizure records to identify trade routes and interviewed 163 individuals involved in trafficking tigers through Bangladesh's air, sea and land ports, including poachers, smugglers, and traders. We identified six ports used to import tigers, 14 ports used for tiger export and three ports showing bi‐directional trade. Elite Bangladeshis were the most important consumer group, and tigers were sourced from populations in NE India, Myanmar and Bangladesh Sundarbans to supply domestic demand. Tiger products were exported to 14 countries, including seven G20 nations, with Bangladeshi expatriates as the consumer group in three countries (United Kingdom, Germany and Qatar). Rising economic development in Bangladesh over the last decade, combined with deep‐rooted cultural ties to tiger consumption, has led to a rise in domestic demand. Additionally, rapid growth in international transport links has increased smuggling and connected local traders with global markets, increasing the complexity of global trade. These findings suggest Bangladesh is poised to play a pivotal role in tiger conservation over the next decade, requiring strong national strategies to reduce trade opportunities, disrupt networks and weaken demand.

Uddin, Nasir↗
DOE OSTI2023

EpiPro, a Novel, Synthetic, Activity-Regulated Promoter That Targets Hyperactive Neurons in Epilepsy for Gene Therapy Applications

Epileptogenesis is characterized by intrinsic changes in neuronal firing, resulting in hyperactive neurons and the subsequent generation of seizure activity. These alterations are accompanied by changes in gene transcription networks, first with the activation of early-immediate genes and later with the long-term activation of genes involved in memory. Our objective was to engineer a promoter containing binding sites for activity-dependent transcription factors upregulated in chronic epilepsy (EpiPro) and validate it in multiple rodent models of epilepsy. First, we assessed the activity dependence of EpiPro: initial electrophysiology studies found that EpiPro-driven GFP expression was associated with increased firing rates when compared with unlabeled neurons, and the assessment of EpiPro-driven GFP expression revealed that GFP expression was increased ~150× after status epilepticus. Following this, we compared EpiPro-driven GFP expression in two rodent models of epilepsy, rat lithium/pilocarpine and mouse electrical kindling. In rodents with chronic epilepsy, GFP expression was increased in most neurons, but particularly in dentate granule cells, providing in vivo evidence to support the “breakdown of the dentate gate” hypothesis of limbic epileptogenesis. Finally, we assessed the time course of EpiPro activation and found that it was rapidly induced after seizures, with inactivation following over weeks, confirming EpiPro’s potential utility as a gene therapy driver for epilepsy.

60 APPLIED LIFE SCIENCES↗