ABSTRACT
The subspecialty of experimental neurotherapeutics trains neurologists in discovering and developing new treatments for neurologic diseases. Based on development of exciting new treatments for genetic and inflammatory diseases, we predict that there will be many other breakthroughs. The job market has expanded rapidly in academia, the pharmaceutical industry, government, and not-for-profit sectors; many new opportunities can be anticipated. The burgeoning opportunities in the field mandate that training address the challenges of overcoming obstacles in therapeutic discovery, implementation science, and development of affordable and equitably available treatments. ANN NEUROL 2023;93:427-430.
Subject(s)
Drug Industry , Tidal Waves , HumansABSTRACT
2-deoxy-D-glucose (2DG) is a glucose analog differing from glucose only by removal of an oxygen atom at the 2 position, which prevents the isomerization of glucose-6-phosphate to fructose-6-phosphate, and thereby reversibly inhibits glycolysis. PET studies of regional brain glucose utilization positron-emitting 18F-2DG demonstrate that brain regions generating seizures have diminished glucose utilization during interictal conditions, but rapidly transition to markedly increased glucose delivery and utilization during seizures, particularly in status epilepticus (SE). 2-deoxy-D-glucose has acute antiseizure actions in multiple in vivo and in vitro seizure models, including models of SE induced by the chemo convulsants pilocarpine and kainic acid, suggesting that focal enhanced delivery of 2DG to ictal brain circuits is a potential novel anticonvulsant intervention for the treatment of SE.
Subject(s)
Deoxyglucose , Status Epilepticus , Humans , Deoxyglucose/therapeutic use , Deoxyglucose/pharmacology , Status Epilepticus/chemically induced , Status Epilepticus/drug therapy , Seizures/drug therapy , Glucose , Glycolysis , Pilocarpine/toxicityABSTRACT
2-Deoxy-d-glucose (2DG), a glucose analog that inhibits glycolysis, has acute and chronic antiepileptic effects. We evaluated 2DG's acute effects on synaptic and membrane properties of CA3 pyramidal neurons in vitro. 2DG (10 mM) had no effects on spontaneously occurring postsynaptic currents (PSCs) in 3.5 mM extracellular potassium concentration ([K+]o). In 7.5 mM [K+]o, 2DG significantly reduced the frequency of epileptiform bursting and the charge carried by postsynaptic currents (PSCs) with a greater effect on inward excitatory compared with outward inhibitory charge (71% vs. 40%). In 7.5 mM [K+]o and bicuculline, 2DG reduced significantly the excitatory charge by 67% and decreased the frequency but not amplitude of excitatory PSCs between bursts. In 7.5 mM [K+]o, 2DG reduced pharmacologically isolated inhibitory PSC frequency without a change in amplitude. The frequency but not amplitude of inward miniature PSCs was reduced when 2DG was applied in 7.5 mM [K+]o before bath application of TTX, but there was no effect when 2DG was applied after TTX, indicating a use-dependent uptake of 2DG was required for its actions at a presynaptic locus. 2DG did not alter membrane properties of CA3 neurons except for reducing the slow afterhyperpolarization in 3.5 but not 7.5 mM [K+]o. The reduction in frequency of spontaneous and inward miniature PSCs in elevated [K+]o indicates a presynaptic mechanism of action. 2DG effects required use-dependent uptake and suggest an important role for glycolysis in neuronal metabolism and energetics in states of high neural activity as occur during abnormal network synchronization and seizures. NEW & NOTEWORTHY 2-Deoxy-d-glucose (2DG) is a glycolytic inhibitor and suppresses epileptiform activity acutely and has chronic antiepileptic effects. The mechanisms of the acute effects are not well delineated. In this study, we show 2DG suppressed abnormal network epileptiform activity without effecting normal synaptic network activity or membrane properties. The effects appear to be use dependent and have a presynaptic locus of action. Inhibition of glycolysis is a novel presynaptic mechanism to limit abnormal neuronal network activity and seizures.
Subject(s)
CA3 Region, Hippocampal/metabolism , Deoxyglucose/pharmacology , Epilepsy/metabolism , Neurons/metabolism , Synaptic Potentials , Animals , Bicuculline/pharmacology , CA3 Region, Hippocampal/cytology , CA3 Region, Hippocampal/physiology , Epilepsy/physiopathology , Glycolysis , Neurons/drug effects , Neurons/physiology , Potassium/pharmacology , Rats , Rats, Sprague-Dawley , Tetrodotoxin/pharmacologyABSTRACT
Kindling is a phenomenon of activity-dependent neural circuit plasticity induced by repeated seizures that results in progressive permanent increases in susceptibility to epilepsy. As the permanent structural and functional modifications induced by kindling include a diverse range of molecular, cellular, and functional alterations in neural circuits, it is of interest to determine if genetic background associated with seizure-induced plasticity might also influence plasticity in neural circuitry underlying other behaviors. Outbred Sprague-Dawley (SD) rats were selected and bred for ~15 generations for "fast' or "slow" rates of kindling development in response to stimulation of the perforant path input to the hippocampus. After 7-8 generations of selection and breeding, consistent phenotypes of "fast" and "slow" kindling rates were observed. By the 15th generation "fast" kindling rats referred to as Perforant Path Kindling Susceptible (PPKS) rats demonstrated a kindling rate of 10.7 ± 1.1 afterdischarges (ADs) to the milestone of the first secondary generalized (Class V) seizure, which differed significantly from "slow" kindling Perforant Path Kindling Resistant (PPKR) rats requiring 25.5 ± 2.0 ADs, and outbred SD rats requiring 16.8 ± 2.5 ADs (p<0.001, ANOVA). Seizure-naïve adult PPKS and PPKR rats from offspring of this generation and age-matched adult outbred SD rats were compared in validated behavioral measures including the open field test as a measure of exploratory activity, the Morris water maze as a measure of hippocampal spatial memory, and fear conditioning as a behavioral paradigm of associative fear learning. The PPKS ("fast" kindling) strain with increased susceptibility to seizure-induced plasticity demonstrated statistically significant increases in motor exploratory activity in the open field test and reduced spatial learning the Morris water maze, but demonstrated normal fear conditioned learning comparable to outbred SD rats and the "slow" kindling-resistant PPKR strain. These results confirm that selection and breeding on the basis of responses to repeated pathway activation by stimulation can produce enduring modification of genetic background influencing behavior. These observations also suggest that genetic background underlying susceptibility or resistance to seizure-induced plasticity in hippocampal circuitry also differentially influences distinct behaviors and learning that depend on circuitry activated by the kindling selection process, and may have implications for associations between epilepsy, comorbid behavioral conditions, and cognition.
Subject(s)
Kindling, Neurologic/physiology , Perforant Pathway/physiopathology , Phenotype , Rats, Sprague-Dawley , Species Specificity , Animals , Animals, Outbred Strains , Auditory Perception/physiology , Conditioning, Psychological/physiology , Electric Stimulation/methods , Exploratory Behavior/physiology , Fear/physiology , Female , Genetic Predisposition to Disease , Male , Maze Learning/physiology , Memory Disorders/physiopathology , Mental Recall/physiology , Motor Activity/physiology , Spatial Memory/physiologyABSTRACT
2-deoxy-D-glucose (2DG) is a glucose analog and reversible inhibitor of glycolysis with anticonvulsant and antiepileptic effects in multiple seizure models. 2DG at a dose of 250 mg/kg intraperitoneally (IP) delays progression of repeated seizures evoked by kindling in rats when administered 30 min prior to twice daily kindling stimulation. As toxicological studies have demonstrated that repeated daily oral administration of 2DG at doses of 60-375 mg/kg/day in rats induces dose-dependent, reversible cardiac myocyte vacuolation, it was of interest to determine if 2DG also slowed kindling progression when administered at or below doses causing cardiac toxicity and at various time points after evoked seizures. We found that: (1) 2DG slowed kindling progression nearly 2-fold when administered at a dose of 37.5 mg/kg given IP 30 min prior to kindling stimulation, and (2) 2DG 37.5 mg/kg IP also slowed kindling progression when given immediately after, and for as long as 10 min after evoked (kindled) seizures. These observations suggest potential clinical usefulness of post-seizure administration of 2DG to reduce seizure clusters and long-term consequences of repeated seizures at human equivalent doses that are likely to be safe and well tolerated in patients.
Subject(s)
Glucose , Kindling, Neurologic , Rats , Humans , Animals , Seizures/drug therapy , Seizures/etiology , Anticonvulsants/pharmacology , Anticonvulsants/therapeutic use , Deoxyglucose/pharmacology , Deoxyglucose/therapeutic useABSTRACT
OBJECTIVE: Conventional anticonvulsants reduce neuronal excitability through effects on ion channels and synaptic function. Anticonvulsant mechanisms of the ketogenic diet remain incompletely understood. Because carbohydrates are restricted in patients on the ketogenic diet, we evaluated the effects of limiting carbohydrate availability by reducing glycolysis using the glycolytic inhibitor 2-deoxy-D-glucose (2DG) in experimental models of seizures and epilepsy. METHODS: Acute anticonvulsant actions of 2DG were assessed in vitro in rat hippocampal slices perfused with 7.5mM [K(+)](o), 4-aminopyridine, or bicuculline, and in vivo against seizures evoked by 6 Hz stimulation in mice, audiogenic stimulation in Fring's mice, and maximal electroshock and subcutaneous pentylenetetrazol (Metrazol) in rats. Chronic antiepileptic effects of 2DG were evaluated in rats kindled from olfactory bulb or perforant path. RESULTS: 2DG (10mM) reduced interictal epileptiform bursts induced by 7.5mM [K(+)](o), 4-aminopyridine, and bicuculline, and electrographic seizures induced by high [K(+)](o) in CA3 of hippocampus. 2DG reduced seizures evoked by 6 Hz stimulation in mice (effective dose [ED]50 = 79.7 mg/kg) and audiogenic stimulation in Fring's mice (ED50 = 206.4 mg/kg). 2DG exerted chronic antiepileptic action by increasing afterdischarge thresholds in perforant path (but not olfactory bulb) kindling and caused a twofold slowing in progression of kindled seizures at both stimulation sites. 2DG did not protect against maximal electroshock or Metrazol seizures. INTERPRETATION: The glycolytic inhibitor 2DG exerts acute anticonvulsant and chronic antiepileptic actions, and has a novel pattern of effectiveness in preclinical screening models. These results identify metabolic regulation as a potential therapeutic target for seizure suppression and modification of epileptogenesis.
Subject(s)
Anticonvulsants/therapeutic use , Deoxyglucose/therapeutic use , Disease Models, Animal , Epilepsy/drug therapy , Hippocampus/drug effects , Animals , Anticonvulsants/pharmacology , Deoxyglucose/pharmacology , Dose-Response Relationship, Drug , Electroshock/methods , Epilepsy/etiology , Epilepsy/pathology , Epilepsy, Reflex/drug therapy , Epilepsy, Reflex/etiology , Evoked Potentials/drug effects , Hippocampus/physiopathology , In Vitro Techniques , Male , Mice , Pentylenetetrazole/toxicity , Potassium Chloride/pharmacology , Rats , Rats, Sprague-Dawley , Time FactorsABSTRACT
We hypothesized that the acute response to traumatic brain injury (TBI) shares mechanisms with brain plasticity in the kindling model. Utilizing two unique, complementary strains of inbred rats, selected to be either susceptible or resistant to seizure-induced plasticity evoked by kindling of the perforant path, we examined acute electrophysiological alterations and differences in brain-derived neurotrophic factor (BDNF) protein concentrations after a moderate-to-severe brain injury. At baseline, limited strain-dependent differences in acute electrophysiological activity were found, and no differences in BDNF. Following injury, pronounced strain-dependent differences in electrophysiologic activity were noted at 0.5 min. However, the divergence is transient, with diminished differences at 5 min after injury and no differences at 10 and 15 min after injury. Strain-specific differences in BDNF protein concentration were noted 4 h after injury. A simple risk score model generated by machine learning and based solely on post-injury electrophysiologic activity at the 0.5-min timepoint distinguished perforant path kindling susceptible (PPKS) rats from non-plasticity-susceptible strains. The findings demonstrate that genetic background which affects brain circuit plasticity also affects acute response to TBI. An improved understanding of the effect of genetic background on the cellular, molecular, and circuit plasticity mechanisms activated in response to TBI and their timecourse is key in developing much-needed novel therapeutic approaches.
ABSTRACT
The intersection of epilepsy and aging has broad, significant implications. Substantial increases in seizures occur both in the elderly population, who are at a higher risk of developing new-onset epilepsy, and in those with chronic epilepsy who become aged. There are notable gaps in our understanding of aging and epilepsy at the basic and practical levels, which have important consequences. We are in the early stages of understanding the complex relationships between epilepsy and other age-related brain diseases such as stroke, dementia, traumatic brain injury (TBI), and cancer. Furthermore, the clinician must recognize that the presentation and treatment of epilepsy in the elderly are different from those of younger populations. Given the developing awareness of the problem and the capabilities of contemporary, multidisciplinary approaches to advance understanding about the biology of aging and epilepsy, it is reasonable to expect that we will unravel some of the intricacies of epilepsy in the elderly; it is also reasonable to expect that these gains will lead to further improvements in our understanding and treatment of epilepsy for all age groups.
Subject(s)
Aging , Epilepsy , Aged , Aged, 80 and over , Epilepsy/epidemiology , Epilepsy/etiology , Female , Humans , Male , Middle AgedABSTRACT
Metabolic regulation of neuronal excitability is increasingly recognized as a factor in seizure pathogenesis and control. Inhibiting or bypassing glycolysis may be one way through which the ketogenic diet provides an anticonvulsant effect. 2-deoxy-D-glucose (2DG), a nonmetabolizable glucose analog that partially inhibits glycolysis, was tested in several acute and chronic seizure models. Acutely, 2DG decreases the frequency of high-K(+)-, bicuculline- and 4-aminopyridine-induced interictal bursts in the CA3 region of hippocampal slices; 2DG also exerts anticonvulsant effects in vivo against perforant path kindling in rats. Chronically, 2DG has novel antiepileptic effects by retarding the progression of kindled seizures. Finally, 2DG has a favorable preliminary toxicity profile. These factors support the possibility that 2DG or other modifiers of glycolysis can be used as novel treatments for epilepsy.
Subject(s)
Anticonvulsants/pharmacology , Deoxyglucose/pharmacology , Glycolysis/drug effects , Hippocampus/drug effects , Neurons/drug effects , Seizures/drug therapy , Animals , Humans , Kindling, Neurologic/drug effects , RatsABSTRACT
Seizure-induced sprouting of the mossy fiber pathway in the dentate gyrus has been observed nearly universally in experimental models of limbic epilepsy and in the epileptic human hippocampus. The observation of progressive mossy fiber sprouting induced by kindling demonstrated that even a few repeated seizures are sufficient to alter synaptic connectivity and circuit organization. As it is now recognized that seizures induce synaptic reorganization in hippocampal and cortical pathways, the implications of seizure-induced synaptic reorganization for circuit properties and function have been subjects of intense interest. Detailed anatomical characterization of the sprouted mossy fiber pathway has revealed that the overwhelming majority of sprouted synapses in the inner molecular layer of the dentate gyrus form recurrent excitatory connections, and are thus likely to contribute to recurrent excitation and potentially to enhanced susceptibility to seizures. Nevertheless, difficulties in detecting functional abnormalities in circuits reorganized by mossy fiber sprouting and the fact that some sprouted axons appear to form synapses with inhibitory interneurons have been cited as evidence that sprouting may not contribute to seizure susceptibility, but could form recurrent inhibitory circuits and be a compensatory response to prevent seizures. Quantitative analysis of the synaptic connections of the sprouted mossy fiber pathway, assessment of the functional features of sprouted circuitry using reliable physiological measures, and the perspective of complex systems analysis of neural circuits strongly support the view that the functional effects of the recurrent excitatory circuits formed by mossy fiber sprouting after seizures or injury emerge only conditionally and intermittently, as observed with spontaneous seizures in human epilepsy. The recognition that mossy fiber sprouting is induced after hippocampal injury and seizures and contributes conditionally to emergence of recurrent excitation has provided a conceptual framework for understanding how injury and seizure-induced circuit reorganization may contribute to paroxysmal network synchronization, epileptogenesis, and the consequences of repeated seizures, and thus has had a major influence on understanding of fundamental aspects of the epilepsies.
Subject(s)
Adult Stem Cells/physiology , Dentate Gyrus/physiopathology , Epilepsy/pathology , Mossy Fibers, Hippocampal/physiopathology , Neurons/physiology , Animals , Cell Differentiation/physiology , Cell Movement/physiology , Cell Proliferation , HumansABSTRACT
The dentate gyrus has long been a focal point for studies on the molecular, cellular, and network mechanisms responsible for epileptogenesis in temporal lobe epilepsy (TLE). Although several hypothetical mechanisms are considered in this chapter, two that have garnered particular interest and experimental support are: (1) the selective loss of vulnerable interneurons in the region of the hilus and (2) the formation of new recurrent excitatory circuits after mossy fiber sprouting. Histopathological data show that specific GABAergic interneurons in the hilus are lost in animal models of TLE, and several lines of electrophysiological evidence, including intracellular analyses of postsynaptic currents, support this hypothesis. In particular, whole-cell recordings have demonstrated a reduction in the frequency of miniature inhibitory postsynaptic currents in the dentate gyrus and other areas (e.g., CA1 pyramidal cells), which provides relatively specific evidence for a reduction in GABAergic input to granule cells. These studies support the viewpoint that modest alterations in GABAergic inhibition can have significant functional impact in the dentate gyrus, and suggest that dynamic activity-dependent mechanisms of GABAergic regulation add complexity to this local synaptic circuitry and to analyses of epileptogenesis. In regard to mossy fiber sprouting, a wide variety of experiments involving intracellular or whole-cell recordings during electrical stimulation of the hilus, glutamate microstimulation, and dual recordings from granule cells support the hypothesis that mossy fiber sprouting forms new recurrent excitatory circuits in the dentate gyrus in animal models of TLE. Similar to previous studies on recurrent excitation in the CA3 area, GABA-mediated inhibition and the intrinsic high threshold of granule cells in the dentate gyrus tends to mask the presence of the new recurrent excitatory circuits and reduce the likelihood that reorganized circuits will generate seizure-like activity. How cellular alterations such as neuron loss in the hilus and mossy fiber sprouting influence functional properties is potentially important for understanding fundamental aspects of epileptogenesis, such as the consequences of primary initial injuries, mechanisms underlying network synchronization, and progression of intractability. The continuous nature of the axonal sprouting and formation of recurrent excitation could account for aspects of the latent period and the progressive nature of the epileptogenesis. Future studies will need to identify precisely how these hypothetical mechanisms and others contribute to the process whereby epileptic seizures are initiated or propagated through an area such as the dentate gyrus. Finally, in addition to its unique features and potential importance in epileptogenesis, the dentate gyrus may also serve as a model for other cortical structures in acquired epilepsy.
Subject(s)
Dentate Gyrus/pathology , Epilepsy/etiology , Epilepsy/pathology , Animals , Disease Models, Animal , HumansABSTRACT
Environmental enrichment produces wide-ranging effects in the brain at molecular, cellular, network, and behavioral levels. The changes in neuronal plasticity are driven by changes in neurotransmitters, neurotrophic factors, neuronal morphology, neurogenesis, network properties of the brain, and behavioral correlates of learning and memory. Exposure to an enriched environment has also demonstrated intriguing possibilities for treatment of a variety of neurodegenerative diseases including Huntington's disease, Alzheimer's disease, and Parkinson's disease. The effect of environmental enrichment in epilepsy, a neurodegenerative disorder with pathological neuronal plasticity, is of considerable interest. Recent reports of the effect of environmental enrichment in the Bassoon mutant mouse, a genetic model of early onset epilepsy, provides a significant addition to the literature in this area.
Subject(s)
Environment , Epilepsy/therapy , Neurodegenerative Diseases/therapy , Animals , Brain/metabolism , Disease Models, Animal , Epilepsy/genetics , Humans , Mice , Nerve Tissue Proteins/genetics , Neurodegenerative Diseases/genetics , Neuronal Plasticity/physiologyABSTRACT
During the past decade, it has become apparent that neural circuits undergo activity-dependent reorganisation. In pathological disorders with recurring episodes of excessive neural activity, such as temporal-lobe epilepsy, brain circuits can undergo continual remodelling. For clinical practice, seizure-induced remodelling implies that after a diagnosis of epilepsy, recurring seizures can cause continuing neural reorganisation and potentially contribute to progressive severity of the epilepsy and to cognitive and behavioural consequences. The alterations induced by seizures include neuronal death and birth, axonal and dendritic sprouting, gliosis, molecular reorganisation of membrane and extracellular-matrix proteins, and intermediates involved in cellular homoeostasis. These changes are influenced by genetic background and seizure type, thus identification of genetic risk factors should be a priority. Therapeutic modification of seizure-induced molecular and cellular responses offers new opportunities for intervention beyond seizure suppression.
Subject(s)
Epilepsy, Temporal Lobe/etiology , Epilepsy, Temporal Lobe/therapy , Animals , Disease Progression , Epilepsy, Temporal Lobe/drug therapy , Epilepsy, Temporal Lobe/pathology , Humans , Risk FactorsABSTRACT
The mossy fiber pathway in the dentate gyrus undergoes sprouting and synaptic reorganization in response to seizures. The types of new synapses, their location and number, and the identity of their postsynaptic targets determine the functional properties of the reorganized circuitry. The goal of this study was to characterize the types and proportions of sprouted mossy fiber synapses in kindled and kainic acid-treated rats. In normal rats, synapses labeled by Timm histochemistry or dynorphin immunohistochemistry were rarely observed in the supragranular region of the inner molecular layer when examined by electron microscopy. In epileptic rats, sprouted mossy fiber synaptic terminals were frequently observed. The ultrastructural analysis of the types of sprouted synapses revealed that 1) in the supragranular region, labeled synaptic profiles were more frequently axospinous than axodendritic, and many axospinous synapses were perforated; 2) sprouted mossy fiber synaptic terminals formed exclusively asymmetric, putatively excitatory synapses with dendritic spines and shafts in the supragranular region and with the soma of granule cells in the granule cell layer; 3) in contrast to the large sprouted mossy fiber synapses in resected human epileptic hippocampus, the synapses formed by sprouted mossy fibers in rats were smaller; and 4) in several cases, the postsynaptic targets of sprouted synapses were identified as granule cells, but, in one case, a sprouted synaptic terminal formed a synapse with an inhibitory interneuron. The results demonstrate that axospinous asymmetric synapses are the most common type of synapse formed by sprouted mossy fiber terminals, supporting the viewpoint that most sprouted mossy fibers contribute to recurrent excitation in epilepsy.
Subject(s)
Epilepsy/pathology , Growth Cones/pathology , Growth Cones/ultrastructure , Mossy Fibers, Hippocampal/pathology , Mossy Fibers, Hippocampal/ultrastructure , Neuronal Plasticity/physiology , Animals , Epilepsy/physiopathology , Growth Cones/physiology , Immunohistochemistry , Kainic Acid , Kindling, Neurologic/physiology , Male , Microscopy, Electron , Mossy Fibers, Hippocampal/physiopathology , Rats , Rats, Sprague-DawleyABSTRACT
Clinical and epidemiological studies have repeatedly demonstrated that a subset of patients with epilepsy have progressive syndromes with increasing seizure frequency and cumulative adverse effects despite optimal anticonvulsant therapy. Recent longitudinal imaging studies and long-term neuropsychological studies have confirmed that a substantial subset of people with epilepsy undergo progressive brain atrophy accompanied by functional declines that worsen with duration of epilepsy. As further evidence of the progressive and adverse effects of inadequately controlled epilepsy, chronic experimental models of epilepsy and the phenomenon of kindling have provided abundant evidence that neural circuits undergo long-term progressive structural and functional alterations in response to seizures. This long-term seizure-induced plasticity in neural circuits appears to be "bidirectional", inducing progressive damage while also inducing resistance to additional damage, as a function of timing or inter-seizure interval. Seizure-induced plasticity has pronounced age-dependence, and influences long-term cognitive consequences of seizures during early life and acquired susceptibility to epilepsy in adulthood. While it is clear from clinical and epidemiological studies that human epilepsy is a heterogeneous disorder and that not all epileptic syndromes are progressive, emerging results from studies of activity-dependent and seizure-induced plasticity and perspectives from "complex systems" analysis are providing new insights into systematic neurobiological processes that are likely to influence the progressive features of epileptic syndromes and patterns of progression in individual patients. The emerging perspective is that phenomena of plasticity and genetic background exert powerful effects in development and adulthood through regulation of activity-dependent structural and functional remodeling of neural circuitry, and that these effects not only influence progression and consequences of seizures, but also offer new opportunities for therapeutic intervention.
Subject(s)
Epilepsy/physiopathology , Nervous System/growth & development , Neuronal Plasticity/physiology , Anticonvulsants/therapeutic use , Disease Progression , Drug Resistance , Epilepsy/drug therapy , Epilepsy/etiology , Epilepsy/genetics , HumansABSTRACT
A statistical approach is presented for the quantitative analysis of diffusion tensor imaging (DTI) directional information using Fisher statistics, which were originally developed for the analysis of vectors in the field of paleomagnetism. In this framework, descriptive and inferential statistics have been formulated based on the Fisher probability density function, a spherical analogue of the normal distribution. The Fisher approach was evaluated for investigation of rat brain DTI maps to characterize tissue orientation in the corpus callosum, fornix, and hilus of the dorsal hippocampal dentate gyrus, and to compare directional properties in these regions following status epilepticus (SE) or traumatic brain injury (TBI) with values in healthy brains. Direction vectors were determined for each region of interest (ROI) for each brain sample and Fisher statistics were applied to calculate the mean direction vector and variance parameters in the corpus callosum, fornix, and dentate gyrus of normal rats and rats that experienced TBI or SE. Hypothesis testing was performed by calculation of Watson's F-statistic and associated p-value giving the likelihood that grouped observations were from the same directional distribution. In the fornix and midline corpus callosum, no directional differences were detected between groups, however in the hilus, significant (p<0.0005) differences were found that robustly confirmed observations that were suggested by visual inspection of directionally encoded color DTI maps. The Fisher approach is a potentially useful analysis tool that may extend the current capabilities of DTI investigation by providing a means of statistical comparison of tissue structural orientation.
Subject(s)
Brain Injuries/physiopathology , Diffusion Magnetic Resonance Imaging/statistics & numerical data , Image Processing, Computer-Assisted/statistics & numerical data , Status Epilepticus/physiopathology , Animals , Brain Injuries/diagnosis , Male , Rats , Rats, Sprague-Dawley , Status Epilepticus/diagnosisABSTRACT
2-Deoxy-D-glucose (2DG), a glucose analog that transiently inhibits glycolysis, has anticonvulsant and antiepileptic disease-modifying properties in experimental in vivo models of seizures and epilepsy. Here we evaluated the effects of 2DG across the range of doses (50-500mg/kg i.p.) shown previously to exert anticonvulsant and antiepileptic effects in rats, on spatial learning and memory using the Morris water maze and on exploratory behavior using the open field test. For water maze testing, both acute and chronic protocols were tested. For acute testing, 2DG was injected for 15min prior to the water maze trial only on testing days. For chronic testing, 2DG was injected daily for 14days before water maze testing began. Neither protocol altered the latency to platform acquisition or retention of platform location by the probe test. For open field testing, 2DG was given at doses of 50-250mg/kg 15 or 30min prior to testing on each testing day. When given 30min prior to testing, exploratory activity in the open field was transiently and reversibly decreased by 2DG at doses of 250mg/kg/day but there were no effects on open field activity at 50mg/kg/day. When given 15min prior to testing, 2DG decreased exploratory activity in a dose-dependent fashion at both 50 and 250mg/kg. There were no toxic effects of 2DG at doses of 500mg/kg/day on body weight or general health. In summary, 2DG is well tolerated at doses associated with anticonvulsant and antiepileptic effects, supporting its potential as an anticonvulsant and antiepileptic agent with a novel mechanism of action.
Subject(s)
Behavior, Animal/drug effects , Deoxyglucose/pharmacology , Exploratory Behavior/drug effects , Maze Learning/drug effects , Motor Activity/drug effects , Animals , Deoxyglucose/adverse effects , Dose-Response Relationship, Drug , Male , Memory/drug effects , Rats , Rats, Sprague-DawleyABSTRACT
The damped-oscillator pseudo-wavelet is presented as a method of time-frequency analysis along with a new spectral density measure, the data power. An instantaneous phase can be defined for this pseudo-wavelet, and it is easily inverted. The data power measure is tested on both computer generated data and in vivo intrahippocampal electrophysiological recordings from a rat. The data power spectral density is found to give better time and frequency resolution than the more conventional total energy measure, and additionally shows intricate time-frequency structure in the rat that is altered in association with the emergence of epilepsy. With epileptogenesis, the baseline theta oscillation is severely degraded and is absorbed into a broader gamma band. There are also broad 600 Hz and 2000 Hz bands which localize to hippocampal layers that are distinct from those of the theta and gamma bands. The 600 Hz band decreases in prominence with epileptogenesis while the 2000 Hz band increases in prominence. The origins of these high frequency bands await further study. In general, we find that the damped-oscillator pseudo-wavelet is easy to use and is particularly suitable for problems where a wide range of oscillator frequencies is expected.