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Gregory L Holmes

Publications and source records attributed to Gregory L Holmes.

At least 19 recordsLinked to original sources
PubMed2006

Effect of levetiracetam on visual-spatial memory following status epilepticus.

Status epilepticus (SE) is often followed by severe cognitive impairment, including memory impairment. Previous studies have shown that SE is associated with impairment of single cells in the hippocampus that fire action potentials when the animal is in a specific location in space, the so-called place cells, and that place cell function correlates well with performance in tasks of visual-spatial memory. Place cell patterns therefore appear to be an excellent measure of spatial memory and may serve as a tool to assess seizure-induced impairment in memory. In this study we determined the relationship between visual-spatial memory and place cell function following SE. In addition, we determined if levetiracetam (LEV), an antiepileptic drug with a novel mechanism of action, can improve cognitive function and place cell firing patterns when administered following SE. SE was induced in adult male rats which were then randomized to post-SE treatment with LEV or normal saline (NS) treatment for 14 days. Non-SE control rats also were randomized to LEV or NS. Following discontinuation of LEV rats were tested for visual-spatial memory in the Morris water-maze and then underwent unit recording in the CA1 region of the hippocampus. Brains were then evaluated for cell loss and mossy fiber sprouting. SE was associated with severely impaired performance in the water-maze with SE rats demonstrating no learning over four days of testing. Paralleling this memory deficit was a marked disturbance in firing patterns of pyramidal neurons in CA1. Non-SE rats learned quickly over four days of water-maze testing and had normal pyramidal cell firing patterns. LEV had no major effects on water-maze performance or place cell function. Histopathological examination of the brains showed severe cell loss in CA1 in all of the SE rats with lesser degrees of injury in CA3 and the hilus. LEV treatment resulted in less histological damage in the hippocampus but had no effect on visual-spatial function or place cell physiology in either control or SE rats.

Animals↗
PubMed2006

Electrical induction of spikes in the hippocampus impairs recognition capacity and spatial memory in rats.

In clinical studies, interictal EEG spikes (IS) have been associated with numerous neuropsychological abnormalities, ranging from transitory cognitive impairment to epileptic encephalopathies. Understanding the pathophysiological mechanisms of IS has been hampered by the lack of validated animal models. To mimic IS, a stimulating microelectrode was implanted in the ventral hippocampal commissure and a recording microelectrode in the CA1 region of the hippocampus of normal male rats. Spike patterns were induced using a series of electrical pulses 10-30 ms in duration with a frequency of 0.5-2Hz and a current of 0.2mA. The commissural stimulation-evoked population discharges in the hippocampus resembled naturally occurring IS in epileptic rats and, in no cases, resulted in behavioral seizures. For behavioral testing, the Morris water maze, radial arm maze, and object recognition tasks were used. Spikes were induced during sleep between the two sets of water maze trials; during the trials in the radial arm maze task; and prior to the sample phase and during the delay periods in the object recognition task. We demonstrated that rats that received spikes took longer to reach the escape platform in the second set of water maze trials; had significantly more reference errors and required more trials to complete the radial arm maze task; and had lower investigation ratios in the object recognition task. The results indicate that induction of spikes in the hippocampus results in impairment of spatial reference and nonspatial object recognition memory.

Animals↗
PubMed2006

Lack of effect of secretin on kindling and seizures.

Secretin infused into rats activates neurons located in brain areas controlling autonomic function and emotion. The brain activity of secretin is mediated, at least in part, through vagal pathways. It is known that afferent stimulation of the vagus nerve results in considerable antiepileptic effects. Whether or not secretin has an effect on seizures is unknown. In this study, we evaluated the efficacy and safety of secretin as an antiepileptogenic agent in electrical kindling and as an anticonvulsant in fully kindled seizures. To assess antiepileptogenic effects, we administered secretin (10, 30, or 100 microg/kg/dose) or normal saline intravenously 5 min before twice-daily kindling stimulation. To assess the anticonvulsant effect of secretin, we administered either normal saline or secretin (100 microg/kg/dose) 5 min before the electrical stimulation to fully kindled rats. We observed no effect on kindling rate or afterdischarge duration. In fully kindled rats, secretin administration had no effect on kindling stage or afterdischarge duration. Thus, in the dose range used in this preliminary acute treatment study, secretin had no discernible antiepileptogenic or anticonvulsant effects. Secretin was very well tolerated in this multidose protocol.

Animals↗
PubMed2006

Effects of uridine in models of epileptogenesis and seizures.

Due to the limited efficacy and side effects of current antiepileptic drugs (AEDs), the search for new therapeutic agents is critical. Uridine, a possible endogenous antiepileptic modulator, has been demonstrated to have anticonvulsant effects in some models of epilepsy, but not others. In this study, we examined possible neuroprotective effects of uridine by administering the agent following lithium-pilocarpine induced status epilepticus. The effects of uridine were assessed on EEG patterns, visual-spatial memory in the water maze and histopathology. There was a trend for reduced EEG spike frequency, improved visual spatial memory and better histology score in rats receiving uridine. The antiepileptogenic and anticonvulsant effects of uridine were studied by administering uridine to rats undergoing rapid kindling or following full kindling. In the rapid kindling models, uridine had a moderate antiepileptogenic and anticonvulsant effect. These results suggest uridine may have potential to aid in the prevention and treatment of epilepsy.

Animals↗
PubMed2006

Role of interictal epileptiform abnormalities in cognitive impairment.

The epileptic encephalopathies are conditions in which neurological deterioration is attributable entirely or partly to epileptic activity and is due to very frequent or severe seizures or severely abnormal electroencephalograms (EEGs), or both. Evidence for the concept that seizures or the abnormal EEGs are responsible for the cognitive deterioration is the observation that patients can improve dramatically when therapy eliminates or reduces seizure frequency and improves or normalizes the EEG. For example, children with the syndrome of continuous spike-wave of sleep (CSWS) have electrical status epilepticus during sleep (ESES) and cognitive regression. Although seizures often occur in the disorder, there are indications that the EEG abnormalities are responsible for the cognitive regression. Interictal spikes, which correspond to a large intracellular depolarization with evoked action potentials, in many ways mimic a "miniseizure." Interictal spikes can result in transitory cognitive impairment with the type of deficit dependent on where in the cortex the spike arises. We suggest that interictal spikes, particularly if frequent and widespread, can impair cognitive abilities, through interference with waking learning and memory, and memory consolidation during sleep.

Child↗
PubMed2006

Effects of seizures on developmental processes in the immature brain.

Infants and children are at a high risk for seizures compared with adults. Although most seizures in children are benign and result in no long-term consequences, increasing experimental animal data strongly suggest that frequent or prolonged seizures in the developing brain result in long-lasting sequelae. Such seizures may intervene with developmental programmes and lead to inadequate construction of cortical networks rather than induction of neuronal cell loss. As a consequence, the deleterious actions of seizures are strongly age dependent: seizures have different effects on immature or migrating neurons endowed with few synapses and more developed neurons that express hundreds of functional synapses. This differential effect is even more important in human beings and subhuman primates who have an extended brain development period. Seizures also beget seizures during maturation and result in a replay of development programmes, which suggests that epileptogenesis recapitulates ontogenesis. Therefore, to understand seizures and their consequences in the developing brain, it is essential to determine how neuronal activity modulates the main steps of cortical formation. In this Review, we present basic developmental principles obtained from animal studies and examine the long-lasting consequences of epilepsy.

Animals↗
PubMed2006

Selective impairment of GABAergic synaptic transmission in the flurothyl model of neonatal seizures.

Neonatal seizures can result in long-term adverse consequences including alteration of seizure susceptibility and impairment in spatial memory. However, little is known about the effects of neonatal seizures on developmental changes occurring in synaptic transmission during the first postnatal weeks. The purpose of the present study was to examine the effect of neonatal seizures on several aspects of gamma-aminobutyric acid (GABA)ergic and glutamatergic synaptic transmission in the developing rat hippocampus. Flurothyl was used to induce multiple recurrent seizures in rat pups during the first postnatal days. Whole-cell patch-clamp recordings from the hippocampal CA3 pyramidal cell and extracellular recordings from the CA3 pyramidal cell layer were made in slice preparations. In rats that experienced neonatal seizures the amplitude of spontaneous inhibitory postsynaptic currents at P15-17 was decreased by 27% compared with controls, whereas neither frequency nor the kinetic properties were altered. Neonatal seizures did not affect the timing of the developmental switch in the GABAA signaling from excitatory to inhibitory. None of the studied parameters of glutamatergic postsynaptic currents was different between the flurothyl and control groups, including the amplitude and frequency of the spontaneous excitatory postsynaptic currents, the ratio of the amplitudes and frequencies of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA)-mediated spontaneous postsynaptic currents, and the kinetics of AMPA and NMDA mediated postsynaptic currents in the age groups P8-10 and P15-17. We suggest that the selective depression of the amplitude of GABAergic synaptic responses may contribute to the adverse neurological and behavioral consequences that occur following neonatal seizures.

Animals↗
PubMed2005

Possible precipitation of myoclonic seizures with oxcarbazepine.

Oxcarbazepine is an antiepileptic drug widely used to treat partial seizures in children and adults. We report two children who developed mycolonic seizures and had abnormal electroencephalograms when oxcarbazepine was introduced. Although it is possible that the emergence of myoclonic seizures and deterioration of the electroencephalograms were due to the natural course of the disorder, clinicians should be aware of the possible detrimental effects of oxcarbazepine in children with seizures.

Adolescent↗
PubMed2005

Effect of neonatal isolation on outcome following neonatal seizures in rats--the role of corticosterone.

Emerging evidence indicates that early maternal care permanently modifies the activity of hypothalamic-pituitary-adrenal (HPA) axis and is a critical factor in determining the capacity of the brain to compensate for later encountered insults. The purpose of this study was to determine the role of corticosterone (CORT) in the detrimental effects of neonatal isolation (NI) on seizures. Rats were assigned randomly to the following five groups: (1) control (CONT) rats; (2) NI rats that underwent daily separation from their dams from postnatal day 2 (P2) to P9; (3) status epilepticus (SE) rats, induced by lithium-pilocarpine (Li-Pilo) model at P10; (4) NI plus SE (NIS) rats and (5) NISM rats, a subset of NIS rats receiving metyrapone (100 mg/kg), a CORT synthesis inhibitor, immediately after SE induction. At P10, plasma CORT levels were compared at baseline in CONT and NI rats and in response to Li-Pilo-induced SE among SE, NIS and NISM rats. We evaluated the spatial memory in the Morris water maze at P50 approximately 55, the expression of hippocampal cyclic adenosine monophosphate (cAMP)-responsive element-binding protein phosphorylation at serine-133 (pCREBSer-133) at P55, hippocampal neuronal damage at P80 and seizure threshold at P100. The isolated rats exhibited higher CORT release in response to SE than non-isolated rats, and the NIS rats had greater cognitive deficits and decreased seizure threshold compared to the CONT, NI and SE groups. By contrast, the NISM group, compared to the NIS group, showed a normal CORT response to SE and better spatial memory but no difference in seizure threshold. Compared to the CONT group, the hippocampal pCREBSer-133 level was significantly reduced in all experimental groups (NI, SE, NIS, NISM) with no differences between groups. All rats were free of spontaneous seizures later in life and had no discernible neuronal loss in the hippocampus. Results in this model demonstrate repetitive NI enhances response of plasma CORT to SE, and exacerbates the neurological consequences of neonatal SE. Amelioration of neurological sequelae following reduction of the SE-induced excessive rise in plasma CORT implicates CORT in the pathogenesis of NI increasing the vulnerability to seizures.

Animals↗
PubMed2005

Anticonvulsant action of GABA in the high potassium-low magnesium model of ictogenesis in the neonatal rat hippocampus in vivo and in vitro.

Previous developmental studies in vitro suggested that the inhibitory neurotransmitter GABA exerts depolarizing and excitatory actions on the immature neurons and that depolarizing GABA is causally linked to ictal activity during the first weeks of postnatal life. However, remarkably little is known on the role of GABA in the generation of neonatal seizures in vivo. Here, using extracellular recordings from CA3 hippocampus, we studied the effects of GABA(A)-acting drugs on electrographic seizures induced by local intrahippocampal injection of the epileptogenic agents (high K(+)/low Mg(2+)) in the nonanesthetized rats in vivo and in the hippocampal slices in vitro during the second postnatal week (postnatal days P8-12). We found that in vivo, the induction of ictal-like events was facilitated by co-infusion of high-K(+)/low Mg(2+) together with the GABA(A) antagonist bicuculline or gabazine. Moreover, the infusion of bicuculline alone caused ictal-like activity in approximately 30% of cases. Co-infusion of the GABA(A) receptor agonist isoguvacine or the GABA(A)-positive allosteric modulator diazepam completely prevented high-K(+)/low Mg(2+)-induced seizures. In in vitro studies using hippocampal slices, we also found that high-K(+)/low Mg(2+) produced ictal activity that was exacerbated by bicuculline and gabazine and reduced by isoguvacine. Thus in the model of high-K(+)/low Mg(2+)-induced seizures both in in vivo and in vitro conditions, GABA, acting via GABA(A) receptors, has an anticonvulsant effect during the critical developmental period of enhanced excitability.

2-Amino-5-phosphonovalerate↗
PubMed2005

Effects of seizures on brain development: lessons from the laboratory.

Both clinical and laboratory studies demonstrate that seizures early in life can result in permanent behavioral abnormalities and enhance epileptogenicity. In experimental rodent models, the consequences of seizures are dependent upon age, etiology, seizure duration, and frequency. Recurrent seizures in immature rats result in long-term adverse effects on learning and memory. These behavioral changes are paralleled by changes in brain connectivity, dendritic morphology, excitatory and inhibitory receptor subunits, ion channels, and neurogenesis. These changes can occur in the absence of cell loss. Although impaired cognitive function and brain changes have been well documented after early onset seizures, the mechanisms of seizure-induced injury remain unclear. Recent studies have demonstrated abnormalities in single cell function that parallel behavioral changes.

Animals↗
PubMed2005

Effect of topiramate on cognitive function and activity level following neonatal seizures.

Topiramate, an antiepileptic drug with a number of mechanisms of action including blockade of AMPA/KA receptor subtypes, was assessed as a neuroprotective agent following seizures. We administered topiramate or saline chronically during and following a series of 25 neonatal seizures. After completion of the topiramate treatment, animals were tested in the water maze for spatial learning and the open field for activity level. Brains were then examined for cell loss and sprouting of mossy fibers. Rats treated with topiramate performed significantly better in the water maze than rats treated with saline. Topiramate treatment also reduced the amount of seizure-induced sprouting in the supragranular region. There were no differences between topiramate- and saline-treated rats in activity level in the open field, swimming speed, or weight gain. These findings show that long-term treatment with topiramate after neonatal seizures changes the long-term consequences of seizures and improves cognitive function.

Age Factors↗
PubMed2005

The multiple facets of gamma-aminobutyric acid dysfunction in epilepsy.

PURPOSE OF REVIEW: The polarity of action of gamma-aminobutyric acid (GABA) changes from inhibition to excitation in the developing brain and in epilepsies. This review deals with recent observations concerning the mechanisms and clinical implications of the shift in GABA's activity from inhibition to excitation. RECENT FINDINGS: GABAergic synapses provide most transmitter-gated inhibition and are the targets of numerous clinically active agents, notably antiepileptic drugs. In a wide range of brain structures and species, GABAergic synapses are excitatory during maturation because of a higher concentration of intracellular chloride. These findings suggest that activation of GABA synapses will excite foetal neurones while inhibiting those of the mother. In epilepsies, recurrent seizures also lead to an accumulation of chloride and an excitatory action of GABA. These observations have major implications for clinical practice and research. They suggest that use of benzodiazepines by pregnant mothers may lead to deleterious consequences when they are taken during the period when GABA is the main excitatory transmitter. Because neuronal activity alters important cell functions, including migration and morphogenesis, aberrant excessive excitation may lead to profound deleterious consequences. SUMMARY: In several physiological and pathological conditions, activation of GABAergic synapses excites neurones instead of producing classical inhibition. This shift, which is due to an intracellular accumulation of chloride, has major consequences for both the operation of networks and the pathogenic effects of epilepsies. This is particularly important in the immature brain, where the excitatory actions of GABA are particularly prominent.

Brain Chemistry↗
PubMed2005

Pilocarpine seizures cause age-dependent impairment in auditory location discrimination.

Children who have status epilepticus have continuous or rapidly repeating seizures that may be life-threatening and may cause life-long changes in brain and behavior. The extent to which status epilepticus causes deficits in auditory discrimination is unknown. A naturalistic auditory location discrimination method was used to evaluate this question using an animal model of status epilepticus. Male Sprague-Dawley rats were injected with saline on postnatal day (P) 20, or a convulsant dose of pilocarpine on P20 or P45. Pilocarpine on either day induced status epilepticus; status epilepticus at P45 resulted in CA3 cell loss and spontaneous seizures, whereas P20 rats had no cell loss or spontaneous seizures. Mature rats were trained with sound-source location and sound-silence discriminations. Control (saline P20) rats acquired both discriminations immediately. In status epilepticus (P20) rats, acquisition of the sound-source location discrimination was moderately impaired. Status epilepticus (P45) rats failed to acquire either sound-source location or sound-silence discriminations. Status epilepticus in rat causes an age-dependent, long-term impairment in auditory discrimination. This impairment may explain one cause of impaired auditory location discrimination in humans.

Aging↗
PubMed2004

Early motor activity drives spindle bursts in the developing somatosensory cortex.

Sensorimotor coordination emerges early in development. The maturation period is characterized by the establishment of somatotopic cortical maps, the emergence of long-range cortical connections, heightened experience-dependent plasticity and spontaneous uncoordinated skeletal movement. How these various processes cooperate to allow the somatosensory system to form a three-dimensional representation of the body is not known. In the visual system, interactions between spontaneous network patterns and afferent activity have been suggested to be vital for normal development. Although several intrinsic cortical patterns of correlated neuronal activity have been described in developing somatosensory cortex in vitro, the in vivo patterns in the critical developmental period and the influence of physiological sensory inputs on these patterns remain unknown. We report here that in the intact somatosensory cortex of the newborn rat in vivo, spatially confined spindle bursts represent the first and only organized network pattern. The localized spindles are selectively triggered in a somatotopic manner by spontaneous muscle twitches, motor patterns analogous to human fetal movements. We suggest that the interaction between movement-triggered sensory feedback signals and self-organized spindle oscillations shapes the formation of cortical connections required for sensorimotor coordination.

Aging↗
PubMed2004

Detrimental effects of the ketogenic diet on cognitive function in rats.

The ketogenic diet (KD) is a high-fat, low-carbohydrate, and low-protein diet that is widely used to treat epilepsy in children. Although the KD has been shown to be efficacious in the treatment of childhood epilepsy, the long-term effects of the KD on brain development are not clear. The objective of this study was to examine the long-term effects of the KD on visual-spatial memory, activity level, and emotionality in immature rats after status epilepticus (SE). Weanling rats were subjected to lithium/pilocarpine-induced SE or saline injections and were then randomized to either the KD or regular rat diet, both fed ad libitum. One month later, rats were evaluated for visual-spatial memory in the water maze, activity level in the open field test, and emotionality with the handling test. Spontaneous recurrent seizures were measured using videotaping, and seizure susceptibility was tested with flurothyl inhalation. Brains were weighed and examined for mossy fiber sprouting and cell loss. Although rats treated with the KD were active and seemed healthy, their weight gain was substantially lower than that in rats that received regular rat diet. The KD reduced the number of spontaneous seizures but had no discernible effect on flurothyl seizure susceptibility. KD-fed rats, with or without SE, had significantly impaired visual-spatial learning and memory compared with rats that were fed regular diet. The KD had minimal effects on activity level and emotionality. Rats that were treated with the KD had significantly impaired brain growth. No differences in pathology scores between the KD and regular diet groups were seen after SE. Despite reducing the number of spontaneous seizures after SE, the KD resulted in severe impairment in visual-spatial memory and decreased brain growth, with no effect on mossy fiber sprouting. This study raises concerns about the long-term effects of the KD on brain development.

Animals↗