Biomedical subjects

Gregory L Holmes

Publications and source records attributed to Gregory L Holmes.

At least 37 records · Page 2Linked to original sources

PubMed2004

Effects of early seizures on later behavior and epileptogenicity.

Both clinical and laboratory studies demonstrate that seizures early in life can result in permanent behavioral abnormalities and enhance epileptogenicity. Understanding the critical periods of vulnerability of the developing nervous system to seizure-induced changes may provide insights into parallel or divergent processes in the development of autism. In experimental rodent models, the consequences of seizures are dependent on age, etiology, seizure duration, and frequency. Recurring seizures in immature rats result in long-term adverse effects on learning and memory. These behavioral changes are paralleled by changes in brain connectivity, changes in excitatory neurotransmitter receptor distribution, and decreased neurogenesis. These changes occur in the absence of cell loss. Although impaired cognitive function and brain changes have been well-documented following early-onset seizures, the mechanisms of seizure-induced dysfunction remain unclear.

Age Factors↗

PubMed2004

Spontaneous recurrent seizure following status epilepticus enhances dentate gyrus neurogenesis.

It is known that evoked seizures can increase neurogenesis in the dentate gyrus in adult rats. Whether spontaneous seizures occurring after status epilepticus (SE) also results in alterations in neurogenesis is not known. Here, we measured neurogenesis in rats with and without spontaneous seizures following SE. Lithium-pilocarpine was used to induce seizures in postnatal (P) day 20 rats. Spontaneous seizure frequency was assessed 2 months using video monitoring. Rats then received bromodeoxyuridine to label dividing DNA and were sacrificed 24 h later. Animals with spontaneous seizures (n = 9) had a modest increase in neurogenesis compared to animals with SE (n = 6) and no spontaneous seizures and control rats (n = 10). These findings demonstrate that the hippocampus is capable of generating new neurons weeks following SE and further that recurrent seizures enhance the production of new neurons. These alterations in neurogenesis may contribute to ongoing pathological changes week and months following SE.

Animals↗

PubMed2004

Interaction of temperature with hematocrit level and pH determines safe duration of hypothermic circulatory arrest.

OBJECTIVE: Previous studies have demonstrated that both hematocrit level and pH influence the protection afforded by deep hypothermic circulatory arrest. The current study examines how temperature modulates the effect of hematocrit level and pH in determining a safe duration of circulatory arrest. The study also builds on previous work investigating the utility of near-infrared spectroscopy as a real-time monitor of cerebral protection during circulatory arrest. METHODS: Seventy-six piglets (9.3 +/- 1.2 kg) underwent circulatory arrest under varying conditions with continuous monitoring by means of near-infrared spectroscopy (hematocrit level of 20% or 30%; pH-stat or alpha-stat strategy; temperature of 15 degrees C or 25 degrees C; arrest time of 60, 80, or 100 minutes). Neurologic recovery was evaluated daily by a veterinarian, and the brain was fixed in situ on postoperative day 4 to be examined on the basis of histologic score in a blinded fashion. RESULTS: Multivariable analysis of total histologic score revealed that higher temperature, lower hematocrit level, more alkaline pH, and longer hypothermic circulatory arrest duration were predictive of more severe damage to the brain (P <.01). Regression modeling revealed that higher temperature exacerbated the disadvantage of a lower hematocrit level and longer arrest times but not pH strategy. Normalized oxyhemoglobin nadir time, derived from near-infrared spectroscopy, was positively correlated with neurologic recovery on the fourth postoperative day and with total histologic injury score (P <.0001). CONCLUSION: Hematocrit level and pH, as well as temperature, determine the safe duration of hypothermic circulatory arrest. Near-infrared spectroscopy is a useful real-time monitor of safe duration of circulatory arrest.

Animals↗

PubMed2004

The treatment of status epilepticus.

Status epilepticus (SE) is a life-threatening emergency that requires prompt treatment, including basic neuroresuscitation principles (the ABCs), antiepileptic drugs to stop the seizure, and identification of etiology. Symptomatic SE is more common in younger children. Treating the precipitating cause may prevent ongoing neurologic injury and facilitates seizure control. A systematic treatment regimen, planned in advance, is needed, including one for refractory status epilepticus (RSE). Here we emphasize definitions, clinical and electroencephalography stages, early treatment, special circumstances that may require immediate seizure control, and treatment of RSE. Because much clinical research in SE has been done in adults, we indicate the patient population studied.

Electroencephalography↗

PubMed2004

Effects of nimodipine on the behavioral sequalae of experimental status epilepticus in prepubescent rats.

OBJECTIVE: The goal of this study was to investigate the potential protective effects of nimodipine (ND), a calcium channel blocker, on the acute manifestations and long-term behavioral sequalae of experimental status epilepticus (SE). METHODS: Three groups of Postnatal Day (P) 35 rats undergoing kainic acid (KA)-induced SE were injected with phenobarbital (PB) and/or ND, and were subsequently compared with rats injected with KA alone and normal control rats. Behavioral parameters were assessed by the Morris water maze, open field, and handling tests at P125-P135. Acute seizures and spontaneous recurrent seizures (SRS) were assessed by videotape techniques. RESULTS: PB reduced the severity of SE acutely, and protected completely against subsequent long-term SRS, memory impairment, and hyperactivity, and partially against aggressivity. ND alone had no effect on acute seizure activity, but did protect against subsequent SRS and memory impairment, and partially against aggressivity. When administered together, PB and ND had effects similar to those seen with PB alone. However, in addition, and unlike the PB- and ND-alone groups, the PB-ND group was completely protected against KA-induced increased aggressivity. CONCLUSIONS: Activation of L-type calcium channels contributes to the long-term behavioral sequalae of KA-induced SE, but is not essential for the development and maintenance of SE. ND has protective effects in SE when given alone or in conjunction with a traditional antiepileptic drug. Calcium channel blockers should be further investigated as add-on protective agents in models of SE and possibly in clinical trials.

Aggression↗

PubMed2004

Effect of food deprivation during early development on cognition and neurogenesis in the rat.

Food deprivation has been recognized as having pronounced beneficial effects in adult animals, increasing longevity, reducing seizure susceptibility, and enhancing resistance to neurotoxins. It is not known whether food deprivation in developing animals is neuroprotective or harmful. To evaluate the effects of food deprivation on brain development, we evaluated visual-spatial learning and memory and neurogenesis in the dentate gyrus of the hippocampus in food-deprived (FD) and well-fed (WF) rats. To induce food deprivation, pups were removed from their dams for 12 hours per day from Postnatal Day (P) 2 to P19. FD and WF rat pups were then subjected to status epilepticus (SE) induced by lithium-pilocarpine at P20. After SE, neurogenesis was measured, while in another group of P38 rats, learning and memory were evaluated using the Morris water maze. Food deprivation was found to reduce neurogenesis when assessed after the period of food deprivation. Although SE reduced neurogenesis in the WF animals, it had little effect additional to food deprivation on neurogenesis in the FD rats. Compared with the WF group, FD rats had a mild impairment in memory in the water maze testing after SE. Our study demonstrates that food deprivation during the neonatal period in rats is associated with a decrease in neurogenesis and mild impairment of visual-spatial memory. Although SE decreased neurogenesis in the WF group, in FD animals, SE did not reduce neurogenesis more than what was seen with food deprivation alone. Our results suggest that although food deprivation during early development reduces dentate gyrus neurogenesis, the reduced neurogenesis is not a major factor in cognitive impairment after SE in FD rats.

Age Factors↗

PubMed2004

Cognitive impairment following status epilepticus and recurrent seizures during early development: support for the "two-hit hypothesis".

Prolonged seizures in immature rats result in minimal behavioral consequences when the animals are studied later in life. Likewise, early-onset seizures are associated with minimal morphological changes. However, it is known that seizures early in life result in changes in the brain that make it more vulnerable to subsequent seizure-induced injury (the so-called two-hit hypothesis). Whether this heightened vulnerability occurs immediately after the first seizure is not known. In this study, immature rats were exposed to status epilepticus (SE) followed by a series of 25 flurothyl-induced seizures, SE alone, 25 flurothyl-induced seizures alone, or no seizures. Rats exposed to SE and flurothyl seizures performed significantly poorer in the water maze 2 weeks following the last seizure compared with the other groups. No histological lesions were seen in any of the four groups. This study suggests that SE renders the immature brain vulnerable to further seizure-induced injury and this enhanced vulnerability occurs very quickly after the SE.

Analysis of Variance↗

PubMed2004

Models for generalized seizures.

It is clear that a variety of gene defects can result in absence seizures. In addition, the problem is complicated by observation that the behavioral and EEG phenotype in some of the models is highly dependent on pedigree. Despite these difficulties, advances in molecular-genetic techniques coupled with electrophysiological studies are likely to be highly revealing. While the relationship between the rat and mice models and the human condition thus far remains tenuous, insights from the animal models have already been very helpful in choosing antiepileptic drugs and providing insights into the pathophysiology of the seizures.

Animals↗

PubMed2004

Developmental changes in GABAergic actions and seizure susceptibility in the rat hippocampus.

The immature brain is prone to seizures but the underlying mechanisms are poorly understood. We explored the hypothesis that increased seizure susceptibility during early development is due to the excitatory action of GABA. Using noninvasive extracellular field potential and cell-attached recordings in CA3 of Sprague-Dawley rat hippocampal slices, we compared the developmental alterations in three parameters: excitatory actions of GABA, presence of the immature pattern of giant depolarizing potentials (GDPs) and severity of epileptiform activity generated by high potassium. The GABA(A) receptor agonist isoguvacine increased firing of CA3 pyramidal cells in neonatal slices while inhibiting activity in adults. A switch in the GABA(A) signalling from excitation to inhibition occurred at postnatal day (P) 13.5 +/- 0.4. Field GDPs were present in the form of spontaneous population bursts until P12.7 +/- 0.3. High potassium (8.5 mm) induced seizure-like events (SLEs) in 35% of slices at P7-16 (peak at P11.3 +/- 0.4), but only interictal activity before and after that age. The GABA(A) receptor antagonist bicuculline reduced the frequency or completely blocked SLEs and induced interictal clonic-like activity accompanied by a reduction in the frequency but an increase in the amplitude of the population spikes. In slices with interictal activity, bicuculline typically caused a large amplitude interictal clonic-like activity at all ages; in slices from P5-16 rats it was often preceded by one SLE at the beginning of bicuculline application. These results suggest that, in the immature hippocampus, GABA exerts dual (both excitatory and inhibitory) actions and that the excitatory component in the action of GABA may contribute to increased excitability during early development.

Aging↗

PubMed2004

Mechanisms of action for the commonly used antiepileptic drugs: relevance to antiepileptic drug-associated neurobehavioral adverse effects.

Antiepileptic drugs exert their anticonvulsant effects by interfering with brain processes that involve structures that are also involved in learning, memory, and emotional behavior. Thus, modulation of ion channels, neurotransmitters, second messengers, and other processes by antiepileptic drugs, although helpful in controlling seizures, can interfere with normal brain function in undesired ways. The specific mechanism(s) of action of an antiepileptic drug can increase the risk for particular types of adverse events. In this review, we examine the cognitive and behavioral effects of antiepileptic drugs in animal models. Although animal studies, in many respects, do not mimic clinical experience, the data suggest a connection between certain mechanisms of antiepileptic action and the occurrence of cognitive adverse effects. Specifically, antiepileptic drugs with traditional gamma-aminobutyric acid (GABA)ergic mechanisms have the most detrimental effects on cognitive function, possibly because they impair attention. Conversely, drugs with the predominant effects at Na+ channels appear to have minimal impact on cognition. Levetiracetam, with its nonconventional GABAergic and Ca2+ channel effects, has shown positive cognitive effects in animal studies. Antiglutamatergic drugs have the potential to be a double-edged sword: they can interfere with consolidation of learning and memory but can also provide neuroprotection in addition to their antiseizure effects.

Animals↗

PubMed2004

Prescribing antiepileptic drugs: should patients be switched on the basis of cost?

To assess the costs of switching from one antiepileptic drug (AED) to another, all associated direct and indirect costs, not only drug acquisition costs, must be considered. The perspective of the healthcare system evaluated in cost-effectiveness analysis is of crucial importance. Multiple clinical factors can influence clinical decisions regarding switching AEDs. The economic cost of poorly controlled epilepsy is enormous and the most cost-effective intervention is an AED that provides total seizure control. Cost-minimisation studies have evaluated costs associated with various medications. If only efficacy and adverse events were considered, then the 'older' AEDs were generally more cost effective than the 'newer' AEDs. Most studies only examine very specific clinical situations and are not suitable for establishing general clinical recommendations. The pharmacoeconomics of AED choice is highly country specific. While switching to generic formulations is, in general, cost effective, some changes may be detrimental and more costly than remaining on the trade name preparation. For example, as a result of differences in bioavailability and possible loss of seizure control, changing patients to generic phenytoin and carbamazepine can be problematic. Fosphenytoin may only be cost effective in certain clinical situations compared with intravenous phenytoin. Seizure control should not be sacrificed on the basis of costs alone, as the major endpoint in treating epilepsy with AEDs is seizure control without adverse effects. Switching AEDs in clinical practice still depends on the individual clinical situation and choosing AED therapy solely on the basis of initial acquisition costs is unlikely to be cost effective in the long-term care of patients with epilepsy.

Anticonvulsants↗

PubMed2003

Seizure-induced changes in place cell physiology: relationship to spatial memory.

Status epilepticus (SE) is a frequent neurological emergency associated with a significant risk of morbidity in survivors. Impairment of hippocampal-specific memory is a common and serious deficit occurring in many of the survivors. However, the pathophysiological basis of cognitive deficits after SE is not clear. To directly address the cellular concomitants of spatial memory impairment, we recorded the activity of place cells from CA1 in freely moving rats subjected to SE during early development and compared this activity to that in control rats. Place cells discharge rapidly only when the rat's head is in a cell-specific part of the environment called the "firing field." This firing field remains stable over time. Normal place cell function seems to be essential for stable spatial memory for the environment. We, therefore, compared place cell firing patterns with visual-spatial memory in the water maze in SE and control rats. Compared with controls, place cells from the SE rats were less precise and less stable. Concordantly, the water maze performance was also impaired. There was a close relationship between precision and stability of place cells and water maze performance. In contrast, a single, acute, chemically induced seizure produced cessation of place cell activity and spatial memory impairment in water maze performance that reversed within 24 hr. These results strongly bolster the idea that there is a relationship between abnormal place cells and spatial memory. Our findings also suggest that the defects in place cell and spatial memory after SE and acute chemically induced seizures result from different processes.

Action Potentials↗

PubMed2003

Anti-kindling effect of slow repetitive transcranial magnetic stimulation in rats.

The cerebrospinal fluid (CSF) of animals exposed to electroconvulsive shock (ECS) has anticonvulsant properties when injected into naive animals. The present study investigated whether the CSF of humans exposed to 1 or 10 Hz repetitive transcranial magnetic stimulation (rTMS) has similar properties. Using a 4 day rat flurothyl kindling seizure model we found that the kindling rate was significantly decreased by intraventricular injection of CSF from depressed patients exposed to 1 Hz rTMS. The CSF from patients that underwent 10 Hz rTMS showed a trend toward an increased kindling rate. These results support the similarity of ECS and rTMS and suggest that 1 Hz and 10 Hz rTMS produce distinct physiologic changes.

Adult↗

PubMed2003

In vitro formation of a secondary epileptogenic mirror focus by interhippocampal propagation of seizures.

We have determined whether seizures generate an epileptogenic focus in distal structures using an in vitro preparation composed of three independent chambers that accommodate two intact hippocampi and their connecting commissures. This enabled us to apply a convulsive agent to one hippocampus, allow the propagation of a given number of seizures to the other side and block the connections reversibly by applying tetrodotoxin (TTX) to the commissural chamber. The propagation of seizures from the kainate-treated side to the naive side transformed the latter into an independent epileptogenic focus that was capable of generating spontaneous and evoked seizures. The induction mechanism required activation of NMDA receptors and the epileptogenic transformation was associated with long-term alterations in GABAergic synapses, which became excitatory because of a shift in the chloride reversal potential, E(Cl). These data indicate that the excitatory actions of GABA may be a fundamental property of epileptogenic structures.

Animals↗

PubMed2003

Prolonged treatment for acute symptomatic refractory status epilepticus: outcome in children.

High-dose suppressive therapy (HDST) is used to treat refractory status epilepticus (RSE). Prolonged therapy is required in some cases, and prognosis is important in making therapeutic decisions. The authors therefore studied the long-term outcome in previously normal children who survived prolonged HDST for acute symptomatic RSE. All have intractable epilepsy, and none returned to baseline.

Acute Disease↗

PubMed2003

Membrane potential of CA3 hippocampal pyramidal cells during postnatal development.

A depolarized resting membrane potential has long been considered to be a universal feature of immature neurons. Despite the physiological importance, the underlying mechanisms of this developmental phenomenon are poorly understood. Using perforated-patch, whole cell, and cell-attached recordings, we measured the membrane potential in CA3 pyramidal cells in hippocampal slices from postnatal rats. With gramicidin perforated-patch recordings, membrane potential was -44 +/- 4 (SE) mV at postnatal days P0-P2, and it progressively shifted to -67 +/- 2 mV at P13-15. A similar developmental change of the membrane potential has been also observed with conventional whole cell recordings. However, the value of the membrane potential deduced from the reversal potential of N-methyl-d-aspartate channels in cell-attached recordings did not change with age and was -77 +/- 2 mV at P2 and -77 +/- 2 mV at P13-14. The membrane potential measured using whole cell recordings correlated with seal and input resistance, being most depolarized in neurons with high, several gigaohms, input resistance and low seal resistance. Simulations revealed that depolarized values of the membrane potential in whole cell and perforated-patch recordings could be explained by a shunt through the seal contact between the pipette and membrane. Thus the membrane potential of CA3 pyramidal cells appears to be strongly negative at birth and does not change during postnatal development.

Animals↗

PubMed2003

Synchronization of kainate-induced epileptic activity via GABAergic inhibition in the superfused rat hippocampus in vivo.

We studied cellular mechanisms of synchronization of epileptiform activity induced by kainic acid in a novel preparation of superfused rat hippocampus in vivo. Under urethane anesthesia, kainate induced epileptic population spikes occurring at 30-40 Hz. Pyramidal cells fired exclusively during population spikes with an average probability of 0.34 on rebound of rhythmic GABA(A)-mediated inhibitory postsynaptic events. Excitatory synaptic events contributed little to seizure activity. Rhythmic epileptiform activity was suppressed by blocking GABA(A) receptors and was slowed by barbiturates. Thus, GABAergic inhibition is instrumental in synchronizing kainate-induced epileptiform rhythmic activity in the gamma frequency band in the intact hippocampus in vivo.

Action Potentials↗

PubMed2003

Neonatal seizures: characteristics of EEG ictal activity in preterm and fullterm infants.

The neonatal EEG remains one of oldest, yet most valuable, diagnostic and prognostic tests in neonates. The goals of this study were to determine the relationships between the morphology, frequency, and distribution of ictal discharges in the neonatal EEG with age, EEG background activity, and etiology. A total of 156 ictal events were evaluated in 11 preterm (PT) and 25 fullterm (FT) infants. Most of the infants had severe abnormalities of background activity although ictal discharges occurred on both normal and abnormal backgrounds. There was a trend for a closer relationship between behavioral changes during the electroencephalographic seizure when the background activity was normal or moderately abnormal than when background activity was severely abnormal. In both PT and FT infants, the most common site of seizure origin was the temporal lobe. FT infants commonly had sharp waves, spikes, sharp and slow waves, and spike and slow waves at the onset of the ictus while rhythmic delta activity was most common in the PT infants. PT infants typically had a regional onset to the ictus whereas FT infants most frequently had a focal onset. Duration of the ictal events was similar in PT and FT infants and a change in morphology or frequency of the discharges was common during propagation of the ictal discharges in both age groups. There was not a clear relationship between onset, morphology, frequency, or propagation patterns and etiology in either the PT or FT infants. Our results demonstrate that while the type of ictal discharge is related to gestational age, there is a rich variety in the onset, morphology, and frequency of the ictal discharges in both PT and FT infants and that neonatal ictal patterns lack a close correlation with underlying pathology.

Brain↗