Search PubMed⌕ Search

Biomedical subjects

G L Holmes

Publications and source records attributed to G L Holmes.

At least 19 recordsLinked to original sources
PubMed2001

Timing of cognitive deficits following neonatal seizures: relationship to histological changes in the hippocampus.

Neonatal seizures are frequently associated with cognitive impairment and reduced seizure threshold. Previous studies in our laboratory have demonstrated that rats with recurrent neonatal seizures have impaired learning, lower seizure thresholds, and sprouting of mossy fibers in CA3 and the supragranular region of the dentate gyrus in the hippocampus when studied as adults. The goal of this study was to determine the age of onset of cognitive dysfunction and alterations in seizure susceptibility in rats subjected to recurrent neonatal seizures and the relation of this cognitive impairment to mossy fiber sprouting and expression of glutamate receptors. Starting at postnatal day (P) 0, rats were exposed to 45 flurothyl-induced seizures over a 9-day period of time. Visual-spatial learning in the water maze and seizure susceptibility were assessed in subsets of the rats at P20 or P35. Brains were evaluated for cell loss, mossy fiber distribution, and AMPA (GluR1) and NMDA (NMDAR1) subreceptor expression at these same time points. Rats with neonatal seizures showed significant impairment in the performance of the water maze and increased seizure susceptibility at both P20 and P35. Sprouting of mossy fibers into the CA3 and supragranular region of the dentate gyrus was seen at both P20 and P35. GluR1 expression was increased in CA3 at P20 and NMDAR1 was increased in expression in CA3 and the supragranular region of the dentate gyrus at P35. Our findings indicate that altered seizure susceptibility and cognitive impairment occurs prior to weaning following a series of neonatal seizures. Furthermore, these alterations in cognition and seizure susceptibility are paralleled by sprouting of mossy fibers and increased expression of glutamate receptors. To be effective, our results suggest that strategies to alter the adverse outcome following neonatal seizures will have to be initiated during, or shortly following, the seizures.

Animals↗
PubMed2001

Enhanced auditory reversal learning by genetic activation of protein kinase C in small groups of rat hippocampal neurons.

The hippocampus has a central role in specific types of learning, but there is only limited evidence identifying the requisite molecular changes in ensembles of hippocampal neurons. To investigate the role of protein kinase C (PKC) pathways in hippocampal mediated learning, a constitutively active, catalytic domain of rat PKC betaII was delivered into hippocampal dentate granule neurons using a Herpes Simplex Virus (HSV-1) vector. This PKC causes a long-lasting, activation-dependent increase in neurotransmitter release from cultured cells. Activation of PKC pathways in a small percentage (< or =0.26%) of dentate granule neurons was sufficient to enhance rat auditory discrimination reversal learning. The affected neurons altered hippocampal physiology as revealed by elevated NMDA receptor densities in specific hippocampal areas. Thus, these results directly suggest that activation of PKC pathways in a specific hippocampal area alters rat auditory discrimination reversal learning. Because each rat may contain a unique pattern of affected neurons, there appears to be considerable flexibility and/or redundancy in the groups of neurons that can modify learning.

Animals↗
PubMed2001

Recurrent neonatal seizures: relationship of pathology to the electroencephalogram and cognition.

Seizures in preterm infants are associated with a high risk of neurological sequelae. In the neonatal rat recurrent seizures have been associated with long-term changes in cerebral excitability and cognition as well as sprouting of mossy fiber terminals in the granule cell layer of the dentate gyrus and hippocampal CA3 subfield. To evaluate the relationship between seizure-induced morphological changes and cognitive function we subjected newborn rats to 55 seizures with flurothyl during the first 12 days of life. During adolescence rats with prior recurrent seizures were compared with controls in electroencephalographic power and performance in the Morris water maze and open field test. Rats subjected to recurrent seizures had marked impairment in water maze performance and never reached the level of learning seen in controls despite a total of 54 trials. Recurrent seizures were also associated with an overall reduction in spectral power which was most pronounced in the theta range. On histological examination rats with recurrent neonatal seizures had sprouting of mossy fiber terminals in CA3 and the granule cell layer of the dentate gyrus without any accompanying cell loss. Sprouting in CA3, but not the granule cell layer of the dentate gyrus, correlated with water maze performance. This study demonstrates that recurrent neonatal seizures can result in profound impairment of water maze performance and reduction of electroencephalographic power despite the lack of discernible cell loss and that this cognitive impairment correlates with mossy fiber sprouting in CA3.

Animals↗
PubMed2001

Epilepsy.

Explore the source record for details and available documents.

Anticonvulsants↗
PubMed2001

Reduced neurogenesis after neonatal seizures.

Although neonatal seizures are quite common, there is controversy regarding their consequences. Despite considerable evidence that seizures may cause less cell loss in young animals compared with mature animals, there are nonetheless clear indications that seizures may have other potentially deleterious effects. Because it is known that seizures in the mature brain can increase neurogenesis in the hippocampus, we studied the extent of neurogenesis in the granule cell layer of the dentate gyrus over multiple time points after a series of 25 flurothyl-induced seizures administered between postnatal day 0 (P0) and P4. Rats with neonatal seizures had a significant reduction in the number of the thymidine analog 5-bromo-2'-deoxyuridine-5'-monophosphate- (BrdU) labeled cells in the dentate gyrus and hilus compared with the control groups when the animals were killed either 36 hr or 2 weeks after the BrdU injections. The reduction in BrdU-labeled cells continued for 6 d after the last seizure. BrdU-labeled cells primarily colocalized with the neuronal marker neuron-specific nuclear protein and rarely colocalized with the glial cell marker glial fibrillary acidic protein, providing evidence that a very large percentage of the newly formed cells were neurons. Immature rats subjected to a single seizure did not differ from controls in number of BrdU-labeled cells. In comparison, adult rats undergoing a series of 25 flurothyl-induced seizures had a significant increase in neurogenesis compared with controls. This study indicates that, after recurrent seizures in the neonatal rat, there is a reduction in newly born granule cells.

Acidosis↗
PubMed2001

Anticonvulsant action and long-term effects of gabapentin in the immature brain.

The anticonvulsant action and the long-term effects on learning, memory and behavior of the new generation antiepileptic drug gabapentin (GBP) were investigated in immature animals. Kainic acid (KA) was administered to rats on postnatal day (P) 35. Animals were treated with GBP or saline from P36 to P75 and spontaneous seizure frequency was monitored. After tapering the drug, the rats were tested in the water maze and open field test. Brains were then analyzed for histological lesions. Animals treated with GBP following KA-induced status epilepticus had a reduced incidence of spontaneous recurrent seizures, a better pathology score, and less aggressiveness compared to saline-treated controls. Effectiveness of GBP on seizure threshold was tested using flurothyl inhalation in 10 separate age groups of animals ranging from the newborn period to adulthood. Furthermore, GBP plasma concentration peaks were determined in all age groups. At all ages, GBP pre-treated animals demonstrated a higher seizure threshold. Plasma GBP concentrations did not significantly change with age. These data suggest that acute administration of a single therapeutic dose of GBP increases the seizure threshold at all ages studied, while chronic treatment following the status reduces spontaneous seizure frequency and cell damage and has no long-term adverse consequences on cognitive processes during development.

Acetates↗
PubMed2001

Brain development and generation of brain pathologies.

The timing of brain development is genetically programmed and can be profoundly altered by a number of abnormal genes that control proliferation, differentiation, migration, synapse formation, and elimination of cells and synapses. With advances in genetic techniques both the gene and gene product responsible for brain malformation are being identified which will permit a better understanding of the pathophysiology of brain malformations. In addition to genetic abnormalities, brain development can be influenced by a variety of acquired disorders. The type of brain abnormality is highly dependent on the stage of brain development during which the insult occurs. While our understanding of experience- or activity-dependent processes on brain development is limited, it is now clear that this activity can significantly alter the timing of a number of maturational events including receptor maturation and neurogenesis. The future challenge will be both to understand the biological basis of these processes and to use this information to enhance brain development.

Animals↗
PubMed2001

Topiramate and metabolic acidosis in pediatric epilepsy.

PURPOSE: Topiramate (TPM) has been widely used as an adjunctive therapy for treating epilepsy. TPM is reported to have multiple mechanisms of action, including inhibition of carbonic anhydrase, which may result in metabolic acidosis from decreased serum bicarbonate (HCO3-). METHODS: Clinical data from 30 children who received TPM as adjunctive therapy for medically refractory epilepsy were reviewed at Children's Hospital, Boston. Serum HCO3- levels were assessed before, during, and after discontinuing TPM (n = 9). When multiple data were available, mean values were used for analysis. RESULTS: Of the 30 patients, 21 had a >10% decrease in HCO3- levels. The mean decrease in HCO3- among the 21 patients was 4.7 mEq/L, and maximum was 10 mEq/L. No clinical symptoms occurred, and HCO3- supplement was not needed, except for one patient who developed tachypnea from worsened acidosis after prolonged status epilepticus during a suspected viral illness. Among the 21 patients, TPM was discontinued in seven children because of a lack of efficacy, and in two because of anorexia. After discontinuing TPM, the serum HCO3- returned to the previous level before starting TPM in all nine. CONCLUSIONS: Decreased HCO3- levels occurred in the majority of patients reviewed, usually only to a small to moderate extent, but by 8 and 10 mEq/L in two cases. In patients at risk for acidosis, the decrease in HCO3- may cause significant consequences, such as severe acidosis or renal calculi. Monitoring HCO3- levels before and during TPM therapy may be indicated, especially with conditions that predispose to acidosis.

Acidosis↗
PubMed2001

Outcome of severe refractory status epilepticus in children.

PURPOSE: Refractory status epilepticus (RSE) is the persistence of seizure activity despite appropriate therapy; it is treated with high-dose suppressive anesthetic agents. We report here the outcome of RSE in a large series of children. METHODS: We retrospectively reviewed cases of RSE treated at Children's Hospital, Boston, between 1992 and 2000. Factors evaluated included age, history of seizures or neurologic impairment, etiology, outcome, including mortality or return to baseline, and initial EEG findings. RESULTS: Twenty-two patients ages 4.5 months to 18 years were admitted to the intensive care unit for RSE. All were treated with high-dose suppressive therapy consisting of pentobarbital, midazolam, propofol infusion, or high-dose phenobarbital, either alone, or in combination, for < or =146 days. The overall mortality was seven of 22. Mortality was related to etiology, age, and EEG findings. No death occurred in the remote symptomatic group, and three of four younger than 3 years died, whereas only four of 18 older than 3 years died. The mortality rate among patients with focal abnormalities on the EEG was lower than that among those with multifocal or generalized abnormalities. None of the children with normal premorbid neurologic status returned to baseline. CONCLUSIONS: Our data demonstrate a high mortality and morbidity for childhood RSE. Mortality is related to etiology and is higher in younger children and with multifocal or generalized abnormalities on the initial EEG.

Adolescent↗
PubMed2001

Prediction of safe duration of hypothermic circulatory arrest by near-infrared spectroscopy.

OBJECTIVE: Hypothermic circulatory arrest is widely used for adults with aortic arch disease as well as for children with congenital heart disease. At present, no method exists for monitoring safe duration of circulatory arrest. Near-infrared spectroscopy is a new technique for noninvasive monitoring of cerebral oxygenation and energy state. In the current study, the relationship between near-infrared spectroscopy data and neurologic outcome was evaluated in a survival piglet model with hypothermic circulatory arrest. METHODS: Thirty-six piglets (9.36 +/- 0.16 kg) underwent circulatory arrest under varying conditions with continuous monitoring by near-infrared spectroscopy (temperature 15 degrees C or 25 degrees C, hematocrit value 20% or 30%, circulatory arrest time 60, 80, or 100 minutes). Each setting included 3 animals. Neurologic recovery was evaluated daily by neurologic deficit score and overall performance category. Brain was fixed in situ on postoperative day 4 and examined by histologic score. RESULTS: Oxygenated hemoglobin signal declined to a plateau (nadir) during circulatory arrest. Time to nadir was significantly shorter with lower hematocrit value (P <.001) and higher temperature (P <.01). Duration from reaching nadir until reperfusion ("oxygenated hemoglobin signal nadir time") was significantly related to histologic score (r (s) = 0.826), neurologic deficit score (r (s) = 0.717 on postoperative day 1; 0.716 on postoperative day 4), and overall performance category (r (s) = 0.642 on postoperative day 1; 0.702 on postoperative day 4) (P <.001). All animals in which oxygenated hemoglobin signal nadir time was less than 25 minutes were free of behavioral or histologic evidence of brain injury. CONCLUSION: Oxygenated hemoglobin signal nadir time determined by near-infrared spectroscopy monitoring is a useful predictor of safe duration of circulatory arrest. Safe duration of hypothermic circulatory arrest is strongly influenced by perfusate hematocrit value and temperature during circulatory arrest.

Analysis of Variance↗
PubMed2001

The neurobiology and consequences of epilepsy in the developing brain.

Epilepsy is a disorder in which the balance between cerebral excitability and inhibition is tipped toward uncontrolled excitability. There is now clear evidence that there are distinct differences between the immature and mature brain in the pathophysiology and consequences of seizures. Both the enhanced excitability of the immature brain compared with the mature brain and the unique pathologic consequences of seizures are related to the sequential development and expression of essential signaling pathways. Although the immature brain is less vulnerable than the mature brain to seizure-induced cell death, seizures in the developing brain can result in irreversible alterations in neuronal connectivity. Developing novel strategies to treat and avert the consequences of seizures in children will require further understanding of the unique mechanisms of seizure initiation and propagation in the immature brain.

Brain↗
PubMed2000

Timing of ketogenic diet initiation in an experimental epilepsy model.

Following kainic acid (KA)-induced status epilepticus (SE), the ketogenic diet (KD) retards the development of epileptogenesis, with fewer spontaneous recurrent seizures (SRS) and less mossy fiber sprouting than rats on a normal diet. In this study, we investigated whether there is a critical period for initiation of the KD, in terms of the diet's effectiveness in reducing SRS. In addition, we investigated whether early treatment with the KD prevents the deficits in spatial learning and memory that ordinarily follow KA-induced SE. Young rats (P30) underwent KA-induced SE, followed by assignment to one of three treatment groups: control diet ('KA'), KD begun 2 days after SE ('KD2'), and KD begun fourteen days after SE ('KD14'). For 12 weeks following SE, rats were monitored by closed circuit video recording (12 h/wk) to detect SRS. KD2 rats had significantly fewer SRS than rats in the control or KD14 groups. On water maze testing to assess spatial learning and memory, KD2 rats had significantly poorer acquisition of place learning than control (KA alone) or KD14 rats. KD2 rats also failed to gain weight well. There was no difference between groups on routine histologic examination of the hippocampus. In summary, P30 rats placed on the KD 2 days after SE were relatively protected from recurrent seizures, but showed behavioral and physical impairment. Rats placed on the KD 14 days after KA-induced SE did not differ from controls with regard to spontaneous seizure rate.

Animals↗
PubMed2000

Protective effects of prenatal choline supplementation on seizure-induced memory impairment.

Choline is an essential nutrient for rats and humans, and its availability during fetal development has long-lasting cognitive effects (Blusztajn, 1998). We investigated the effects of prenatal choline supplementation on memory deficits associated with status epilepticus. Pregnant rats received a control or choline-supplemented diet during days 11-17 of gestation. Male offspring [postnatal day 29 (P29)-32] were tested for their ability to find a platform in a water maze before and after administration of a convulsant dose of pilocarpine at P34. There were no differences between groups in water maze performance before the seizure. One week after status epilepticus (P41-P44), animals that had received the control diet prenatally had a drastically impaired performance in the water maze during the 4 d testing period, whereas prenatally choline-supplemented rats showed no impairment. Neither the seizures nor the prenatal availability of choline had any effect on hippocampal choline acetyltransferase or acetylcholinesterase activities. This study demonstrates that prenatal choline supplementation can protect rats against memory deficits induced by status epilepticus.

Acetylcholinesterase↗
PubMed2000

Increased susceptibility to generalized seizures after immunolesions of the basal forebrain cholinergic neurons in rats.

We investigated whether basal forebrain cholinergic neurons influence the expression of generalized seizures. Animals received intracerebroventricular injections of saporin (lesioned) or saline (controls) and were tested for susceptibility to flurothyl- or pentylenetetrazole-induced seizures. Lesioned rats had significantly shorter latencies to onset of generalized tonic-clonic seizures than controls. Our findings suggest that basal forebrain cholinergic neurons may participate in the modulation of generalized seizures.

Acetylcholinesterase↗
PubMed2000

Flurothyl-induced seizures in rats activate Fos in brainstem catecholaminergic neurons.

Autonomic changes accompany seizures in both animals and humans. While ictal autonomic dysfunction can be life-threatening, the participating neural networks involved are poorly understood. In this study we examined the activation of Fos following generalized seizures in brainstem structures known to mediate autonomic function. Adult female rats were sacrificed 2 h after flurothyl-induced seizures. Double-immunostaining for c-Fos and dopamine-beta-hydroxylase (DBH), and c-Fos and phenylethanol-N-methyl-transferase (PNMT) were performed in brainstem slices. Numbers of DBH-labeled neurons expressing Fos-like immunoreactivity (FLI) (DBH/Fos) and PNMT labeled neurons expressing FLI (PNMT/Fos) were counted in the noradrenergic (A1, A2, A5, A7) and adrenergic (C1, C2) cell groups localized in pons and medulla oblongata. Among the experimental animals, the highest degree of co-localization of DBH/Fos neurons was observed in the locus coeruleus (A6; 87.7%), and in the A1(72.8%) cell group located in the caudal ventrolateral medulla (VLM). No co-localization of DBH/Fos neurons was observed in control animals. The highest degree of co-localization of PNMT/Fos neurons was observed in the C1 adrenergic cell group (84.2%) located in the rostral VLM. Control animals showed very few (5.5%) PNMT/Fos co-localized neurons in the C1 adrenergic cell group. Our results indicate that flurothyl-induced generalized seizures in rats activate catecholaminergic neurons in the pons and medulla oblongata. Further studies are necessary to determine whether activation of brainstem catecholaminergic neurons contribute to the autonomic manifestations that frequently accompany epileptic seizures.

Animals↗