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E W Lothman

Publications and source records attributed to E W Lothman.

At least 55 records · Page 3Linked to original sources
PubMed1992

Reverberatory seizure discharges in hippocampal-parahippocampal circuits.

Previously, a unique type of epileptiform discharge, recorded in the dentate gyrus, has been identified and termed maximal dentate activation. Maximal dentate activation is defined by the presence of bursts of large amplitude population spikes, associated with a secondary rise in the extracellular potassium and a negative shift of the dc potential. Prior work has linked maximal dentate activation to lengthening of afterdischarges when they are elicited in the hippocampus or outside of the hippocampus in the amygdala. The current study used two approaches to further examine the relationship of maximal dentate activation to seizures in limbic circuits in urethane-anesthetized rats. First, simultaneous recordings were employed to document that during maximal dentate activation, synchronous discharges occurred in the dentate gyrus, cornu Ammonis, subiculum, and entorhinal cortex. From anatomical work, these structures are known to be connected in a hippocampal-parahippocampal loop. The second approach used lesions of the entorhinal cortex to document the importance of this loop in the initiation and maintenance of maximal dentate activation. Both electrolytic and chemical (focal injections of tetrodotoxin) lesions of the entorhinal cortex blocked maximal dentate activation on the side of the lesion. However, maximal dentate activation was maintained on the opposite side, where the hippocampal-parahippocampal loop was intact. Altogether, these data support the hypothesis that maximal dentate activation is a marker for the presence of reverberatory, synchronized paroxysmal activity throughout the hippocampal-parahippocampal loop and that this loop behaves as a unit in epileptogenesis.

Animals↗
PubMed1992

Bilateral maximal dentate activation is critical for the appearance of an afterdischarge in the dentate gyrus.

Recently, a phenomenon has been described in the dentate gyrus termed maximal dentate activation, which is defined by the appearance of bursts of large amplitude population spikes associated with a negative shift of the d.c. potential and a secondary rise of the extracellular potassium level. Previous work has linked maximal dentate activation to kindling of afterdischarges, either when they are elicited in the hippocampus or outside of the hippocampus in the amygdala. Recording bilaterally in the dentate gyrus, it was found that maximal dentate activation occurred on both sides, with the side ipsilateral to the stimulus (either CA3 or angular bundle) being activated first. An afterdischarge did not appear unless bilateral maximal dentate activation had occurred. With repeated stimulation, the time to onset of maximal dentate activation on the two sides of the brain became nearly equal. This was associated with the appearance of afterdischarges. However, complete synchronization of the onset of maximal dentate activation was not necessary for afterdischarge production. Maximal dentate activation and afterdischarges could be readily elicited in rats in which the hippocampal commissures had been cut. It appears that, in the intact brain, the lack of maximal dentate activation on one side of the brain can function as a "brake" for epileptic activity, preventing afterdischarges. Once this brake is removed, by cutting the hippocampal commissures or by initiating maximal dentate activation, the dentate gyrus readily expresses afterdischarges.

Amygdala↗
PubMed1992

Loss of type II calcium/calmodulin-dependent kinase activity correlates with stages of development of electrographic seizures in status epilepticus in rat.

Understanding the molecular basis of altered neuronal excitability in epilepsy is a major challenge in neuroscience research. The present study suggests an inverse correlation between changes in neuronal excitability in status epilepticus and the activity of type II multifunctional calcium/calmodulin-dependent kinase II (CaM kinase II), a major Ca(2+)-signal transducing system in brain. 'Continuous' hippocampal stimulation (CHS), a new model of non-convulsive limbic status epilepticus (SE), mimics the progression of electrographic changes characteristic in human SE and allows for quantitation of post-stimulus seizure severity. In the present study, hippocampus and anterior neocortex from CHS-stimulated rats and paired surgical controls were assayed for CaM kinase II activity by incorporation of radiolabeled phosphate from [gamma-32P]ATP into the 50-kDa subunit of the kinase itself (autophosphorylation). In all instances, CHS induced sustained interictal bursting and/or electrographic seizures. Decreased CaM kinase II activity was seen in all preparations from electrically stimulated hippocampus. CaM kinase II activity in CHS animals was diminished by 37% relative to controls (P less than 0.01; Student's paired t-test). The progressive intensity of the EEG discharges correlated directly with the decrement of CaM kinase II activity (P less than 0.05; Spearman's rank correlation test, n = 5). This is the first report of a dynamic modulation of a biochemical system that has been implicated in neuronal excitability in coordination with the characterized developmental stages of SE.

Animals↗
PubMed1992

Influence of electrical stimulus parameters on afterdischarge thresholds in the rat hippocampus.

The influence of electrical stimulus parameters on focal seizure production was studied. Stimulations and recordings were carried out with bipolar electrodes stereotactically positioned in the ventral hippocampus of kindled rats. After discharge thresholds were determined for stimulus trains with different combinations of train durations (0.5, 1, 2, 5, 10 s), intratrain frequencies (10, 20, 50, 60, 100 Hz), and pulse widths (0.5 and 1.0 ms). For a given combination of pulse width and intratrain frequency, thresholds decreased as train duration increased; the effect was profound with shorter durations but markedly attenuated with train durations > or = 5 s. For a particular train duration and pulse width, thresholds varied inversely with intratrain frequency; the degree of variation in the thresholds with frequency was greater the shorter the train. For the train durations studied, thresholds were lower with 1.0-ms pulses for intratrain frequencies > or = 20 Hz. However, for 10 Hz, the 0.5-ms pulses were more effective for 2-, 5- and 10-s trains. After discharge thresholds were found to also vary with the number of pulses in the stimulus trains. For stimuli with fewer pulses, thresholds were higher and showed marked variation with train duration, intratrain frequency, and pulse width. For stimuli with more pulses, thresholds fell to a lower limit and the influence of train duration was substantially lessened. This study provides a systematic examination of the influence of stimulus parameters on generation of focal seizures and should prove useful in designing and interpreting future experiments studying the neurobiology of seizures in the hippocampus and related structures and helpful in antiepileptic drug testing.

Animals↗
PubMed1992

Developmental changes in tritium autoabsorption.

Developmental changes in autoabsorption of tritium emissions were examined in 30 brain regions in the rat at Postnatal Days 0, 4, 7, 10, 14, 21, and 28 and adulthood. Rats received tritiated 2-deoxyglucose in vivo. Alternate brain sections were extracted in chloroform, and autoradiographs were developed from extracted and nonextracted sections. The ratio of optical density values in extracted vs nonextracted sections was used to determine autoabsorption for each structure. Three principal temporal patterns in the development of adult levels of autoabsorption, determined by the optical density ratios, were identified: (1) a minimal increase pattern in which autoabsorption rose only slightly between birth and adulthood; (2) a plateau pattern in which a rapid early increase was followed by stable values; and (3) a late increase pattern in which autoabsorption remained relatively constant until Postnatal Day 28, with a large increase between Day 28 and adulthood. In addition, optical density ratios fluctuated during the second postnatal week in close to one-third of the structures. The data suggest that developmental events affecting the ratio of gray to white matter produce substantial local variations in the development of adult levels of autoabsorption that are distinct for each structure. To correct for autoabsorption effects in ontogenetic studies using tritium autoradiography, it is necessary to determine directly the degree of autoabsorption at a particular time point for the structure of interest. Our results indicate that the technique of in vivo administration of tritiated 2-deoxyglucose followed by chloroform extraction appears to be a sensitive and reproducible method for assessing autoabsorption at all ages.

Absorption↗
PubMed1992

The dentate gyrus as a control point for seizures in the hippocampus and beyond.

Considerable in vitro work has pointed to a resistance of dentate gyrus granule cells for expressing epileptiform paroxysms. However, in vivo work has shown that these neurons, under appropriate conditions, support and sustain seizure discharges. This range of activity of granule cells, along with their location in the middle of a pathway that connects hippocampal regions with high propensities for generating seizures, allows the dentate gyrus to act as a critical regulator of seizures. In the following report we review experiments on a stereotyped, robust paroxysmal discharge, maximal dentate activation (MDA), that occurs in granule cells, and we examine the role of MDA in reinforcing seizures in hippocampal circuits. In addition, work is presented that indicates MDA regulates seizures at sites beyond the hippocampus and its connections. Other studies that examine morphological and functional changes in the local circuits of granule cells and other neurons in the dentate gyrus in different models of epilepsy are discussed. We conclude that the dentate gyrus functions in several modes during seizures, even in the naive brain, and that in chronic epilepsy alterations take place that provide an even greater diversity of functional capabilities. Explicating these heterogeneous conditions will provide important insight into basic mechanisms of seizures and epileptogenesis.

Afferent Pathways↗
PubMed1992

Basic mechanisms of the epilepsies.

To understand the fundamental pathophysiology of the epilepsies, the chronic changes of structure and function in the brain that distinguish them must be identified and the basic mechanisms by which these changes come about need to be delineated. Recently, progress has been made along these lines, identifying morphological and operational differences in epileptic brains, both those from humans and those from animals, as well as alterations in gene activation brought about by seizures.

Animals↗
PubMed1991

A comparison of the ontogeny of excitatory and inhibitory neurotransmission in the CA1 region and dentate gyrus of the rat hippocampal formation.

In vivo electrophysiological experiments were used to chart the ontogeny of excitatory and inhibitory neurotransmission in the hippocampal formation of rats. Using standardized protocols, responses in the dentate gyrus were quantified and systematically compared to similar measurements obtained in the CA1 region. Measurements were taken at numerous ages, ranging from postnatal day (PN) 6 to adults (PN 60). Excitation was monitored by two parameters recorded with extracellular electrodes in response to monosynaptic inputs to CA1 pyramidal cells or to dentate gyrus granule cells: maximum population spike (PSmax) amplitudes and maximum population excitatory postsynaptic potential slopes (pEPSP slopemax). Inhibition was assessed by a paired-pulse protocol to measure maximal inhibition (the potency of inhibition at an interpulse interval of 20 ms) and duration of inhibition (the interpulse interval at which paired-pulse inhibition changed to paired-pulse facilitation). Excitatory parameters matured later in the dentate gyrus than in CA1, consistent with the later appearance of granule cells. Until PN 21, pEPSPmax values in the dentate gyrus paralleled those in CA1; thereafter they diverged with far larger values in the dentate gyrus. Inhibitory parameters reached adult values between PN 14 and 18. In both regions paired-pulse responses consisted of three phases: (1) an initial inhibition; (2) a second facilitatory phase; and (3) a later inhibition. The maximal inhibition in the initial phase was comparable in both regions, but lasted longer in the CA1 region. The facilitation in the second phase was greater in the dentate gyrus, and the inhibition in the third phase was greater in the dentate gyrus. Results are discussed in terms of neurogenesis of principal cells and GABAergic cells in the regions of interest.

Animals↗
PubMed1991

An in vivo study of the ontogeny of long-term potentiation (LTP) in the CA1 region and in the dentate gyrus of the rat hippocampal formation.

The influences of stimulus intensity, intratrain frequency, and number of trains were studied for their effects on the development of long-term potentiation (LTP) in the hippocampal formation. LTP was analyzed with full input-output curves for population spike (PS) amplitudes (PS-LTP) calculated from responses elicited in the CA1 region and in the dentate gyrus by monosynaptic activation. A standardized protocol employing a sequence of stimuli was devised to systematically compare LTP in the dentate gyrus to that in the CA1 region in rats of various ages ranging from postnatal day (PN) 6 to adults (PN 60). In adult animals, the degrees of LTP were comparable in the dentate gyrus and CA1 region for the 3 stimulus strengths studied (intensity just subthreshold for PS, intensity giving 1/4 maximal PS, and intensity giving 1/2 maximal PS). LTP developed at different rates in the two regions, reaching adult values about two weeks after birth in CA1 but about 3 weeks after birth in the dentate gyrus. We postulate that differences in the rate of development in CA1 and in the dentate gyrus are related to the later neurogenesis of dentate granule cells and also possibly to a later functional maturation of N-methyl-D-aspartate (NMDA) receptor-channel complexes on these cells.

Action Potentials↗
PubMed1991

An ontogenetic study of kindling using rapidly recurring hippocampal seizures.

The present study investigated the acquisition and retention of kindling in immature rats. Postnatal (PN) 7-28-day-old rats were electrically kindled in the ventral hippocampus. Ten-second, 20-Hz stimulus trains were delivered every 5 min for 6 h on one day (short interval rapidly recurring hippocampal seizures, RRHS) or every 30 min for 9 h on each of two consecutive days (long interval RRHS). Afterdischarge durations (ADD) and behavioral seizure scores (BSS) were recorded following each stimulation. Animals of all ages kindled with both short and long interval RRHS, as manifested by lengthening of ADD and increasing BSS. With short interval RRHS, the course of kindling was erratic; with long interval RRHS, kindling proceeded smoothly over both test days. In PN 14-28 rats, the degree of kindling obtained on the first day of long interval RRHS was retained at the start of the second experimental day. In contrast, PN 7 rats showed a transient decrease in ADD and BSS from day 1 to day 2. Afterdischarge thresholds declined with maturation. Among the PN 14-28 animals, younger rats exhibited longer seizures at the outset of kindling and proceeded through kindling faster. Once established, kindled motor seizures also occurred with 2-s, 50-Hz stimulus trains. We conclude that rapid kindling occurs at all ages; however, PN 7 rats are less capable of retaining the kindling effect than are older rats.

Aging↗
PubMed1991

Maximal dentate activation is produced by amygdala stimulation in unanesthetized rats.

In urethane-anesthetized rats, a process termed maximal dentate activation has been shown to be associated with the lengthening of afterdischarges that occurs with repeated hippocampal stimulation. Maximal dentate activation is a unique paroxysmal form of epileptiform discharges consisting of large amplitude population spikes in the dentate gyrus. The current experiments examined the relationship of maximal dentate activation to kindling of motor seizures in the awake animal. Both long duration (5 or 10 s) and short duration (1 s) stimulus trains in either the hippocampus or the amygdala were effective in eliciting maximal dentate activation. Repeated stimulation of the amygdala produced lengthening of afterdischarges and kindling of motor responses, but only after maximal dentate activation had appeared in response to the stimulus. Over the course of amygdala kindling, the duration of maximal dentate activation lengthened with increasing severity of behavioral seizures. This evidence supports the hypothesis that maximal dentate activation is a marker for the presence of seizures distributed throughout limbic circuits. In addition, the data suggest that maximal dentate activation may be an important process involved in the acquisition of kindled responses.

Amygdala↗
PubMed1991

Electrophysiological characterization of associational pathway terminating on dentate gyrus granule cells in the rat.

The functional topography and parameters of excitation and inhibition were determined in the in situ associational pathway of the rat dentate gyrus. The functional topography was found to be consistent with previous anatomical studies. The greatest amplitude population spikes and the strongest paired-pulse inhibition were generated with the stimulating electrode placed in the hilus at least 1.5 mm caudal to the ipsilateral dentate gyrus recording electrode. With this standard electrode configuration, neither long-term potentiation of the population spike nor of the population excitatory postsynaptic potential occurred. Hilar associational pathway activation of dentate gyrus granule cells elicited paired-pulse responses similar to those produced in granule cells by perforant path stimulation. Thus, the associational pathway provides another way to assess dentate granule cell function electrophysiologically.

Animals↗
PubMed1991

The role of the perforant pathway as a trophic factor for neurotransmission in the rat dentate gyrus.

Changes in electrophysiological function in the hilar associational pathway terminating on dentate granule cells in the rat hippocampal formation were studied following unilateral entorhinal cortex lesions. In rats lesioned as pups (postnatal day 4 [PN 4]) or as adults (PN 60) there was a profound loss of paired-pulse inhibition at 30 days postlesion. Inhibition was unaffected at 10 days postlesion. Entorhinal cortex lesions did not affect population spike amplitude, population excitatory postsynaptic potentials slopes, or long-term potentiation compared to the unlesioned hemisphere. The presence of a complete hippocampal commissurotomy had no effect on excitatory or inhibitory parameters. Laminar analyses of extracellular field potentials from animals lesioned as adults revealed an expansion of functional synapses outward into the dentate molecular layer. This expansion was complete by 10 postlesion days. The changes observed with laminar analyses were not contemporaneous with the changes in paired-pulse inhibition. The loss of inhibition in the hilar associational pathway of entorhinal cortex-lesioned animals thus implies a change in local circuit function rather than an effect from sprouted associational fibers directly onto granule cells. The lack of inhibition in the associational pathway in lesioned animals was not due to a failure of local circuit inhibitory function to develop, since the same findings were obtained when lesions were made neonatally or as adults. Rather, the authors suggest that the present findings arise because of the formation of functional, recurrent, excitatory mossy fiber collateral synapses following entorhinal cortex lesions.

Afferent Pathways↗
PubMed1991

Ambulatory EEG cassette recorders for prolonged electroencephalographic monitoring in animals.

We describe the use of ambulatory cassette EEG recorders for monitoring in vivo neurophysiologic signals from multiple animals over prolonged periods of time. This technique centers around a simple interface device that attenuates the intracerebral signals to the input range of the recording device and around a common indifferent input for all animals. The resulting analog recordings have the advantage of good signal resolution and rapid review of 24 h of recorded data.

Animals↗
PubMed1991

Cholinergic and adrenergic agents modify the initiation and termination of epileptic discharges in the dentate gyrus.

A unique type of limbic seizures, maximal dentate activation, was used to examine the effects of cholinergic and adrenergic agents on the processes involved in epileptogenesis. The time to onset of maximal dentate activation was used to monitor the initiation of seizures while the duration of maximal dentate activation monitored termination of seizures. The cholinergic agonist pilocarpine shortened maximal dentate activation at 20 mg/kg and lengthened maximal dentate activation at 50 mg/kg, while both doses delayed the onset of maximal dentate activation. Atropine, a cholinergic antagonist, at 50 mg/kg, slowed the rate of lengthening of maximal dentate activation that occurred with repeated stimulation. The beta-adrenergic antagonist propranolol also slowed the rate of lengthening of maximal dentate activation at 3 mg/kg and shortened maximal dentate activation at 10 mg/kg. The alpha 2-agonist clonidine, at 0.5 mg/kg, shortened maximal dentate activation and increased the time to onset; at 0.1 mg/kg, clonidine did not affect maximal dentate activation. Pretreatment with reserpine had no effect on either the time to onset or duration of maximal dentate activation. These results indicate that both cholinergic and adrenergic mechanisms play important roles in the initiation and termination of limbic seizures.

Animals↗
PubMed1991

Self-sustaining limbic status epilepticus. I. Acute and chronic cerebral metabolic studies: limbic hypermetabolism and neocortical hypometabolism.

Regional cerebral glucose utilization (RCGU) increases during seizures whereas hypometabolism occurs in postictal and interictal states. Recently, we developed a model of nonconvulsive, self-sustaining limbic status epilepticus (SSLSE) in which electrographic seizures persist 12 to 24 hours after 90 minutes of continuous hippocampal stimulation. The present studies define the functional anatomy of SSLSE and the states thereafter. RCGU was studied by 2-deoxyglucose autoradiography in (1) a group of rats acutely (1 hour after induction) during SSLSE, and (2) two groups of rats chronically (1 week or 1 month) after SSLSE. RCGU measurements in these groups were compared with those obtained in naive and electrode-implanted control rats. In the acute group, there were bilateral increases in RCGU in the hippocampus, retrohippocampal structures, and associated limbic and subcortical nonlimbic regions; hypometabolism was found in several neocortical structures. Chronically, RCGU was elevated in certain limbic areas at 7 days but returned to control values at 30 days. On the basis of our findings, we postulate a feedback network involving the hippocampus and neighboring parahippocampal structures (the hippocampal-parahippocampal "loop") as a critical substrate for establishing limbic system status epilepticus. In addition, the results indicate that metabolic responses can persist long after the cessation of status epilepticus and that both increases and decreases in RCGU can be seen in acute limbic status epilepticus.

Acute Disease↗
PubMed1991

Self-sustaining limbic status epilepticus. II. Role of hippocampal commissures in metabolic responses.

In prior work, we developed a model of self-sustaining limbic status epilepticus (SSLSE) induced by continuous hippocampal stimulation (CHS). Previous electrographic studies showed that SSLSE was synchronized between the cerebral hemispheres. On the basis of this initial work, we postulated that hippocampal commissures were critical for the initiation and maintenance of SSLSE. In the current experiments, we tested this hypothesis by applying CHS in animals with (CMX) or without (-CMX) hippocampal commissurotomies. In the -CMX group, electrographic SSLSE was synchronized between the stimulated and contralateral sides. In the CMX group, SSLSE developed only on the stimulated sides. Regional cerebral glucose utilization (RCGU) was also studied acutely (1 hour) after CHS using 2-deoxyglucose autoradiography. In the -CMX group, there was symmetrically increased RCGU in the hippocampus, retrohippocampal structures, and associated limbic and subcortical nonlimbic regions. In the CMX group, a similar pattern was found, but confined to the side of stimulation. CMX alone did not change RCGU values from those in control (-CMX, nonstimulated) brain in any of the regions studied. Areas of bilateral neocortical hypometabolism were found in both (CMX and -CMX) SSLSE groups. These results lead to rejection of the hypothesis that hippocampal commissures play an essential role in the initiation and maintenance of SSLSE. Instead, a feedback circuit involving the hippocampus and its adjacent structures seems to be the critical anatomic substrate for SSLSE. The presence of neocortical hypometabolism after CMX indicates that the structures other than the hippocampal commissure (eg, the thalamus or other forebrain commissures) mediate this effect.

Animals↗