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Biomedical subjects

E W Lothman

Publications and source records attributed to E W Lothman.

At least 109 records · Page 6Linked to original sources
PubMed1981

Kainic acid-induced limbic seizures: electrophysiologic studies.

Surface and depth electroencephalograms (EEGs) were studied after intravenous injections of kainic acid (KA). High frequency oscillations and spikes appeared in the hippocampus at a dose (1 mg per kilogram) that did not affect other structures. Higher doses (greater than or equal to 4 mg per kilogram) led to electrical seizures in limbic structures, similar to those in temporal lobe epilepsy. In hippocampal slices maintained in vitro, 0.1 to 1.0 microM KA produced spontaneous epileptiform spikes, originating in CA3, and increased evoked potentials. Systemic KA is a potent means of inducing limbic seizures with a primary action in the hippocampus. We propose that this selective activation arises when KA augments excitatory glutamatergic synapses in critical epileptogenic areas, such as the CA3 region of the hippocampus.

Animals↗
PubMed1976

Reflex effects and postsynaptic membrane potential changes during epileptiform activity induced by penicillin in decapitate spinal cords.

The administration of a convulsant dose of penicillin enhanced the transmission of monosynaptic reflexes in spinal cords in which reflex transmission was feeble before the drug treatment, but it had little effect in cords where monosynaptic reflexes were powerful to begin with. Post-tetanic potentiation was not altered by penicillin. Polysynaptic reflexes were invariably enhanced by convulsant amounts of penicillin. Postsynaptic ("direct") inhibition was not affected in the seizure-free intervals in spinal cords treated with penicillin, but it seemed to be suppressed during tonic seizures. The disability of reflex inhibition during ictal discharges may be due to presynaptic depolarization of inhibitory terminals. Recurrent inhibition was partially suppressed in spinal cords treated with penicillin. Neurons in the dorsal and intermediate gray matter were sometimes excited, sometimes inhibited, and sometimes unaffected by seizure activity of their segment. Motoneurons in the ventral horns invariably participated in the interictal and ictal activity. The timing of clonic seizure sequences coincided with bursts of Renshaw cell discharges. Action potential of abnormal amplitude and configuration were frequently observed in convulsing motoneurons. Paroxysmal depolarizing shifts (PDSs) of motoneurons were similar to those observed by other investigators in neurons in experimental epileptic foci of the cerebral cortex, except that spinal PDSs were not followed by hyperpolarizing waves.

Animals↗
PubMed1976

Motor and electrical signs of epileptiform activity induced by penicillin in the spinal cords of decapitate cats.

Convulsive activity was induced in functionally decapitate cat preparations by topical and by systemic administration of toxic amounts of penicillin. The paroxysmal movement patterns and the electrographic signs of spinal seizure activity recorded from spinal ventral and dorsal roots and from the dorsal surface of the spinal cord are described. Paroxysms of interictal myoclonic twitching as well as tonic and clonic ictal seizures reminiscent of epileptiform convulsions of intact animals were seen in the absence of descending influences from the brain. Tonic seizures consisted of flexion--extension sequences; co-contraction of antagonistic muscles was the rule. Clonic activity consisted of rhythmic discharges at 4--6/sec, In dorsal roots, electrotonically conducted paroxysmal negative potential shifts as well as antidromically conducted trains of impulses were recorded. Ictal paroxysmal waves of the cord dorsum potential consisted of either biphasic positive--negative sequences or of purely negative waves. Diphenylhydantoin effectively controlled spinal seizures in the absence of a functioning cerebellum. Diphenylthiohydantoin changed the pattern of seizures, suppressing all ictal activity and greatly enhancing the amplitude and frequency of interictal bursts. Three different barbiturates suppressed seizure activity, but diazepam was ineffective, indicating that the site of its clinical anticonvulsant action may be supraspinal. Seizure activity, once induced, continued for up to 18 h. Intravenous administration of penicillinase abolished seizures indicating that their usual persistence is caused by the presence of the drug in the tissue, not by an irreversible biochemical lesion.

Animals↗
PubMed1976

Functions of primary afferents and responses of extracellular K+ during spinal epileptiform seizures.

Paroxysmal activity in ventral roots induced by penicillin in decapitate cat spinal cords is associated with waves of depolarization of primary afferent fiber terminals. These paroxysmal depolarizations can be detected as spontaneously occurring negative dorsal root potentials (DRPs) and are associated with antidromic discharge of nerve impulses in dorsal root fibers; they can also be detected by testing the excitability of afferent nerve terminals by focal stimulation. Negative DRPs evoked by afferent nerve volleys are altered in waveform but not in amplitude during seizures induced by penicillin, although they are blocked by the administration of picrotoxin. While blocking afferent-evoked DRPs, picrotoxin does not interfere with paroxysmal DRP'S, INDICATING DIFFERENCES IN THE GENERATION OF THE Two phenomena, which nevertheless have some link in common, for the paroxysmal waves occlude the evoked DRP. Such occlusion would appear as blockade, if DRPs were recorded by condenser-coupled amplifiers. In the presence of pentobarbital penicillin suppresses evoked DRPs, but under such circumstances seizure activity is not observed. Extracellular potassium activity within spinal gray matter transiently increases during seizure activity. Such increments of potassium activity are maximal in the ventral horns. This and several other observations suggest that in decapitate spinal cords systemically administered penicillin induces seizures which originate in the ventral gray matter. Accumulation of excess potassium may be the cause of paroxysmal depolarization of afferent nerve terminals. Excess potassium while not playing a principal role in initiating seizures, may influence the course of seizures by depolarizing afferent terminals. Such depolarization probably enhances tonic background release of transmitter substance, may modify the effect of synaptic input, and may favor synchronization of waves of neural excitability through extrasynaptic mechanisms.

Action Potentials↗
PubMed1975

Extracellular potassium activity, intracellular and extracellular potential responses in the spinal cord.

1. Microcapillary electrode assemblies of two or three channels were used to record extracellular and intracellular potentials together with the extracellular activity of potassium ions, from essentially single locations within the substance of the decapitate spinal cord of cats. A liquid ion exchanger filled the tip of the potassium sensing microprobe. Activity was evoked by electrical stimulation of afferent peripheral nerves (ventral roots were cut). 2. Within the substance of the spinal grey matter increments of extracellular potassium activity evoked by repetitive afferent volleys were precisely correlated with magnitudes of sustained shifts of extracellular electric potential. Raising [K+]o from 3 to 4 mM was associated with a negative shift of potential of 2-5 +/- 0-5 mV, regardless of the position of the electrode in the tissue, and regardless of treatment by convulsant or depressant drugs. 3. The spatial distribution of the responses of potassium activity was mapped by the spatial distribution of the negative sustained potential shifts. 4. Depolarization shifts of potential recorded from within neuroglia cells ran parallel with changes of extracellular potassium potential. Even though the magnitude of extracellular sustained potential shifts was precisely correlated with the responses of both extracellular potassium and intracellular glial potentials, the trajectory of sustained potential shifts did not exactly mirror the two other variables. Onset and offset of sustained potential shifts were faster than those of glial potentials or of extracellular potassium. 5. The responses of the true transmembrane potential (intracellular less extracellular potential shifts) of neuroglia cells in the spinal grey matter can fully be described by the Nernst equation. 6. Membrane potentials of neurones, potentials recorded from dorsal root filaments, or from white matter, appeared unrelated to the activity of potassium ions in extracellular fluid. 7. The results are compatible with the suggestions that changes of the membrane potential of spinal neuroglia cells are fully determined by the change of the activity of extracellular potassium, and that glia cells supply most of the current which generates sustained shifts of the extracellular potential of spinal grey matter. The results are hard to reconcile with suggestions that under conditions of moderate excitation (i.e. in the absence of convulsive neuronal activity) changes of extracellular potassium would significantly influence the membrane potential of spinal neurones, or of primary afferent nerve fibres.

Action Potentials↗
PubMedDate not supplied

Alterations in neurotransmitter amino acids in hippocampal kindled seizures.

Rats were rapidly kindled with electrical stimuli to the hippocampus, and the concentrations of GABA and related amino acids were measured in several brain regions, both in the baseline kindled state and during active seizures. In the baseline kindled state, a consistent pattern was found throughout the hippocampus where GABA levels were depressed and glutamate and glutamine levels were elevated. During seizures GABA rose slightly while glutamate and glutamine increased to twice control values. These changes were seen to various degrees in other brain areas. Turnover in the GABA-glutamate-glutamine cycle was measured in kindled rats experiencing seizures and compared to control animals. During seizures there was an increased turnover of the excitatory compounds glutamate and aspartate relative to GABA. The data indicate that kindling produces a change of presynaptic GABA metabolism which results in diminished inhibition.

Amino Acids↗
PubMedDate not supplied

Response properties of rapidly recurring hippocampal seizures in rats.

Previous work has shown that closely spaced stimuli can activate short-term and long-term inhibitory processes that suppress kindling and the expression of kindled responses. The present experiments employed stimulus trains of longer duration than traditionally used in kindling work. Hippocampal seizures were triggered in rats at rates considerably faster than those reported to activate these inhibitory processes. Such rapidly recurring hippocampal seizures (RRHS) promptly led to a persistent, fully kindled state in which consistent kindled motor responses, constant duration electrographic seizures and stable afterdischarge thresholds were present. These kindled responses could be elicited every 30 min for 6-8 h/day on an alternate day schedule, but the kindled responses depended on delivery of supramaximal stimuli. Extending the number of RRHS on a given test day led to the appearance of a slowly developing but enduring suppression of kindled responses and an elevation of afterdischarge thresholds. Restricting the study period to 6 h on a given day, but using a consecutive instead of alternate day schedule, also led to a long-duration suppression of kindled responses. These results show that the short-duration inhibitory processes associated with kindled seizures can be more easily overcome than long-duration processes. The latter seem to involve an elevation of afterdischarge thresholds. The experiments also establish procedures by which detailed investigations of the effects of experimental manipulations on kindled responses can be examined.

Animals↗
PubMedDate not supplied

Screening and characterization of antiepileptic drugs with rapidly recurring hippocampal seizures in rats.

A method to efficiently screen antiepileptic drugs (AED) for their actions against complex partial and secondarily generalized seizures is presented. The procedure relies on rapidly recurring hippocampal seizures (RRHS) in rats which are first used to bring epileptic responses to a stable, fully kindled state and then to test 3 parameters--behavioral seizures, electrographic seizures, and afterdischarge thresholds--before and after drug administration. With the methods described, the effects of a given drug treatment can be thoroughly determined in a single study period. Quantitative determinations of dose-response, time-action and relative potency characteristics are readily ascertained. A battery of known AED, encompassing those in common clinical use, was studied with this system. Kindled motor seizures (classes 4 and 5) were more readily suppressed than limbic behavioral seizures (classes 1-3). Electrographic seizures were usually, but not always, shortened concurrently with suppression of behavioral seizures. Under the conditions of this study, afterdischarge thresholds were not elevated, indicating that a critical role of AED is to counteract seizure spread and prolongation. The overall behavior of the RRHS test system with AED was identical to that with traditional amygdala kindled seizures and results were in good agreement with the clinical responsiveness of the kinds of seizures that these experimental systems model. The features of RRHS make it a useful system for screening new agents for antiepileptic effects, even in circumstances where little or no information about the drug under study is available.

Animals↗
PubMedDate not supplied

Model of spontaneous hippocampal epilepsy in the anesthetized rat: electrographic, [K+]0, and [Ca2+]0 response patterns.

These experiments present a model of spontaneous epileptiform activity that can be produced acutely in the urethane-anesthetized rat. Extracellular potential changes were recorded in CA1 or the dentate gyrus along with measurements of extracellular potassium ([K+]0) and calcium ([Ca2+]0) throughout 90 min of continuous stimulation to the contralateral CA3 region and for up to 4 h afterwards. During the continuous stimulation, both brain regions showed a cyclic pattern of electrographic seizures. Immediately upon stopping the stimulation, spontaneous epileptiform activity continued for up to 90 min in both CA1 and dentate gyrus. A quiescent period without electrographic activity was followed by the return of spontaneous epileptiform activity an average of 2 h after the end of stimulation. The excitability of the system was depressed after the continuous stimulation and gradually recovered during the quiescent period before the onset of the spontaneous epileptiform activity. [K+]0 increased during, not before, each seizure (both during the continuous stimulation and during the delayed spontaneous epileptiform activity) and remained elevated as long as neuronal discharges occurred. [Ca2+]0 transiently decreased with the onset of electrographic activity and never decreased before the appearance of epileptiform discharges.

Action Potentials↗
PubMedDate not supplied

Evidence for a chronic loss of inhibition in the hippocampus after kindling: electrophysiological studies.

Rats were kindled with either of 2 protocols: (1) a rapidly recurring hippocampal seizure (RRHS) paradigm in which 10 sec stimulus trains were delivered every 5 min through hippocampal electrodes; and (2) a traditional approach in which 1 sec stimulus trains were given to the amygdala once daily. Three groups of kindled rats were prepared: (1) one of amygdala-kindled rats that had experienced 9-15 seizures; (2) one of RRHS-kindled rats that had experienced 96 seizures; and (3) one of RRHS-overkindled rats that had experienced 144-336 seizures. After a 1 month seizure-free period, the animals were anesthetized with urethane and measurements were made on the potency of paired pulse inhibition in the CA1 region of the hippocampus. All groups of kindled animals were found to have significantly less paired pulse inhibition than control rats. This decrement was confined to interpulse intervals less than or equal to 70 msec. The amount of inhibition lost correlated with the number of seizure that had occurred. The GABAergic agonist muscimol restored paired pulse inhibition in kindled animals for interpulse intervals less than or equal to 70 msec towards normal values. These results indicate that not only RRHS, but also other modes of kindling, reduced GABAergic inhibition in the CA1 region of the hippocampus and that this diminution was long-lasting, if not permanent.

Animals↗
PubMedDate not supplied

Evidence for a chronic loss of inhibition in the hippocampus after kindling: biochemical studies.

Brain tissue from kindled animals prepared 1 month after their last seizure was compared to tissue from matched surgical control animals. Quantitative film autoradiography was used to study muscimol binding in the CA1 region and 3 other brain areas (dentate gyrus, cerebral cortex, and thalamus). The Kd values so obtained were constant from region to region and comparable to those published by others. Bmax values varied; of the 4 regions studied CA1 had the lowest value of Bmax. There were no differences in either Kd or Bmax values in any region studied between kindled and surgical control rats. The release of GABA from nerve terminals was assessed with hippocampal tissue maintained in vitro and perfused with different solutions in which the concentrations of K+ and Ca2+ were varied. This allowed the examination of K+-induced depolarization release and the Ca2+ dependence of this process. K+-induced, Ca2+-dependent release of GABA from hippocampus derived from kindled animals was significantly less than that from hippocampus derived from controls. The biochemical studies reported here provide additional support for the hypothesis that there is a chronic decrease in GABA-mediated inhibition in the hippocampus associated with kindling. The data point to a dysfunction at the presynaptic level, within the GABAergic interneuron, but do not exclude changes at a level postsynaptic to the GABAergic interneuron not detected with the methods employed.

Animals↗
PubMedDate not supplied

Self-sustaining limbic status epilepticus induced by 'continuous' hippocampal stimulation: electrographic and behavioral characteristics.

A model of status epilepticus centered in the limbic system and elicited by 'continuous' focal electrical stimulation of the hippocampus is presented. Under appropriate conditions, the status epilepticus persisted for many hours after discontinuing the electrical stimulus. The critical determinant for the establishment of this self-sustaining limbic status epilepticus (SSLSE) was the length of stimulation, rather than the side (left vs. right) of stimulation or kindling before stimulation. Observations, obtained from stimulus-free intervals spaced regularly during the stimulus protocol and from the period after stimulation had been completed, revealed a distinct and stereotyped electrographic progression of SSLSE though several stages. Brief monitoring periods throughout the stimulus protocol yielded electrographic criteria that predicted which animals would experience experience SSLSE. The presence of synchronous, stimulus-independent seizure activity bilaterally in the hippocampi during stimulation was necessary to establish SSLSE. Intense motor seizure activity, like that seen with kindled motor seizures, occurred intermittently during SSLSE. However, 'limbic' behavioral seizures identical to those seen after low doses of kainic acid or during the early stages of kindling were nearly continuous. These studies indicate that there is a predictable course to limbic status epilepticus and point to the hippocampus as a key element involved in initiating and maintaining this syndrome.

Action Potentials↗