Biomedical subjects

M A Whittington

Publications and source records attributed to M A Whittington.

At least 19 recordsLinked to original sources

PubMed2002

A comparison of the efficacy of carbamazepine and the novel anti-epileptic drug levetiracetam in the tetanus toxin model of focal complex partial epilepsy.

1. The tetanus toxin seizure model, which is associated with spontaneous and intermittent generalized and non-generalized seizures, is considered to reflect human complex partial epilepsy. The purpose of the present study was to investigate and compare the anticonvulsant effects of carbamazepine with that of levetiracetam, a new anti-epileptic drug in this model. 2. One microl of tetanus toxin solution (containing 12 mLD(50) microl(-1) of tetanus toxin) was placed stereotactically into the rat left hippocampus resulting in generalized and non-generalized seizures. 3. Carbamazepine (4 mg kg(-1) h(-1)) and levetiracetam (8 and 16 mg kg(-1) h(-1)) were administered during a 7 day period via an osmotic minipump which was placed in the peritoneal cavity. Carbamazepine (4 mg kg(-1) h(-1)) exhibited no significant anticonvulsant effect, compared to control, when the entire 7 day study period was evaluated but the reduction in generalized seizures was greater (35.5%) than that for non-generalized seizures (12.6%). However, during the first 2 days of carbamazepine administration a significant reduction in both generalized seizure frequency (90%) and duration (25%) was observed. Non-generalized seizures were unaffected. This time-dependent anticonvulsant effect exactly paralleled the central (CSF) and peripheral (serum) kinetics of carbamazepine in that steady-state concentrations declined over time, with the highest concentrations achieved during the first 2 days. Also there was a significant 27.3% reduction in duration of generalized seizures during the 7 day study period (P=0.0001). 4. Levetiracetam administration (8 and 16 mg kg(-1) h(-1)) was associated with a dose-dependent reduction in the frequency of both generalized (39 v 57%) and non-generalized (36 v 41%) seizures. However, seizure suppression was more substantial for generalized seizures. Also a significant dose-dependent reduction in overall generalized seizure duration was observed. 5. These data provide experimental evidence for the clinical efficacy of levetiracetam for the management of patients with complex partial seizures. Furthermore, levetiracetam probably does not act by preventing ictogenesis per se but acts to reduce seizure severity and seizure generalization.

Animals↗

PubMed2001

Gap junctions between interneuron dendrites can enhance synchrony of gamma oscillations in distributed networks.

Gamma-frequency (30-70 Hz) oscillations in populations of interneurons may be of functional relevance in the brain by virtue of their ability to induce synchronous firing in principal neurons. Such a role would require that neurons, 1 mm or more apart, be able to synchronize their activity, despite the presence of axonal conduction delays and of the limited axonal spread of many interneurons. We showed previously that interneuron doublet firing can help to synchronize gamma oscillations, provided that sufficiently many pyramidal neurons are active; we also suggested that gap junctions, between the axons of principal neurons, could contribute to the long-range synchrony of gamma oscillations induced in the hippocampus by carbachol in vitro. Here we consider interneuron network gamma: that is, gamma oscillations in pharmacologically isolated networks of tonically excited interneurons, with frequency gated by mutual GABA(A) receptor-mediated IPSPs. We provide simulation and electrophysiological evidence that interneuronal gap junctions (presumably dendritic) can enhance the synchrony of such gamma oscillations, in spatially extended interneuron networks. There appears to be a sharp threshold conductance, below which the interneuron dendritic gap junctions do not exert a synchronizing role.

Animals↗

PubMed2001

Self-organized synaptic plasticity contributes to the shaping of gamma and beta oscillations in vitro.

gamma (30-70 Hz) followed by beta (10-30 Hz) oscillations are evoked in humans by sensory stimuli and may be involved in working memory. Phenomenologically similar gamma-->beta oscillations can be evoked in hippocampal slices by strong two-site tetanic stimulation. Weaker stimulation leads only to two-site synchronized gamma. In vitro oscillations have memory-like features: (1) EPSPs increase during gamma-->beta; (2) after a strong one-site stimulus, two-site stimulation produces desynchronized gamma; and (3) a single synchronized gamma-->beta epoch allows a subsequent weak stimulus to induce synchronized gamma-->beta. Features 2 and 3 last >50 min and so are unlikely to be caused by presynaptic effects. A previous model replicated the gamma-->beta transition when it was assumed that K(+) conductance(s) increases and there is an ad hoc increase in pyramidal EPSCs. Here, we have refined the model, so that both pyramidal-->pyramidal and pyramidal-->interneuron synapses are modifiable. This model, in a self-organized way, replicates the gamma-->beta transition, along with features 1 and 2 above. Feature 3 is replicated if learning rates, or the time course of K(+) current block, are graded with stimulus intensity. Synaptic plasticity allows simulated oscillations to synchronize between sites separated by axon conduction delays over 10 msec. Our data suggest that one function of gamma oscillations is to permit synaptic plasticity, which is then expressed in the form of beta oscillations. We propose that the period of gamma oscillations, approximately 25 msec, is "designed" to match the time course of [Ca(2+)](i) fluctuations in dendrites, thus facilitating learning.

Analgesics, Opioid↗

PubMed2001

Impaired electrical signaling disrupts gamma frequency oscillations in connexin 36-deficient mice.

Neural processing occurs in parallel in distant cortical areas even for simple perceptual tasks. Associated cognitive binding is believed to occur through the interareal synchronization of rhythmic activity in the gamma (30-80 Hz) range. Such oscillations arise as an emergent property of the neuronal network and require conventional chemical neurotransmission. To test the potential role of gap junction-mediated electrical signaling in this network property, we generated mice lacking connexin 36, the major neuronal connexin. Here we show that the loss of this protein disrupts gamma frequency network oscillations in vitro but leaves high frequency (150 Hz) rhythms, which may involve gap junctions between principal cells (Schmitz et al., 2001), unaffected. Thus, specific connexins differentially deployed throughout cortical networks are likely to regulate different functional aspects of neuronal information processing in the mature brain.

Aging↗

PubMed2001

Genetically altered AMPA-type glutamate receptor kinetics in interneurons disrupt long-range synchrony of gamma oscillation.

Gamma oscillations synchronized between distant neuronal populations may be critical for binding together brain regions devoted to common processing tasks. Network modeling predicts that such synchrony depends in part on the fast time course of excitatory postsynaptic potentials (EPSPs) in interneurons, and that even moderate slowing of this time course will disrupt synchrony. We generated mice with slowed interneuron EPSPs by gene targeting, in which the gene encoding the 67-kDa form of glutamic acid decarboxylase (GAD67) was altered to drive expression of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor subunit GluR-B. GluR-B is a determinant of the relatively slow EPSPs in excitatory neurons and is normally expressed at low levels in gamma-aminobutyric acid (GABA)ergic interneurons, but at high levels in the GAD-GluR-B mice. In both wild-type and GAD-GluR-B mice, tetanic stimuli evoked gamma oscillations that were indistinguishable in local field potential recordings. Remarkably, however, oscillation synchrony between spatially separated sites was severely disrupted in the mutant, in association with changes in interneuron firing patterns. The congruence between mouse and model suggests that the rapid time course of AMPA receptor-mediated EPSPs in interneurons might serve to allow gamma oscillations to synchronize over distance.

Animals↗

PubMed2001

Differential expression of synaptic and nonsynaptic mechanisms underlying stimulus-induced gamma oscillations in vitro.

Gamma frequency oscillations occur in hippocampus in vitro after brief tetani delivered to afferent pathways. Previous reports have characterized these oscillations as either (1) trains of GABA(A) inhibitory synaptic events mediated by depolarization of both pyramidal cells and interneurons at least in part mediated by metabotropic glutamate and acetylcholine receptors, or (2) field potential oscillations occurring in the near absence of an inhibitory synaptic oscillation when cells are driven by depolarizing GABA responses and local synchrony is produced by field effects. The aim of this study was to investigate factors involved in the differential expression of these synaptically and nonsynaptically gated oscillations. Field effects were undetectable in control recordings but manifested when slices were perfused with hypo-osmotic solutions or a reduced level of normal perfusate. These manipulations also reduced the amplitude of the train of inhibitory synaptic events associated with an oscillation and enhanced the depolarizing GABA component underlying the post-tetanic depolarization. The resulting field oscillation was still dependent, at least in part, on inhibitory synaptic transmission, but spatiotemporal aspects of the oscillation were severely disrupted. These changes were also accompanied by an increase in estimated [K(+)](o) compared with control. We suggest that nonsynaptic oscillations occur under conditions also associated with epileptiform activity and constitute a phenomenon that is distinct from synaptically gated oscillations. The latter remain a viable model for in vivo oscillations of cognitive relevance.

Action Potentials↗

PubMed2001

A possible role for gap junctions in generation of very fast EEG oscillations preceding the onset of, and perhaps initiating, seizures.

PURPOSE: We propose an experimentally and clinically testable hypothesis, concerning the origin of very fast (> approximately 70 Hz) EEG oscillations that sometimes precede the onset of focal seizures. These oscillations are important, as they may play a causal role in the initiation of seizures. METHODS: Subdural EEG recordings were obtained from children with focal cortical dysplasias and intractable seizures. Intra- and extracellular recordings were performed in rat hippocampal slices, with induction of population activity, as follows: (a) bath-applied tetramethylamine (an intracellular alkalinizing agent, that opens gap junctions); (b) bath-applied carbachol, a cholinergic agonist; and (c) focal pressure ejection of hypertonic K+ solution. Detailed network simulations were performed, the better to understand the cellular mechanisms underlying oscillations. A major feature of the simulations was inclusion of axon-axon gap junctions between principal neurons, as supported by recent experimental data. RESULTS: Very fast oscillations were found in children before seizure onset, but also superimposed on bursts during the seizure, and on interictal bursts. In slice experiments, very fast oscillations had previously been seen on interictal-like bursts; we now show such oscillations before, between, and after epileptiform bursts. Very fast oscillations were also seen superimposed on gamma (30-70 Hz) oscillations induced by carbachol or hypertonic K+, and in the latter case, very fast oscillations became continuous when chemical synapses were blocked. Simulations replicate these data, when axonal gap junctions are included. CONCLUSIONS: Electrical coupling between principal neurons, perhaps via axonal gap junctions, could underlie very fast population oscillations, in seizure-prone brain, but possibly also in normal brain. The anticonvulsant potential of gap-junction blockers such as carbenoxolone, now in clinical use for treatment of ulcer disease, should be considered.

Animals↗

PubMed2001

Altered dentate filtering during the transition to seizure in the rat tetanus toxin model of epilepsy.

The dentate gyrus is thought to be a key area in containing the spread of seizure discharges in temporal lobe epilepsy. We investigated whether it actively contributes to the transition to seizure in vivo using the tetanus toxin chronic experimental epilepsy. Brief epileptic discharges lasted <2 s in freely moving animals and were clearly distinguishable from spontaneous seizures that lasted tens of seconds. This suggested that the changes underpinning the transition to seizure started within the first few seconds of seizure onset. During this period, we found that the amplitude of dentate gyrus population spikes depressed initially, but from 1.1 s after seizure onset, they potentiated. The amplitude and number of CA3 population spikes paralleled the pattern found in the dentate gyrus. We used hippocampal slices to study dentate filtering in more detail. The perforant pathway was stimulated repetitively at the frequency of field postsynaptic potentials found during epileptic discharges in vivo. The amplitude of dentate gyrus population spikes decreased to a steady state in naïve hippocampal slices. In hippocampal slices prepared from rats previously injected with tetanus toxin, population spike amplitude decreased transiently and then potentiated. We found that the biphasic profile and rate of potentiation of dentate population spikes in vivo can be reproduced in naïve hippocampal slices by blocking GABA(B) receptors. We conclude that the filtering properties of the dentate gyrus are altered in the tetanus toxin model of epilepsy and propose how this contributes to the transition to seizure in our animals.

Animals↗

PubMed2000

Inhibition-based rhythms: experimental and mathematical observations on network dynamics.

An increasingly large body of data exists which demonstrates that oscillations of frequency 12-80 Hz are a consequence of, or are inextricably linked to, the behaviour of inhibitory interneurons in the central nervous system. This frequency range covers the EEG bands beta 1 (12-20 Hz), beta 2 (20-30 Hz) and gamma (30-80 Hz). The pharmacological profile of both spontaneous and sensory-evoked EEG potentials reveals a very strong influence on these rhythms by drugs which have direct effects on GABA(A) receptor-mediated synaptic transmission (general anaesthetics, sedative/hypnotics) or indirect effects on inhibitory neuronal function (opiates, ketamine). In addition, a number of experimental models of, in particular, gamma-frequency oscillations, have revealed both common denominators for oscillation generation and function, and subtle differences in network dynamics between the different frequency ranges. Powerful computer and mathematical modelling techniques based around both clinical and experimental observations have recently provided invaluable insight into the behaviour of large networks of interconnected neurons. In particular, the mechanistic profile of oscillations generated as an emergent property of such networks, and the mathematical derivation of this complex phenomenon have much to contribute to our understanding of how and why neurons oscillate. This review will provide the reader with a brief outline of the basic properties of inhibition-based oscillations in the CNS by combining research from laboratory models, large-scale neuronal network simulations, and mathematical analysis.

Electroencephalography↗

PubMed2000

Pathway-specific habituation of induced gamma oscillations in the hippocampal slice.

Brief tetanic stimulation (eight pulses at 100 Hz) of afferent fibers innervating area CA1 of the hippocampus produce gamma oscillations. When delivered every minute the oscillation habituated markedly after the first stimulus. This habituation could be transiently reversed by stimulating a different pathway to the recorded area. Gamma oscillation-induced beta frequency oscillations were only seen in response to the first (novel) stimulus and the gamma oscillation itself was markedly attenuated by on-going, non-oscillogenic, synaptic activity. The NMDA receptor antagonist ketamine abolished the response to novel stimuli but left the habituated response relatively unaffected. The pattern of habituation parallelled that seen for sensory induced gamma and beta oscillations in the clinical EEG.

Anesthetics, Dissociative↗

PubMed2000

Gamma rhythms and beta rhythms have different synchronization properties.

Experimental and modeling efforts suggest that rhythms in the CA1 region of the hippocampus that are in the beta range (12-29 Hz) have a different dynamical structure than that of gamma (30-70 Hz). We use a simplified model to show that the different rhythms employ different dynamical mechanisms to synchronize, based on different ionic currents. The beta frequency is able to synchronize over long conduction delays (corresponding to signals traveling a significant distance in the brain) that apparently cannot be tolerated by gamma rhythms. The synchronization properties are consistent with data suggesting that gamma rhythms are used for relatively local computations whereas beta rhythms are used for higher level interactions involving more distant structures.

Animals↗

PubMed2000

Neuronal fast oscillations as a target site for psychoactive drugs.

Neuronal oscillations within the electroencephalogram beta and gamma bands (15-80 Hz) are associated with intense mental activity and cognitive function in general. Specifically, recent advances have implicated gamma oscillations in the processing of sensory stimuli and demonstrated that synchronous gamma oscillations, appearing concurrently in spatially separate brain regions, can induce beta activity. beta activity generated in this manner represents established synchronous communication between brain regions and is thought to represent a neuronal network correlate of the "binding phenomenon" in cognitive theory. This review will outline the mechanisms of generation of these oscillations at the cellular and network level, and will highlight the effects of drugs that may modify these mechanisms. Possible modification of fast oscillations by disease processes and clinical intervention are discussed.

Animals↗

PubMed2000

A model of gamma-frequency network oscillations induced in the rat CA3 region by carbachol in vitro.

Carbachol (> 20 microM) and kainate (100 nM) induce, in the in vitro CA3 region, synchronized neuronal population oscillations at approximately 40 Hz having distinctive features: (i) the oscillations persist for hours; (ii) interneurons in kainate fire at 5-20 Hz and their firing is tightly locked to field potential maxima (recorded in s. radiatum); (iii) in contrast, pyramidal cells, in both carbachol and kainate, fire at frequencies as low as 2 Hz, and their firing is less tightly locked to field potentials; (iv) the oscillations require GABAA receptors, AMPA receptors and gap junctions. Using a network of 3072 pyramidal cells and 384 interneurons (each multicompartmental and containing a segment of unmyelinated axon), we employed computer simulations to examine conditions under which network oscillations might occur with the experimentally determined properties. We found that such network oscillations could be generated, robustly, when gap junctions were located between pyramidal cell axons, as suggested to occur based on studies of spontaneous high-frequency (> 100 Hz) network oscillations in the in vitro hippocampus. In the model, pyramidal cell somatic firing was not essential for the oscillations. Critical components of the model are (i) the plexus of pyramidal cell axons, randomly and sparsely interconnected by gap junctions; (ii) glutamate synapses onto interneurons; (iii) synaptic inhibition between interneurons and onto pyramidal cell axons and somata; (iv) a sufficiently high rate of spontaneous action potentials generated in pyramidal cell axons. This model explains the dependence of network oscillations on GABA(A) and AMPA receptors, as well as on gap junctions. Besides the existence of axon-axon gap junctions, the model predicts that many of the pyramidal cell action potentials, during sustained gamma oscillations, are initiated in axons.

Action Potentials↗

PubMed1999

On the mechanism of the gamma --> beta frequency shift in neuronal oscillations induced in rat hippocampal slices by tetanic stimulation.

Tetanic stimulation of the CA1 region of rat hippocampal slices can induce gamma frequency population oscillations (30-100 Hz) after a latency of 50-150 msec that are synchronized to within 1-2 msec when simultaneous stimuli are delivered to two sites 2 mm or more apart. When tetanic stimuli, twice-threshold for eliciting gamma oscillations, are used, new phenomena occur. (1) After a period of gamma, there is a switch to beta frequencies (10-25 Hz); (2) during the switch, pyramidal cell spike afterhyperpolarizations (AHPs) increase and rhythmic EPSPs occur in pyramidal cells; and (3) after an episode of single-site, twice-threshold-induced gamma/beta oscillations, simultaneous two-site threshold stimuli induce gamma oscillations that are locally synchronized, but no longer are capable of long-range synchrony. We studied the cellular mechanisms of the gamma/beta switch with electrophysiological techniques and computer simulations. Our model predicts that the observed increases in both pyramidal cell AHPs and in pyramidal/pyramidal cell EPSPs are necessary and sufficient for the beta switch to occur. Firing patterns generated by the model, both for pyramidal cells and for interneurons, resemble experimental records. A one-site twice-threshold stimulus might lead to an inability of the two sites to synchronize at gamma frequencies, after subsequent two-site stimulation, via this mechanism. If depression is induced at synapses coupling pyramidal cells at one site to interneurons at the other site, then two-site stimulation cannot produce interneuron doublets; hence, as shown previously, the two sites will be unable to synchronize. This mechanism works in simulations, and we provide experimental evidence that synaptic depression and loss of doublets occur after a sufficiently strong local tetanus to one site. We suggest that long-range excitatory connections onto interneurons determine whether different pyramidal cell "assemblies" can synchronize at gamma frequencies, whereas excitatory connections onto pyramidal cells determine whether such assemblies can synchronize at beta frequencies.

Animals↗

PubMed1999

Blood and cerebrospinal fluid pharmacokinetics of the novel anticonvulsant levetiracetam (ucb L059) in the rat.

The temporal pharmacokinetic interrelationship of levetiracetam in blood and cerebrospinal fluid (CSF) was studied after acute intraperitoneal administration of levetiracetam (20, 40 and 80 mg/kg), using an animal model that permits concurrent blood and CSF sampling in freely moving rats. After administration, levetiracetam rapidly appeared in both serum (time to maximum concentration (Tmax) mean range 0.25 0.50 h) and CSF (Tmax mean range 1.33-1.92 h), suggesting ready penetration of the blood brain barrier. Both serum and CSF levetiracetam concentrations rose essentially linearly and dose-dependently, suggesting that transport across the blood-brain barrier is not rate limiting over the levetiracetam concentration range observed in the present study. However, while apparent elimination half-life (t1/2) values for both serum and CSF were dose-independent (mean value range 1.8-2.8 and 4.4-4.9 h, respectively), t1/2 values for CSF were significantly larger. As the serum free/total serum levetiracetam concentration ratio (free fraction) was 1.01+/-0.02 (mean+/-S.E.M.), it can be concluded that levetiracetam is not protein bound. Furthermore, the free fraction was indistinguishable from that of the CSF/serum levetiracetam concentration ratio at equilibrium. It can be concluded that the kinetics of levetiracetam, in the rat, is simple and, thus, dosing strategies in studies designed to elucidate its mechanism of action should be straightforward.

Animals↗

PubMed1999

Anaesthetic/amnesic agents disrupt beta frequency oscillations associated with potentiation of excitatory synaptic potentials in the rat hippocampal slice.

1. Anaesthetic agents produce disruption in cognitive function typified by reductions in sensory perception and memory formation. Oscillations within the EEG gamma and beta bands have been linked to sensory perception and memory and have been shown to be modified by anaesthetic agents. 2. Synchronous gamma oscillations generated by brief tetanic stimulation in two regions of hippocampal area CA1 in slices in vitro were seen to potentiate excitatory synaptic communication between the areas. This synaptic potentiation, was seen to contribute to a transition from gamma frequency (30 - 70 Hz) to beta frequency (12 - 30 Hz) oscillations. 3. Four drugs having anaesthetic/hypnotic and amnesic properties were tested on this synchronous gamma-induced beta oscillation. Thiopental 10 - 200 microM, Diazepam 0.05 - 1.0 microM, Morphine 10 - 200 microM, and Ketamine 10 - 200 microM were all added to the bathing medium. Each drug markedly disrupted the formation of beta oscillations in a manner consistent with their primary modes of action. Thiopental and morphine disrupted synchrony of gamma oscillations and prevented potentiation of recurrent excitatory potentials measured in stratum oriens (fEPSPs). Neither diazepam, nor ketamine produced such marked changes in synchrony at gamma frequencies or reduction in potentiation of fEPSPs. However, each disrupted expression of subsequent beta oscillation via changes in the magnitude of inhibitory network gamma oscillations and the duration and magnitude of tetanus-induced depolarization respectively. 4. The degree of disruption of fEPSP potentiation correlated quantitatively with the degree of disruption in synchrony between sites during gamma oscillations. The data indicate that synchronous gamma-induced beta oscillations represent a mode of expression of excitatory synaptic potentiation in the hippocampus, and that anaesthetic/amnesic agents can disrupt this process markedly.

Anesthetics↗

PubMed1999

Functionally relevant and functionally disruptive (epileptic) synchronized oscillations in brain slices.

Focal seizurelike events can be induced in experimental preparations by means of a number of distinct manipulations that differ in synaptic mechanisms. Nevertheless, the form of the seizurelike events can be explained with common principles, including long-lasting excitation of pyramidal cell dendrites and recurrent excitation between pyramidal cells that provides synchronization. One means of induction of seizurelike events, tetanic stimulation, induces a more physiologic type of activity before seizures are elicited, that is, gamma-frequency (> 20 Hz) oscillations. Such oscillations, called 40-Hz oscillations, are believed to be important for cognition in vivo. Experimental gamma oscillations depend critically on synaptic inhibition between interneurons, from interneurons to pyramidal cells, and on a tonic drive to pyramidal cells and interneurons by metabotropic glutamate receptors. The function of gamma oscillations appears to be imposition of a precise temporal structure on the firing patterns of pyramidal cells while still allowing the pyramidal cells to influence each other and be influenced by afferents selectively. We suggest that a relative loss of synaptic inhibition, occurring by any of a number of mechanisms, prevents the occurrence of gamma activity, allows recurrent pyramidal cell-pyramidal cell excitation to predominate, and thereby allows neuronal networks to generate functionally disruptive seizures.

Animals↗

PubMed1998

Gamma frequency oscillations gate temporally coded afferent inputs in the rat hippocampal slice.

Gamma (25-60 Hz) oscillations are associated with cognitive processing in the cortex. They can be generated by excitation of populations of mutually inhibitory, interconnected interneurons. Such oscillations can entrain the firing patterns of excitatory projection neurons and have been shown both to facilitate the synchronization of spatially separate populations of neurons and mediate changes in synaptic strength that alter the ability of populations to synchronize. Here we demonstrate that gamma oscillations also act as a powerfully selective gate for trains of afferent inputs to an oscillating area, based on the 'precise timing of inputs' as opposed to their absolute magnitude or frequency.

Action Potentials↗