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Biomedical subjects

Peter L Carlen

Publications and source records attributed to Peter L Carlen.

At least 19 recordsLinked to original sources
PubMed2006

Lag synchrony measures dynamical processes underlying progression of seizure states.

We investigate the dynamics of bursting behavior in an intact hippocampal preparation using causal entropy, an adaptive measure of lag synchrony. This analysis, together with a heuristic model of coupled bursting networks, separates experimentally observed bursting dynamics into two dynamical regimes, when bursting is driven by (1) the intranetwork dynamics of a single region, or (2) internetwork feedback between spatially disjoint neural populations. Our results suggest that the abrupt transition between these two states heralds the gradual desynchronization of bursting activity. These results illustrate how superficially homogeneous behavior across loosely coupled networks may harbor hidden, but robust, dynamical processes.

Action Potentials↗
PubMed2006

Online prediction of onsets of seizure-like events in hippocampal neural networks using wavelet artificial neural networks.

It has been previously shown that wavelet artificial neural networks (WANNs) are able to classify the different states of epileptiform activity and predict the onsets of seizure-like events (SLEs) by offline processing (Ann. Biomed. Eng. 33(6):798-810, 2005) of the electrical data from the in-vitro hippocampal slice model of recurrent spontaneous SLEs. The WANN design entailed the assumption that time-varying frequency information from the biological recordings can be used to estimate the times at which onsets of SLEs would most likely occur in the future. Progressions of different frequency components were captured by the artificial neural network (ANN) using selective frequency inputs from the initial wavelet transform of the biological data. The training of the WANN had been established using 184 SLE episodes in 34 slices from 21 rats offline. Nine of these rats also exhibited periods of interictal bursts (IBs). These IBs were included as part of the training to help distinguish the difference in dynamics of bursting activities between the preictal- and interictal type. In this paper, we present the results of an online processing using WANN on 23 in-vitro rat hippocampal slices from 9 rats having 93 spontaneous SLE episodes generated under low magnesium conditions. Over the test cases, three of the nine rats exhibited over 30 min of IB activities. We demonstrated that the WANN was able to classify the different states, namely, interictal, preictal, ictal, and IB activities with an accuracy of 86.6, 72.6, 84.5, and 69.1%, respectively. Prediction of state transitions into ictal events was achieved using regression of initial "normalized time-to-onset" estimates. The SLE onsets can be estimated up to 36.4 s ahead of their actual occurrences, with a mean error of 14.3 +/- 27.0 s. The prediction errors decreased progressively as the actual time-to-onset decreased and more initial "normalized time-to-onset" estimates were used for the regression procedure.

Action Potentials↗
PubMed2006

General anesthetics inhibit gap junction communication in cultured organotypic hippocampal slices.

Gap junctions are protein channels that directly connect the cytosol of neighboring cells, thus forming electrical synapses and promoting synchronous neuronal activities. Such activities lead to the initiation and propagation of electroencephalogram oscillations implicated in cognition and consciousness. In this study, we investigated the effects of propofol, thiopental, and halothane on gap junction communication in cultured organotypic hippocampal slices by recovery of fluorescence after photo bleaching (FRAP) technique and electrophysiological recordings. Propofol 15 microM and thiopental 10 microM attenuated gap junction communication in slice cultures by 46.7% +/- 4.5% and 48.8% +/- 5.5%, respectively, as measured by FRAP. Smaller concentrations of propofol 5 microM and thiopental 2 microM did not change gap junction coupling. Accompanying the decreased gap junction communication, hippocampus slice cultures exposed to propofol 15 microM and thiopental 10 microM were found to have reduced electrophysiologic spontaneous discharges and primary after discharges evoked by a tetanic train of 50 Hz for 2 s. On the other hand, halothane 0.64 mM, a concentration slightly larger than twice its minimum alveolar concentration had no effect on gap junction coupling while halothane 2.8 mM blocked FRAP by 70%. The current study illustrates that anesthetic concentrations of propofol and thiopental, but not halothane, attenuate gap junction communication in cultured hippocampal slices. Suppression of gap junction function could compound the mechanisms of anesthetic actions.

Anesthetics, General↗
PubMed2005

The effects of high-frequency oscillations in hippocampal electrical activities on the classification of epileptiform events using artificial neural networks.

The existence of hippocampal high-frequency electrical activities (greater than 100 Hz) during the progression of seizure episodes in both human and animal experimental models of epilepsy has been well documented (Bragin A, Engel J, Wilson C L, Fried I and Buzsáki G 1999 Hippocampus 9 137-42; Khosravani H, Pinnegar C R, Mitchell J R, Bardakjian B L, Federico P and Carlen P L 2005 Epilepsia 46 1-10). However, this information has not been studied between successive seizure episodes or utilized in the application of seizure classification. In this study, we examine the dynamical changes of an in vitro low Mg2+ rat hippocampal slice model of epilepsy at different frequency bands using wavelet transforms and artificial neural networks. By dividing the time-frequency spectrum of each seizure-like event (SLE) into frequency bins, we can analyze their burst-to-burst variations within individual SLEs as well as between successive SLE episodes. Wavelet energy and wavelet entropy are estimated for intracellular and extracellular electrical recordings using sufficiently high sampling rates (10 kHz). We demonstrate that the activities of high-frequency oscillations in the 100-400 Hz range increase as the slice approaches SLE onsets and in later episodes of SLEs. Utilizing the time-dependent relationship between different frequency bands, we can achieve frequency-dependent state classification. We demonstrate that activities in the frequency range 100-400 Hz are critical for the accurate classification of the different states of electrographic seizure-like episodes (containing interictal, preictal and ictal states) in brain slices undergoing recurrent spontaneous SLEs. While preictal activities can be classified with an average accuracy of 77.4 +/- 6.7% utilizing the frequency spectrum in the range 0-400 Hz, we can also achieve a similar level of accuracy by using a nonlinear relationship between 100-400 Hz and <4 Hz frequency bands only.

Action Potentials↗
PubMed2005

General anesthetics attenuate gap junction coupling in P19 cell line.

Gap junction communication is widespread throughout the mammalian nervous system among neurons as well as glia. We addressed the hypothesis that general anesthetics attenuate gap junction mediated coupling in P19 cell line that can differentiate into neuronal-like cells and astrocytes and oligodendrocytes. We characterized the extent of dye coupling over time in the P19 cell line using colocalization of chlormethylbenzamido-1,1 dioctadecyl-3,3,3',3'-tetramethylindocarbocyamine (CM-DiI) and calcein-AM in donor and recipient cells in cocultures. After seeding, the gap junction permeant dye calcein spreads from donor to recipient cells. CM-DiI and calcein fluorescence identified donor and recipient cells, respectively. The extent of intercellular connections was evaluated using cell counting and flow cytometry up to 2 hr after treatment. Clinically relevant concentrations of the intravenous anesthetics propofol (15 microM) and thiopental (10 microM) attenuated gap junction permeability in P19 cell cultures. In contrast, halothane, a volatile anesthetic in a concentration (0.64 mM) relevant to its free aqueous EC50 had no effect on gap junction coupling; however, very high halothane concentrations (2.8 mM) blocked dye transfer by approximately 90%. The results indicate that halothane concentrations pertinent to clinical anesthesia were unable to attenuate gap junction communication in a cell line that can express neuronal and glial gap junction proteins; however, clinically relevant concentrations of propofol and thiopental depressed gap junction coupling.

Anesthetics, General↗
PubMed2005

Calcium chelation improves spatial learning and synaptic plasticity in aged rats.

Impaired regulation of intracellular calcium is thought to adversely affect synaptic plasticity and cognition in the aged brain. Comparing young (2-3 months) and aged (23-26 months) Fisher 344 rats, stratum radiatum-evoked CA1 field EPSPs were smaller and long-term potentiation (LTP) was diminished in aged hippocampal slices. Resting calcium, in presynaptic axonal terminals in the CA1 stratum radiatum area, was elevated in aged slices. Loading the slice with the calcium chelator, BAPTA-AM, depressed LTP in young slices, but enhanced this plasticity in old slices. Forty-five minutes following LTP-inducing high frequency stimulation, resting calcium levels were significantly increased in both young and old presynaptic terminals, and significantly reduced by pretreatment with BAPTA-AM. In vivo, intraperitoneal administration of BAPTA-AM prior to training in the reference memory version of the Morris water maze test, significantly improved the acquisition of spatial learning in aged animals, without a significant effect in young rats. These results support the hypothesis that increasing intracellular neuronal buffering power for calcium in aged rats ameliorates age-related impaired synaptic plasticity and learning.

Aging↗
PubMed2005

Prediction of seizure onset in an in-vitro hippocampal slice model of epilepsy using Gaussian-based and wavelet-based artificial neural networks.

We propose that artificial neural networks (ANNs) can be used to predict seizure onsets in an in-vitro hippocampal slice model capable of generating spontaneous seizure-like events (SLEs) in their extracellular field recordings. This paper assesses the effectiveness of two ANN prediction schemes: Gaussian-based artificial neural network (GANN) and wavelet-based artificial neural network (WANN). The GANN prediction system consists of a recurrent network having Gaussian radial basis function (RBF) nonlinearities capable of extracting the estimated manifold of the system. It is able to classify the underlying dynamics of spontaneous in-vitro activities into interictal, preictal and ictal modes. It is also able to successfully predict the onsets of SLEs as early as 60 s before. Improvements can be made to the overall seizure predictor design by incorporating time-varying frequency information. Consequently, the idea of WANN is considered. The WANN design entails the assumption that frequency variations in the extracellular field recordings can be used to compute the times at which onsets of SLEs are most likely to occur in the future. Progressions of different frequency components can be captured by the ANN using appropriate frequency band adjustments via pruning, after the initial wavelet transforms. In the off-line processing comprised of 102 spontaneous SLEs generated from 14 in-vitro rat hippocampal slices, with half of them used for training and the other half for testing, the WANN is able to predict the forecoming ictal onsets as early as 2 min prior to SLEs with over 75% accuracy within a 30 s precision window.

Animals↗
PubMed2005

Increased seizure susceptibility of the hippocampus compared with the neocortex of the immature mouse brain in vitro.

PURPOSE: The temporal lobe seems particularly susceptible to seizure activity. Mesial temporal lobe structures, including the hippocampus, have the lowest seizure thresholds in the brain. Conversely, thresholds in the frontal neocortex are significantly higher. The development of intact, isolated preparations of hippocampus and neocortex in vitro allows for study into mechanisms governing seizure threshold. METHODS: Epileptiform discharges in isolated mouse neocortical blocks were compared with the contralateral intact hippocampus, isolated from the same brain, by using the low-Mg2+, 4 aminopyridine (4-AP), and low-Ca2+ in vitro seizure models. The pharmacology of low Mg(2+)-induced ictal-like events (ILEs) generated in the hippocampus and neocortex was then compared by using glutamatergic antagonists DL-2-amino-5-phosphonovaleric acid (APV) and 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX), and the Ca2+ channel antagonist, nifedipine. RESULTS: Neocortical blocks generated both recurrent, spontaneous ILEs and interictal-like events under low-Mg2+ artificial CSF (aCSF) perfusion, distinct from those generated in the hippocampus. ILEs from the hippocampus displayed lower thresholds and longer durations as compared with isolated neocortical blocks. Similar results were obtained during 4-AP perfusion. Perfusion with low-Ca2+ ACSF did not produce stereotypical ILEs in the neocortical block, producing instead recurrent, slow depolarizations. Both ILEs and recurrent, slow depolarizations were produced in the hippocampus. Application of APV and nifedipine exacerbated low Mg(2+)-induced ILEs in the hippocampus but not the neocortex, indicating a distinct pharmacology for partial seizures of different brain regions. CONCLUSIONS: The developing mouse hippocampus demonstrates increased ictogenesis compared with the developing neocortex in vitro, consistent with clinical observations and in vivo experimental models.

2-Amino-5-phosphonovalerate↗
PubMed2005

Increased high-frequency oscillations precede in vitro low-Mg seizures.

PURPOSE: High-frequency oscillations (HFOs) in the range of > or = 80 Hz have been recorded in neocortical and hippocampal brain structures in vitro and in vivo and have been associated with physiologic and epileptiform neuronal population activity. Frequencies in the fast-ripple range (> 200 Hz) are believed to be exclusive to epileptiform activity and have been recorded in vitro, in vivo, and in epilepsy patients. Although the presence of HFOs is well characterized, their temporal evolution in the context of transition to seizure activity is not well understood. METHODS: With an in vitro low-magnesium model of spontaneous seizures, we obtained extracellular field recordings (hippocampal regions CA1 and CA3) of interictal, preictal, and ictal activity. Recordings were subjected to power-frequency analysis, in time, by using a local multiscale Fourier transform. The power spectrum was computed continuously and was quantified for each epileptiform discharge into four frequency ranges spanning subripple, ripple, and two fast-ripple frequency bands. RESULTS: A statistically significant increasing trend was observed in the subripple (0-100 Hz), ripple (100-200 Hz), and fast-ripple 1 (200-300 Hz) frequency bands during the epoch corresponding to the transition to seizure (preictal to ictal). CONCLUSIONS: Temporal patterns of HFOs during epileptiform activity are indicative of dynamic changes in network behavior, and their characterization may offer insights into pathophysiologic processes underlying seizure initiation.

Animals↗
PubMed2004

Electrotonic coupling between stratum oriens interneurones in the intact in vitro mouse juvenile hippocampus.

Using the isolated juvenile (7-14 days) mouse whole hippocampus preparation, which contains intact complex local circuitry, 145 dual whole cell recordings were made from stratum oriens (s.o.) interneurones under infrared microscopy. In 11.7% of paired recordings, evidence for direct electrotonic coupling between the s.o. interneurones was obtained from the response of one interneurone to a long (400-600 ms) constant current pulse passed into the coupled interneurone. When specifically orienting the dual recordings in the transectional plane of the hippocampus, 18.5% of paired recordings showed electrotonic coupling. The coupling coefficient, estimated from averaged data, was 6.9 +/- 4.7%, ranging from 1.3 to 17.6%. The time constant of the electrotonically transmitted hyperpolarization was inversely related to the coupling coefficient between the two neurones. The electrotonic responses of one neurone to constant current pulses injected into the other coupled neurone were intermittent. Spikes in one of the coupled neurones were associated with small electrotonic EPSPs (spikelets) in the other coupled neurone, in those neuronal pairs with coupling coefficients greater than 10%. Failure of spikelet production following a spike in the coupled cell occurred 5-10% of the time. Electrotonic coupling and spikelets persisted in the presence of chemical synaptic transmission blockade by CNQX, APV and bicuculline, or in zero Ca(2+) perfusate, but were abolished by carbenoxolone (100 microm), a gap junctional blocker. These data confirm the existence of electrotonic coupling between s.o. interneurones, presumably via gap junctions located in dendrites.

Action Potentials↗
PubMed2004

Ethanol inhibits gap-junctional coupling between P19 cells.

BACKGROUND: Gap junctions are plaques of multiple intercellular channels that connect the cytoplasm of adjacent cells. They provide both electrical and metabolic coupling and are an essential element in normal growth, development, and physiology. Little research exists on the relationship between alcohol administration and gap-junctional function or expression. This study looks at the function and expression of gap junctions after incubation and withdrawal of ethanol with P19 cell cultures. METHODS: Gap-junctional communication was assessed after 24 and 48 hr of exposure to 20 and 40 mM ethanol and after a 24-hr withdrawal period. The seeding technique was used, and diacyl-3,3'-indocarbocyanine iodide/calcein-stained donor cells were seeded on an unstained monolayer and then reviewed by confocal microscope and counted by flow cytometry. Analysis of connexin (Cx) proteins was performed by Western blot, gel electrophoresis, and immunoblots with antibodies for Cx26 and Cx43. RESULTS: All treatment regimens produced similar results, reducing dye coupling by more than 50% without recovery after a 24-hr withdrawal period. Exposing the cells to 20 mM ethanol for 48 hr did not significantly change the levels of Cx26 protein, but ethanol significantly decreased the levels of Cx43 in cultured P19 cells. CONCLUSIONS: This study illustrates that ethanol can inhibit gap-junction function in the P19 cell line. Chronic exposure to 20 mM ethanol selectively decreased the levels of Cx43 protein in the membrane fraction of the cell cultures.

Animals↗
PubMed2003

Cognitive effects of long-term benzodiazepine use in older adults.

This study examined the potential for cognitive morbidity associated with the long-term use of benzodiazepine (BZ) sedative-hypnotics in a sample of healthy older adults. Tests of memory, attention and processing speed were conducted prior to and 1 month after drug discontinuation for 25 BZ-users and at similar intervals for 26 healthy control subjects. After controlling for differences in affective status between BZ-users and controls, there were no significant group differences in cognitive performance. However, BZ-users showed greater gains on tests of attention and speed of processing at repeat testing compared with controls this improvement was not attributable to a change in affective status. These findings suggest that there may be subtle and reversible effects of long-term BZ use on speed-dependent tasks in older adults. However, the magnitude of these effects is quite small and may be of little clinical significance in the healthy elderly.

Aged↗
PubMed2003

The control of seizure-like activity in the rat hippocampal slice.

The sudden and transient hypersynchrony of neuronal firing that characterizes epileptic seizures can be considered as the transitory stabilization of metastable states present within the dynamical repertoire of a neuronal network. Using an in vitro model of recurrent spontaneous seizures in the rat horizontal hippocampal slice preparation, we present an approach to characterize the dynamics of the transition to seizure, and to use this information to control the activity and avoid the occurrence of seizure-like events. The transition from the interictal activity (between seizures) to the seizure-like event is aborted by brief (20-50 s) low-frequency (0.5 Hz) periodic forcing perturbations, applied via an extracellular stimulating electrode to the mossy fibers, the axons of the dentate neurons that synapse onto the CA3 pyramidal cells. This perturbation results in the stabilization of an interictal-like low-frequency firing pattern in the hippocampal slice. The results derived from this work shed light on the dynamics of the transition to seizure and will further the development of algorithms that can be used in automated devices to stop seizure occurrence.

Animals↗
PubMed2003

Epileptiform activity in hippocampal slice cultures exposed chronically to bicuculline: increased gap junctional function and expression.

Chronic (18 h) exposure of cultured hippocampal slices to the type-A GABA receptor blocker, bicuculline methiodide (BMI) 10 micro m increased the levels of connexin 43 (Cx43) and connexin 32 (Cx32) mRNAs, but not connexin 26 and connexin 36, as demonstrated by RNase protection assays. The levels of Cx43 and Cx32 proteins in membrane fractions detected by western blotting were also significantly increased. Immunoblotting indicated that BMI also promoted a significant expression of the transcription protein c-fos. The rate of fluorescence recovery after photobleaching, an index of gap junctional coupling, was also significantly increased, whereas it was blocked by the gap junctional blocker, carbenoxolone (100 micro m). Extracellular recordings in CA1 stratum pyramidale, performed in BMI-free solution, demonstrated that BMI-exposed cultures possessed synaptic responses characteristic of epileptiform discharges: (i) significantly greater frequency of spontaneous epileptiform discharges, (ii) post-synaptic potentials with multiple population spikes, and (iii) significantly longer duration of primary afterdischarges. Carbenoxolone (100 micro m), but not its inactive analog, oleanolic acid (100 micro m), reversibly inhibited spontaneous and evoked epileptiform discharges. The findings of BMI-induced parallel increases in levels of gap junction expression and function, and the increase in epileptiform discharges, which were sensitive to gap junctional blockers, are consistent with the hypothesis that increased gap junctional communication plays an intrinsic role in the epileptogenic process.

Animals↗
PubMed2003

Changes in neuronal migration in neocortex of connexin43 null mutant mice.

To identify a neural phenotype in connexin43 null mutant mice, electrophysiological properties, intercellular communication and neuronal migration were studied in the developing neocortex. In acute slice preparations from newborn mice, electrophysiological characteristics of cortical and hippocampal neurons were not significantly different between wild type and null mutant mice. However, gap junctional coupling as assessed by fluorescence recovery after photobleaching was significantly attenuated in neocortical brain slices of null mutant mice. To assess neuronal migration, dividing cells were labeled with bromodeoxyuridine (BrdU) on embryonic days 12, 14 and 16, respectively, corresponding to the period of cortical neurogenesis, and the neocortex examined 2 or 3 days after the labeling. BrdU-labeled cells were distributed in the neocortical wall with a significant change in the pattern in the neocortex of the null mutant, where labeled cells accumulated in the intermediate zone or in the inner part of the cortical plate. The result suggests a significant delay in neocortical neuronal migration in the connexin43 null mutants, and a possible role of connexin43 in this process through yet unidentified mechanisms.

Animals↗
PubMed2003

Panic attack semiology in right temporal lobe epilepsy.

BACKGROUND: Panic attack semiology as a manifestation of epileptic seizures may lead to difficulties and delay in diagnosis. We present a case series to demonstrate the association of ictal panic and anxiety symptoms with partial seizures lateralized to the right temporal lobe. METHODS: From 112 consecutive patients with intractable temporal lobe epilepsy (59 right, 53 left) referred for video-EEG monitoring, five patients were identified whose seizures had been diagnosed as panic attacks in the past. Their ictal symptomatology included feelings of panic and impending doom, hyper-ventilation, palpitation, diaphoresis, shortness of breath and generalized paresthesiae. Ictal panic was not identified in 72 patients with extra temporal epilepsy investigated during the same period. RESULTS: EEG documented a right anterior to mid-temporal focus in all five patients. Brain MRI or pathology showed right mesial temporal sclerosis in four and a right temporal ganglioglioma in one. Ictal tachycardia was documented with EEG-EKG recording in the latter patient, prior to right anterior temporal lobectomy and amygdalohippocampectomy. Reinvestigation of this patient five years later for recurrent seizures, no longer associated with panic symptomatology, showed right temporal ictal onsets with seizure spread to the left temporal lobe, now associated with ictal bradycardia. CONCLUSIONS: Our case series provides further evidence to support a relationship between panic attack symptomatology and ictal involvement of the right mesial temporal region [Published with video sequences].

Adult↗
PubMed2003

Video-EEG evidence of lateralized clinical features in primary generalized epilepsy with tonic-clonic seizures.

BACKGROUND: Whether cortical or subcortical structures, specifically the thalamus, play the dominant role in generating primary generalized seizures has been the subject of long debate. Most experimental data implicate a hyperexcitable cortical generator of spike-and-wave activity, with the thalamus quickly recruited to sustain the generalized oscillations through a reverberating thalamocortical network. However, there is little clinical evidence to support the cortical generator hypothesis. We present video-EEG recordings of generalized tonic-clonic seizures in three patients with proven primary generalized epilepsy (PGE), all of whom showed a consistent pattern of lateralized seizure onset compatible with a focal frontal lobe generator. METHODS: Among 300 patients referred for video-EEG monitoring for intractable epilepsy, three were found to have PGE with tonic-clonic convulsions. All had a positive family history for epilepsy and no other epilepsy risk factors. Epilepsy onset was during adolescence (2/3) or childhood (1/3). Patients were taking 1-4 antiepileptic drugs (AEDs) at admission, none of which was valproic acid. RESULTS: Interictal EEG showed very active, bilaterally synchronous generalized spike-and-wave or polyspike-and-wave discharges between 2.5-4.5 Hz, maximal over the midfrontal structures symmetrically in all patients. Ictal EEG showed generalized rhythmic activity without lateralization at seizure onset. Surprisingly, in all 6 recorded tonic-clonic seizures there was a sustained (10-15 seconds), stereotyped, clinical lateralization at onset, which took the form of a tonic "fencing posture" in one patient (two seizures) and forced head/eye/torso version in two patients (four seizures). Two patients became seizure-free shortly after switching to valproate monotherapy. One patient refused valproate but has improved more than 90% with a change in AEDs to lamotrigine and phenobarbital (follow-up in all patients>18 months). CONCLUSIONS: Tonic-clonic seizures are presumed to be generalized from onset in patients with PGE. However, video-EEG monitoring in these patients is rarely performed and the actual clinical features of the seizures maybe underappreciated. The demonstration of sustained lateralization at onset in our patients, with features clinically indistinguishable from focal onset frontal lobe seizures, is compatible with the hypothesis of a focal region of cortical hyperexcitability situated in the frontal lobes of some patients with PGE. Whether this cortical generator is autonomous or "triggered" by ascending, possibly normal, thalamocortical volleys is unresolved.

Adult↗