Biomedical subjects

G V Wallenstein

Publications and source records attributed to G V Wallenstein.

14 recordsLinked to original sources

PubMed2006

Abatacept improves both the physical and mental health of patients with rheumatoid arthritis who have inadequate response to methotrexate treatment.

OBJECTIVE: To examine the impact of added abatacept treatment on health related quality of life (HRQoL) in patients with rheumatoid arthritis (RA) who have inadequate response to methotrexate (MTX). METHODS: The impact of abatacept treatment on HRQoL was examined in a longitudinal, randomised double blind, placebo controlled clinical trial. Effects of treatment on HRQoL were examined using repeated measures analysis of covariance and comparing rates of change in HRQoL across treatment groups. The relationship between American College of Rheumatology (ACR) clinical markers and disease duration with changes in HRQoL indicators was also examined. Finally, a responder analysis was used to examine the percentage of patients who improved by 0.5 SD in 12 months or who reached the normative levels seen in the US general population. RESULTS: Statistically significant improvements in the abatacept group relative to controls were observed across a range of HRQoL measures, including physical function, fatigue, all eight domains of the SF-36, and the physical and mental component summaries (PCS and MCS). Improvements were seen as early as day 29 for fatigue and for five out of eight SF-36 domains. By day 169, all HRQoL measures were significantly better with abatacept than with placebo. HRQoL gains were associated with greater ACR clinical improvement, and the effects were consistent for patients with different disease duration. A significantly greater percentage of patients treated with abatacept reached normative levels of PCS, MCS, physical functioning, and fatigue compared with patients treated with MTX alone. CONCLUSION: Combined abatacept and MTX treatment produces significant improvements across a wide range of HRQoL domains in patients with RA.

Abatacept↗

PubMed2006

Improved health-related quality of life for rheumatoid arthritis patients treated with abatacept who have inadequate response to anti-TNF therapy in a double-blind, placebo-controlled, multicentre randomized clinical trial.

OBJECTIVE: Rheumatoid arthritis (RA) patients who have inadequate response to anti-tumour necrosis factor (TNF) therapy currently have treatment options that are limited and less than optimal in their risk-to-benefit ratio. Abatacept provides a new generation of RA medications that has previously been demonstrated to have positive clinical outcomes with this population. The current study sought to demonstrate the efficacy of abatacept on quality of life (QoL) for RA patients with inadequate response to anti-TNF therapy. METHODS: Patients were entered into a double-blind, placebo-controlled, multicentre randomized clinical trial, with 258 patients randomized to abatacept + disease-modifying anti-rheumatic drugs (DMARDs) and 133 patients randomized to placebo + DMARDS. The QoL was measured with the Short Form Health Survey (SF-36), Health Assessment Questionnaire (HAQ) and fatigue visual analogue scale, and was analysed with basic (ANOVA, chi-square) and multigroup growth curve techniques to assess differential change over time. RESULTS: Treatment group QoL improved significantly more than placebo on the HAQ and fatigue indices, as well as seven of the eight SF-36 scales and SF-36 physical and mental summary scores. Improvement rate was faster for abatacept than for placebo on the QoL measures, and the improvements from abatacept related to normal levels of QoL on many domains. CONCLUSION: Clinically relevant benefits of abatacept over placebo are discussed regarding improving QoL. Importantly, the larger rate of change for abatacept over placebo provides clinicians with a medication that can lead to meaningful changes in a patient's life within a few weeks, even when the patient previously failed anti-TNF therapy.

Abatacept↗

PubMed2001

Intrahippocampal scopolamine impairs both acquisition and consolidation of contextual fear conditioning.

Lesions of the dorsal hippocampus have been shown to disrupt both the acquisition and the consolidation of memories associated with contextual fear (fear of the place of conditioning), but do not affect fear conditioning to discrete cues (e.g., a tone). Blockade of central muscarinic cholinergic receptor activation results in selective acquisition deficits of contextual fear conditioning, but reportedly has little effect on consolidation. Here we show for the first time that direct infusion of the muscarinic cholinergic receptor antagonist, scopolamine, into the dorsal hippocampus produces a dose-dependent deficit in both acquisition and consolidation of contextual fear conditioning, while having no impact on simple tone conditioning.

Animals↗

PubMed2000

Testing neural network models of memory with behavioral experiments.

In recent years, a number of computational neural networks have been proposed aimed at describing memory functions associated with different subregions of the hippocampus, namely dentate gyrus, CA3 and CA1. Recent evidence suggests that indeed specific subregions of the hippocampus may subserve different computational functions, such as spatial and temporal pattern separation, short-term or working memory, pattern association, and temporal pattern completion.

Animals↗

PubMed1999

Gamma frequency-range abnormalities to auditory stimulation in schizophrenia.

BACKGROUND: Basic science studies at the neuronal systems level have indicated that gamma-range (30-50 Hz) neural synchronization may be a key mechanism of information processing in neural networks, reflecting integration of various features of an object. Furthermore, gamma-range synchronization is thought to depend on the glutamatergically mediated interplay between excitatory projection neurons and inhibitory neurons utilizing gamma-aminobutyric acid (GABA), which postmortem studies suggest may be abnormal in schizophrenia. We therefore tested whether auditory neural networks in patients with schizophrenia could support gamma-range synchronization. METHODS: Synchronization of the electroencephalogram (EEG) to different rates (20-40 Hz) of auditory stimulation was recorded from 15 patients with schizophrenia and 15 sex-, age-, and handedness-matched control subjects. The EEG power at each stimulation frequency was compared between groups. The time course of the phase relationship between each stimulus and EEG peak was also evaluated for gamma-range (40 Hz) stimulation. RESULTS: Schizophrenic patients showed reduced EEG power at 40 Hz, but not at lower frequencies of stimulation. In addition, schizophrenic patients showed delayed onset of phase synchronization and delayed desynchronization to the click train. CONCLUSIONS: These data provide new information on selective deficits in early-stage sensory processing in schizophrenia, a failure to support the entrainment of intrinsic gamma-frequency oscillators. The reduced EEG power at 40 Hz in schizophrenic patients may reflect a dysfunction of the recurrent inhibitory drive on auditory neural networks.

Acoustic Stimulation↗

PubMed1998

The hippocampus as an associator of discontiguous events.

The hippocampus has long been thought to be an important cortical region for associative learning and memory. After several decades of experimental and theoretical studies, a picture is emerging slowly of the generic types of learning tasks that this neural structure might be essential for solving. Recently, there have been attempts to unify electrophysiological and behavioral observations from rodents performing spatial learning tasks with data from primates performing various tests of conditional and discrimination learning. Most of these theoretical frameworks have rested primarily on behavioral observations. Complementing these perspectives,we ask the question: given certain physiological constraints at the neuronal and cortical level, what class of learning problems is the hippocampus, in particular, most suited to solve? From a computational point of view, we argue that this structure is involved most critically in learning and memory tasks in which discontiguous items must be associated, in terms of their temporal or spatial positioning, or both.

Animals↗

PubMed1997

Functional transitions between epileptiform-like activity and associative memory in hippocampal region CA3.

Clinical and experimental observations indicate that the hippocampus is critical in the formation of declarative memories. Interestingly, electrophysiological studies have demonstrated that the region also has a particularly low seizure threshold, where globally synchronous synaptic activity can occur. By using a detailed biophysical model of area CA3, it is shown how septal cholinergic modulation, through three distinct mechanisms, can interact with intrinsic and synaptic conductances to influence population behavior. A dissection of each mechanism demonstrates a variety of population firing activity ranging from fully synchronized behavior to a mixture of repetitive bursting and oscillations in reduced subsets of neurons, ideal for forming accurate associations during a learning and recall task.

Acetylcholine↗

PubMed1997

GABAergic modulation of hippocampal population activity: sequence learning, place field development, and the phase precession effect.

A detailed biophysical model of hippocampal region CA3 was constructed to study how GABAergic modulation influences place field development and the learning and recall of sequence information. Simulations included 1,000 multicompartmental pyramidal cells, each consisting of seven intrinsic and four synaptic currents, and 200 multicompartmental interneurons, consisting of two intrinsic and four synaptic currents. Excitatory rhythmic septal input to the apical dendrites of pyramidal cells and both excitatory and inhibitory input to interneurons at theta frequencies provided a cellular basis for the development of theta and gamma frequency oscillations in population activity. The fundamental frequency of theta oscillations was dictated by the driving rhythm from the septum. Gamma oscillation frequency, however, was determined by both the decay time of the gamma-aminobutyric acid-A (GABA(A))-receptor-mediated synaptic current and the overall level of excitability in interneurons due to alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid and N-methyl-D-aspartate (NMDA)-receptor-gated channel activation. During theta population activity, total GABA(B)-receptor-mediated conductance levels were found to gradually rise and fall in rhythmic fashion with the predominant population frequency (theta rhythm). This resulted in periodic GABA(B)-receptor-mediated suppression of excitatory synaptic transmission at recurrent collaterals (intrinsic fibers) of pyramidal cells and suppression of inhibitory synaptic transmission to both pyramidal cells and interneurons. To test the ability of the model to learn and recall temporal sequence information, a completion task was employed. During learning, the network was presented a sequence of nonorthogonal spatial patterns. Each input pattern represented a spatial "location" of a simulated rat running a specific navigational path. Hebbian-type learning was expressed as an increase in postsynaptic NMDA-receptor-mediated conductances. Because of several factors including the sparse, asymmetric excitatory synaptic connections among pyramidal cells in the model and a sufficient degree of random "background" firing unrelated to the input patterns, repeated simulated runs resulted in the gradual emergence of place fields where a given cell began to respond to a contiguous segment of locations on the path. During recall, the simulated rat was placed at a random location on the previously learned path and tested to see whether the sequence of locations could be completed on the basis of this initial position. Periodic GABA(B)-receptor-mediated suppression of excitatory and inhibitory transmission at intrinsic but not afferent fibers resulted in sensory information about location being dominant during early portions of each theta cycle when GABA(B)-receptor-related effects were highest. This suppression declined with levels of GABA(B) receptor activation toward the end of a theta cycle, resulting in an increase in synaptic transmission at intrinsic fibers and the subsequent recall of a segment of the entire location sequence. This scenario typically continued across theta cycles until the full sequence was recalled. When the GABA(B)-receptor-mediated suppression of excitatory and inhibitory transmission at intrinsic fibers was not included in the model, place field development was curtailed and the network consequently exhibited poor learning and recall performance. This was, in part, due to increased competition of information from intrinsic and afferent fibers during early portions of each theta cycle. Because afferent sensory information did not dominate early in each cycle, the current location of the rat was obscured by ongoing activity from intrinsic sources. (ABSTRACT TRUNCATED)

Animals↗

PubMed1996

Encoding and retrieval of episodic memories: role of cholinergic and GABAergic modulation in the hippocampus.

This research focuses on linking episodic memory function to the cellular physiology of hippocampal neurons, with a particular emphasis on modulatory effects at cholinergic and gamma-aminobutyric acid B receptors. Drugs which block acetylcholine receptors (e.g., scopolamine) have been shown to impair encoding of new information in humans, nonhuman primates, and rodents. Extensive data have been gathered about the cellular effects of acetylcholine in the hippocampus. In this research, models of individual hippocampal subregions have been utilized to understand the significance of particular features of modulation, and these hippocampal subregions have been combined in a network simulation which can replicate the selective encoding impairment produced by scopolamine in human subjects.

Acetylcholine↗

PubMed1996

Adenosinic modulation of 7-14 Hz spindle rhythms in interconnected thalamic relay and nucleus reticularis neurons.

Intrathalamic spindle rhythms have been shown in vitro and in vivo to recur at frequencies of 0.1-0.3 Hz and last for periods of 1-3 s depending on the species observed. Although it is now generally agreed that both the intrinsic properties of relay and reticularis neurons, as well as their circuit dependency, contribute to the 7-14 Hz interburst spindle frequency, it is not presently known what mechanisms generate these slower oscillations. A model of interconnected thalamocortical relay and nucleus reticularis thalami cells was developed to investigate these properties. The model suggests that modulation of the hyperpolarization-activated cation current, Ib, by the nucleoside adenosine can serve to regulate both the duration of spindling and frequency of recurrence. These results suggest that the waxing and waning characteristics of thalamic spindle rhythms are, in part, dependent on the changing levels of extracellular adenosine and its influence on Ib in thalamocortical relay cells within this neuronal network.

Adenosine↗

PubMed1995

Frequency and phase characteristics of slow cortical potentials preceding bimanual coordination.

The aim of the present study was to derive quantities which relate behavioral and neurophysiological levels of observation during a bimanual coordination task. We recorded the scalp electroencephalographic (EEG) signal preceding a sequence of 4 bimanual finger flexions of varying response rates in 12 subjects. A slow negative-going Bereitschaftspotential (BP) displayed larger mean amplitudes and earlier onset times for the faster required response rates. The amplitude of the BP was also larger for electrode locations contralateral to the side initiating the behavioral response. A Fourier transform showed two predominant frequencies (0.5 and 2.0 Hz) to be amplitude modulated as a function of the required response rate in addition to increased power on the contralateral side of the finger initiating the response. A measure of the phase relationship between the left (C3) and right (C4) hemispheres of the fronto-central cortex at each of these spectral frequencies was calculated as well as the variance in this measure and found to correspond closely to the variance in inter-response times derived from the subjects' movements. These findings indicate that changes in the stability and rate of a patterned movement are generally preceded by similar changes in the stability and amplitude of components observed on the neurophysiological level.

Acoustic Stimulation↗

PubMed1994

The role of thalamic IGABAB in generating spike-wave discharges during petit mal seizures.

Recent studies have suggested that 7-14 Hz spindle rhythms which appear during slow wave sleep and the 3 Hz spike-wave discharge accompanying petit mal seizures share common thalamocortical circuitry. A computational model was used to investigate the manner in which differential changes in the synaptic currents, IGABAA and IGABAB, observed in these cells can transform normal sleep spindles into the pathological oscillations recorded in primate exhibiting generalized petit mal epilepsy. The model suggests that inhibition by GABAergic interneurons and possibly nucleus reticularis thalami cells which reduce IGABA, increases the amplitude of the slower IGABAB. These events produce an extended inhibitory period in relay cells and also lead to the exaggerated post-inhibitory rebound Ca(2+)-dependent burst observed during seizures.

Animals↗

PubMed1994

Simulation of GABAB-receptor-mediated K+ current in thalamocortical relay neurons: tonic firing, bursting, and oscillations.

Until recently, the presence of gamma-aminobutyric acid (GABA) in the thalamus has usually been associated with the 'classical' GABAA Cl(-)-dependent receptor. However, the discovery of a slower, long-lasting, K(+)-dependent inhibitory postsynaptic potential (IPSP) mediated by GABAB receptors in projection cells of the dorsal lateral geniculate nucleus has led researchers to reconsider its role in modulating the behavior of these cell groups (Crunelli et al. 1988; Crunelli and Leresche 1991). Of particular interest is the role of this K+ current in the activation of the low-threshold Ca2+ current, IT, of thalamocortical relay (TCR) neurons responsible for bursting activity (Jahnsen and Llinás 1984a,b). Considering the time scale on which the GABAB-receptor-activated K+ current operates, it is ideally suited to foster sustained rhythmicity in TCR cells reciprocally connected to neurons of the nucleus reticularis thalami (NRT) as well as interneurons at frequencies observed in vivo (Steriade and Llinás 1988). In this study we show that small changes in the duration and amplitude of the K(+)-dependent IPSPs can have marked effects on TCR cell groups including a shift from single-spike firing (tonic) to bursting behavior. We further show that a single GABAB-mediated IPSP is sufficient to activate the low-threshold Ca2+ response and that sustained oscillations are possible given the presence of excitatory TCR connections to GABAergic NRT cells or interneurons of the dorsal lateral thalamus. These combined effects are examined with regard to their role in generating the well known 7-14 Hz spindle rhythm as well as slower 6-8 Hz oscillations observed in TCR cells in vivo (Steriade and Llinás 1988).

Action Potentials↗

PubMed1994

A model of the electrophysiological properties of nucleus reticularis thalami neurons.

A model of the electrophysiological properties of rodent nucleus reticularis thalami (NRT) neurons of the dorsal lateral thalamus was developed using Hodgkin-Huxley style equations. The model incorporated voltage-dependent rate constants and kinetics obtained from recent voltage-clamp experiments in vitro. The intrinsic electroresponsivity of the model cell was found to be similar to several empirical observations. Three distinct modes of oscillatory activity were identified: 1) a pattern of slow rhythmic burst firing (0.5-7 Hz) usually associated with membrane potentials negative to approximately -70 mV which resulted from the interplay of ITs and IK(Ca); 2) at membrane potentials from approximately -69 to -62 mV, rhythmic burst firing in the spindle frequency range (7-12 Hz) developed and was immediately followed by a tonic tail of single spike firing after several bursts. The initial bursting rhythm resulted from the interaction of ITs and IK(Ca), with a slow after-depolarization due to ICAN which mediated the later tonic firing; 3) with further depolarization of the membrane potential positive to approximately -61 mV, sustained tonic firing appeared in the 10-200-Hz frequency range depending on the amplitude of the injected current. The frequency of this firing was also dependent on the maximum conductance of the leak current, IK(leak), and an interaction between the fast currents involved in generating action potentials, INa(fast) and IK(DR), and the persistent Na+ current, INa(P). Transitions between different firing modes were identified and studied parametrically.

Action Potentials↗