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P C Molenaar

Publications and source records attributed to P C Molenaar.

At least 19 recordsLinked to original sources
PubMed2001

Stability of genetic and environmental influences on P300 amplitude: a longitudinal study in adolescent twins.

This study examined the stability of genetic and environmental influences on individual differences in P300 amplitude during adolescence. The P300 component is an event-related brain potential (ERP) that has attracted much attention as a biological marker for disturbed cognitive processing in psychopathology. Understanding the genetics of this biological marker may contribute to understanding the genetics of the associated psychopathologies. In a group of 213 adolescent twin pairs, the P300 component was measured twice, the first time at age 16 and the second time 18 months later. A large part of the variance of the P300 amplitude could be explained by familial factors, with estimates ranging from 30% to 81%. Whether the familial resemblance was due to genetic or shared environmental factors depended on sex. For males, genetic factors explained familial resemblance in P300 amplitude, but for females such resemblance was likely due to shared environmental factors. The phenotypic stability of the P300 amplitude from 16 to 18 years was high in both sexes, and stability could be attributed largely to the same familial factors. There was no evidence that new familial influences emerged at age 18.

Adolescent↗
PubMed2001

Simultaneous MEG and EEG source analysis.

A method is described to derive source and conductivity estimates in a simultaneous MEG and EEG source analysis. In addition the covariance matrix of the estimates is derived. Simulation studies with a concentric spheres model and a more realistic boundary element model indicate that this method has several advantages, even if only a few EEG sensors are added to a MEG configuration. First, a simultaneous analysis profits from the 'preferred' location directions of MEG and EEG. Second, deep sources can be estimated quite accurately, which is an advantage compared to MEG. Third, superficial sources profit from accurate MEG location and from accurate EEG moment. Fourth, the radial source component can be estimated, which is an advantage compared to MEG. Fifth, the conductivities can be estimated. It is shown that conductivity estimation gives a substantial increase in precision, even if the conductivities are not identified appropriately. An illustrative analysis of empirical data supports these findings.

Computer Simulation↗
PubMed2001

Anti-GQ1b ganglioside antibodies mediate complement-dependent destruction of the motor nerve terminal.

Miller-Fisher syndrome is an autoimmune neuropathy characterized by ataxia, areflexia and ophthalmoplegia, and in the majority of cases the presence of high titres of anti-GQ1b ganglioside antibodies. In an ex vivo model, human and mouse anti-GQ1b antibodies have been shown previously to induce a complement-dependent alpha-latrotoxin-like effect on the murine motor endplate, i.e. they bring about massive quantal release of acetylcholine and eventually block neuromuscular transmission. Using immunofluorescence microscopy with image analysis, we show here that the late stages of this electrophysiological effect temporally coincide with the loss of heavy neurofilament (200 kDa) and type III beta-tubulin immunostaining and structural breakdown of the nerve terminal, as demonstrated by electron microscopy. Ultrastructurally, axon terminals were disorganized, depleted of vesicles, and subdivided by the infiltrating processes of capping Schwann cells. These findings provide clear pathological evidence to support a role for anti-ganglioside antibodies in mediating nerve terminal injury and further advance the view that this site may be of importance as a target in some human neuropathies.

Alkaline Phosphatase↗
PubMed2001

Estimated generalized least squares electromagnetic source analysis based on a parametric noise covariance model.

Estimated generalized least squares (EGLS) electromagnetic source analysis is used to downweight noisy and correlated data. Standard EGLS requires many trials to accurately estimate the noise covariances and, thus, the source parameters. Alternatively, the noise covariances can be modeled parametrically. Only the parameters of the model describing the noise covariances need to be estimated and, therefore, less trials are required. This method is referred to as parametric egls (PEGLS). In this paper, PEGLS is developed and its performance is tested in a simulation study and in a pseudoempirical study.

Chi-Square Distribution↗
PubMed2001

Finite mixture distribution models of simple discrimination learning.

Through the application of finite mixture distribution models, we investigated the existence of distinct modes of behavior in learning a simple discrimination. The data were obtained in a repeated measures study in which subjects aged 6 to 10 years carried out a simple discrimination learning task. In contrast to distribution models of exclusively rational learners or exclusively incremental learners, a mixture distribution model of rational learners and slow learners was found to fit the data of all measurement occasions and all age groups. Hence, the finite mixture distribution analysis provides strong support for the existence of distinct modes of learning behavior. The results of a second experiment support this conclusion by crossvalidation of the models that fit the data of the first experiment. The effect of verbally labeling the values on the relevant stimulus dimension and the consistency of behavior over measurement occasions are related to the mixture model estimates.

Bayes Theorem↗
PubMed2001

Comparison between the Fourier and Wavelet methods of spectral analysis applied to stationary and nonstationary heart period data.

The aim of this study was to assess the error made by violating the assumption of stationarity when using Fourier analysis for spectral decomposition of heart period power. A comparison was made between using Fourier and Wavelet analysis (the latter being a relatively new method without the assumption of stationarity). Both methods were compared separately for stationary and nonstationary segments. An ambulatory device was used to measure the heart period data of 40 young and healthy participants during a psychological stress task and during periods of rest. Surprisingly small differences (<1%) were found between the results of both methods, with differences being slightly larger for the nonstationary segments. It is concluded that both methods perform almost identically for computation of heart period power values. Thus, the Wavelet method is only superior for analyzing heart period data when additional analyses in the time-frequency domain are required.

Adolescent↗
PubMed2001

Mutant P/Q-type calcium channel electrophysiology and migraine.

The pathophysiological mechanisms of migraine are not yet very well understood. The gene CACNA1A, coding for the alpha 1A subunit of neuronal P/Q-type Ca2+ channels is mutated in the rare Mendelian inherited variant, familial hemiplegic migraine. This finding suggests a role for disturbed neuronal Ca2+ influx and/or homeostasis in the pathophysiology of migraine. It has stimulated in vitro electrophysiological investigations into the function of mutant human and mouse P/Q-type channels at cell bodies and synapses. A complex picture has emerged from this work, showing that different CACNA1A mutations lead to different effects on Ca2+ channel behavior and that synaptic transmission may become affected. We will review these studies and discuss the possible implications for the understanding of migraine pathophysiology.

Animals↗
PubMed2000

Anti-GQ1b antibodies and evoked acetylcholine release at mouse motor endplates.

Miller Fisher syndrome (MFS) is clinically characterized by ataxia, areflexia, and ophthalmoplegia, and is associated with serum anti-GQ1b-ganglioside antibodies. We have previously shown that anti-GQ1b antibodies induce complement-dependent, alpha-latrotoxin-like effects at mouse neuromuscular junctions (NMJs) in vitro. This effect comprises a massive increase in spontaneous quantal acetylcholine (ACh) release, accompanied by block of evoked release and muscle paralysis. This mechanism may contribute to the motor features of MFS. Whether the block of evoked ACh release is a primary effect of anti-GQ1b antibodies or occurs secondary to massive complement-dependent spontaneous release is unknown. Using conventional micro-electrode methods, we measured in detail ACh release evoked with low- and high-rate nerve stimulation, and studied the effect on it of a purified MFS IgG and a mouse monoclonal anti-GQ1b IgM (without added complement). We found that evoked transmitter release was unaffected. Control experiments proved binding of anti-GQ1b antibody at the NMJ. We conclude that the block of nerve-evoked ACh release at the NMJ is not a primary effect of anti-GQ1b antibodies, but is dependent on antibody-mediated complement activation. It remains to be determined whether the block of nerve-evoked ACh release is the consequence of massive spontaneous ACh release or occurs as a concomitant event.

Acetylcholine↗
PubMed2000

The temporal factor of change in stressor-strain relationships: a growth curve model on a longitudinal study in east Germany.

Several theoretical models describing how stressor-strain relationships unfold in time (e.g., M. Frese & D. Zapf, 1988) were tested with a longitudinal study, with 6 measurement waves, using multivariate latent growth curve models. The latent growth curve model made it possible to decompose trait and state components of strains and to show that both trait and state components are affected by work stressors. Because East Germany constitutes a high-change environment, it is an appropriate setting in which to study the relationship between work stressors and strains. The results showed that both the state and trait components of strains were affected by stressors. For example, individual trends in uncertainty (stressor) and worrying (strain) were related, whereas worrying also showed a short-term relationship with time pressure (another stressor). In particular, the decomposition into trait and state components was only possible with the growth curve method that was used.

Adolescent↗
PubMed2000

Abnormal transmitter release at neuromuscular junctions of mice carrying the tottering alpha(1A) Ca(2+) channel mutation.

Neurotransmitter release at many synapses is regulated by P/Q-type Ca(2+) channels containing the alpha(1A) pore-forming subunit. Mutations in alpha(1A) cause cerebral disorders including familial hemiplegic migraine (FHM) and ataxia in humans. Tottering (tg) alpha(1A) mutant mice display ataxia and epilepsy. It is not known whether alpha(1A) mutations induce impairment of synaptic function, which could underlie the symptoms of these cerebral disorders. To assess whether alpha(1A) mutations influence neurotransmitter release, we studied P-type Ca(2+) channel-mediated acetylcholine (ACh) release at tg neuromuscular junctions (NMJs) with micro-electrode measurements of synaptic potentials. We found a Ca(2+)-, Mg(2+)- and K(+)-dependent increase of spontaneous ACh release at both homo- and heterozygote tg NMJs. Furthermore, there was increased run-down of high-rate evoked release at homozygous tg NMJs. In isotonic contraction experiments this led to block of synaptic transmission at lower concentrations of the ACh antagonist tubocurarine than were needed in wild-type muscles. Our results suggest that in tg motor nerve terminals there is increased influx of Ca(2+) under resting conditions. This study shows that functional consequences of alpha(1A) mutations causing cerebral disorders can be characterized at the NMJ.

Acetylcholine↗
PubMed2000

Confidence intervals for hidden Markov model parameters.

Three methods for computing confidence intervals (CIs) of hidden Markov model parameters are compared in the context of 'long' time series, T > 100, namely likelihood profiling, bootstrapping and CIs based on a finite-differences approximation to the Hessian. First it is shown that with 'long' time series computing the exact Hessian is not feasible. In simulation studies quadratic and cubic interpolation polynomials for the likelihood profiles are compared. Likelihood profiling and bootstrapping produce similar CIs, whereas the CIs from the finite-differences approximation of the Hessian are mostly too small.

Humans↗
PubMed1999

Miller Fisher anti-GQ1b antibodies: alpha-latrotoxin-like effects on motor end plates.

In the Miller Fisher syndrome (MFS) variant of the Guillain-Barré syndrome, weakness is restricted to extraocular muscles and occasionally other craniobulbar muscles. Most MFS patients have serum antibodies against ganglioside type GQ1b of which the pathophysiological relevance is unclear. We examined the in vitro effects of MFS sera, MFS IgG, and a human monoclonal anti-GQ1b IgM antibody on mouse neuromuscular junctions (NMJs). It was found that anti-GQ1b antibodies bind at NMJs where they induce massive quantal release of acetylcholine from nerve terminals and eventually block neuromuscular transmission. This effect closely resembled the effect of the paralytic neurotoxin alpha-latrotoxin at the mouse NMJs, implying possible involvement of alpha-latrotoxin receptors or associated downstream pathways. By using complement-deficient sera, the effect of anti-GQ1b antibodies on NMJs was shown to be entirely dependent on activation of complement components. However, neither classical pathway activation nor the formation of membrane attack complex was required, indicating the effects could be due to involvement of the alternative pathway and intermediate complement cascade products. Our findings strongly suggest that anti-GQ1b antibodies in conjunction with activated complement components are the principal pathophysiological mediators of motor symptoms in MFS and that the NMJ is an important site of their action.

Animals↗
PubMed1999

Acetylcholinesterase activity of skeletal muscle in a non-immunogenic model for myasthenia gravis in rats.

Myasthenia gravis is caused by an autoimmune attack to acetylcholine receptors of skeletal muscle. Acetylcholine release from motor nerve terminals is upregulated in patients with myasthenia gravis and also in rat "myasthenic" models, dependent on the reduction of the number of acetylcholine receptors. This study addresses the question as to whether at "myasthenic" endplates there are changes in the activity of acetylcholinesterase. To this end we studied acetylcholinesterase activity in junctional and extrajunctional regions of dilator naris, extensor digitorum longus, and hemidiaphragm muscles from rats with alpha-bungarotoxin-induced myasthenia gravis. In all studied muscles from "myasthenic" rats there was no significant change of junctional acetylcholinesterase activity. In contrast, in dilator naris and extensor digitorum longus muscles, there was a 60% and 30% increase of extrajunctional acetylcholinesterase activity. There was no significant change in the extrajunctional activity in hemidiaphragm muscles. Velocity sedimentation analysis revealed that the increase in extrajunctional activity in extensor digitorum longus muscles could be attributed to an increase of the activity of the G4 form of acetylcholinesterase. Treatment of rats with 6.4 microgh(-1) neostigmine bromide for 29 days had no influence on junctional and extrajunctional acetylcholinesterase activity of extensor digitorum longus muscles from rats with alpha-bungarotoxin-induced myasthenia gravis.

Acetylcholinesterase↗
PubMed1999

Monoclonal antibodies raised against Guillain-Barré syndrome-associated Campylobacter jejuni lipopolysaccharides react with neuronal gangliosides and paralyze muscle-nerve preparations.

Guillain-Barré syndrome and its variant, Miller-Fisher syndrome, are acute, postinfectious, autoimmune neuropathies that frequently follow Campylobacter jejuni enteritis. The pathogenesis is believed to involve molecular mimicry between sialylated epitopes on C. jejuni LPSs and neural gangliosides. More than 90% of Miller-Fisher syndrome cases have serum anti-GQ1b and anti-GT1a ganglioside antibodies that may also react with other disialylated gangliosides including GD3 and GD1b. Structural studies on LPS from neuropathy-associated C. jejuni strains have revealed GT1a-like and GD3-like core oligosaccharides. To determine whether this structural mimicry results in pathogenic autoantibodies, we immunized mice with GT1a/GD3-like C. jejuni LPS and then cloned mAb's that reacted with both the immunizing LPS and GQ1b/GT1a/GD3 gangliosides. Immunohistology demonstrated antibody binding to ganglioside-rich sites including motor nerve terminals. In ex vivo electrophysiological studies of nerve terminal function, application of antibodies either ex vivo or in vivo via passive immunization induced massive quantal release of acetylcholine, followed by neurotransmission block. This effect was complement-dependent and associated with extensive deposits of IgM and C3c at nerve terminals. These data provide strong support for the molecular mimicry hypothesis as a mechanism for the induction of cross-reactive pathogenic anti-ganglioside/LPS antibodies in postinfectious neuropathies.

Animals↗
PubMed1998

Acquired slow-channel syndrome: a form of myasthenia gravis with prolonged open time of the acetylcholine receptor channel.

A 32-year-old female presented with a 2-year history of fluctuating generalized weakness including extraocular, bulbar, and limb muscles, suggesting myasthenia gravis, but with poor response to pyridostigmine and unusual electromyographic findings. After rest, power increased on repeated maximal contractions, followed by progressive weakness. There were decremental responses at low-frequency stimulation, but incremental responses at high frequencies, and single stimuli evoked repetitive compound muscle action potentials. Plasmapheresis was ineffective. In a conventional assay, antibodies against acetylcholine receptors (AChRs) were borderline. However, in an assay using cells expressing mainly adult-type human AChRs, the patient's serum was positive. Thymectomy revealed a hyperplastic thymus. An intercostal muscle specimen revealed small miniature end-plate potentials, 0.22+/-0.02 mV instead of 0.56+/-0.05 mV in controls. The number of 125I-alpha-bungarotoxin binding sites was normal. The decay time constant of end-plate potentials was increased from 5.3+/-0.6 msec in controls to 23+/-3.6 msec in the patient. Ultrastructurally, there was no destruction of the end plate. Transfer of the patient's plasma to mice in vivo produced similar physiological changes in their diaphragms. We conclude that the patient has an immune-mediated disorder, in which an antibody specific to the adult form of the AChRs alters the channel properties, reducing total current and slowing the closure. We propose the name "acquired slow-channel syndrome" for this variant of myasthenia gravis.

Adult↗
PubMed1998

Individual differences in P300 amplitude: a genetic study in adolescent twins.

Using quantitative genetic research designs, we decomposed phenotypic variance in P300 parameters into genetic and environmental components. The twin method was used to carry out this decomposition. Event related potentials (ERPs) were measured during a visual oddball paradigm in a sample of 213 adolescent twin pairs. The presence of male and female same-sex and opposite-sex twins in the sample enabled us to study sex differences in the contributions of genetic and environmental effects to P300 parameters. For targets and nontargets, half of the variance in the P300 amplitude is attributable to factors shared by the family members. However, it remains unclear whether this resemblance is attributable to shared environmental or genetic influences. The same factors (genetic or shared environmental) were found to contribute to the individual differences in males and females. The contributions do, however, differ across gender. Multivariate genetic analyses investigated the covariance among various brain areas to determine whether the covariance between two or more leads is attributable to the same genetic and/or the same environmental factors. The covariance of the P300 amplitude measured at different locations was attributable both to unshared environmental and to shared factors. Again it was not possible to show that the shared factors where either genetic or shared environmental.

Adolescent↗
PubMed1998

Genetic and environmental influences on EEG coherence.

EEG coherence measures the covariation in electrical brain activity between two locations on the scalp and is used to study connectivity between cortical regions. The aim of this study was to determine the heritability of EEG coherence. Coherence was measured in a group of 213 16-yr-old twin pairs. By including male and female twin pairs in the sample, sex differences in genetic architecture were systematically examined. The EEG was obtained during quiet supine resting. Coherence was estimated for short and long distance combinations of electrode pairs along the anterior-posterior axis within a hemisphere for four frequency bands (delta, theta, alpha and beta). Averaged over all electrode combinations about 60% of the variance was explained by genetic factors for coherence in the theta, alpha and beta bands. For the delta band, the heritability was somewhat lower. No systematic sex differences in genetic architecture were found. All environmental influences were nonshared, i.e., unique factors including measurement error. Environmental factors shared by twin siblings did not influence variation in EEG coherence. These results suggest that individual differences in coherence form a potential candidate for (molecular) genetic studies on brain function.

Adolescent↗