[Auto-immune disorders as a possible cause of neuropsychiatric syndromes]. / Auto-immuunaandoeningen als mogelijke oorzaak van neuropsychiatrische syndromen.

BACKGROUND: Changes that occur in the behaviour of voltage-gated ion channels and ligand-gated receptor channels due to gene mutations or auto-immune attack are the cause of channelopathies in the central and peripheral nervous system. Although the relation between molecular channel defects and clinical symptoms has been explained in the case of many neuromuscular channelopathies, the pathophysiology of auto-immunity in neuropsychiatric syndromes is still unclear. AIM: To review recent findings regarding neuronal auto-immune reactions in severe neuropsychiatric syndromes. METHOD: Using PubMed, we consulted the literature published between 1990 and August 2014 relating to the occurrence of auto-immune antibodies in severe and persistent neuropsychiatric syndromes. RESULTS: Auto-antibodies have only limited access to the central nervous system, but if they do enter the system they can, in some cases, cause disease. We discuss recent findings regarding the occurrence of auto-antibodies against ligand-activated receptor channels and potassium channels in neuropsychiatric and neurological syndromes, including schizophrenia and limbic encephalitis. CONCLUSION: Although the occurrence of several auto-antibodies in schizophrenia has been confirmed, there is still no proof of a causal relationship in the syndrome. We still have no evidence of the prevalence of auto-immunity in neuropsychiatric syndromes. The discovery that an antibody against an ion channel is associated with some neuropsychiatric disorders may mean that in future it will be possible to treat patients by means of immunosuppression, which could lead to an improvement in a patient's cognitive abilities.

Abnormal myotonic dystrophy protein kinase levels produce only mild myopathy in mice.

Myotonic dystrophy (DM) is commonly associated with CTG repeat expansions within the gene for DM-protein kinase (DMPK). The effect of altered expression levels of DMPK, which is ubiquitously expressed in all muscle cell lineages during development, was examined by disrupting the endogenous Dmpk gene and overexpressing a normal human DMPK transgene in mice. Nullizygous (-/-) mice showed only inconsistent and minor size changes in head and neck muscle fibres at older age, animals with the highest DMPK transgene expression showed hypertrophic cardiomyopathy and enhanced neonatal mortality. However, both models lack other frequent DM symptoms including the fibre-type dependent atrophy, myotonia, cataract and male-infertility. These results strengthen the contention that simple loss- or gain-of-expression of DMPK is not the only crucial requirement for development of the disease.

Cross-sectional and longitudinal correlations between the Arm Function in Multiple Sclerosis Questionnaire (AMSQ) and other outcome measures in multiple sclerosis.

BACKGROUND: The Arm Function in Multiple Sclerosis Questionnaire (AMSQ) is the first validated disease specific patient-reported outcome measure (PROM) designed to assess upper extremity function in patients with multiple sclerosis (MS). OBJECTIVE: To determine correlations between the AMSQ and established physician- and performance based outcome measures. METHODS: In a cross-sectional cohort of 533 patients correlations between the AMSQ and the Expanded Disability Status Scale (EDSS), its functional systems, the 9-Hole Peg Test (9-HPT) and the Timed-25 Foot Walk (T25FW) were determined. Subgroup analyses were performed as well. Also, correlations were determined in 110 of 533 patients with available longitudinal data. RESULTS: Strongest correlations were found in the cross-sectional cohort between the AMSQ and the EDSS (ß 0.60, p<.001), the 9-HPT dominant hand (ß 0.52, p<.001) and 9-HPT non-dominant hand (ß 0.46, p<.001), the Pyramidal (ß 0.57 p<.001) and the Cerebellar functional system (ß 0.54, p<.001) of the EDSS. CONCLUSION: The moderate correlations between the AMSQ and several established physician- and performance based outcome measures underline that the AMSQ, an easily at long-distance administrable PROM, could be considered as a reliable outcome measure for the monitoring of MS in daily practice. Additional research is needed to support these findings.

Increased noise level of purkinje cell activities minimizes impact of their modulation during sensorimotor control.

While firing rate is well established as a relevant parameter for encoding information exchanged between neurons, the significance of other parameters is more conjectural. Here, we show that regularity of neuronal spike activities affects sensorimotor processing in tottering mutants, which suffer from a mutation in P/Q-type voltage-gated calcium channels. While the modulation amplitude of the simple spike firing rate of their floccular Purkinje cells during optokinetic stimulation is indistinguishable from that of wild-types, the regularity of their firing is markedly disrupted. The gain and phase values of tottering's compensatory eye movements are indistinguishable from those of flocculectomized wild-types or from totterings with the flocculus treated with P/Q-type calcium channel blockers. Moreover, normal eye movements can be evoked in tottering when the flocculus is electrically stimulated with regular spike trains mimicking the firing pattern of normal simple spikes. This study demonstrates the importance of regularity of firing in Purkinje cells for neuronal information processing.

A relative weak leg muscle in the rolling Nagoya mouse as a model for Lambert-Eaton myasthenic syndrome.

The Lambert-Eaton myasthenic syndrome (LEMS) is caused by auto-antibodies that affect the activity of presynaptic calcium channels at the neuromuscular junction. Weakness in LEMS is particularly affecting the legs. Here we used leg muscles from the rolling Nagoya (RN) mouse with a R1262G mutation in the alpha-1 subunit of the P/Q-type (Ca(v)2.1) calcium channel. We found that in homozygote flexor digitorum brevis (FDB) muscles the contractions by single pulses, expressed as relative to contractions by direct stimulation, were smaller (43%) than in controls (94%) with 0.5 mM Ca(2+) in the medium. In both homozygote RN and control animals the contractions of the FDB by single pulses were affected more than the corresponding contractions of the diaphragm; RN muscles with 0.5 mM Ca(2+), FDB 42% and Dia 91%, respectively; control muscles with 0.25 mM Ca(2+), FDB 9% and Dia 39%, respectively. At 40 Hz stimulation this difference was 35% and 76% with 0.35 mM Ca(2+). In RN and control mice both muscles were about equally sensitive to 200 and 400 microM tubocurarine. The results suggest that leg weakness in LEMS may result from a relatively small safety factor of neuromuscular transmission and that this could become particularly prominent when the activity of calcium channels is diminished.

Optimal control of psychological processes: a new computational paradigm.

In this paper, we use general mathematical-statistical theorems to prove that developmental processes must be studied at the intra-individual level. We demonstrate how to model intra-individual variation using single-participant time series analysis with time-varying parameters. We use advanced signal analysis techniques based on nonlinear state-space modeling to present simulation results obtained with a new Maximum Likelihood technique based on Extended Kalman Filtering with Iteration and Smoothing (EKFIS) embedded in an Expectation Maximization (EM) loop. After showing how EKFIS results yield state-space models with time-varying parameters, we then couple EKFIS to recursive optimal control techniques to produce a receding horizon feedback-feedforward controller. In this way, we obtain a flexible on-line computational paradigm with which we can optimally control observed behavioral processes for an individual person in real time. We will present optimal control techniques using simulated data and outline preliminary applications to real time patient-specific treatment of type I diabetic patients and asthma patients.

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.

The future of dynamic factor analysis in psychology and biomedicine.

The currently dominant approach to statistical analysis in psychology and biomedicine is based on analysis of inter-individual variation. Differences between subjects drawn from a population of subjects provide the information to make inferences about states of affairs at the population level (e.g., mean and/or covariance structure). Recently it has been shown that in general the inferred states of affairs at the population level do not apply at the level of intra-individual variation characterizing the life trajectories of individual subjects making up the population. This is a direct consequence of the so-called classical ergodic theorems of Birkhoff and Wiener which has important implications for the way in which psychological and biomedical processes have to be analyzed. The classical ergodic theorems are introduced below in order to show the necessity of using an alternative approach which is valid for the analysis of intra-individual variation. This approach has to be based on single-subject time series analysis. Next an overview is presented of dynamic factor models for the analysis of multivariate time series and the various ways to fit these models to the data. We then turn to an empirical application of factor analysis of personality data obtained in a replicated time series design, showing substantial heterogeneity in intra-individual factorial personality structure. The next topic is entirely innovative--for the first time I present my new dynamic factor model for the analysis of nonstationary time series. In the conclusion I will sketch some biomedical research initiatives in which this new model will be used.

Eaton-Lambert syndrome: acetylcholine and choline acetyltransferase in skeletal muscle.

In biopsied intercostal muscle from six patients with Eaton-Lambert syndrome, we measured acetylcholine content and release and choline acetyltransferase. Both the spontaneous and the KCl-evoked release of acetylcholine were abnormally low. On the other hand, the acetylcholine content and the level of choline acetyltransferase activity were within the range of values earlier found in healthy human intercostal muscle. These results are consistent with the view that the defect in this syndrome lies not in the synthesis or storage of the transmitter but in the mechanism of release itself.

Congenital paucity of secondary synaptic clefts (CPSC) syndrome in 2 adult sibs.

We studied 2 elderly sibs with a congenital form of myasthenia who had ptosis since early childhood. The extraocular muscles were weak and the proximal limb muscles became slowly weaker throughout life. Laboratory investigations of biopsies of intercostal muscle from these patients showed the following abnormalities: the amplitude of miniature end-plate potentials was small and the binding of 125I-alpha-bungarotoxin at the end-plate area was reduced, suggesting a considerable reduction of acetylcholine receptors (AChRs). Secondary synaptic clefts were scarce, whereas the number of end-plates per muscle fiber was increased. There was no indication of impaired transmitter release as the quantal content was within the range of controls. We conclude that these patients suffered from the congenital paucity of secondary synaptic clefts (CPSC) syndrome, described recently in 2 cases of myasthenic children, and suggest that the CPSC syndrome is a developmental disorder in which a deficiency of AChRs may be caused by a decreased clustering or insertion of AChRs. The increased number of end-plates per muscle fiber in both patients could serve as a compensatory mechanism.

Stagewise cognitive development: an application of catastrophe theory.

In this article an overview is given of traditional methodological approaches to stagewise cognitive developmental research. These approaches are evaluated and integrated on the basis of catastrophe theory. In particular, catastrophe theory specifies a set of common criteria for testing the discontinuity hypothesis proposed by Piaget. Separate criteria correspond to distinct methods used in cognitive developmental research. Such criteria are, for instance, the detection of spurts in development, bimodality of test scores, and increased variability of responses during transitional periods. When a genuine stage transition is present, these criteria are expected to be satisfied. A revised catastrophe model accommodating these criteria is proposed for the stage transition in cognitive development from the preoperational to the concrete operational stage.

Effect of ephedrine on muscle weakness in a model of myasthenia gravis in rats.

In addition to therapy with anticholinesterases, ephedrine is sometimes used to improve muscle strength in myasthenia gravis, with variable results. The efficacy of ephedrine was tested in rats with a alpha-bungarotoxin-induced model of myasthenia gravis. The rats showed a drooping lower lip and impaired capability of drinking. Injections of neostigmine caused an improvement of the position of the lip. Ephedrine caused some improvement. However, ephedrine had no effect, either on the lower lip or on water consumption, when the sleep-wake cycle was reversed and the rats had their active period during day time. It was concluded that the effect of ephedrine was unspecific and probably due to arousal from drowsiness. The results suggest, therefore, that the variability of the effect of ephedrine in myasthenic patients is unrelated to neuromuscular transmission per se but rather due to a difference in susceptibility to arousal.

Stimulation by atropine of acetylcholine release and synthesis in cortical slices from rat brain.

1. Cortical slices from rat brain were incubated in media containing the irreversible cholinesterase inhibitor soman and a high KCl concentration, and the release and synthesis of acetylcholine (ACh) were determined.2. Atropine enhanced the release and synthesis of ACh.3. Tetrodotoxin, a substance which blocks nervous conduction, did not influence the release and synthesis of ACh, in the absence or in the presence of atropine. Therefore the nerve endings are probably the site at which atropine acts when stimulating the release and synthesis of ACh.4. Pretreatment of the slices with botulinum type A toxin partially blocked the release and synthesis of ACh and reduced the extra amounts of ACh released and synthesized under the influence of atropine.5. Lowering the calcium or raising the magnesium concentration in the incubation medium reduced the release and synthesis of ACh and their enhancement by atropine.6. Physostigmine decreased the total extractable ACh content of the slices during incubation in a 25 mM KCl containing medium. This decrease was nearly prevented when the release and synthesis of ACh were inhibited by omission of the calcium ions from the medium, but was enhanced by atropine.7. The observations made with pretreatment by botulinum type A toxin, with changes in the calcium and magnesium concentration as well as with physostigmine, all support the theory that it is primarily the release of ACh which is enhanced by atropine and that its stimulating action on the synthesis results from the increased release.

Preferential release of newly synthesized 3 H-acetylcholine from rat cerebral cortex slices in vitro.

1. Slices of rat cerebral cortex after treatment with the irreversible cholinesterase inhibitor soman, were incubated for 5 min in a Krebs-Henseleit solution containing 25 mM KCl and (3)H-choline. Subsequently incubation was continued in a medium containing non-radioactive choline and this medium was replaced at 5 min intervals. The amounts of labelled and total acetylcholine (ACh) released into the medium and extracted from the slices were determined at intervals.2. After the initial 5 min contact with (3)H-choline, 44% of the newly synthesized ACh contained a choline moiety originating from the choline in the medium. During the initial 5 min and the subsequent incubation part of the labelled ACh was released. While the rate of total ACh release remained constant, that of the release of labelled ACh was highest in the 5 min period following the initial incubation with (3)H-choline and then declined exponentially.3. The ratio of labelled ACh/total ACh in the ACh released during the initial 5 min incubation with (3)H-choline and during the subsequent 5 min was about three times as high as that in the ACh extracted from the slices at the end of these incubation periods.4. The ratio of labelled ACh/total ACh in superficial layers of the slices was not higher than that in the total slices.5. The rates of release of labelled and unlabelled ACh decreased when calcium was omitted from the incubation medium and were restored when the calcium was added. This suggests that both labelled and unlabelled ACh were released from nerve endings. The efflux of (3)H-choline was not calcium dependent.6. It is concluded that labelled ACh newly synthesized from externally applied (3)H-choline does not exchange immediately with all other ACh in the tissue and has a greater chance of being released than unlabelled ACh.

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.

Recovery of acetylcholine release and choline acetyltransferase activity after freezing-induced degeneration of rat soleus muscle.

In order to study the effect of synaptic contact on the amounts of choline acetyltransferase (ChAT) and acetylcholine (ACh) in the nerve terminals and on their ability to release ACh, a freeze-thaw procedure was developed as a means to induce long lasting degeneration of rat soleus muscle. It was found that 4 days after the freeze thaw procedure the preparation did not contract upon direct electric stimulation and the level of creatine kinase (CK) was below detection. The preparation contained about 15% of the ChAT activity and 15% of the ACh content of the controls. The ACh release evoked by 50 mM KCl was 25% of controls, but it was, when expressed as a fraction of the ACh content, about twice as high as that in control muscles. At day 12, the preparation still did not contract and the level of CK was less than 5% of controls. The ChAT activity and the ACh content were 40% and 20% of controls, respectively. However, no release of ACh could be evoked by 50 mM KCl. At days 28 and 58 the preparation contracted upon stimulation of the nerve; the CK activity had recovered to about 20% and the ACh content to 40%, while the ChAT activity did not increase above 40%. The KCl-evoked ACh release had recovered to 20-30% of controls. The results indicate that freezing destroyed muscle cells and most intramuscular nerve branches. Subsequent regeneration of muscle fibres was slow, probably because freezing had killed many satellite cells in the muscle. Because the ChAT activity at day 12 had recovered when CK was almost absent and the preparation failed to contract, we conclude that there was expression of ChAT activity in 'nerve terminals' which do not make contact with regenerated muscle cells, although little if any ACh was released from these sites.

A congenital myasthenic disorder with paucity of secondary synaptic clefts: deficiency and altered distribution of acetylcholine receptors.

Congenital myasthenia (CM) constitutes a heterogeneous group of disorders with different underlying defects. The authors investigated a case of CM, presenting with congenital contractures. Endplate studies in the first year of life showed a developmental disorder of postsynaptic membranes. Clinical follow-up demonstrated a beneficial effect of pyridostigmine, resulting in normal motor development. Results of a second biopsy at age 4 are reported in this paper. Microelectrode study showed small Mepp amplitudes, which returned to nearly normal in the presence of neostigmine. In the electronmicroscope the postsynaptic membranes showed a paucity of infoldings, as in the first biopsy. These membranes showed only scanty, patchy enhancement with two different methods for localization of AChR. The extrajunctional membranes showed evidence of local presence of AChR. Our results show a developmental disorder of postsynaptic membranes with a deficiency and altered distribution of AChRs.

Effect of potassium propionate on free and bound acetylcholine in frog muscle.

Frog sartorius muscles were homogenized under various conditions which allowed, by means of mass spectrometry, the measurement of total ACh, and different ACh compartments in the tissue: 'bound', 'free-1' and 'free-2' ACh. Bound ACh presumably corresponded to the vesicular compartment, and the free-1 and free-2 fractions to the cytoplasmic compartments of ACh. Stimulation of ACh release by La3+ ions for 60 min caused a decrease of both bound and free-2 ACh, but at 20 min bound ACh was reduced much more than free-2 ACh. Stimulation of ACh release by isotonic potassium propionate (KPr) solution for only 5 min caused a decrease of bound ACh, in contrast to free-1 and free-2 ACh which were not significantly changed. When muscles after 5 min stimulation in KPr were allowed to recover in normal Ringer, free-1 ACh did not change, but free-2 and bound ACh increased; after 180 min in Ringer bound ACh had recovered to control values. When ACh synthesis was prevented by hemicholinium-3 during recovery of the muscles in Ringer, bound ACh increased at the expense of free-2 ACh. In deuterium labeling experiments, in which the Ringer contained choline-d9, much more ACh-d9 was formed in stimulated than in unstimulated muscles. It appeared that almost all newly formed ACh was ACh-d9, since no significant synthesis of unlabeled ACh (ACh-d0) took place. Yet again, the amount of bound ACh-d0 significantly increased, apparently at the expense of preformed free-2 ACh-d0.(ABSTRACT TRUNCATED AT 250 WORDS)

A non-immunogenic myasthenia gravis model and its application in a study of transsynaptic regulation at the neuromuscular junction.

A non-immunological model for myasthenia gravis was developed in rats: 'toxin-induced myasthenia gravis'. Rats were injected once every 48 h with 3-5 micrograms alpha-bungarotoxin for periods of up to 5 weeks. This treatment caused weakness, especially of facial muscles. Respiration, however, was unaffected. Miniature endplate potentials and 125I-alpha-bungarotoxin binding in the extensor digitorum longus muscles were severely reduced. Acetylcholine release evoked by electrical and chemical (50 mM KCl) stimulation was higher in diaphragms from alpha-bungarotoxin-treated rats than in those from control animals. Histological investigation of the tibialis anterior muscle provided no evidence that the endplates were enlarged. It is concluded that the activity of acetylcholine receptors influences the rate of transmitter release in the neuromuscular junction and it is suggested that a transsynaptic regulation process may be active in myasthenia gravis. The present animal model for myasthenia gravis seems very suitable for studying such a regulation of transmitter release.

Potassium propionate causes preferential loss of 'bound' acetylcholine in frog muscle.

Bound and free acetylcholine (ACh) were measured in frog sartorius muscles by mass fragmentography. Upon incubation of the muscles for 5 min with potassium propionate, which stimulated the release of ACh, there was a 2-fold reduction of bound ACh. In contrast, the amount of free ACh remained unchanged. After 65 min recovery from stimulation in normal Ringer solution containing deuterium-labelled choline, free ACh was labelled to a higher degree than bound ACh. The results are in agreement with the idea that ACh is synthesized in the cytoplasmic compartment of the motor nerve terminal, and subsequently transferred to the vesicles from which it is released upon stimulation.