Focusing versus distraction and the response to clinical electric shocks.

This study pertains to assessing the effects of electric shocks that are used in the treatment of severe self-injurious behavior. With pain sensation and startle response as the dependent variables and focusing versus distraction of recipient's attention to the electric shocks as the independent variable, these stimuli were administered to 60 paid volunteers. Using ANOVA, no significant effect of the independent variable was found on either measure. However, repeated administration of the electric shock produced a significant increment of pain sensation, with a concomitant significant decrease of magnitude of the startle response. No interaction effect was found.

Experienced consent in geriatrics research: a new method to optimize the capacity to consent in frail elderly subjects.

OBJECTIVES: Cognitive and sensory difficulties frequently jeopardize informed consent of frail elderly patients This study is the first to test whether preliminary research experience could enhance geriatric patients' capacity to consent. DESIGN/SETTING: A step-wise consent procedure was introduced in a study on fluid balance in geriatric patients. Eligible patients providing verbal consent participated in a try-out of a week, during which bioelectrical impedance and weight measurements were performed daily. Afterwards, written informed consent was requested. Comprehension, risk and inconvenience scores (ranges: 0-10) were obtained before and after the try-out by asking ten questions about the study's essentials and by asking for a risk and inconvenience assessment on a ten-points rating scale. SUBJECTS AND RESULTS: Seventy of the 78 eligible subjects started the try-out and 53 (68%) provided written consent. The comprehension score increased from 5.0 (+/- 2.3) to 7.0 (+/- 1.9) following the try-out (P < 0.001). The number of subjects capable of weighing risks and inconveniences increased from 32 to 48 (P < 0.001). CONCLUSIONS: Research experience improved the capacity to consent, still enabling an acceptable participation rate. Therefore, experienced consent seems a promising tool to optimize informed consent in frail elderly subjects.

The contribution of risk factors to the effect of early otitis media with effusion on later language, reading, and spelling.

A cohort of 946 children who were screened for otitis media with effusion (OME) from the ages of 2 to 4 were studied for language, reading, and spelling at 7 years of age. The effects of OME in combination with single risk factors and with increasing numbers of risk factors were investigated. An interaction with an additional risk factor was found only for gender and OME, with boys' spelling influenced negatively by a history of OME. OME in combination with preterm birth and low birthweight also appears to put children at risk for later language and educational problems. Although a negative linear relation between the number of risk factors and later functioning was found, it is suggested that OME, even when combined with a number of other risk factors, produces only minor effects on later language, reading, and spelling.

Diagnostic classification by experts and novices.

The present study examines differences between experts and novices in classifying symptoms and the effect of the nature of the task on classifying. The study involved three groups of subjects, two expert groups (n = 12, n = 10) and one novice group (n = 12). Thinking-aloud protocols were collected for two classification tasks: sorting of behavioural symptoms into predefined categories and intuitive clustering of behavioural symptoms. In a third task, experts and novices were asked to make typicality ratings of behavioural symptoms. The protocols were analyzed with respect to seven cognitive operations: (a) asking or giving information, (b) associating, (c) abstracting or labelling, (d) explaining, (e) neutral matching, (f) identifying, and (g) differentiating. Results showed an effect of experience and an effect of the task on the relative frequencies of these operations. No differences were found in typicality rating of experts versus novices. These contradictory findings are discussed in relation to Kolodner's model about the evolution of expertise.

Bimanual simultaneous motor performance and impaired ability to shift attention in Parkinson's disease.

The ability to share time and to shift attention between bimanual simultaneous motor tasks were studied in 18 patients with Parkinson's disease (PD) and 19 age- and intelligence-matched controls. The task consisted of drawing triangles with the dominant hand and squeezing a rubber bulb with the nondominant hand. Motor performance was measured using the variables: amplitude of squeezing, frequency of squeezing and velocity of drawing triangles. After eliminating variance due to baseline differences in single-handed performance, the bimanual simultaneous performance of PD and controls turned out to be similar to the frequency of squeezing and the velocity of drawing triangles. The amplitude of squeezing, however, differed between the two groups: it was significantly reduced in PD. Arguably the disturbance in the bimanual performance of PD patients was not due to a disorder of time sharing, but to a decreased ability to shift attention from the visually cued task to the non visually cued task. The results agree with current evidence that PD patients are more impaired when they have to rely upon internal control for the regulation of shifting attention than when external cues are available.

Neurotoxicological effects and the mode of action of pyrethroid insecticides.

Neuroexcitatory symptoms of acute poisoning of vertebrates by pyrethroids are related to the ability of these insecticides to modify electrical activity in various parts of the nervous system. Repetitive nerve activity, particularly in the sensory nervous system, membrane depolarization, and enhanced neurotransmitter release, eventually followed by block of excitation, result from a prolongation of the sodium current during membrane excitation. This effect is caused by a stereoselective and structure-related interaction with voltage-dependent sodium channels, the primary target site of the pyrethroids. Near-lethal doses of pyrethroids cause sparse axonal damage that is reversed in surviving animals. After prolonged exposure to lower doses of pyrethroids axonal damage is not observed. Occupational exposure to pyrethroids frequently leads to paresthesia and respiratory irritation, which are probably due to repetitive firing of sensory nerve endings. Massive exposure may lead to severe human poisoning symptoms, which are generally treated well by symptomatic and supportive measures.

Haloperidol and cognitive shifting.

In this study haloperidol appeared to affect the performance on a selected category of cognitive tasks considered to represent shifting aptitude. A pretest--post-test design was used with two groups of subjects: 17 patients suffering from idiopathic spasmodic torticollis, and 17 controls who were matched for age and intelligence. The results are discussed in relation to previous findings on haloperidol and cognition, shifting disorder in Parkinson's disease and changes in behavioural organization found in animals with an experimentally induced dopaminergic hypoactivity.

Increase of sodium current after pyrethroid insecticides in mouse neuroblastoma cells.

The effects of 4 different pyrethroid insecticides on sodium channel gating in internally perfused, cultured mouse neuroblastoma cells (N1E-115) were studied using the suction pipette, voltage clamp technique. Pyrethroids increased the amplitude of the sodium current, sometimes by more than 200%. Activation of the sodium current occurred at more hyperpolarized potentials than under control conditions. The declining phase of the sodium current during depolarization was markedly slowed down and after repolarization of the membrane a large, slowly decaying sodium tail current developed. Pyrethroids did not affect the sodium current reversal potential, steady-state sodium inactivation or recovery from sodium channel inactivation. The amplitude of the pyrethroid-induced slow tail current was always proportional to the sodium current at the end of the preceding depolarizing pulse. The rate of decay of the slow tail current strongly depended on pyrethroid structure and increased in the order deltamethrin, cyphenothrin, fenfluthrin and phenothrin. The rate of decay further depended on membrane potential and temperature. Below -85 m V the instantaneous current-voltage relationship of the slow tail current showed a negative slope conductance. The tail current decayed more slowly at low temperatures. Arrhenius plots indicated that the relaxation of open sodium channels to a closed state involved a higher energy barrier for pyrethroid-affected than for normal channels. The energy barrier was higher after deltamethrin than after the non-cyano pyrethroid fenfluthrin. It is concluded that in mammalian neuronal membrane pyrethroids selectively reduce the rate of closing of sodium channels both during depolarization and after repolarization of the nerve membrane.

The dopamine response in mouse neuroblastoma cells is mediated by serotonin 5HT3 receptors.

Serotonin (5HT) and dopamine (DA) induce, in neuroblastoma N1E-115 cells, a transient membrane depolarization associated with an inward current. The half-maximum response is obtained with 2 microM 5HT or 200 microM DA. The maximum response to 5HT is 2-3 times that to DA. The selective 5HT3 receptor antagonists ICS 205-930 and MDL 72222 at nanomolar concentrations block both the 5HT- and the DA-induced response. High concentrations (10 microM) of 5HT2 receptor antagonists are without effect. It is concluded that, in N1E-115 cells, 5HT and DA activate a single population of 5HT3 receptors.

Cognitive and motor shifting aptitude disorder in Parkinson's disease.

Eighteen patients suffering from Parkinson's disease and nineteen control subjects, who were matched for age and intelligence, were compared in tests measuring "shifting aptitude" at cognitive and motor levels (word production, sorting blocks or animals, and finger pushing sequences). It was found that Parkinson patients produced fewer different names of animals and professions in one minute than control subjects, needed more trials for detecting a shift in a sorting criterion, and produced fewer finger responses in a change of pushing sequence than control subjects. These results are interpreted as reflecting a central programming deficit that manifests itself in verbal, figural and motor modalities, that is, a diminished "shifting aptitude" characteristic of patients with dysfunctioning basal ganglia. The results are discussed in relation to changes of behaviour organisations in animals with dysfunctioning basal ganglia.

Temperature- and structure-dependent interaction of pyrethroids with the sodium channels in frog node of Ranvier.

(1) The interaction of a series of pyrethroid insecticides with the Na+ channels in myelinated nerve fibres of the clawed frog, Xenopus laevis, was investigated using the voltage clamp technique. (2) Out of 11 pyrethroids 9 insecticidally active compounds induce a slowly decaying Na+ tail current on termination of a step depolarization, whereas the Na+ current during depolarization was hardly affected. These tail currents are most readily explained by a selective reduction of the rate of closing of the activation gate in a fraction of the Na+ channels that have opened during depolarization. (3) The rate of decay of the Na+ tail current varies considerably with pyrethroid structure. After alpha-cyano pyrethroids the decay is at least one order of magnitude slower than after non-cyano pyrethroids. The decay always follows a single-exponential time course and is reversibly slowed when the temperature is lowered from 25 to 0 degrees C. Arrhenius plots in this temperature range are linear. (4) These results indicate that the relaxation of the activation gate in pyrethroid-affected Na+ channels is governed by an apparent first order, unimolecular process and that the rate of relaxation is limited by a single energy barrier. Application of transition state theory shows that after alpha-cyano pyrethroids this energy barrier is 9.6 kJ/mol higher than after non-cyano pyrethroids. (5) Differences in rate of decay of the Na+ tail current account for the reported differences in repetitive nerve activity induced by various pyrethroids. In addition, the effect of temperature on the rate of decay explains the increase in repetitive activity with cooling.

Annotation. Action of pyrethroid insecticides on the vertebrate nervous system.

The neurotoxic action of the synthetic pyrethroid insecticides has received much interest in recent years, as the number of available pyrethroids and their practical applications have greatly increased. Although the majority of pyrethroids have a low oral toxicity to mammals, they may cause severe neurotoxic symptoms whenever they reach the nervous system in sufficient amount. The principal effect of pyrethroids in the vertebrate nervous system is to induce repetitive activity, particularly in the sensory nervous system. This repetitive activity originates from a prolongation of the transient increase in sodium permeability of the nerve membrane associated with excitation. Available evidence indicates that pyrethroids primarily interfere with the sodium channels in the nerve membrane. All active pyrethroids affect sodium channel gating in a similar manner, but marked differences in neurotoxic activity exist between the various pyrethroids, especially between alpha-cyano and non-cyano compounds.

Evidence for a role of the caudate nucleus in the sequential organization of behavior.

Behavioural effects of the cholinergics carbachol and atropine given by means of telestimulation were studied in small groups of freely moving Java monkeys. The sequential structure of behavior was analyzed by assessing the contribution of the preceding behaviours of the treated monkey and its partners to the subsequent behaviour of the treated monkey, in terms of information-theoretical statistics. Carbachol increased the overall variability of behaviour in the treated monkey, enhanced the dependency between the preceding and subsequent behaviour of the treated monkey, and slightly decreased the dependency between the current behaviour of the treated monkey and the preceding behavior of its partners. Atropine only increased the dependency between the treated monkey's current behaviour and the preceding behaviour of its partners. The morphology of overt behaviour remained unaffected following the chosen treatments. Analysis of changes in the frequencies of behaviours belonging to different motivational categories (maintenance, sex, aggression, submission and affiliation) revealed that, after intracaudate injections, all categories were affected to the same degree; in contrast, amygdala injections only affected the categories 'aggression' and 'submission'. It is concluded that the caudate nucleus establishes the relative priority of intra-individual and inter-individual constraints on the programming of behaviour, thereby providing flexibility in the execution of ongoing behaviour; the caudate nucleus is not primarily involved in motor control, nor in the control of particular categories of behaviour.

Effects of ototoxic antibiotics on sensory hair cell functioning.

The isolated lateral-line organ of Xenopus laevis was used to study reversible effects of low concentrations of aminoglycoside antibiotics on sensory hair cell functioning. Extracellular receptor potentials and single fibre afferent nerve activity were recorded during stimulation of the lateral-line organ with sinusoidal water movements. The results show that dihydrostreptomycin in concentrations between 2.5 and 17.5 micrograms/ml caused an increase in spontaneous afferent nerve activity, probably by increasing the spontaneous transmitter release at the afferent synapse. In addition, the same concentrations of dihydrostreptomycin markedly affected the mechano-electric transduction process, resulting in a phase lag in th receptor potential, the magnitude of which increased with increasing concentration up to a value of 0.4 pi radians. The effect of dihydrostreptomycin on the amplitude of the receptor potentials depended on the stimulus frequency. Other aminoglycoside antibiotics, namely streptomycin, gentamycin and kanamycin, produced similar effects but at different concentrations. It is concluded that low concentrations of aminoglycoside antibiotics have a dual action upon the sensory hair cells. They increase the spontaneous activity by affecting the hair cell membrane and at the same time they impair the mechano-electric transduction process resulting in a large phase lag in the receptor potentials. The latter effect, which is antagonized by Ca2+, may be due to interference by the antibiotics with the mode of motion of the sensory hairs.

Structure and function in neurobiology: a conceptual framework and the localization of functions.

A framework of concepts on structure and function of the nervous system is presented, in which we attempt to formulate the intended meanings of some ambiguous statements on structure and function in neurobiology in a set of strictly defined concepts. Function. The word "function" as generally used has different meanings. Two meanings of the question "What is the function of B?" are particularly relevant for this subject: (1) "What does B do?" and (2) "Why did B evolve?" It is shown that question 1 must be answered before question 2. Function of brain region S. The question "What does brain region S do?" has a meaning identical to the question "What is the relation between inputs and outputs of S, at specified conditions of S?" The answer to this question is the I/O-function. The I/)-function can be described at different levels, for instance at the molecular or cellular level. When neuroscientists ask "What is the function of brain region S?", the intended meaning appears to be either "What is the extra-CNS I/O-function of S?," or "Why did S evolve?" The "extra-CNS I/O-function of CNS subsystem S" is "the I/O-function of S in which input and output elements are outside the CNS". In many cases, neuroscientists want to know the "behavioral I/O-function of CNS subsystem S," i.e., the "I/O-function of S in which input and output elements are outside the organism"; they want to know "what is represented by the inputs of S outside the organism, and what are the effects of the outputs of S outside the organism." Loosely speaking, when a neuroscientist wants to know "the function of brain region S," he wants to know "the meaning of its neural messages, and their behavioral effects." Some examples of generally accepted behavioral I/O-functions of clearly sensory and motor parts of the CNS are presented. Localization of function. The following conclusions are drawn for "localization of function F." (1) "Function F" must be specified as "I/O-function F' " referring to input and output elements outside the CNS. (2) "Localization of I/O-function F' " is a kind of shorthand for "identification of the neural activity representing the states of these input and output elements." (3) If neurons exist whose activity only (or mainly) represents this input ("pontifical cells"), and/or only (or mainly) generates this output ("command neurons") (or, in other words, whose behavioral I/O-function is F'), it might be said metaphorically that "function F is localized in these neurons." In most cases, the existence of such neurons is still on open question.

Frequency-dependent effects of the pyrethroid insecticide decamethrin in frog myelinated nerve fibres.

The pyrethroid insecticide decamethrin (10(-6) M) caused a frequency-dependent depression of the action potential in frog myelinated nerve fibres which was associated with a progressive membrane depolarisation brought about by summation of depolarising after-potentials. Voltage clamp experiments with single nodes of Ranvier showed that this afterpotential was most probably due to a long-lasting prolongation of the transient increase in sodium permeability of the membrane. The results indicate that decamethrin, like the other pyrethroids, specifically affects the sodium channels of the nerve membrane.

Effects of ACTH4-10 on synaptic transmission in frog sympathetic ganglion.

The influence of ACTH4-10, a behaviourally active fragment of adrenocorticotropic hormone (ACTH) devoid of endocrine activity, on synaptic transmission in the paravertebral sympathetic ganglion of the frog was investigated. Postsynaptic potentials evoked by electrical stimulation of pregnanglionic nerves were recorded using a sucrose gap method. Fast excitatory postsynaptic potentials (EPSPs), which are mediated via nicotinic cholinergic synapses, were not affected by 10(-6) M ACTH4-10. Application of ACTH4-10 in a concentration as low as 10(-8) M for 60 min caused a marked augmentation of the amplitude of slow inhibitory postsynaptic potentials (IPSPs) which are mediated via dopaminergic synapses. The increase in amplitude developed gradually after a latency of 60--90 min and outlasted the application of the peptide. In addition, ACTH4-10 at 10(-6) M increased the hyperpolarising response of the ganglion to exogenous dopamine, as studied by a micro-application method. There was no significant effect of ACTH4-10 on the muscarinic cholinergic depolarising response of the ganglion towards exogenous acetylcholine. The behaviourally active vasopressin fragment DG-LVP (10(-6) M) had no effect on slow IPSPs. The results demonstrate that ACTH4-10 specifically affects slow synaptic inhibition in frog sympathetic ganglion, probably by acting upon the postsynaptic membrane. The possibility is discussed that ACTH4-10 affects one of the intermediate steps between dopaminergic receptor interaction and generation of the slow IPSP.