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An integrated system for video and telemetric EEG recording, measuring beavioural and physiological parameters, as a tool in safety pharmacology testing for assessing CNS-side effects
Get PDFLa valutazione combinata ed integrata della fisiologia e del comportamento permette una completa e coerente valutazione pre-clinica delle funzioni del sistema nervoso centrale. E’ stato sviluppato un sistema integrato di elettroencefalografia per via telemetrica e di video (Video-tEEG), che permette la registrazione simultanea e continua per lunghi periodi delle tracce EEG e delle immagini video. La presente ricerca e’ stata focalizzata sul set-up strumentale e sulla messa a punto della tecnica chirurgia per la registrazione combinata dei segnali EEG corticale, EEG ippocampale e elettromiogramma (EMG) mediante telemetria nel ratto. Il recupero post-operatorio degli animali e’ stato monitorato per periodi di 24 ore circa in occasione del Giorno 1, 6 e 15 dopo la chirurgia, mediante la registrazione delle trace EEG e dell’attivita’ motoria generale utilizzando i video. I risultati ottenuti suggeriscono che la tecnica chirurgica applicata per l’impianto del trasmettitoro telemetrico consente un recupero graduale degli animali entro 15 giorni dall’intervento chirurgico. Durante tutto il periodo di recupero post-chirurgico, i paramateri comportamentali e locomotori non hanno messo in evidenza cambiamenti del ritmo circadiano-giornaliero di buoi-luce e ritornano ai loro valori basali entro un periodo di 15 giorni. Utilizzando una connessine meccanica tra l’elletrodo penetrante in area profonda del cervello e l’elettrodo telemetrico, il sistema e’ in grado di acquisire segnali di EEG ippocampale di buona qualita’ a partire da 15 giorni dopo l’impianto. La ricerca ha dimostrato il possibile uso di questa tecnica di impianto chirurgico e l’applicazione del sistema integrato di Video-tEEG in diverse aree di ricerca pre-clinica compresa la Safety Pharmacology, con vantaggi per un uso etico degli animali nella ricerca.The combined evaluation of physiology and behaviour allows a complete and comprehensive pre-clinical assessment of central nervous system (CNS) functions. An integrated video-telemetric electroencephalography (Video-tEEG) system, which allows the simultaneous and continuous recording of EEG and video images for long periods, was developed. This research work focuses on the equipment set-up and surgical methodology for combined recording of cortical, hippocampal EEG and electromyogram (EMG) waveforms by telemetry in freely moving rats. The post-operative recovery of animals was monitored by recording of EEGs and the general activity by videos for approximately 24 hours on Day 1, 6 and 15 after surgery. The results suggest that the applied surgical technique for the implantation of telemetric transmitter allows a gradual recovery of animals within 15 days. During all the recovery period the behavioural and locomotor parameters showed that there were no changes of the light-dark circadian cycle and they return to background values within a 15-day period. Using a mechanical connection between the deep and the telemetric electrodes, the recording system is able to acquire hippocampal EEG of good quality starting from 15 days after surgical implantation. The present research work demonstrated the possible use of this surgical technique and the application of the integrated Video-tEEG system in different pre-clinical research areas and also in Safety Pharmacology, with advantages for an ethical use of animals
Neurobehavioural Assessment in Preclinical Species: Rodents, Dog and Monkeys
No full textUnwanted side-effects on the nervous system are occasionally seen both in clinical trials of new drugs, and during therapeutic use of marketed products. Most of the common adverse effects in humans are not easily identifiable in pre- clinical species. This area of safety is therefore of particular importance in the assessment of new potential pharmaceutical compounds and it has been included as part of the “core battery’ of assessment of vital organ functions in the ICH S7A safety pharmacology guidance document. The so called “Irwin test” was initially introduced as a rapid psychotropic screening procedure adapted from observations described first by Irwin in mice. Following modification Functional Observational Batteries (FOBs) were developed for use in other rodents and more recently adapted for use in the most common non-rodent species used in pharmaceutical development, which are usually the dog or the monkey. It is of particular importance when assessing neurobehaviour to carefully control and to standardise all factors involved in the test (the animal, the observer, the observation battery and environmental conditions) to make these data objective, repeatable and relevant for the species.
Detailed neurobehavioural observation batteries were developed for use in pre- clinical species: rodents (rats and mice), dogs and non human primates. The rodent FOB assesses such functions as home cage and open field activity, stimulus reactivity, and neuromuscular functions. The dog FOB is focused on the interaction with humans and emphasises evaluation of gait, postural reactions and reflex functions. The monkey FOB has been developed from rodent and dog FOBs and it is considered to be the most suitable assessment when effects on higher-level cognitive and behavioural processes are expected with a direct relevance for humans. However some points such as social variables, ethical issues and costs need to be taken into account
An Optimized Methodology for the Neurobehavioural Assessment in Rodents
No full textIntroduction: The most widely used test to identify undesired effects of drugs on the central and the peripheral nervous system is the neurobehavioural observation battery adapted from that first described by Irwin in mice. As a neurobehavioural assessment is based on observations; thus, all factors involved need to be controlled and standardised to make the data collected objective, reproducible, reliable and predictive of safety liabilities. Methods: An observation battery comprising 58 signs with assigned full details of numerical scores was defined, and a standard design with associated recording, presenting and analysing data system was established. Validation studies were conducted with chlorpromazine, amphetamine, diazepam or clonidine given orally to rats or mice, in order to assess if this methodology could clearly differentiate the profile of effects produced by these compounds. The analysis of data from 80 control rats allowed for the assessment of the normal behaviour in order to characterise the inter-individual, daytime-related variability and the habituation of animals to the procedure. Results: The reference compounds induced their typical and expected transient effects on neurobehaviour, observed both in the home cage and open-arena, and on body temperature. In particular, amphetamine induced a stimulation of the nervous system activities and marked hyperthermia. Chlorpromazine, diazepam and clonidine induced depressive, anxiolytic or sedative effects associated with hypothermia. The analysis of data collected in control animals allowed for the identification of 6 signs which scored differently from the assigned normality at the first handling occasion due to the characteristic fear reactions to the unknown, and 9 signs at 8 h post-dose due to the animal's habituation to experimental conditions and handling. Discussion: The neurobehavioural changes expected by reference compounds administration were detected. These results confirm that by using this methodology the normal behaviour of the rat and the mouse, the daytime-related variability and the habituation of animals can be characterised, allowing a refined, reliable and reproducible neurobehavioural assessment of test substances in rodents
A canine model used to simultaneously assess potential neurobehavioural and cardiovascular effects of candidate drugs
No full textIntroduction
Unwanted effects of drugs on neurobehavioural and cardiovascular functions are normally assessed in separate studies and using different animals. A new model using dogs which allows for the integration of these assessments into a single study was established and validated, adopting the most sophisticated technologies for both monitoring behaviour by video recordings and cardiovascular parameters by telemetry.
Methods
Conscious male beagle dogs (n = 4) were given single oral doses of vehicle, and d-amphetamine (0.25, 0.75, 1.5 mg/kg) or acepromazine (0.05, 0.3, 2 mg/kg) within two different studies. Blood pressure, heart rate, electrocardiogram (EKG), body temperature, motor activity and behaviour (by video) were monitored continuously for 24 h post-dose. Animals underwent a full neurobehavioural examination the day before dosing, at the time to the maximal plasma concentration (Tmax) and 24 h post-dose.
Results
d-Amphetamine: a dose-dependent increase in arterial blood pressure was noted at all doses and was generally associated with an increase in the QA interval, an index of cardiac contractility. Heart rate also increased but only at the 1.5 mg/kg dose. A dose-dependent general excitatory state of the nervous system was observed, characterised mainly by hyper-reactivity, and stereotyped activities. Acepromazine: a decrease in systolic blood pressure was detected at 0.3 and 2 mg/kg generally associated with a decrease in pulse pressure reflecting a negative inotropic effect. A dose-related increase in heart rate accompanied this effect. Dose-dependent general depression of the nervous system was noted; mainly characterised by half-closed eyes, subdued behaviour and impaired posture. In both studies, all dogs completely recovered at approximately 16 h after treatment.
Discussion
Cardiovascular and neurobehavioural changes expected from the pharmacology of test substances were accurately detected. No significant fluctuations of the telemetric parameters recorded were noted as a consequence of the handling associated with the direct neurobehavioural examination. These results confirm the validity of this combined model capable of providing a reliable neurobehavioural and cardiovascular assessment of drugs
An optimised neurobehavioural observation battery integrated with the assessment of cardiovascular function in the beagle dog
No full textIntroduction
The objective of this study was to describe an optimised neurobehavioural observation battery in the beagle dog and to demonstrate that it can be used for an integrated assessment of cardiovascular and neurobehavioural functions within a single Safety Pharmacology study.
Methods
A standardised and detailed observation battery was established based on the direct examination of 44 signs, including behavioural responses and a full, systematic neurological examination, using clearly defined numerical scores. To complete the neurobehavioural assessment the remote observation of animals by video recording was also performed. Results from two studies, where cardiovascular and neurobehavioural parameters were assessed using drugs that either showed or did not show cardiovascular effects, are presented to show the influence of the direct neurobehavioural exam on the telemetrically acquired cardiovascular parameters.
Results
Heart rate and systolic blood pressure were affected by the handling required for the neurobehavioural procedure for a total of approximately 25 min, consisting in 20 min needed for the sequential neurobehavioural observation of four dogs (requiring approximately 5 min each) and approximately 5 min to return to baseline. Drug related cardiovascular effects were not affected by the changes associated with these neurobehavioural observations. More evident cardiovascular changes were observed with other routine procedures such as feeding.
Discussion
The direct neurobehavioural examination caused fluctuations of the telemetric cardiovascular parameters for no more than 5 min from the end of the procedure and this did not alter or jeopardise the analysis and interpretation of the cardiovascular parameters. These results confirmed that this optimised neurobehavioural observation battery can be used in the beagle dog for a reliable integrated assessment of neurobehavioural and cardiovascular changes during the course of Safety Pharmacology evaluations
An integrated cardiovascular and neurobehavioural functions assessment in the conscious telemetered Cynomolgus monkey
No full textIntroduction
Unwanted effects of drugs on neurobehavioural and cardiovascular functions are normally assessed in separate studies and using different animals. The purpose of this study was to validate, in the monkey, a model that incorporates the neurobehavioural assessment into the Safety Pharmacology cardiovascular study, allowing for an integrated evaluation of these two physiological systems.
Methods
Conscious male cynomolgus (Macaca fascicularis) monkeys (n = 4) were given single oral doses of vehicle, d-amphetamine (0.5, 1 and 2 mg/kg) or diazepam (0.5, 1 and 2.5 mg/kg) in a dose-escalation study design. Blood pressure, heart rate, electrocardiogram (ECG), body temperature, locomotor activity and behaviour (by video) were monitored continuously for 24 h post-dose. Animals underwent a standardised neurobehavioural test battery which allowed the direct examination of 31 signs, including behavioural responses and neurological examinations, conducted the day before dose, at maximal plasma concentration time (Tmax), and 24 h post-dose. The study was carried out in a first phase with telemetric cardiovascular recording only, and a second phase with telemetric cardiovascular recording and neurobehavioural observations. Results from the second phase of the study were used to evaluate the influence of the direct neurobehavioural examination on the telemetrically acquired cardiovascular parameters.
Results
The expected cardiovascular and neurobehavioural changes, based on the pharmacological properties of the compounds tested, were accurately detected. In the second phase of the study the direct neurobehavioural examination caused fluctuations of the telemetric cardiovascular parameters for no more than 20 min from the end of the procedure and this did not alter or jeopardise the analysis and interpretation of the cardiovascular parameters.
Discussion
These results confirm the validity of this combined model capable of providing in the cynomolgus monkey a reliable and reproducible neurobehavioural and cardiovascular assessment of candidate drugs during the course of safety pharmacology evaluations
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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