Excitation, inhibition, models, LFP, neurovascular.
This project will address the fundamental question regarding the balance and interaction between neural excitation and inhibition in the intact brain. It will also investigate the dynamic relationship between changes in neural excitation and inhibition, and the ensuing changes in haemodynamic variables.
The proposed mathematical model of neural activity has a framework which is significantly simpler than the existing computational models in the current literature. This means that the model structure can be extended to include cortical depth and surface information, hence the extension to EEG modelling, with much ease compared with those using complex computational neural models. The ability of the model to separate neural recordings into components of excitation and inhibition means that the balance between these components can be monitored even if they cannot be measured directly. Furthermore as EEG is increasingly used for the medical diagnosis of diseases such as epilepsy, the interpretation of EEG in terms of the underlying neural mechanisms will significantly enhance its ability to diagnosis disorders in which the balance between neural excitation and inhibition is interrupted.
A rat model will be used, and the number of animals required under this project is estimated at 500 (maximum) over 5 years.
The animal will be anaesthetised while all physiological variables will be monitored closely to ensure they are within appropriate ranges. Infection is uncommon during surgery and the subsequent experiment. Should complications arise due to infection (<5%), the animal will be euthanised humanely. During the thinned cranial window preparation, small amounts of bleeding may occur from the bone. In most cases the bleeding is insignificant and swabs may be used to clean the surface of the skull. Should the bleeding becomes significant, swabs and bone wax will be used to stop the bleeding after which a layer of cyanoacrylate will be used to stabilise the thinned cranial window. Due to the duration of the experiment and the intervention needed, it will not be appropriate to re-use the animal. Thus the level of severity is non-recovery. At the end of the procedure the animals will be euthanised humanely, or by transcardial perfusion fixation with an appropriate fixative. If any procedural complications do arise veterinary advice will be sought immediately, or the animal will be euthanised humanely.
The proposed electrophysiological experiments and pharmacological intervention cannot be conducted safely in humans. Also in order to investigate haemodynamic responses to neural activity, blood flow and transmural pressure to the cerebral blood vessels must be maintained, hence the ex vivo preparation (e.g. brain slices) will not be suited for this research.
To minimise animal usage, we will use concurrent recordings of neural and haemodynamic signals to establish models of neural activity and of neurovascular coupling, and a repeated measures design, if possible. We will also eliminate as much experimental noise as possible in order to maximise signal to noise ratio, further reducing the number of animals needed per experimental condition. At all stages of the project, we will consult a professional statistician, when required, to ensure an optimal statistical design and the number of animals required is minimised, yet sufficient precision and power are maintained.
A rat model will be used as they have a very well understood cerebral anatomy. Also there exists a wealth of research and data which we can use to compare our results with in the literature. All animals will be under terminal anaesthesia which will be carefully monitored throughout the experiment to ensure that all physiological parameters (e.g., body temperature, heart rate, respiration rate, blood pressure, blood saturation) are within appropriate ranges and are stable to minimise animal suffering. To prevent overheating during drilling, the skull surface will be cooled with saline.