Understanding neural excitation and inhibition: implications for the interpretation of extracellular field potentials and neurovascular coupling

The balance between neural excitation and inhibition is crucial to normal brain function. Impairment in this balance has been shown to be related to many neurological and neurodegenerative diseases such as epilepsy, autism, Parkinson's, Alzheimer's and schizophrenia. 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 such as blood flow, volume and oxygenation. Importantly, by separating components of neural excitation and inhibition, we will investigate how haemodynamic variables change as the balance between these two neural components is shifted. This marks a significant departure from the conventional approach which treats the measured neural signal from Electroencephalography (EEG) or micro-electrodes as representative of 'neural activity'. Preliminary work by us [1] has shown that it is possible to decompose the measured neural signal from extracellular recordings into components of excitation and inhibition.
Based on our preliminary work, the proposed research will (1) investigate to what extent the extracellular field potentials measured by a micro-electrode and non-invasive scalp EEG can be used to identify underlying neural excitatory and inhibitory components; and (2) investigate how the haemodynamic changes typically used by functional magnetic resonance imaging (fMRI) techniques are related to neural excitation and inhibition.
In order to achieve the stated objectives, we will combine mathematical modelling approaches with carefully designed physiological experiments which measure, concurrently, neural and haemodynamic responses in vivo from the somato-sensory cortex of the anaesthetised rodent. The advantage of using concurrent measurements is the reduction in the number of animals required to complete the study. Data from these experiments will not only inform the structure of the mathematical model but also validate the model predictions.
Achieving the first objective will have a direct impact on the interpretation of EEG signals and its potential applications. Specifically, if scalp EEG can be used to monitor the balance between neural excitation and inhibition of cortical neural population(s), it will become a powerful tool for the earlier diagnosis of various disorders in which the balance between neural excitation and inhibition is interrupted.
The achievement of the second objective will lead to enhanced interpretation of haemodynamic signals measured by optical imaging techniques and fMRI, the latter being widely used in human subjects for understanding the neural correlates of various cognitive processes. By linking the haemodynamic response to neural excitation and inhibition, which underpin its generation, we hope to establish a coherent explanation for the neural correlates of the haemodynamic signal. Thus the outcome of this research will directly inform the interpretation of fMRI signals.

1. Y Zheng, J. J. Luo, S. Harris, A. Kennerley, J. Berwick, S. Billings, J. Mayhew. (2012). "Balanced excitation and inhibition: model based analysis of local field potentials", submitted to NeuroImage, under second revision.

The proposed research aims to 1) establish that local field potentials (LFPs) can be used to identify the underlying neural excitatory and inhibitory components; and 2) investigate how haemodynamic signals are related to neural excitation and inhibition. These can be achieved by establishing mathematical models of neural and haemodynamic responses, and by carefully designed physiological experiments to disrupt the proportional balance between excitation and inhibition in the somatosensory cortex of anaesthetised rodent. We will use intracellular models of synaptic activity to provide insights to the relationship between the excitatory and inhibitory synaptic conductances and post-synaptic currents (PSCs). Key to this relationship is the intracellular finding that excitatory and inhibitory conductances are co-tuned and temporarily shifted, thus imposing similar constraints on the PSCs. The structure of the LFP model will allow PSCs in different cortical layers to be estimated base on the law of charge conservation. To evaluate the LFP model, we will inject the GABAA antagonist bicuculline to the contra-lateral and ipsi-lateral barrel cortex in succession. This will eliminate the inhibitory post-synaptic activity in the drug-affected region, making it possible to examine, in isolation, the evoked excitatory synaptic activity as measured by LFP in both the contra-lateral and ipsi-lateral barrel cortex. In order to investigate the coupling between neural excitation and inhibition and the ensuing haemodynamic responses, physiological data will be collected under three modalities concurrently: electrophysiology, laser Doppler flowmetry and optical imaging spectroscopy. An existing neurovascular coupling model will be combined with the LFP model to provide a coherent account of the coupling between the haemodynamic variables and neural excitation and inhibition. The outcome of the research will have the potential to provide better interpretation of EEG and fMRI signals.

The nature of the proposed research is multi-disciplinary, requiring in depth knowledge and understanding in mathematical modelling, neuroscience and neurophysiology. Thus the immediate beneficiaries will be the PDRAs who will be working in a multi-disciplinary environment and acquiring translational skills that will enhance their career development in areas of computational neuroscience, neurophysiology, systems biology and synthetic biology.
In the medium to long term, EEG manufacturers will benefit by developing new EEG equipment targeted at detecting the biomarkers of the imbalance between neural excitation and inhibition. This, combined with existing signal processing techniques in the time and frequency domain, will provide more complete information about the neural signals that underlie the generation of the EEG signals.
In the long term, clinicians who use EEG as a diagnostic tool for neurodegenerative diseases will benefit from the development of new EEG equipment which will enable them to interpret the EEG signal in terms of the underlying neural excitation and inhibition, leading to early diagnosis of these diseases.
Furthermore fMRI physicists and radiologists can benefit from our neurovascular coupling model by providing better interpretation of fMRI signals in terms of the neural signals.
Ultimately patients with neurodegenerative diseases will benefit from early diagnosis, and potentially more effective therapeutic treatment targeted at re-dressing the balance between neural excitation and inhibition.
The wider public will benefit from our research because we will continue to engage with schools and colleges by giving talks related to our current research. We will design our website to include interactive activities, such as videos or simple animations of interaction between excitation and inhibition, to allow public to engage with us and increase their knowledge about the functions of brain.