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

Lead Research Organisation: University of Sheffield
Department Name: Psychology

Abstract

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.

Technical Summary

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.

Planned Impact

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.

Publications


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Related Projects

Project Reference Relationship Related To Start End Award Value
BB/K010123/1 10/04/2013 31/03/2014 £615,105
BB/K010123/2 Transfer BB/K010123/1 01/04/2014 31/08/2016 £411,603
 
Description The major finding of this project is related to the neuro-genesis of the local field potential (LFP) recordings. Using pharmacological intervention to manipulate inhibitory synaptic activity, we demonstrated that the temporal dynamics of the LFP within an initial time window is dependent solely on the excitatory synaptic activity of the local pyramidal neural population. We further conducted concurrent LFP/EEG experiments (which was beyond the original objectives of the grant) and confirmed that not only LFP, but also the somatosensory evoked potential (SEP) recorded via EEG probes had similar temporal characteristic: the first positive peak P1 observed in the SEP was not altered by the elimination of inhibitory synaptic activity. In other words, both evoked LFP and EEG during early sensory processing were purely dependent on synchronised local excitatory synaptic events. Our findings offer the opportunity for more accurate interpretations of LFP and EEG recordings, and provide an important constraint when establishing mathematical models of neural populations within the cerebral cortex. In addition, as changes in P1 could be used to indicate changes in synaptic excitation of the local cortical network, there is potential for this knowledge to grant further insight into pathological and normal brain function when interpreting extracellular recording techniques such as EEG.
The results from the grant have led to two pilot studies, one was related to the ageing brain, the other to the effect of vitamin B supplementation on the balance between neural excitation and inhibition. Using our findings from the grant, we were able to interpret neural signals from both pilot studies, suggesting that LFP/EEG could be used to evaluate and compare neural synaptic activity changes as brain ages, and how these changes might be partially 'restored' through dietary supplementation of Vitamin B. These pilot studies have led to a full PhD programme to investigate the shift of balance between neural excitation and inhibition as brain develops and ages, and a collaboration research between my Laboratory and two other laboratories (in psychology and food science respectively) within Reading University to investigate the effect of Vitamin B supplementation on brain signal and cognition, via an animal model and in humans.
Exploitation Route Our findings can be used by all researchers using EEG and LFP as part of their research tool to study brain function. Potentially it can be used to estimate the balance, or lack of it, between neural excitation and inhibition. This has wide ranging applications. Our methodology can be used to investigate if neural excitation and inhibition in a normal brain change with aging, and if these changes are disrupted in age-related diseases such as dementia. It may also be used to enhance the interpretation of brain signals after dietary or drug interventions. For example, our results may allow research into the effect of energy drinks on the excitatory brain signals, or the effect of intense training on the brain synaptic activity of athletes. In the long term, it has the potential to be used by medical workers as part of diagnostic tools for neurological diseases in which the balanced between neural excitation and inhibition is disturbed.
More research is needed to model sensory evoked EEG responses to synaptic activities, expanding the dipole model currently used in the literature.
Sectors Digital/Communication/Information Technologies (including Software),Education,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology
 
Description Our findings have laid the foundation for two directions of investigation, one is towards the understanding of the aging brain, the other is a collaborative study on the effect of vitamin B supplementation on neural activity, which will potentially impact on the well-being of elderly people, and the prevention and treatment of dementia. These are on-going research.
Sector Digital/Communication/Information Technologies (including Software),Education,Healthcare,Leisure Activities, including Sports, Recreation and Tourism,Pharmaceuticals and Medical Biotechnology
Impact Types Societal
 
Description EPSRC DTG Studentship
Amount £55,000 (GBP)
Organisation University of Reading 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2013 
End 09/2016
 
Title Concurrent EEG/LFP recording in rodent 
Description We designed a simple set up to record EEG and LFP in the same cortical location and concurrently in rodent. The EEG probe was a spider electrode of 6mm in diameter. The spacing in the probe allows a micro-electrode to be inserted into the cortex through the EEG probe. This set up is simple but very effective. 
Type Of Material Physiological assessment or outcome measure 
Provided To Others? No  
Impact By allowing EEG and LFP to be simultaneously recorded at the same site, the number of animals needed to investigate the relationship between EEG and LFP is halved. 
 
Title Concurrent EEG/LFP 
Description Concurrent EEG and local field potential recordings 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact The data set can be used to evaluate and validate existing neural mass/field models under sensory evoked conditions, and develop new models relating neural activity across cortical depths to EEG recordings. 
 
Title Concurrent LFP and LDF data for different stim duration 
Description Stimulus: electrical stimulation of the whole whisker pad. 1.2mA, square pulse of 0.3ms. Stim frequency: 5Hz. Stim duration: 2s, 8s and 16s. Probing stim: 2s at inter-block-intervals 0.6s,1s,2s,3s,4s,6s,8s Each trial: 60s consisting of a conditioning block (2,8 or 16s) followed by a probing block (2s) at 7 different intervals Each run: 21 different trials interleaved Each experiment: 10 runs 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact A mathematical model of neurovascular coupling was derived. The data also implied blood vessel dilation and constriction during neural activity. This finding formed part of the investigation of my current grant from the BBSRC. 
 
Title LFP data with bicuculline injection 
Description Stimulus: Electrical stimulation of the whole whisker pad. 1.6mA, square pulse of 0.3ms. Interstimulus interval: 25s. Each trial: a single pulse stimulation Each run: 55 trials. The first 5 trials are control trials. Bicuculline injection starts at trial 6 at the rate 0.1microlitre per min, for 2 minutes. Each experiment: 5 runs 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact The data can be used to decompose the LFP into excitatory and inhibitory components, which was not possible before. 
 
Description Use concurrent EEG/LFP to investigate neural excitation and inhibition 
Organisation Florida International University (FIU)
Department Biomedical Engineering Department
Country United States of America 
Sector Academic/University 
PI Contribution We contributed to this collaboration our mathematical modelling expertise, specifically the neurovascular model we developed to fit epileptic data. We also invited Dr Riera to visit our Laboratory in 2014.
Collaborator Contribution Our collaborators share with us their expertise in concurrent EEG/LFP recording techniques and provided us with some EEG probes for free. They also hosted a visit by Prof Ying Zheng in 2014.
Impact joint publication: Song Y, Torres R, Garcia S, Frometa Y, Bae J, Deshmukh A, Lin WC, Zheng Y, Riera J. (2016) Dysfunction of Neuro-vascular/metabolic Coupling in Chronic Focal Epilepsy. IEEE Trans on Biomed Eng. 63(1): 97-110. doi: 10.1109/TBME.2015.2461496 The collaboration is multi-disciplinary, involving research in electrophysiology, neuroscience and mathematical modelling.
Start Year 2014
 
Description Workshop on Balanced excitation and inhibition 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact WE organised a EEG/LFP workshop in Sept 2015 at the University of Sheffield. The workshop is titled
'Understanding neural excitation and inhibition: implications for typical brain function and clinical disorders'

6 international speakers were invited across widely different disciplines, with researchers working at single cell level, cell population level, clinical academics working closely with patients, and mathematical modelling researchers. The Workshop was attended by academics, PDRAs, postdoc students across UK.
Year(s) Of Engagement Activity 2015
URL http://eeg-lfp-workshop.reading.ac.uk/