Development of human EEG-ASL-BOLD neuroimaging and math modelling framework to quantify neuronal, haemodynamic and metabolic responses to stimulation

Human neuroimaging is the science of measuring brain function non-invasively, meaning without physically entering the body in any way. This collaboration between researchers at the Universities of Birmingham and Nottingham will develop new imaging techniques and mathematical models to improve understanding of the biological meaning of human brain imaging measurements.Studying the function of the healthy human brain is vitally important. Improving knowledge of normal brain function helps the understanding of what goes wrong in the diseased brain and aids medical diagnoses, drug design and treatment for disorders such as stroke, epilepsy, Parkinson's, and Alzheimer's.The functional magnetic resonance imaging (FMRI) technique is crucially important because it can accurately pinpoint the brain regions that are active when we experience sensations and feelings, or perform an action such as grasping a cup or watching a movie. Conventional FMRI uses a method that is sensitive to changes in both blood flow and the level of oxygen in the brain's blood (BOLD). A second less-common FMRI method, called ASL, provides absolute measurements of the delivery of nutrient blood to the brain's signalling cells, called neurons. However, both BOLD and ASL responses take 5 seconds to reach their maximum level. Obviously, brain processes occur on a much shorter timescale. A third technique called electroencephalography (EEG) directly records the electrical activity of neurons from electrodes on the patient's scalp. EEG provides information on when different parts of the brain are active with millisecond precision.These three techniques are widely used in brain research and increasingly in clinical practise. However, none of them alone provides a conclusive measurement of brain activity. Accurately identifying unique brain sources of the EEG signal is often not possible. Changes in BOLD signal can be measured that are caused only by differences in blood flow without any change in electrical signaling. Without an EEG measurement of that event the researcher would not know that it was a 'false' BOLD response, and without an ASL measurement of blood flow the researcher would not know why it was a 'false' BOLD response.This research project will overcome these limitations by developing combined EEG-BOLD-ASL as a multi-dimensional imaging technique. Simultaneous EEG-BOLD-ASL measurement will provide a more complete picture of the changes in blood flow, energy usage and electrical activity that occur when neurons are signaling.Mathematical models of the coupling between changes in blood flow, neuronal activity and brain energy usage will be used to re-create brain imaging results on computers. These models are simplified versions of the biological reality but are based on well-founded assumptions from scientific literature. The models output will be compared to real EEG and fMRI data to help understand the significance of individual biological variables in creating the observed brain signals.The proposed imaging development is crucial as EEG and ASL measurements are required so that models can be used to extract physiological variables from the combined signals. Only by combining multi-dimensional imaging with modelling can we untangle some of the factors that influence the BOLD signal, enabling a much more detailed description of the processes accompanying neuronal activity to be made.This project ultimately aims to answer two very important questions that are currently poorly understood: 1) What common aspects of brain activity are represented in the measurements made by EEG and FMRI? 2) What is the relationship between the brain's energy usage and the neuronal activity measured by EEG?A better understanding of the relationship between EEG and FMRI signals will help all researchers and clinicians that use these methods individually and improve our interpretation of healthy brain imaging signals and how they change with aging and disease.

Two wider groups are likely to benefit for the outcome of this project: 1) improving the clinical diagnostic tools of various neurological disorders, such as stroke, epilepsy, diabetes; 2) commercial MRI companies (such as Philips) through the development of new MR sequences. 1) Clinical applications fMRI has the potential to be a powerful tool in the diagnosis and targeted treatment of disease orientated problems caused by an ageing population. Since many pathological conditions are accompanied by alterations in vasculature, clinical use of fMRI will not be reliable unless corrections for neurovascular coupling differences are made. In the short term, the experimental and modelling strategies developed throughout this fellowship will improve the quantification of EEG and fMRI signals. Especially in epilepsy research, where interpretation of the metabolic demands of neural activity measured by EEG is important. In the longer term, this research has potential to translate into clinical settings and improve the reliability of studies, diagnoses and treatment of brain disorders such as epilepsy and diseases of old age. An additional benefit is the development of fMRI-based tools for the assessment of cerebrovascular health. This would improve patient care as well as increase the value of the current MRI infrastructure in the UK. Consequently, potential beneficiaries include the general public, who may benefit from the availability of improved clinical brain imaging methods. For example, the translation of more comprehensive, quantitative imaging strategies such as that outlined in this proposal could impact the quality of treatment of patients with brain disorders such as stroke, or diabetes. Surgical resection of brain regions is the last resort treatment for medically intractable epilepsy, with the often unavoidable side-effect of some loss of normal, healthy brain function. Improved understanding and localization of epileptic generators would help minimize brain tissue removed during surgery and could aid the development of new, better-targeted drug treatments. The use of EEG-fMRI for clinical evaluation of epilepsy is still small but interest is growing as collaborations between clinicians and researchers increase and strengthen. BUIC will play its part in active dissemination about the availability of new techniques of potential use to local neurologists. Through BUICs existing clinical contacts with Dr Soryal and Dr McCorry at Birmingham's Queen Elizabeth Hospital and Dr Bagary and Dr Cavanna at the Barberry National Centre for Medical Health (also Birmingham) the benefits of improved techniques could filter through to patients over a realistic time-scale of 5-10 years. 2) Commercial The development of new MRI techniques could impact the commercial and industrial sector. Both the Birmingham and Nottingham collaborating MRI centres sustain an excellent working relationship with Philips Healthcare. Their engineers are supportive of work to develop and improve techniques. To aid the dissemination and impact of work from this project, all MRI sequence code would be made available to Philips. This would enable the developed technique to be incorporated into future software packages, available to MRI users at both research and industrial facilities worldwide. It is feasible that beneficiaries could include medical research or pharmaceutical companies. Increasingly, FMRI is used by Pfizer or Merck &Co, Inc. to study the spatial binding sites and functional effects of drugs. However, administration of pharmacological compounds causes alterations in fMRI signal itself. These changes can be quantified with this project's tools and used to improve interpretation of fMRI results. Further application could occur in software used to analyse imaging results.