Subcortical neurovascular coupling: how does it differ from the cortex?

A central aim of leading neuroscientific research is to characterise basic and advanced functions of the human brain, and their changes in health (eg, learning) and disease (eg, schizophrenia). Functional magnetic resonance imaging (fMRI) plays a crucial role in this research, by allowing non-invasive, radiation-free mapping of brain activity with high spatial and temporal resolution. However, fMRI does not measure brain activity directly, which occurs as transmission of electrical pulses through special conductor cells, called neurons. It rather maps the effect of brain activity on the energy used by the neurons. That is to say that, when neurons transmit electrical pulses, they use more energy than at rest, and this energy is provided by increased blood flow, in the same way as increased muscular activity increases blood flow to the muscles. Thus fMRI maps haemodynamic changes (ie, changes in blood flow and metabolism) induced by neuronal activity. Since our primary interest in fMRI is to map and measure the brain's neuronal activity, it is necessary to translate the haemodynamic changes (measured by fMRI) into changes in neuronal activity. However, neurovascular coupling (ie, the relationship linking haemodynamic changes to neural activity) is not known for every brain region, and thus fMRI results are often difficult to interpret and exploit for the study of brain function. It is therefore necessary to characterise neurovascular coupling, and for this purpose, both neuronal and fMRI signals should be measured. In order to measure the neuronal signals from a specific part of the brain, a highly invasive procedure is required whereby small needles (electrodes) are inserted in the relevant brain areas to record the signal. As a result, studies of neurovascular coupling are performed on experimental animals rather than humans, and they have been focused exclusively on the outer parts of the brain, where good quality fMRI measurements can be obtained with relative ease. However, outer (cortical) and deeper (subcortical) brain areas are both indispensable in understanding brain function, and given that these areas have markedly different structure, it is uncertain whether the same rules of coupling in the cortex also exist subcortically. The objective of the proposed research is to characterise the regional differences of the haemodynamic responses, the neurovascular coupling and its mechanisms between cortical and subcortical brain regions with a view to improving interpretation and practical exploitation of functional neuroimaging. For this purpose, we will exploit the brain's property that a given stimulus is propagated and processed at cortical and subcortical brain areas, which form the stations of a neuronal pathway. Specifically, we will study the coupling at the stations of the well-characterised whisker-to-barrel (WTB) pathway in the rat, using experimentation not ordinarily possible in human fMRI studies. The research will use home-built MRI technology that enables good quality fMRI signals in deep brain areas of small animals in combination with two major areas of expertise in our lab: (i) physiological and pharmacological studies of brain functions, and (ii) modelling and analysis of brain signals. The results of this work will make it possible to translate the measured fMRI signals into neural activity, a direct measure of brain function. Thus, the proposed research will improve understanding of brain function; especially when comparing activity of different brain areas. It will also enhance our understanding of neurological clinical conditions (such as migraine, stroke and Alzheimer's disease), where the coupling is disturbed, strengthening the scope for drug discovery and therapy of these conditions.

Functional magnetic resonance imaging (fMRI), the leading functional neuroimaging modality, maps brain activity indirectly by measuring activity-induced haemodynamic changes. The relationship between the brain's electrical activity and haemodynamics (termed neurovascular coupling) is essential for the interpretation and practical exploitation of fMRI results. Although neurovascular coupling and its mechanisms are expected to differ between cortical and subcortical brain areas, it has been studied in the cortex only. The proposed research aims to characterise the regional differences of the haemodynamic responses, neurovascular coupling and its mechanisms between cortical and subcortical regions with a view to improving interpretation and practical exploitation of functional neuroimaging. The main stations of the well defined whisker-to-barrel (WTB) pathway (trigeminal, thalamus and cortex) will be studied in the anaesthetised rat using experimentation not ordinarily possible in human studies. Haemodynamic and neural responses will be measured at these stations by whole-brain fMRI and multi-site multi-channel electrophysiology. Our group's analysis techniques will be used to derive neurovascular coupling parameters from these data. We will study the dependence of the responses (neural and haemodynamic) and their coupling across the wtb pathway on stimulation parameters (intensity, frequency) and types (electrical, naturalistic), and on the level of background neural and haemodynamic activity. Furthermore, mechanisms of neurovascular coupling will be investigated across the pathway, by studying the role of candidate coupling agents on responses and coupling parameters. In addition to improving interpretation of human fMRI results, where uniform coupling is assumed over the brain, this research will enhance our understanding of neurological clinical conditions (eg, migraine, stroke and Alzheimer's disease), where the neurovascular coupling is disturbed.