Development of preclinical imaging to refine studies of dysfunctional blood flow in the brain

The brain has the highest energy demand of any organ in the body, but despite this, has very little energy reserves. Because of this, the brain rapidly redirects blood flow, in response to changes in demand, through the process of neurovascular coupling. In the healthy brain, a 5% increase in oxygen demand is met by a 50% increase in blood flow, providing sufficient energy for normal activity. However, with age, or in pathological conditions such as hypertension or ischaemic stroke, this coupling is disrupted, which is thought to contribute to cognitive impairment in these conditions. To understand the processes behind this, non-invasive imaging of animal models would be beneficial.

Functional magnetic resonance imaging (fMRI) is a non-invasive imaging modality which uses changes in oxyhaemoglobin and deoxyhaemoglobin to image changes in brain activity (the Blood Oxygen Level Dependent, or BOLD, signal). Its use in longitudinal preclinical studies is currently limited by factors including appropriate anaesthesia, as current anaesthetic agents can be harmful or impair the vascular response detected.

This PhD aims to address the limitations of preclinical fMRI through development of a novel anaesthesia protocol, and use of additional MRI sequences to supplement BOLD fMRI, incuding functional magnetic resonance spectroscopy (fMRS) and perfusion MRI using arterial spin labelling (ASL). When these methods were applied to a rodent model of healthy ageing, fMRI using forepaw stimulation showed a decrease in the size of the activated region in the somatosensory cortex with age, coupled with a decrease in glutamate turnover, while cerebral blood flow remained the same. This suggests that the change in BOLD signal observed in ageing is a consequence of a reduction in neuronal metabolism, rather than impairment of neurovascular coupling. When applied to a rodent model of hypertension, the opposite was observed, in which an increase in resting CBF was observed as hypertension progressed, followed by a decrease in the size of the BOLD signal, with no significant change in glutamate turnover, suggesting the changes in BOLD signal are vascular in origin. Due to the high variability in lesion volume, stroke experiments were inconclusive.

This thesis shows that propofol is a suitable anaesthetic agent for longitudinal fMRI, and that other less common MRI modalities combined with BOLD fMRI can provide new insights into long term changes in neurovascular function.