AbstractAntipsychotic medication remains the primary treatment for schizophrenia. MRI research has been instrumental in developing our understanding of the therapeutic mechanism of these drugs and how they modulate the structure and function of the brain. However, imaging drug effects is known to be affected by several potential confounds which can alter interpretation of changes measured with MRI.
In addition to studies in patients, single dose investigations in healthy volunteers show changes in brain structure and function. Alterations in standard structural measurement have been observed within a few hours using MRI. These same doses are also capable of causing significant physiological changes such as cerebral blood flow (CBF) which may potentially influence T1-weighted images. Similarly, observed functional changes due to exposure to these compounds may be partly due to indirect effects, such as drug influence on the vasculature. Although these issues are well known, their effect on our ability to accurately image antipsychotic drug effect remains poorly characterised.
This thesis will attempt to bring increased precision to this area by addressing these confounds using single dose administrations of three different antipsychotics (risperidone, olanzapine and haloperidol) in placebo-controlled, double-blind studies in healthy volunteers.
First, quantitative relaxometry was employed to gain a precise measure of T1 within each voxel in addition to standard volumetric analysis. Quantitative measures of blood flow were also collected and assessed alongside structural metrics. A supplementary preclinical study also examined the effect of a single dose of one of the drugs on T1 maps in rats. While dose and drug-dependent effects on CBF were seen, there was no indication of T1 or structural alterations.
Second, the effects of these drugs were assessed on task based activation, specifically within the reward network (which has consistently shown to be dysfunctional in schizophrenia and reliably shown to be manipulated by dopaminergic modulation). The monetary incentive delay task showed clear drug-related differences on both anticipatory and consummatory reward related activation. Importantly these analyses controlled for measures of blood flow and vascular reactivity (by means of a breath hold task), which were also differentially altered by the drugs.
|Date of Award||2018|
|Supervisor||Mitul Mehta (Supervisor) & Anthony Vernon (Supervisor)|