Effects of Cholinesterase Inhibition on Brain Function

Pharmacological-functional imaging provides a non-invasive method by which the actions of neurotropic drugs on the human brain can be explored. Simply put, it assesses how neural activity patterns associated with cognitive functions of interest are modified by a drug challenge. Since one of the most widely-used cognitive-enhancing drugs in clinical practice are cholinesterase inhibitors, this thesis applies pharmacological functional imaging to the question of understanding how such drugs work both in healthy people and dementia. The experiments in this thesis describe how brain activations – as revealed by functional magnetic resonance imaging (fMRI) – are modulated by the cholinesterase inhibitor physostigmine, during tasks designed to isolate sensory, attentional, and memory processes. While non-human and human psychophysical studies suggest that all three of these cognitive functions are under the control of the endogenous cortical cholinergic system, understanding how neurobiological models of cholinergic function translate into human brain activation modulations is unclear. One main question that is particularly relevant in this regard, that recurs through all the experiments, is how physostigmineinduced neuromodulations differ between sensory-driven ‘bottom-up’, and task-driven ‘top-down’, brain activations. The results are discussed with reference both to non-human physiological data and to existing human cholinergic-functional imaging studies (fifty studies published to date), which are themselves reviewed at the outset. Furthermore, assumptions based upon the physical and physiological principles of pharmacological functional imaging, being critical to interpretation, are discussed in detail within a general methods section.