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Effects of Cholinesterase Inhibition on Brain Function

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Effects of Cholinesterase Inhibition on Brain Function Effects of Cholinesterase Inhibition on Brain Function Paul Bentley 2010 A thesis submitted to University College London for the degree of Doctor of Philosophy Dedicated to my parents, Annie, Mia, Tess and Noah Acknowledgements This thesis would not have been possible without the pivotal help of my two supervisors Ray Dolan and Jon Driver – the former for launching me off the starting blocks, uncompromising coaching, and ensuring that I complete; the latter for steering me around some tight methodological and theoretical turns en route. My other collaborators are Christian Thiele – who was patient enough to teach me ‘the ropes’, Patrik Vuilleumier, and Masud Husain. I would also like to thank Joel Winston and Bryan Strange for their valuable pearls along the way, as well as Martin Rosser who facilitated patient recruitment from the Dementia Research Group, UCL. Finally, pursuing an academic career and seeing this through, at least to PhD, would have been most unlikely without the guiding wisdom from my father Harvey Isenberg PhD for whom I am quite indebted. The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without prior written consent of the author. 2 Abstract 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 physostigmine- induced 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. 3 Contents ABSTRACT……………………………………………………… 3 1: INTRODUCTION……………………………………………10 Purpose……………………………………………………………………………… 11 Aims…………………………………………………………………………………. 13 Layout……………………………………………………………………………….. 20 2: BACKGROUND…………………………………………….. 23 Cholinergic Neuroanatomy …………………………………………………………. 24 Cholinergic Neurophysiology – General vs Specific Neuromodulation……………. 30 Diffuse, tonic effects…………………………………………………………….. 30 Focal, phasic effects……………………………………………………………... 32 Cholinergic Neurophysiology - Cellular Actions…………………………………… 37 Cholinergic Neurophysiology – Systems…………………………………………….43 Sensory ……………………………………………………………...……………… 45 Attention…………………………………………………………………………….. 49 Memory and Learning………………………………………………………………. 54 Nucleus basalis – neocortical cholinergic system…………………………….. 55 Septohippocampal cholinergic system……………………………………....... 57 Common memory mechanisms of acetylcholine in neocortex and hippocampus……………………………………………………….58 Cholinergic Receptor Pharmacology………………………………………………... 62 Brain Cholinesterases……………………………………………………………….. 63 Cholinesterase Inhibitors - Behavioural Effects…………………………………..... 64 Cholinesterase Inhibitors - Chemical Effects………………………………………..67 Alzheimer’s Disease – “The Cholinergic Hypothesis”…………………………….. ..69 Evidence for Cholinergic Hypofunction in Alzheimer's Disease…………….. 69 Challenges to the Cholinergic Hypothesis……………………………………. 71 Cholinesterase Inhibitors in Alzheimer’s Disease…………………………………... 74 3: HUMAN CHOLINERGIC FUNCTIONAL NEUROIMAGING REVIEW………..…………………….. 77 Role of Pharmacological - Functional Imaging……………………………………. 78 Types of Pharmacological Functional Imaging……………………………………. 80 Literature Review of Cholinergic Functional Imaging……………………….......... 82 Interpretation……………………………………………………………………….. 95 Sensory cortex modulations…………………………………………………….. 95 Directionality of cholinergic modulation of sensory cortex is task-dependent…………………………………………………………. 95 4 Frontoparietal cortex modulations…………………………………………….. 102 Hypercholinergic or hypocholinergic states reduce neural markers of top-down orienting………………………………………… 102 Hypercholinergic reductions in activity may reflect enhanced processing efficiency…………………………………………………... 104 Hypercholinergic-induced deactivations of the ‘default network’ may reflect a shift from internal to external processing ………………. 107 Hypercholinergic-mediated increases in frontoparietal activity may reflect recruitment of cortical processes………………………….. 110 Memory-associated modulations……………………………………………... 114 Medial temporal regions………………………………………………… 114 Sensory cortex…………………………………………………………… 116 Prefrontal cortex………………………………………………………… 119 Questions Addressed by the Experiments of this Thesis………………………… 122 4. METHODS…………………………………………………. 124 Introduction………………………………………………………………………... 125 Functional Magnetic Resonance Imaging (fMRI)………………………………… 127 MRI – Physical principles…………………………………………………….. 127 MRI – Signal………………………………………………………………….. 130 Functional MRI – Signal contrast…………………………………………….. 134 MRI – Localization………………………………………………………….... 136 Functional MRI – Pulse sequence……………………………………………. 141 Echo-Planar Imaging – advantages and disadvantages………………………. 146 fMRI Image Processing…………………………………………………………… 147 Introduction…………………………………………………………………… 147 Spatial registration and realignment………………………………………….. 149 Temporal realignment………………………………………………………… 150 Spatial normalization…………………………………………………………. 151 Spatial smoothing…………………………………………………………….. 153 Co-Registration……………………………………………………………….. 154 Statistical Analysis of fMRI Time Series………………………………………… .155 Introduction…………………………………………………………………... 155 Generalised linear model (GLM)…………………………………………….. 157 Haemodynamic response function and its neural equivalent………………… 161 Design matrix specification in event-related fMRI………………………….. 165 Data scaling………………………………………………………………….. 170 Hypothesis testing…………………………………………………………… 171 Correction for multiple comparisons………………………………………… 174 Random-effects analysis……………………………………………………... 178 Experimental design………………………………………………………….. 182 Design efficiency…………………………………………………………….. 183 5 Pharmacological and Clinical fMRI…………………………………………………186 Confounding effects of drugs and disease in fMRI…………………………...186 Measures to control for confounding in clinical and pharmacological fMRI……………………………………………………... 194 Evidence for cholinergic modulation of the neural-BOLD relationship…………………………………………………………………. 201 5: EXPERIMENT 1: Effects of ChEI on attention and emotion………………... 204 Introduction……………………………………………………………………….. 205 Methods……………………………………………………………………………207 Subjects……………………………………………………………………….. 207 Drug-treatment………………………………………………………………… 208 Cognitive task…………………………………………………………………. 209 Imaging and image processing………………………………………………... 211 Statistical analysis of images…………………………………………………. 212 Results…………………………………………………………………………….. 214 Physiological data, subjective reports, and eye tracking…………………….. 214 Behavioural……………………………………………………………………. 215 fMRI data: effects of physostigmine on attentional modulation……………… 217 fMRI data: effects of physostigmine on response to fearful expression……… 221 fMRI data: effects of physostigmine on the interaction of attention with emotion……………………………………………………… 225 Discussion………………………………………………………………………… 228 Cholinergic modulation of attentional effects within visual cortex…………… 228 Cholinergic modulation of emotional effects within visual cortex……………. 231 Cholinergic modulation of attention-emotion interactions in frontoparietal cortex……………………………………………………… 233 Conclusion……………………………………………………………………. 235 6: EXPERIMENT 2: Effects of ChEI on repetition priming…...……………….. 236 Introduction……………………………………………………………………….. 237 Methods……………………………………………………………………………239 Subjects……………………………………………………………………….. 239 Drug-treatment………………………………………………………………… 239 Cognitive task…………………………………………………………………. 239 Imaging and image processing………………………………………………... 243 Statistical analysis of images…………………………………………………. 243 Results…………………………………………………………………………….. 245 Physiological data, subjective reports, and eye tracking…….……………….. 245 Behavioural……………………………………………………………………. 245 fMRI data: effects of selective attention on face-repetition ………..….……… 248 fMRI data: effects of emotion on face-repetition ……….……………….…….252 6 fMRI data: effects of cholinergic enhancement on repetition ……..…………. 256 Discussion………………………………………………………………………… 259 Effects of cholinergic enhancement on repetition priming and its neural correlates…………………………………………………………….. 259 Conclusion……………………………………………………….……………. 261 7: EXPERIMENT 3: Effects of
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