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Download Thesis This electronic thesis or dissertation has been downloaded from the King’s Research Portal at https://kclpure.kcl.ac.uk/portal/ The functional anatomy of working memory training using chunking in Alzheimer's disease Huntley, Jonathan David Awarding institution: King's College London The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without proper acknowledgement. END USER LICENCE AGREEMENT Unless another licence is stated on the immediately following page this work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence. https://creativecommons.org/licenses/by-nc-nd/4.0/ You are free to copy, distribute and transmit the work Under the following conditions: Attribution: You must attribute the work in the manner specified by the author (but not in any way that suggests that they endorse you or your use of the work). Non Commercial: You may not use this work for commercial purposes. No Derivative Works - You may not alter, transform, or build upon this work. Any of these conditions can be waived if you receive permission from the author. Your fair dealings and other rights are in no way affected by the above. Take down policy If you believe that this document breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 04. Oct. 2021 THE FUNCTIONAL ANATOMY OF WORKING MEMORY TRAINING USING CHUNKING IN ALZHEIMER'S DISEASE Jonathan Huntley Thesis submitted for the degree of Doctor of Philosophy King’s College London University of London June 2014 1 ABSTRACT AIMS A randomised controlled trial of a novel cognitive training regime based on chunking was conducted in participants with early Alzheimer’s Disease. Functional neuroimaging was performed to examine re- organisation of brain activity following cognitive training. The study tested the following hypotheses: 1) Training individuals with early AD in the use of chunking strategies would improve their working memory (WM) capacity. 2) Following training in chunking, improvement in WM capacity would generalise across different modalities of WM tasks and measures of general cognitive functioning. 3) Improvement in WM capacity following cognitive training would be associated with re-organisation of functional activity in the prefrontal cortex (PFC) and posterior parietal cortex (PPC). METHODS 30 patients with early AD were recruited and assessed on WM and general cognitive tasks. They also performed a verbal WM chunking task whilst undergoing fMRI. They were then randomised to either an active control group or cognitive training group. The cognitive training group had 18 sessions of adaptive WM training using chunking strategies, whilst the control subjects practised a non adaptive WM task. All subjects were then reassessed using the same measures of cognitive function, WM and fMRI protocol, allowing the above hypotheses to be tested. RESULTS At baseline, all participants benefitted from chunking to improve WM (p < 0.001). Following training, the training group demonstrated a significant improvement on the chunking WM task (p < 0.05) compared with the control group. There were also significant improvements in measures of general cognitive function (MMSE and ADAS-Cog) and verbal episodic memory in the training group compared to controls (p < 0.05). Training was significantly associated with a reduction in activation in the PFC-PPC network following cognitive training. 2 DISCUSSION The impact of this novel approach to improving WM in early AD is discussed, in the context of existing knowledge of cognitive training and functional plasticity in AD. 3 ACKNOWLEDGMENTS I wish to thank my supervisors Professors Robert Howard and Adrian Owen for their support, encouragement and enthusiasm over the last 4 years. Thanks especially to Rob for his guidance since 2005. I am also extremely grateful for the support and friendship of Dr Adam Hampshire and Dr Daniel Bor, particularly for their assistance with the fMRI analysis and interpretation. I have received informal support from many people at the Institute of Psychiatry. I’d like to thank all the radiographers the Centre for Neuroimaging, for their expertise and patience during the fMRI scanning. I’d like to thank Professor Steve Williams and Jeff Dalton for their technical expertise and support in designing the protocol and programming the task. Within the Department of Old Age Psychiatry I’d like to thank Dr Becky Gould, Dr Kathy Liu and Melody Smith for help with the meta-analysis; Dr Dominic Ffytche, Dr Sergi Costafreda-Gonzalez and Dr Natalie Marchant for help with fMRI analyses, and all the Dementia Research Nurses for their help with recruitment. I’m also grateful to clinical services at SLAM for their help with recruiting. I am grateful to the MRC for funding my clinical research training fellowship. I want to especially thank all of the participants and their families who took part in this study with such commitment, enthusiasm, generosity and dignity. Finally thank you to Alice, Noah, Amelie and Joshua for their love, support and patience with me over the last 4 years (and especially the last 6 months!). Wo Ai Ni. 4 ABBREVIATIONS AC/PC Anterior Commissure/ Posterior Commissure ACC/SMA Anterior Cingulate Cortex/Supplementary Motor Area AD Alzheimer's Disease ADL Activities of Daily Living ADAS-Cog Alzheimer's Disease Assessment Scale – Cognitive section ANOVA Analysis of Variance BOLD Blood Oxygen Level Dependent BPSD Behavioural and Psychological Symptoms of Dementia CI Confidence Interval CONT Control Group CR Cognitive Rehabilitation CS Cognitive Stimulation CT Cognitive Training DARTEL Diffeomorphic Anatomical Registration Through Exponential Lie Algebra DEMQoL Dementia Quality of Life questionnaire DLPFC Dorso-Lateral Prefrontal Cortex EPI Echo Planar Imaging fMRI Functional Magnetic Resonance Imaging FWHM Full Width at Half Maximum GDS Geriatric Depression Scale GLM General Linear Model GR Grammatical Reasoning IOP Institute of Psychiatry IQ Intelligence Quotient JH Jonathan Huntley LDLPFC Left Dorso-lateral Prefrontal Cortex LPC Left Parietal Cortex 5 MarsBar MARSeille Boîte À Région d'Intérêt MCI Mild Cognitive Impairment MCID Minimum Clinically Important Difference MCTS Mixed Cognitive Training and Stimulation MD Multiple Demand MEDS Medication MIA Meta-memory in Adulthood questionnaire MMSE Mini Mental State Examination MNI Montreal Neurological Institute MP-RAGE Magnetization-Prepared Rapid Gradient-Echo MRI Magnetic Resonance Imaging NA Non Active control group NART National Adult Reading Test NPI Neuropsychiatric Inventory OOO Odd One Out Test PPC Posterior Parietal Cortex PPI Psycho-physiological interactions RAIFO Right Anterior Inferior Frontal area RCT Randomised Controlled Trial RDLPFC Right Dorso-Lateral Pre – Frontal Cortex ROI Region of Interest RPC Right Parietal Cortex SD Standard Deviation SEM Standard Error of the Mean SMD Standardised Mean Difference SOS Self Ordered Search Task SPM Statistical Parametric Mapping SPSS Statistical Package for the Social Sciences T Tesla TE Echo Time 6 TR Repetition Time TRAIN Training Group TSDiffAna Time Series Difference Analysis VBM Voxel Based Morphology VOI Volumes of Interest WM Working Memory 7 TABLE OF CONTENTS Chapter 1 INTRODUCTION .................................................................................................................. 25 1.1 ALZHEIMER’S DISEASE (AD) - EPIDEMIOLOGY ..................................................................... 25 1.2 DIAGNOSIS AND FEATURES OF AD ........................................................................................ 25 1.3 THE WORKING MEMORY (WM) MODEL .................................................................................. 28 1.4 WORKING MEMORY AND AD ................................................................................................... 29 1.5 CHUNKING STRATEGIES IN WM ............................................................................................. 29 1.6 NEURAL BASIS OF WM: FUNCTIONAL NEUROIMAGING ...................................................... 30 1.7 FUNCTIONAL NEUROIMAGING OF WORKING MEMORY ...................................................... 31 1.8 COGNITIVE TRAINING AND CHUNKING.................................................................................. 32 1.9 COGNITIVE TRAINING IN HEALTHY ELDERLY SUBJECTS ................................................... 33 1.10 PLASTICITY .............................................................................................................................. 33 1.11 COGNITIVE TRAINING IN EARLY AD AND MCI ..................................................................... 34 1.12 FUNCTIONAL IMAGING OF COGNITIVE TRAINING .............................................................. 34 1.13 FUNCTIONAL IMAGING IN MCI AND EARLY AD ................................................................... 34 1.14 PILOT STUDY - CHUNKING IN EARLY AD ............................................................................. 35 1.15 IMPLICIT MEMORY AND COGNITIVE TRAINING IN AD ........................................................ 36 1.16 SUMMARY AND NEED FOR PROPOSED TRIAL ................................................................... 36 Chapter 2 COGNITIVE INTERVENTIONS IN DEMENTIA - META-ANALYSIS AND META- REGRESSION. ....................................................................................................................................
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