the functional anatomy of working memory training using chunking in alzheimer's disease

296 Pages·2017·6.17 MB·English

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
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:
 Share: 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.

D ownload date: 06. Nov. 2017
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. ..................................................................................................................................... 38
2.1 INTRODUCTION ......................................................................................................................... 38
2.2 METHODS ................................................................................................................................... 40
2.2.1 SELECTION OF STUDIES ................................................................................................... 40
8
2.2.2 INCLUSION AND EXCLUSION CRITERIA .......................................................................... 40
2.2.3 ASSESSMENT OF TRIAL QUALITY.................................................................................... 42
2.2.4 DATA EXTRACTION ............................................................................................................ 42
2.2.5 CALCULATION OF EFFECT SIZES .................................................................................... 42
2.3 STATISTICAL ANALYSIS ........................................................................................................... 43
2.3.1 META-ANALYSES ................................................................................................................ 43
2.3.2 META-REGRESSION ANALYSES ....................................................................................... 44
2.3.3 CLINICAL SIGNIFICANCE AND SENSITIVITY ANALYSES ............................................... 45
2.4 RESULTS .................................................................................................................................... 45
2.4.1 IDENTIFICATION AND CHARACTERISTICS OF INCLUDED STUDIES ........................... 45
2.5 COMPARISON OF DIFFERENT COGNITIVE INTERVENTIONS USING GENERAL
COGNITION OUTCOMES ................................................................................................................ 47
2.5.1 QUALITY OF STUDIES ........................................................................................................ 47
2.5.2 META-ANALYSIS ................................................................................................................. 47
2.5.3 META-REGRESSION ANALYSES ....................................................................................... 53
2.5.4 CLINICAL SIGNIFICANCE AND SENSITIVITY ANALYSES ............................................... 55
2.6 EXAMINATION OF SPECIFIC COGNITIVE OUTCOMES IN CT AND MCTS STUDIES. ......... 56
2.6.1 COGNITIVE TRAINING STUDIES- EPISODIC MEMORY OUTCOMES ............................ 62
2.6.2 COGNITIVE TRAINING STUDIES – EXECUTIVE FUNCTION OUTCOMES ..................... 63
2.6.3 COGNITIVE TRAINING STUDIES- WORKING MEMORY OUTCOMES ............................ 64
2.6.4 COGNITIVE TRAINING AND ATTENTION OUTCOME MEASURES ................................. 65
2.6.5 MCTS STUDIES- EPISODIC MEMORY OUTCOMES ........................................................ 66
2.6.6 MCTS STUDIES WITH EXECUTIVE FUNCTION OUTCOMES .......................................... 67
2.7 DISCUSSION .............................................................................................................................. 68
2.7.1 GENERAL COGNITIVE FUNCTION .................................................................................... 68
2.7.2 SPECIFIC COGNITIVE OUTCOMES IN CT AND MCTS STUDIES ................................... 69
Chapter 3 METHODS – RCT ................................................................................................................ 82
3.1 SUMMARY OF TRIAL ................................................................................................................. 82
3.2 RECRUITMENT .......................................................................................................................... 82
9