GLUCOSE MODULATION OF VERBAL
EPISODIC MEMORY IN ADOLESCENTS
Michael Andrew Smith B.A. (Hons)
School of Paediatrics and Child Health
University of Western Australia
This thesis is presented for the degree of
Doctor of Philosophy of the University of Western Australia
September 2009
i
Declaration
The work presented in this thesis was performed between March 2006 and
September 2009 at the School of Paediatrics and Child Health, University of Western
Australia under the supervision of Associate Professor Jonathan Foster and Dr Anke van
Eekelen. Study 4 was conducted between July 2008 and October 2008 at the Brain,
Performance and Nutrition Research Centre, Northumbria University, United Kingdom
under the supervision of Dr Leigh Riby.
All of the work presented in this thesis has been performed by the candidate.
The cortisol assays conducted as part of Study 5 and Study 6 were conducted under the
guidance of, and with assistance from, Ms Hilary Hii in the Developmental
Neuroscience Laboratory, Telethon Institute for Child Health Research and at the
School of Animal Biology, University of Western Australia.
In regard to Regulation 1.3.1.33 (points 2 and 3) from the Regulations
Governing Research Higher Degrees of the Postgraduate Research School, University
of Western Australia, all study design and development, participant recruitment and
testing, data entry, data analysis, manuscript preparation and revision of manuscripts for
papers that have been published on the basis of the work conducted as part of this thesis
was conducted by the candidate.
__________________________________ __________________
Michael Smith (Candidate) Date
__________________________________ __________________
Jonathan Foster (Coordinating supervisor) Date
ii
__________________________________ __________________
Anke van Eekelen (Co-supervisor) Date
__________________________________ __________________
Leigh Riby (Study 4 supervisor/co-author) Date
__________________________________ __________________
Hilary Hii (Research Assistant/co-author) Date
__________________________________ __________________
Sandra Sünram-Lea (Co-author) Date
iii
Summary
The ingestion of oral glucose has been observed to facilitate memory performance in
both elderly individuals and in young adults. In young adults, glucose appears to
reliably enhance verbal episodic memory only when to-be-remembered items are
encoded under conditions of divided attention. However, fewer studies have
investigated the effect of glucose on memory in children or adolescents, in whom the
central nervous system is in a putatively more plastic and adaptable state. The present
thesis addressed the question of whether the ‗glucose memory facilitation effect‘ can be
extended to healthy adolescents. This question is of particular interest, given that the
adolescent period is characterised by a higher basal cerebral metabolic rate relative to
adults. Of further interest was the investigation of a number of factors hypothesised to
modulate the glucose memory facilitation effect (including executive capacity, divided
attention, glucoregulatory efficiency, baseline stress, trait anxiety and hypothalamic-
pituitary-adrenal (HPA) axis function). In addition, the influence of encoding negative
emotionally arousing stimuli on the glucose memory facilitation effect was further
investigated as part of the present thesis. On the basis of the empirical study findings
reported in this thesis, it is concluded that the glucose memory facilitation effect can be
extended to healthy adolescents when encoding of memory materials takes place under
conditions of divided attention, but only in situations where inter-individual differences
in memory capacity are controlled for by employing a repeated measures procedure.
Further, it is suggested that a) glucoregulatory efficiency and b) trait anxiety, modulate
the glucose memory facilitation effect in adolescents. Moreover, in relation to the
purported ‗hippocampus hypothesis‘ pertaining to the glucose memory facilitation
effect, it was concluded on the basis of an event-related potential (ERP) study that
glucose enhances memory by additionally targeting extra-hippocampal brain regions.
iv
Table of Contents
Declaration ................................................................................................................. i
Summary................................................................................................................... iii
Table of Contents ..................................................................................................... iv
List of Figures......................................................................................................... xiv
List of Tables .......................................................................................................... xvi
Acknowledgements ................................................................................................ xix
Publications and Presentations ............................................................................... xxi
Chapter One: A literature review of the glucose memory facilitation effect ............ 1
Introduction ............................................................................................................... 2
The glucose memory facilitation effect ..................................................................... 2
‗Healthy‘ ageing................................................................................................. 3
Glucoregulatory efficiency ....................................................................... 10
Clinical populations with underlying memory deficits .................................... 12
Alzheimer‘s disease .................................................................................. 13
Schizophrenia ........................................................................................... 15
Down‘s syndrome..................................................................................... 16
Mild head injury and mild cognitive impairment ..................................... 17
Healthy young individuals: The role of divided attention ............................... 18
Glucose modulation of memory in children .................................................... 28
Influence of glycaemic load on memory performance ............................................ 29
‗Mechanisms of susceptibility‘ ................................................................................ 34
Divided attention/ cognitive demand ............................................................... 35
Glucoregulatory efficiency .............................................................................. 38
Neurocognitive mechanisms ................................................................................... 39
Brain regions thought to mediate glucose enhancement of memory ............... 39
v
The ‗hippocampus hypothesis‘ ................................................................. 39
The ‗central executive hypothesis‘ ........................................................... 42
Specific mechanisms ........................................................................................ 44
Insulin ....................................................................................................... 45
ACh synthesis ........................................................................................... 46
KATP channel function .............................................................................. 47
Brain glucose availability ......................................................................... 48
The emotional memory effect.................................................................................. 51
Summary and Conclusions ...................................................................................... 53
Chapter Two: Outline of the present thesis ................................................................ 59
Chapter Three: The glucose memory facilitation effect: role of executive load ..... 65
Abstract .................................................................................................................... 66
Introduction ............................................................................................................. 67
Study 1A .................................................................................................................. 70
Aims ................................................................................................................. 70
Hypotheses ....................................................................................................... 70
Method ............................................................................................................. 71
Participants ............................................................................................... 71
Treatment and design ............................................................................... 72
Materials ................................................................................................... 73
Executive battery .............................................................................. 73
Modified California Verbal Learning Test (CVLT) ......................... 76
Modified Bond-Lader Questionnaire. ............................................... 79
Blood glucose monitoring equipment ............................................... 79
Procedure .................................................................................................. 80
vi
Statistical analysis .................................................................................... 83
Results .............................................................................................................. 84
Blood glucose concentrations ................................................................... 84
Bond-Lader Scale ..................................................................................... 84
CVLT........................................................................................................ 85
Immediate free recall ........................................................................ 85
Delayed recall ................................................................................... 85
Forgetting analysis ............................................................................ 86
Executive battery ...................................................................................... 86
Discussion ........................................................................................................ 90
Study 1B .................................................................................................................. 93
Aims ................................................................................................................. 95
Hypotheses ....................................................................................................... 96
Method ............................................................................................................. 96
Participants ............................................................................................... 96
Treatment and design ............................................................................... 97
Materials ................................................................................................... 98
Procedure .................................................................................................. 98
Statistical analysis .................................................................................. 100
Results ............................................................................................................ 100
Blood glucose concentrations ................................................................. 100
Bond-Lader Scale ................................................................................... 101
CVLT...................................................................................................... 102
Immediate free recall ...................................................................... 102
Delayed recall ................................................................................. 102
Remembering/forgetting analysis ................................................... 102
vii
Executive battery .................................................................................... 103
Discussion ...................................................................................................... 104
General Summary and Conclusions ...................................................................... 108
Chapter Four: Investigating the influence of executive capacity and divided
attention on the glucose memory facilitation effect ................................................. 111
Abstract .................................................................................................................. 112
Introduction ........................................................................................................... 113
Study 2 ................................................................................................................... 116
Aims ............................................................................................................... 116
Hypotheses ..................................................................................................... 116
Method ........................................................................................................... 116
Participants ............................................................................................. 116
Treatment and design ............................................................................. 117
Materials ................................................................................................. 118
Modified Rey Auditory-Verbal Learning Test (RAVLT). ............. 118
Executive battery. ........................................................................... 119
Modified California Verbal Learning Test (CVLT). ...................... 119
Bipolar Profile of Mood States (POMS-Bi). .................................. 120
Blood glucose monitoring equipment. ............................................ 121
Procedure ................................................................................................ 121
Statistical analysis .................................................................................. 124
Results ............................................................................................................ 125
Blood glucose concentrations ................................................................. 125
POMS-Bi ................................................................................................ 126
Modified CVLT ...................................................................................... 127
Immediate free recall. ..................................................................... 127
viii
Short delay and long delay recall. ................................................... 127
Remembering/forgetting indices..................................................... 131
Executive battery .................................................................................... 131
Discussion.............................................................................................................. 134
Summary and Conclusions .................................................................................... 138
Chapter Five: Glucose and glucoregulatory influences on memory in healthy
adolescents ................................................................................................................... 141
Abstract.................................................................................................................. 142
Introduction ........................................................................................................... 143
Study 3 ................................................................................................................... 144
Aims ............................................................................................................... 144
Hypotheses ..................................................................................................... 145
Method ........................................................................................................... 145
Participants ............................................................................................. 145
Treatment and design ............................................................................. 146
Materials ................................................................................................. 146
Modified California Verbal Learning Test-II (CVLT-II) ............... 146
Modified Bond-Lader Questionnaire .............................................. 147
Blood glucose monitoring equipment ............................................. 147
Procedure ................................................................................................ 148
Statistical analysis .................................................................................. 150
Results ............................................................................................................ 152
Blood glucose concentrations ................................................................. 152
Bond-Lader Scale ................................................................................... 152
Modified CVLT-II .................................................................................. 153
Immediate free recall ...................................................................... 153
ix
Delayed recall. ................................................................................ 153
Treatment x treatment order interactions. ....................................... 154
Glucose regulation .......................................................................... 156
Discussion .............................................................................................................. 160
Summary and Conclusions .................................................................................... 166
Chapter Six: Glucose modulates event-related potential components of recollection
and familiarity in healthy adolescents ....................................................................... 169
Abstract .................................................................................................................. 170
Introduction ........................................................................................................... 171
Study 4 ................................................................................................................... 175
Aims ............................................................................................................... 175
Hypotheses ..................................................................................................... 175
Method ........................................................................................................... 176
Participants ............................................................................................. 176
Treatment and design ............................................................................. 176
Materials ................................................................................................. 177
Recognition memory task. .............................................................. 177
Blood glucose monitoring equipment ............................................. 178
Procedure ................................................................................................ 179
EEG recording and data reduction ......................................................... 180
Statistical analysis .................................................................................. 181
Results ............................................................................................................ 182
Blood glucose concentrations ................................................................. 182
Behavioural results ................................................................................. 183
Response accuracy. ......................................................................... 183
Response time. ................................................................................ 183
x
ERP results ............................................................................................. 183
Mid-frontal old/ new effect ............................................................. 187
Left parietal old/ new effect ............................................................ 187
Recognition plurality effect ............................................................ 188
Discussion.............................................................................................................. 188
Summary and Conclusions .................................................................................... 194
Chapter Seven: Glucose enhancement of memory: modulation by adolescent
stress, trait anxiety and basal HPA axis function? .................................................. 195
Abstract.................................................................................................................. 196
Introduction ........................................................................................................... 197
Study 5 ................................................................................................................... 200
Aims ............................................................................................................... 200
Hypotheses ..................................................................................................... 200
Method ........................................................................................................... 201
Participants ............................................................................................. 201
Treatment and design ............................................................................. 201
Materials ................................................................................................. 202
Saliva sampling equipment and free cortisol analysis .................... 202
Adolescent Stress Questionnaire (ASQ) ......................................... 202
State-Trait Anxiety Inventory (STAI) ............................................ 203
Modified California Verbal Learning Test-II (CVLT-II) ............... 203
Bond-Lader Questionnaire .............................................................. 203
Blood glucose monitoring equipment ............................................. 203
Procedure ................................................................................................ 203
Statistical analysis .................................................................................. 206
Results ............................................................................................................ 209
xi
Basal HPA axis function ........................................................................ 209
Blood glucose concentrations ................................................................. 209
Bond-Lader Scale ................................................................................... 210
Modified CVLT-II .................................................................................. 210
Immediate free recall ...................................................................... 210
Delayed recall ................................................................................. 211
Glucose regulation .......................................................................... 213
Basal HPA axis function ................................................................. 213
ASQ and trait anxiety ..................................................................... 213
Discussion .............................................................................................................. 216
Summary and Conclusions .................................................................................... 221
Chapter Eight: Memory for negative emotionally arousing items after oral glucose
ingestion ....................................................................................................................... 223
Abstract .................................................................................................................. 224
Introduction ........................................................................................................... 225
Study 6 ................................................................................................................... 227
Aims ............................................................................................................... 227
Hypotheses ..................................................................................................... 228
Method ........................................................................................................... 228
Participants ............................................................................................. 228
Treatment and design ............................................................................. 229
Materials ................................................................................................. 230
Saliva sampling equipment and free cortisol analysis .................... 230
Adolescent Stress Questionnaire (ASQ) ......................................... 230
State-Trait Anxiety Inventory (STAI) ............................................ 230
Memory test .................................................................................... 230
xii
Bipolar Profile of Mood States (POMS-Bi) ................................... 232
Satiety questionnaire ....................................................................... 232
Blood glucose monitoring equipment ............................................. 232
Procedure ................................................................................................ 232
Statistical analysis .................................................................................. 236
Results ............................................................................................................ 238
Basal HPA axis function ........................................................................ 238
Blood glucose concentrations ................................................................. 238
Satiety questionnaire .............................................................................. 240
POMS-Bi Questionnaire......................................................................... 240
Salivary free cortisol response ............................................................... 240
Memory test ............................................................................................ 242
Immediate recall ............................................................................. 242
Delayed recall ................................................................................. 243
Glucose regulation .......................................................................... 243
Basal HPA axis function ................................................................. 243
ASQ and trait anxiety ..................................................................... 243
Acute cortisol response ................................................................... 244
POMS-Bi ........................................................................................ 244
Discussion.............................................................................................................. 245
Summary and Conclusions .................................................................................... 250
Chapter Nine: General Discussion ............................................................................ 251
Introduction ........................................................................................................... 252
Summary and general discussion of key findings ................................................. 252
Significance of the findings in context of the extant literature ............................. 256
The glucose memory facilitation effect ......................................................... 256
xiii
One-week recall ............................................................................................. 257
Glycaemic load .............................................................................................. 257
The central executive and hippocampus hypotheses ..................................... 258
Glucoregulatory efficiency ............................................................................ 260
Baseline stress ................................................................................................ 261
Glucose and the emotional memory effect .................................................... 262
Limitations ............................................................................................................. 263
Future research directions ...................................................................................... 266
Summary and Conclusions .................................................................................... 268
References .................................................................................................................... 273
xiv
List of Figures
Figure 1.1 ........................................................................................................................ 43
Figure 1.2 ........................................................................................................................ 56
Figure 3.1 ........................................................................................................................ 84
Figure 3.2 ...................................................................................................................... 101
Figure 3.3 ...................................................................................................................... 103
Figure 4.1 ...................................................................................................................... 126
Figure 5.1 ...................................................................................................................... 152
Figure 6.1 ...................................................................................................................... 182
Figure 6.2 ...................................................................................................................... 185
Figure 6.3 ...................................................................................................................... 186
Figure 6.4 ...................................................................................................................... 188
Figure 7.1 ...................................................................................................................... 210
Figure 7.2 ...................................................................................................................... 211
Figure 7.3 ...................................................................................................................... 213
Figure 8.1 ...................................................................................................................... 239
Figure 8.2 ...................................................................................................................... 241
Figure 9.1 ...................................................................................................................... 270
List of Tables
xv
Table 1.1 ............................................................................................................................ 8
Table 1.2 .......................................................................................................................... 23
Table 3.1 .......................................................................................................................... 71
Table 3.2 .......................................................................................................................... 82
Table 3.3 .......................................................................................................................... 85
Table 3.4 .......................................................................................................................... 88
Table 3.5 .......................................................................................................................... 97
Table 3.6 .......................................................................................................................... 98
Table 3.7 .......................................................................................................................... 99
Table 3.8 ........................................................................................................................ 102
Table 4.1 ........................................................................................................................ 117
Table 4.2 ........................................................................................................................ 123
Table 4.3 ........................................................................................................................ 128
Table 4.4 ........................................................................................................................ 130
Table 4.5 ........................................................................................................................ 132
Table 5.1 ........................................................................................................................ 147
Table 5.2 ........................................................................................................................ 149
Table 5.3 ........................................................................................................................ 150
Table 5.4 ........................................................................................................................ 153
xvi
Table 5.5........................................................................................................................ 154
Table 5.6........................................................................................................................ 155
Table 5.7........................................................................................................................ 156
Table 5.8........................................................................................................................ 158
Table 5.9........................................................................................................................ 159
Table 6.1........................................................................................................................ 180
Table 7.1........................................................................................................................ 206
Table 7.2........................................................................................................................ 212
Table 7.3........................................................................................................................ 215
Table 8.1........................................................................................................................ 230
Table 8.2........................................................................................................................ 235
Table 8.3........................................................................................................................ 242
Acknowledgements
First and foremost, I would like to thank my two supervisors: Jonathan Foster
and Anke van Eekelen. Jonathan, your exhaustive knowledge in the field of cognitive
neuroscience and your dedication to your work are amazing and inspiring. Anke, thank
you for your guidance and for always offering such kind words of encouragement. I am
eternally grateful to the two of you for the constant support and advice that you have
offered me over the past three and a half years. Thanks also to the other two members of
the ‗Developmental Neuroscience Group‘: Eugen Mattes and our wonderful Research
Assistant, Hilary Hii. I have thoroughly enjoyed being part of the team during the
xvii
course of my PhD. Hilary, I would particularly like to thank you for all of your help
with the cortisol assays, and for your patience when teaching me the art (or should that
be ‗science‘) of pipetting! Thanks also to Kate Merkley for your assistance with the
blood glucose monitoring in Study 2.
I would also like to thank everyone who has been associated with the UWA
School of Paediatrics and Child Health over the past few years. Working alongside such
a great group of people has made my PhD journey so much more enjoyable. Although
there are way too may of you to thank individually, there are a few people whom I
would especially like to mention. To my office mate, May Ali, thanks so much for your
sound advice, the West Perth coffees/lunches, your wonderful sense of humour and
most importantly, for your friendship over the past few years. I would also like to thank
the following postdocs and senior researchers who have been such a great source of
information, advice and inspiration at various times over the past three and a half years:
Andrew Currie, Sunalene Devadason, Catherine Hayden, Lea-Ann Kirkham, Paul
Noakes and Selma Wiertsema. Your support and friendship is much appreciated!
This thesis could not have been completed without the numerous schools (and
associated staff) that helped me out with recruiting and the students that participated in
the studies reported in this thesis. Thanks to each and every one of you. Thanks also to
those participants and their parents in Newcastle upon Tyne who took part in Study 4.
I would also like to thank the staff and students of the Division of Psychology
and the Brain, Performance and Nutrition Research Centre at Northumbria University,
United Kingdom for hosting my research visit in 2008. Most notably, I would like to
thank Leigh Riby for all of his help with the ERP work which has formed the basis of
Study 4, and for making me feel very welcome in Newcastle. Thanks also to Dave
Kennedy, Crystal Haskell and Anthea Wilde for your assistance during my visit.
xviii
This thesis was supported by a University of Western Australia Postgraduate
Award (2006-2008) and an Australian Postgraduate Award (2009). I would also like to
acknowledge the following organisations for funding my exceptionally worthwhile
travel to conferences during the course of my PhD, as well as my study visit to the UK
in 2008: The Experimental Psychology Society, Convocation (the UWA Graduates
Association), the Australian Neuroscience Society, the Australian Research Alliance for
Children and Youth, the UWA Postgraduate Students Society, the UWA Graduate
Research School and the UWA School of Paediatrics and Child Health.
I would also like to take this opportunity to thank Sandra Sünram-Lea for all of
your assistance with the various questions that I‘ve had for you over the past few years,
and of course, for the delicious Italian lunch in Manchester!
Last, but certainly not least, I would like to thank my family and friends. To
Mum, Dad, Brendan, Di, Bill and my grandparents thank you for your continued
support over the years. And finally, thank you to Rachael, for being so wonderful
always and for giving me a reason to smile every single day.
xix
Publications and Presentations
The following publications have arisen during the course of my PhD candidature:
Smith, M. A., Hii, H. L., Foster, J. K., & van Eekelen, J. A. M. (in press). Glucose
enhancement of memory is modulated by trait anxiety in healthy adolescent
males. Journal of Psychopharmacology (Accepted 24 June 2009). [Study 5]
Smith, M. A., Riby, L. M., Sünram-Lea, S. I., van Eekelen, J. A. M., & Foster, J. K.
(2009). Glucose modulates event-related potential components of recollection
and familiarity in healthy adolescents. Psychopharmacology, 205, 11-20. [Study
4]
Smith, M. A., & Foster, J. K. (2008). The impact of a high versus a low glycaemic
index breakfast cereal on verbal episodic memory in healthy adolescents.
Nutritional Neuroscience, 11, 219-227. [Study 1B]
Smith, M. A., & Foster, J. K. (2008). Glucoregulatory and order effects on verbal
episodic memory in healthy adolescents after oral glucose administration.
Biological Psychology, 79, 209-215. [Study 3]
Foster, J. K., Smith, M. A., Woodman, M., Zombor, R., & Ashton, J. (2007). Impact of
a wholegrain breakfast cereal meal on blood glucose level, mood and affect.
Food Australia, 59, 593-596.
The following conference contributions have arisen during my PhD candidature:
Smith, M. A., Foster, J. K., & van Eekelen, J. A. M. (2009, February). Neurohormonal
mechanisms underlying memory: an evolutionary perspective. Paper presented
at the Evolution: The Experience Conference, Melbourne, Australia.
Smith, M. A., Foster, J. K., Hii, H., & van Eekelen, J. A. M. (2008, July). Stress,
glucose and memory in adolescents. Paper presented at the 29th
International
Congress of Psychology, Berlin, Germany. [Study 5, Study 6]
xx
Smith, M. A., Foster, J. K., Hii, H., & van Eekelen, J. A. M. (2008, June). Basal HPA
axis influences on glucose modulation of verbal episodic memory in adolescent
males. Paper presented at the Australian Society for Medical Research (ASMR)
Medical Research Week Symposium, Perth, Australia. [Study 5]
Smith, M. A. (2007, August). Sweet memories: Memory performance subsequent to
glucose ingestion in adolescents. Paper presented at the Telethon Institute for
Child Health Research Postgraduate Research Forum, Perth, Australia. [Study 3]
Smith, M. A., & Foster, J. K. (2007, July). Glucose delivery via breakfast cereal
enhances memory in healthy adolescents. Poster presented at the 7th
International Brain Research Organization World Congress of Neuroscience,
Melbourne, Australia. [Study 1B]
Smith, M. A., & Foster, J. K. (2006, November). The glucose memory facilitation
effect: the role of executive load. Paper presented at the 12th
Annual Conference
of the APS College of Clinical Neuropsychologists, Sydney, Australia. [Study
1A]
1
Chapter One
A literature review of the glucose memory facilitation effect
2
Introduction
A large number of research reviews have addressed the issue of memory
modulation subsequent to glucose ingestion over the past 20 years (Wenk, 1989; Sieber
& Traystman, 1992; Rogers & Lloyd, 1994; Gold, 1995; Messier & Gagnon, 1996;
Korol & Gold, 1998; Dye, Lluch, & Blundell, 2000; Benton, 2001; Scholey, 2001;
Gibson & Green, 2002; Korol, 2002; McNay & Gold, 2002; Benton & Nabb, 2003;
Greenwood, 2003; Bellisle, 2004; Messier, 2004; Riby, 2004; Watson & Craft, 2004;
Gold, 2005; Riby & Riby, 2006; Gibson, 2007; Benton, 2008; Hoyland, Lawton, &
Dye, 2008; Ooi, Yassin, Tengku-Aizan, & Loke, 2008; Stone & Seidman, 2008;
Gilsenan, de Bruin, & Dye, 2009). The purpose of the present review is not to
comprehensively replicate the material covered in these previous reviews, but to ‗set the
scene‘ for the present thesis by reviewing a number of salient studies which have
investigated the influence of glucose ingestion on neurocognitive performance in
individuals with a) compromised neurocognitive capacity, as well as b) normally
functioning individuals (with a focus on research conducted with human participants).
The proposed neurocognitive mechanisms purported to underlie the modulatory effect
of glucose on neurocognitive performance will then be considered, before a discussion
of a possibly related phenomenon – ‗emotional memory‘. Finally, on the basis of the
review, a number of unresolved questions pertaining to glucose modulation of memory
will be posed, which the present thesis aimed to address.
The glucose memory facilitation effect
The brain relies upon glucose as its primary fuel (Sieber & Traystman, 1992).
This has important implications for patients with diabetes and related glucoregulatory
complications who experience acute hypoglycaemia (i.e. a decrease in blood glucose
concentration to below 2.8 mmol/L, Sieber & Traystman, 1992), a condition which has
3
been associated with adverse neurocognitive functioning (Warren & Frier, 2005).
Conversely, in recent years, a rich literature has developed from both human and animal
studies indicating that increases in circulating blood glucose can facilitate cognitive
functioning. This phenomenon has been termed the ‗glucose memory facilitation effect‘
(Foster, Lidder, & Sünram, 1998). A number of neurocognitive mechanisms have been
proposed to mediate the enhancing effect of glucose on memory. The hippocampus is a
brain region that is heavily implicated in learning and memory (Shastri, 2002); therefore
this brain structure is implicated in many theories of the glucose memory facilitation
effect (Riby & Riby, 2006).
The suggestion that glucose ingestion enhances cognition was first reported by
Lapp (1981), in a study which found that healthy adolescents with higher blood glucose
levels following a carbohydrate-rich meal displayed enhanced recall of word pairs
relative to a fasting control group (Lapp, 1981; Messier, 2004). Subsequent early studies
focused on glucose facilitation of memory in populations with cognitive deficits, such
as the elderly, and patients with disorders involving memory impairment, including
dementia, schizophrenia and Down‘s syndrome. It has been suggested that older
individuals may benefit to a greater degree from glucose administration, as healthy
young individuals are near to their ‗cognitive peak‘ (Foster et al., 1998). However,
there is now an abundant literature to suggest that under certain conditions, glucose can
also enhance memory in healthy young adults.
‘Healthy’ ageing
Ageing is typically associated with some degree of forgetting and memory loss
(Winocur, 1988; Craik, 1994; Grady & Craik, 2000; Salthouse, 2003). Much of the
early work in humans investigating the influence of glucose ingestion on neurocognitive
performance focused on elderly individuals. The rationale for theories which implicated
4
glucose as a potential cognitive enhancer in elderly individuals was that ageing is
accompanied by neuroendocrine dysregulation (Korol & Gold, 1998), including
deficiencies in the regulation of key hormones involved in both memory storage and
glucose regulation, such as adrenaline (Korol & Gold, 1998; Gold, 2005). In addition,
poor glucose regulation is particularly prevalent in older individuals (Parsons & Gold,
1992; Messier & Gagnon, 1996; Awad, Gagnon, Desrochers, Tsiakas, & Messier, 2002;
Messier, 2004, 2005).
The typical methodological procedure employed in this line of research involves
the administration of different tests of cognitive functioning subsequent to the ingestion
of either a) a glucose laden drink, or b) a sweetness-matched placebo drink (the latter
usually comprising saccharin or aspartame). Blood glucose concentration is also
generally measured at baseline, post-treatment and at pre-determined intervals during
cognitive testing. Within-subjects designs are most typically employed in research
conducted with healthy elderly individuals, with each participant consuming one
treatment on the first testing day and the complementary treatment on the second testing
day, thereby acting as their own control. Participants are typically requested to fast
overnight prior to treatment administration (Riby, 2004).
Table 1.1 displays the findings of studies which have specifically investigated
the influence of oral glucose ingestion in healthy elderly individuals (versus saccharin
placebo) on various measures of neurocognitive performance. Verbal episodic memory
was the domain of cognitive functioning that was most frequently considered in these
studies, with the majority of these studies concluding that glucose improves verbal
episodic memory performance in healthy elderly individuals (Hall, Gonder-Frederick,
Chewning, Silvera, & Gold, 1989; Manning, Hall, & Gold, 1990; Manning, Parsons, &
Gold, 1992; Parsons & Gold, 1992; Manning, Parsons, Cotter, & Gold, 1997; Manning,
Stone, Korol, & Gold, 1998b; Riby, Meikle, & Glover, 2004; Riby, McMurtrie,
5
Smallwood, Ballantyne, Meikle, & Smith, 2006). Glucose was also observed to enhance
performance in additional cognitive domains in this age group, including attention
(Messier, Gagnon, & Knott, 1997), design fluency, verbal fluency and visual memory
(Allen, Gross, Aloia, & Billingsley, 1996).
One study in older individuals reported that glucose facilitation of verbal
episodic memory occurred irrespective of whether glucose was administered a) pre-
encoding or b) post-encoding of the to-be-remembered stimuli (Manning et al., 1992),
while a further study by the same group found that glucose facilitated memory
performance when glucose was administered a) pre-encoding or b) pre-retrieval of the
to-be-remembered stimuli (Manning et al., 1998b). On this basis, it can be inferred that
an increase in blood glucose concentration via the administration of oral glucose
enhances verbal episodic memory performance in older adults via a range of possible
mechanisms (i.e. glucose modulation of memory is not specific to encoding,
consolidation or retrieval). In both of these studies (Manning et al., 1992; Manning et
al., 1998b), glucose was observed to enhance verbal episodic memory when retrieval
took place after a 24 hour delay.
One study in elderly individuals investigated the influence of carbohydrate
delivery via potato and barley, with neither of these treatments yielding significantly
improved neurocognitive performance relative to placebo (although glucose also failed
to induce an enhancing effect on neurocognitive performance in this study; Kaplan,
Greenwood, Winocur, & Wolever, 2000). In addition, two further studies also
investigated the role of glucose administration on verbal episodic memory under
conditions of divided attention during encoding in older adults (involving performance
of a secondary card sorting task; Riby et al., 2004; Riby et al., 2006). One of these
studies reported that glucose was observed to improve memory performance
irrespective of whether a secondary task was implemented (Riby et al., 2004), while the
6
other found that the glucose memory enhancement effect was not present under dual-
task conditions (Riby et al., 2006).
In the study by Parsons and Gold (1992), participants presented for testing on
four different days, separated by an interval of at least one week. In a counterbalanced
order, participants received one of three glucose doses (10 g, 25 g, 50 g) or a saccharin
placebo in each of the four test sessions. While glucose enhancement of verbal episodic
memory was observed subsequent to ingestion of the 25 g glucose dose (relative to
placebo), the 10 g and 50 g glucose doses did not induce a significant memory
improvement when compared to placebo. It was therefore concluded that i) 25 g glucose
is the optimal glucose dose to be administered in order to observe memory facilitation in
elderly humans, and ii) the glucose memory facilitation effect follows an inverted-U
shaped dose response curve in humans (Parsons & Gold, 1992). A meta-analytic review
of the glucose memory facilitation effect subsequently replicated the finding that 25 g is
the optimal glucose dose for inducing a memory enhancement effect subsequent to
glucose ingestion (Riby, 2004). However, these findings (Parsons & Gold, 1992; Riby,
2004) are not consistent with other investigations of the glucose memory facilitation
effect in older adults which have found that glucose improves verbal episodic memory
performance subsequent to a 50 g glucose dose (Hall et al., 1989; Manning et al., 1990;
Manning et al., 1992; Manning et al., 1997; Manning et al., 1998b). On this basis,
Parsons and Gold (1992) suggest that it may not be the size of the glucose dose per se
that determines the effectiveness of glucose administration in facilitating memory
performance. More specifically, the blood glucose concentration following the delivery
of glucose appears to be the most relevant parameter (blood glucose concentration
subsequent to a glucose load is modulated by various factors including, but not limited
to, glucoregulatory efficiency and body mass index). Some animal studies have
attempted to address the issue of body size as a potentially confounding factor, by
7
administering a glucose dose that is dependent on body weight, and which therefore
differs between participants (e.g. Stone, Rudd, & Gold, 1992; Winocur, 1995; Messier,
1997; Winocur & Gagnon, 1998; Salinas & Gold, 2005). However this procedure is not
typically used in human studies (c. f. Messier, Pierre, Desrochers, & Gravel, 1998).
Based on the results reported by Parsons and Gold (1992), it appears that the most
effective blood glucose range for observing enhancement of verbal episodic memory in
elderly individuals is approximately 8-10 mmol/L.
8
Table 1.1
Outcomes of studies investigating glucose modulation of memory in healthy elderly individuals. All studies below employed a repeated
measures design and incorporated an overnight fasting regimen. Ticks indicate glucose enhancement of the specified cognitive domain,
relative to a saccharin placebo. Dashes indicate that the specified cognitive domain was investigated, but no significant difference was
observed between glucose and saccharin placebo conditions.
Reference Age (years) Glucose Dose (g)
Att
enti
on
Des
ign F
luen
cy
Impli
cit
Mem
ory
Moto
r F
unct
ion
Pro
cess
ing S
pee
d
Sem
anti
c M
emory
Ver
bal
Epis
odic
Mem
ory
Ver
bal
Flu
ency
Vis
ual
Mem
ory
Work
ing M
emory
Hall et al. (1989) 58-77 50 — —
Manning et al. (1990) 62-84 50 — — — —
Manning et al. (1992)a
60-81 50
Parsons & Gold (1992) 60-82 10 —
Parsons & Gold (1992) 60-82 25
Parsons & Gold (1992) 60-82 50 —
Allen et al. (1996) 61-87 50 — —
9
Manning et al. (1997) 61-80 50 —
Messier et al. (1997)b >55 50 — — —
Manning et al. (1998b)c
60-83 50
Kaplan et al. (2000) 60-82 50d — —
Riby et al. (2004) 60-80 25 — e — —
Riby et al. (2006) M = 68, SD = 5.9 25 — f
—
aGlucose modulation of memory was observed in this study irrespective of whether glucose was administered pre-encoding or post-
encoding. bThis study included ‗glucoregulatory efficiency‘ as a further condition, which yielded numerous treatment x glucoregulatory
efficiency interaction effects in addition to the main effects of treatment (demonstrating overall enhanced cognitive performance
subsequent to glucose ingestion). cGlucose modulation of memory was observed in this study irrespective of whether glucose was
administered pre-encoding or pre-retrieval. dTwo further conditions delivered 50g carbohydrate via a) mashed potato and b) barley,
however neither of these conditions were associated with enhanced memory performance. eGlucose enhancement observed irrespective of
whether a secondary task was administered. fGlucose enhancement not observed when a secondary task was administered.
10
Glucoregulatory efficiency
As mentioned above, it is likely that glucose regulation modulates the glucose
memory facilitation effect. This may especially be the case in older adults, who are
more likely than younger individuals to experience glucoregulatory abnormalities
(Dahle, Jacobs, & Raz, 2009). In healthy individuals, blood glucose concentration
typically peaks approximately 30 minutes following the ingestion of food, before
decreasing to baseline levels within two hours. However, blood glucose typically
remains higher for a longer period in individuals with poor glucose regulation (Donohoe
& Benton, 2000). Poor glucoregulation is associated with memory impairment in both
aged humans (Messier et al., 1997; Kaplan et al., 2000; Convit, Wolf, Tarshish, & de
Leon, 2003; Messier, Tsiakas, Gagnon, Desrochers, & Awad, 2003; Riby et al., 2004;
Convit, 2005; Messier, 2005; Dahle et al., 2009; Lamport, Lawton, Mansfield, & Dye,
2009) and rodents (Winocur, 1995; Greenwood & Winocur, 2001). On a related note,
brain glucose metabolism (including reduced and slowed capacity for facilitated glucose
transport across the blood-brain barrier) is also known to become impaired as a
consequence of ageing (Korol & Gold, 1998; Convit, 2005). This deficit may be
mediated by the glucocorticoid stress hormone, cortisol (Convit, 2005). Impairments in
glucoregulatory efficiency and brain glucose metabolism may be important when
considering the role of glucose in modulating neurocognitive performance in the
elderly.
A number of studies have specifically investigated the influence of
glucoregulatory efficiency on the glucose memory facilitation effect in elderly humans.
Craft and colleagues (1994) investigated the effects of age, gender and glucoregulation
on cognitive performance. In this study, episodic memory improvements were observed
in older adults exhibiting relatively better glucoregulatory efficiency following glucose
ingestion, but not in older adults exhibiting relatively poorer glucoregulatory efficiency.
11
Conversely, memory enhancement following glucose ingestion was also observed in
younger males exhibiting relatively poorer glucoregulatory efficiency, but not younger
men exhibiting relatively better glucoregulatory efficiency. However, these findings
(Craft et al., 1994) should be treated with caution. Overall, the older adults in this study
had much poorer glucose recovery indices (used as a measure of glucoregulation) than
the younger adults. Therefore, even those older adults exhibiting ‗good‘ glucoregulatory
efficiency in these studies may not be considered as ‗normal‘ glucoregulators relative to
the general population, given that their glucose recovery indices were comparable to the
‗poor‘ glucoregulators in the young adult age group. Although speculative, it may well
be the case that i) the blood glucose concentrations of the older adults with relatively
better glucoregulatory efficiency and the younger adults with relatively poorer
glucoregulatory efficiency in this study were within the optimal limit for inducing a
facilitative effect on memory, rather than ii) glucoregulatory efficiency per se having a
modulatory influence on the glucose memory facilitation effect. In addition to these
findings by Craft and colleagues (1994), Messier and colleagues (1997) reported that in
a study with elderly individuals, glucose enhanced the primacy effect on a paragraph
recall task for better, but not poorer, glucoregulators (Messier et al., 1997).
More recently, research conducted by Kaplan and colleagues (2000) has
demonstrated that poor glucoregulatory efficiency in healthy elderly individuals is
associated with compromised cognitive ability, and that ingestion of glucose can reverse
this deficit. Specifically, a regression analysis revealed that glucoregulatory efficiency
predicts baseline episodic memory performance, with poorer glucoregulators exhibiting
poorer baseline episodic memory ability (Kaplan et al., 2000). Further, glucose delivery
to the bloodstream via a 50 g glucose drink, or via ingestion of barley or mashed potato
was associated with episodic memory improvement relative to a placebo only for the
relatively poorer glucoregulators in this study. Similarly, Messier and colleagues (2003)
12
also reported that oral glucose ingestion attenuated the observed deficits in episodic
memory performance in those elderly participants who exhibited relatively poorer
glucoregulatory efficiency.
Previous findings regarding the influence of glucoregulatory efficiency on the
glucose memory facilitation effect in the elderly are therefore mixed. While glucose
regulation appears to be an important modulatory variable, the results of some studies
suggest that elderly individuals exhibiting relatively better glucoregulatory efficiency
are more likely to demonstrate the glucose memory facilitation effect (e.g. Craft et al.,
1994; Messier et al., 1997), while the findings of other previous work suggests that
glucose enhancement of memory is more likely in poorer glucoregulators (e.g. Kaplan
et al., 2000; Messier et al., 2003). This discrepancy between studies is difficult to
explain, but may be related to the fact that most studies determine glucoregulatory
efficiency groups by performing a median split on some measure of glucose response
(such as recovery index). Due to the relatively small sample size of most studies in this
area, the definition of ‗good‘ and ‗poor‘ glucose regulation can vary drastically between
studies due to this method of defining glucoregulatory groups. This can bring about vast
differences between studies in terms of whether the glucose concentration of the ‗good‘
or ‗poor‘ glucoregulators is within the optimal range to induce a cognitive benefit at the
time of testing (according to the inverted-U dose-repose curve suggested by Parsons &
Gold, 1992).
Clinical populations with underlying memory deficits
Thus far, the present review has considered the effect of glucose administration
on cognitive performance in healthy elderly individuals. The ingestion of oral glucose
has also been robustly demonstrated to improve cognitive performance in a number of
patients suffering from clinical syndromes associated with cognitive impairment.
13
Disorders that have been considered in previous human studies investigating the role of
glucose ingestion in modulating neurocognitive performance include Alzheimer‘s
disease, Down‘s syndrome, schizophrenia, mild head injury and mild cognitive
impairment.
Alzheimer’s disease
It is unsurprising that glucose has been investigated as a possible cognitive
enhancer in patients suffering from Alzheimer‘s disease, given that this condition is
associated with glucoregulatory abnormalities (Messier & Gagnon, 1996; Watson &
Craft, 2004). Three key studies have specifically investigated whether glucose
influences memory performance in patients with Alzheimer‘s disease. Firstly, it was
reported by Manning and colleagues (Manning, Ragozzino, & Gold, 1993) that the
ingestion of 75 g oral glucose attenuates deficits in episodic memory performance
relative to a saccharin placebo in patients with Alzheimer‘s disease. Craft and
colleagues (Craft, Zallen, & Baker, 1992) further reported that oral glucose ingestion
enhanced verbal episodic memory performance in patients suffering from Alzheimer‘s
disease exhibiting relatively poorer glucoregulatory efficiency, but not in healthy adults
of a similar age who exhibited relatively better glucoregulatory efficiency. In a further
study by the same group, cognitive performance was assessed in Alzheimer‘s patients
under three conditions (fasting glucose, blood glucose concentration = 9.7 mmol/L and
blood glucose concentration = 12.5 mmol/L), with a hyperglycaemic clamping
procedure used to achieve target blood glucose concentrations (Craft, Dagogo-Jack,
Wiethop, Murphy, Nevins, Fleischman et al., 1993). Verbal episodic memory
performance was significantly enhanced following an increase in blood glucose to 12.5
mmol/L only, relative to performance following an overnight fast, for participants with
very mild Alzheimer‘s dementia. At a subsequent follow-up 18 months following the
14
original testing session, this same pattern of memory enhancement was observed for
patients maintaining diagnostic criteria for very mild Alzheimer‘s disease. However, for
those participants whose Alzheimer‘s dementia had progressed beyond the classification
of ‗very mild‘ over the 18-month interval between test phases, glucose facilitation of
memory was no longer observed in either of the two glucose conditions (Craft et al.,
1993).
From the findings of these three aforementioned studies (Craft et al., 1992; Craft
et al., 1993; Manning et al., 1993), it can be inferred that glucose is effective as a
cognitive enhancer in at least some patients with Alzheimer‘s disease. These findings
also demonstrate the potential clinical significance of the glucose memory facilitation
effect, in that glucose has been demonstrated to serve as an effective intervention
against the key memory deficits experienced by Alzheimer‘s patients in these previous
studies (Craft et al., 1992; Craft et al., 1993; Manning et al., 1993). However, it is
important to note that only the study by Craft and colleagues (Craft et al., 1992) actually
employed a group of healthy controls in order to directly compare the cognitive
performance of Alzheimer‘s patients and healthy aged matched controls. It is therefore
difficult to gauge from this series of studies whether glucose is more or less effective in
terms of cognitive enhancement in patients with Alzheimer‘s disease or in healthy
individuals. However, Manning and colleagues (Manning et al., 1993) mention that
while attenuation of memory deficits was observed in Alzheimer‘s patients subsequent
to glucose ingestion, the level of performance on the cognitive tests administered in the
Alzheimer‘s patients did not reach the level that would be expected by a healthy
individual. Future work in this area should a) focus on more detailed comparisons of
memory performance subsequent to glucose ingestion in individuals with Alzheimer‘s
disease and healthy controls, and b) further investigate the relationship between glucose
ingestion, memory performance and glucoregulatory efficiency in Alzheimer‘s patients.
15
It is of interest that Craft and colleagues observed a dissociation in terms of memory
performance between individuals with Alzheimer‘s disease and healthy controls that
was dependent on glucoregulatory efficiency. As mentioned previously in this literature
review, the relationship between glucose ingestion, memory performance and
glucoregulatory efficiency is likely to be complex. This may especially be the case in
Alzheimer‘s disease, which is characterised by glucoregulatory abnormalities,
potentially related to the apolipoprotein (APOE) ε4 allele. Alzheimer‘s patients who are
non-carriers of this allele are known to be at risk of developing glucoregulatory
complications (Messier, 2003; Watson & Craft, 2004). In addition, this relationship is
further complicated by reports that increases in blood insulin (in the absence of blood
glucose increases) also enhance cognitive performance in individuals with Alzheimer‘s
disease (Craft, Newcomer, Kanne, Dagogo-Jack, Cryer, Sheline et al., 1996).
Schizophrenia
Episodic memory impairment is one of a number of prominent clinical features
of schizophrenia (Stone & Seidman, 2008), and the role of glucose in attenuating
cognitive impairment in this disorder has been investigated previously. Stone and
colleagues (Stone, Seidman, Wojcik, & Green, 2003) reported an improvement in
verbal episodic memory performance in patients with schizophrenia subsequent to oral
glucose ingestion. An additional study also observed an enhancement effect for verbal
episodic memory subsequent to glucose ingestion (relative to placebo) in individuals
with schizophrenia, but not in healthy or psychiatric (i.e. bipolar) controls (Newcomer,
Craft, Fucetola, Moldin, Selke, Paras et al., 1999). A further study by this same group
also investigated the dose- and age-dependent nature of the relationship between
glucose ingestion and cognitive performance in patients with schizophrenia (Fucetola,
Newcomer, Craft, & Melson, 1999). In this study, recognition memory performance
16
was improved subsequent to ingestion of 50 g and 75 g glucose (relative to placebo) in
older (> 42 years), but not younger (< 42 years), individuals with schizophrenia.
However, enhancement of recognition memory performance was also observed
subsequent to the 75g glucose dose in older healthy controls in this study. Spatial
memory performance was also improved subsequent to ingestion of 50 g glucose in
older patients with schizophrenia, and ingestion of 75 g glucose was observed to
facilitate attention in younger patients with schizophrenia (Fucetola et al., 1999). On the
combined weight of this evidence, glucose appears to be an effective cognitive enhancer
in schizophrenia patients.
Down’s syndrome
An additional study (Manning, Honn, Stone, Jane, & Gold, 1998a) investigated
the influence of glucose on neurocognitive performance in adults with Down‘s
syndrome. In this previous study, ingestion of 50 g glucose was observed to enhance
performance on the Memory, Apraxia and Language subtests of the Down‘s Syndrome
Mental Status Exam (DSMSE), as well as the total score for the DSMSE (relative to
placebo). Further, word recall (assessed via a modified version of the Rey Auditory
Verbal Learning Test; RAVLT) was also improved subsequent to glucose ingestion,
relative to placebo. This previous study provides further evidence for the clinical
significance of the glucose memory facilitation effect. However, this study is the only
previous investigation in the literature of glucose effects on neurocognitive performance
in Down‘s syndrome, and the investigators neglected to include a sample of healthy
controls. Therefore, on the basis of this study, it is difficult to ascertain whether the
observed improvements in memory subsequent to glucose ingestion are comparable to
those seen in healthy adults. Moreover, whether glucose induced an improvement in
17
memory performance in the individuals with Down‘s syndrome to the level typical of
healthy individuals is also uncertain.
Mild head injury and mild cognitive impairment
The clinical significance of the glucose memory facilitation effect has been
further demonstrated by two studies which have investigated the role of glucose in the
enhancement of memory in individuals with mild sports-related head injury (Pettersen
& Skelton, 2000) and in older adults with mild cognitive impairment (Riby, Marriott,
Bullock, Hancock, Smallwood, & McLaughlin, 2009). In the study by Pettersen and
Skelton (2000), healthy young adults who had sustained at least one concussion in the
previous 10 years performed better on a test of verbal episodic memory subsequent to
oral glucose ingestion, relative to placebo. Riby and colleagues (2009) also observed a
glucose enhancement effect (relative to placebo) for elderly patients with mild cognitive
impairment (defined as episodic memory impairment in the absence of executive
dysfunction, impaired capacity for normal daily living, depression or delirium).
However, a group of healthy elderly participants were also included in this study (Riby
et al., 2009), with the healthy and mild cognitive impairment groups being
indistinguishable in terms of the relative degree of glucose induced memory
enhancement. In addition, the difference in verbal episodic memory performance
between the glucose and placebo conditions in the study by Riby and colleagues (2009)
did not reach statistical significance. On the basis of these two studies, there appears to
be some support for the glucose memory facilitation effect in individuals with mild head
injury or mild cognitive impairment, however more studies are needed to corroborate
the findings of Pettersen and Skelton (2000) and Riby and colleagues (2009).
18
Healthy young individuals: The role of divided attention
Over the course of the past 20 years, a number of studies have addressed the
question of whether glucose can additionally influence neurocognitive performance in
younger individuals, who are less likely to be suffering from cognitive difficulties than
other participant groups (see Table 1.2). Similar to the body of research that has been
conducted in elderly humans, much of this work has investigated glucose enhancement
of verbal episodic memory, with a number of studies reporting that oral glucose
ingestion enhances verbal episodic memory performance in healthy young adults
(Benton, Owens, & Parker, 1994; Parker & Benton, 1995; Foster et al., 1998; Messier et
al., 1998; Sünram-Lea, Foster, Durlach, & Perez, 2001, 2002a, 2002b; Meikle, Riby, &
Stollery, 2004; Sünram-Lea, Foster, Durlach, & Perez, 2004; Meikle, Riby, & Stollery,
2005; Riby et al., 2006; Morris, 2008; Riby, McLaughlin, & Riby, 2008a). Notably,
divided attention appears to play an important role in glucose facilitation of verbal
episodic memory in younger individuals.
Some studies have incorporated a dual tasking paradigm, with participants
performing a secondary task (e.g. performing sequences of hand movements) during
encoding of a supraspan memory list (Foster et al., 1998; Sünram-Lea et al., 2001,
2002a, 2002b, 2004; Riby et al., 2006). Studies that incorporated a dual tasking
procedure have all reported that glucose improves verbal episodic memory performance
when memory materials are encoded under conditions of divided attention. However, a
number of studies have failed to observe a glucose enhancement effect in healthy young
adults for tests of verbal episodic memory in which memory materials were encoded
under single task conditions (Hall et al., 1989; Azari, 1991; Benton & Owens, 1993b;
Manning et al., 1997; Winder & Borrill, 1998; Scholey, Harper, & Kennedy, 2001;
Scholey & Kennedy, 2004). In addition, further studies that have observed a glucose
enhancement effect in the domain of verbal episodic memory under single task
19
conditions in healthy young adults have reported an improvement only for primacy
and/or recency items (Benton et al., 1994; Messier et al., 1998), or when a dichotic
listening paradigm is employed (Parker & Benton, 1995). Morris (2008) observed a
glucose enhancement effect in the domain of verbal episodic memory task under single
task conditions. However, this was not a typical task of verbal episodic memory as the
to-be-remembered information was incorporated within the narrative of a lengthy (~9
minutes) public safety video (Morris, 2008). Therefore, it is likely that this task was
considerably more difficult than a typical verbal episodic memory task comprising
recall of a supraspan word list. On the basis of the evidence discussed here, it can be
concluded that glucose only reliably facilitates verbal episodic memory in healthy
young adults when memory materials are encoded under conditions of divided attention.
In a related study (Scholey, Sünram-Lea, Greer, Elliott, & Kennedy, 2009), a
dual tasking paradigm was employed in which participants were required to perform an
attention task which involved tracking a moving stimulus on a computer screen
simultaneously with encoding of a supraspan word list, subsequent to ingestion of
glucose or a saccharin placebo. Word list retention was tested by a recognition memory
procedure, in which participants were required to distinguish studied words from foils
(in the absence of the tracking task). Glucose ingestion was observed to improve
tracking performance, but not recognition memory performance, in the healthy young
adult participants. This study demonstrates that oral glucose ingestion can improve
performance on non-memory tasks in healthy young adults, possibly by enhancing an
individual‘s capacity to divide attention between two or more concurrent tasks (Scholey
et al., 2009).
In accordance with the findings of Scholey and colleagues (2009) discussed
above, the findings of other previous studies have suggested that the ingestion of oral
glucose can enhance domains of cognitive function beyond verbal episodic memory.
20
Previous findings support a role for glucose in facilitating attention (Benton, 1990;
Meikle et al., 2004; Reay, Kennedy, & Scholey, 2006), face recognition (Metzger,
2000), semantic memory (Riby et al., 2006), verbal fluency (Donohoe & Benton,
1999b), visuospatial functioning (Scholey & Fowles, 2002), visuospatial long-term
memory (Sünram-Lea et al., 2001, 2002a, 2002b) and working memory (Hall et al.,
1989; Kennedy & Scholey, 2000; Scholey et al., 2001; Sünram-Lea et al., 2002b;
Meikle et al., 2004; Sünram-Lea et al., 2004; Reay et al., 2006). Further, in addition to
verbal episodic recall, oral glucose ingestion has been reported to enhance recognition
memory for a supraspan word list in healthy young adults (Sünram-Lea et al., 2001,
2002a, 2002b, 2004; Sünram-Lea, Dewhurst, & Foster, 2008). Glucose has also been
investigated as a possible cognitive enhancer when administered in combination with
additional substances with known cognitively enhancing properties, such as caffeine
(Scholey & Kennedy, 2004), ginkgo biloba (Scholey & Kennedy, 2004) and ginseng
(Scholey & Kennedy, 2004; Reay et al., 2006). Specifically, glucose has been
demonstrated to improve attention in healthy young adults when administered in
combination with ginseng (Reay et al., 2006), and to improve attention and episodic
memory when administered in combination with caffeine, ginseng and ginkgo biloba
(Scholey & Kennedy, 2004).
Messier and colleagues (1998) conducted a study to investigate the dose-
response relationship between glucose ingestion and verbal episodic memory
performance in healthy young women. A unique aspect of this study was that the
glucose doses administered were based upon a specific quantity of glucose per kilogram
of body weight. As mentioned previously, this procedure has been more typically
employed in animal studies investigating glucose modulation of memory (e.g. Gold,
1986; Messier, Durkin, Mrabet, & Destrade, 1990; Stone et al., 1992; Winocur, 1995;
Messier, 1997; Winocur & Gagnon, 1998; Greenwood & Winocur, 2001; Salinas &
21
Gold, 2005), whereas human studies typically involve the administration of a standard
glucose dose that does not account for body weight. This may be a critically important
factor in determining whether glucose ingestion modulates cognitive performance, as
glucoregulatory efficiency differs between individuals of different body weights. In
addition, the quantity of glucose delivery to the brain would be expected to differ
between individuals of different body weights due to a number of factors including a)
different rates of glucose utilisation as an energy substrate, and b) differences in
circulating blood volumes. The only glucose dose that was reported to enhance verbal
episodic memory performance in this study was the 300 mg/kg dosage, which was
observed to enhance immediate recall of the first five items of a supraspan word list
relative to placebo. Higher and lower glucose doses failed to confer any benefit in terms
of immediate recall performance (Messier et al., 1998).
Interestingly, there are a number of differences with respect to the research
methodology employed between the younger and older adult studies investigating the
role of glucose as a cognitive enhancer. For example, all of the older adult studies
presented in Table 1.1 utilised a within-subjects (repeated measures) design, whereas
the younger adult studies have employed both within- and between-subjects designs.
Additionally, as discussed above, several of the studies conducted with young adult
participants have employed a dual-tasking procedure, with the weight of evidence
suggesting that glucose only reliably facilitates verbal episodic memory under
conditions of divided attention. Only two older adult studies have incorporated a dual-
tasking procedure (Riby et al., 2004; Riby et al., 2006). In contrast to the findings with
younger adults, one of the aforementioned studies in the elderly actually reported that
glucose failed to enhance verbal episodic memory performance when a secondary task
was administered (Riby et al., 2006). However, one similarity between the older and
younger adult studies relates to the finding that glucose is effective in facilitating verbal
22
episodic memory performance irrespective of whether glucose is administered pre- or
post-encoding (Manning et al., 1992; Sünram-Lea et al., 2002a).
23
Table 1.2
Outcomes of studies investigating glucose modulation of memory in younger adults. Ticks indicate glucose enhancement of the specified
cognitive domain, relative to a saccharin or aspartame placebo. Dashes indicate that the specified cognitive domain was investigated, but
no significant difference was observed between glucose and placebo conditions. The divided attention column indicates whether
participants were required to encode memory materials under dual task conditions in studies in which verbal episodic memory was
investigated. The design column indicates whether a between- or within- subjects design was employed for the glucose versus placebo
comparison.
Reference Age (years)
Glucose
Dose
Divided
Attention Design
Att
enti
on
Exec
uti
ve
Funct
ionin
g
Fac
e R
eco
gnit
ion
Rec
ognit
ion M
emory
Sem
anti
c M
emory
Ver
bal
Epis
odic
Mem
ory
Ver
bal
Flu
ency
Vis
uosp
atia
l F
unct
ionin
g
Vis
uosp
atia
l M
emory
Work
ing M
emory
Hall et al. (1989) 18-23 50 g No Within — —
Benton (1990) M = 20.3, SD = 1.7 25 g N/A Between
Azari (1991) 19-25 30 g No Within — —
Azari (1991) 19-25 100 g No Within — —
Benton & Owens (1993b)a
M = 21.6, SD = 4.8 50 g No Between — —
24
Benton et al. (1994) M = 21.5 50 + 25 gb
No Between — — c
Parker & Benton (1995)
M = 20.2 50 + 25 gb
No Between —
d
Manning et al. (1997) 17-22 50 g No Within — —
Foster et al. (1998) 18-22 25 g Yes Between — — —
Messier et al. (1998) 17-48 10 mg/kg No Between —
Messier et al. (1998) 17-48 100 mg/kg No Between —
Messier et al. (1998) 17-48 300 mg/kg No Between e
Messier et al. (1998) 17-48 500 mg/kg No Between —
Messier et al. (1998) 17-48 800 mg/kg No Between —
Messier et al. (1998) 17-48 1000 mg/kg No Between —
Winder & Borrill (1998) 18-55 50 g No Between —
Donohoe & Benton (1999b)f
M = 21.8, SD = 5.1 50 g N/A Between — —
Metzger (2000) 17-45 50 g N/A Between
Kennedy & Scholey (2000) 19-30 25 g N/A Within —
Morris & Sarll (2001) M = 21.2, SD = 4.4 50 g N/A Between —
Scholey et al. (2001) 20-30 25 g No Within — —
Sünram-Lea et al. (2001)g
18-28 25 g Yes Between —
25
Scholey & Fowles (2002) M = 23.6, SD = 6.5 25 g N/A Between
Sünram-Lea et al. (2002a)h
19-26 25 g Yes Between —
Sünram-Lea et al. (2002b) 18-29 25 g Yesi Between
Meikle et al. (2004) M = 21.8, SD = 3.3 25 g No Within — — — — —
Meikle et al. (2004) M = 21.8, SD = 3.3 50 g No Within — — — — —
Meikle et al. (2004) M = 38.4, SD = 6.7 25 g No Within — — —
Meikle et al. (2004) M = 38.4, SD = 6.7 50 g No Within — — —
Scholey & Kennedy (2004) 18-32 37.5 gj
No Within — — —
Sünram-Lea et al. (2004) 18-28 25 gk Yes Between —
Meikle et al. (2005) 17-48 25 g No Between
Reay et al. (2006) M = 21.9, SD = 4.6 25 g N/A Within l
Riby et al. (2006) M = 30.1, SD = 4.6 25 g Yes Within —
Morris et al. (2008) 19-38 50 g No Between
Riby et al. (2008a) 35-55 25 g No Within — — —
Riby et al. (2008a) 35-55 50 g No Within — —
Sünram-Lea et al. (2008) 18-25 25 g N/A Between
Scholey et al. (2009)m
M = 21.6, SD = 4.9 25 g Yes Between —
26
aThe specific treatment ingested (glucose or placebo) did not influence performance, but verbal episodic memory performance was
significantly correlated with blood glucose concentration post-treatment ingestion. bA 25 g glucose top-up was administered 30 minutes
subsequent to ingestion of the original treatment. cGlucose enhanced the primacy and recency effect (combined) only.
dGluose enhanced
verbal episodic memory only for items dichotically presented to the right ear (i.e. left cerebral hemisphere). eGlucose enhanced the primacy
effect only. fAlthough executive functioning performance was not found to be improved by glucose as measured by the Water Jars, Logical
Reasoning, Block Design and Porteus Maze tasks, response times were faster on the Porteus Maze task in the glucose condition. gThe
glucose effects were observed regardless of whether glucose was administered subsequent to a) overnight fast, b) 2-hour fast following
standardised breakfast, c) 2-hour fast following standardised lunch. hMemory was enhanced regardless of whether glucose was
administered before or after encoding. iThree divided attention conditions were included: hand movements, key tapping, no divided
attention. jThis quantity of glucose was effective in facilitating memory and attention when combined with 75 mg caffeine, 12.5 mg
ginseng and 2 mg ginkgo biloba. kGlucose was administered in conjunction with a) full-fat yoghurt or b) fat-free yoghurt in this study, with
glucose effects only being detected in the fat-free condition. lGlucose enhanced attention when administered alone or in combination with
200 mg ginseng. m
In this study, an attention (visual-motor tracking) task was used as a secondary task during word encoding; however,
glucose enhanced performance of this task but not the primary recognition memory task.
27
In addition to the studies presented in Table 1.2, Owens and Benton (1994)
investigated the role of oral glucose ingestion on inspection time and reaction time in
healthy young adults. However, the authors of this study neglected to compare directly
the influence of glucose ingestion on task performance. By contrast, performance was
compared in individuals (from either the glucose or placebo treatment group) who
exhibited an increase in blood glucose concentration by the arbitrary value of greater
than 1 mmol/L, relative to those who exhibited a decrease in blood glucose
concentration of greater than 0.5 mmol/L (again, an arbitrary value). Faster reaction
times were observed for the participants who exhibited increasing blood glucose
concentration, relative to those participants who were found to exhibit a decrease in
blood glucose concentration during the test session. The findings of this study (Owens
& Benton, 1994) should be treated with caution, as it is difficult to determine on the
basis of the results presented by the authors whether glucose ingestion per se has
influenced reaction time, or whether some other factor(s) known to influence blood
glucose concentration (such as stress hormone release) in fact contributed to the
reported findings. Other aforementioned studies by this group have also used a similar,
questionable data analysis strategy in concluding that glucose influences verbal episodic
memory (Benton & Owens, 1993b) and attention performance (Benton et al., 1994).
An additional study which investigated the influence of oral glucose ingestion
on memory performance in healthy middle-aged adults (40-63 years) was not included
in either Table 1.1 or Table 1.2, as the participant group of this study cannot be
classified as being either young or elderly individuals (Best, Bryan, & Burns, 2008). In
this previous study glucose was not observed to influence verbal episodic memory or
working memory performance relative to a treatment comprising a) a combination of
saccharides or b) a placebo comprising natural sweetener (Best et al., 2008). The
authors of this study suggest that the use of a natural sweetener placebo, as opposed to
28
an artificial sweetener (e.g. aspartame, which would typically be used as a placebo in
research investigations of memory modulation subsequent to oral glucose ingestion),
may have contributed to this finding (Best et al., 2008). However, encoding of to-be-
remembered materials in the verbal episodic memory task took place only under single
task conditions. As mentioned above, studies in younger adults suggest that such task
conditions may not be conducive to reliably observing a glucose memory enhancement
effect.
Glucose modulation of memory in children
Very few studies have investigated the influence of oral glucose ingestion on
acute neurocognitive performance in infants, children and adolescents. Children may be
particularly sensitive to glucose enhancement of neurocognitive performance, given that
the basal cerebral metabolic rate of children and adolescents is greater than that of
adults (Chiron, Raynaud, Maziere, Zilbovicius, Laflamme, Masure et al., 1992). This
higher cerebral metabolic rate in children is related to the larger brain size of children,
relative to body weight, in comparison to adults (Benton & Stevens, 2008). As
mentioned at the beginning of this review, the first study to report the enhancing effect
of glucose on verbal episodic memory performance was conducted with adolescent
participants (Lapp, 1981; Messier, 2004). Subsequent to ingestion of a standardised oral
glucose tolerance test (OGTT) preparatory breakfast and 150 g glucose, improved
performance was observed in this study in healthy adolescent participants for recall of
low- and high-imagery paired associates, relative to a fasting control condition (Lapp,
1981). In addition, two studies by Benton and colleagues have investigated the influence
of glucose ingestion on neurocognitive performance in younger children. In one of these
studies, children aged between 6 and 7 years demonstrated an enhanced capacity to
sustain attention subsequent to a 25 g glucose load, relative to placebo, as measured by
29
performance on a reaction time task (Benton, Brett, & Brain, 1987). However, a
subsequent study by the same authors failed to replicate these findings in children aged
between 9 and 10 years (Benton & Stevens, 2008). Further, glucose failed to modulate
spatial episodic memory performance in this age group (Benton & Stevens, 2008). On
the other hand, oral glucose ingestion was associated with facilitation of verbal episodic
memory, relative to placebo, in the 9-10 year old participants in this study (Benton &
Stevens, 2008). Finally, it is worthwhile noting that oral glucose ingestion has also been
associated with memory enhancement (less frequent turning of the head towards the
source of spoken words as an index of habituation) in 2-4 day old infants (Horne, Barr,
Valiante, Zelazo, & Young, 2006).
Influence of glycaemic load on memory performance
Several studies have investigated the influence of carbohydrate ingestion via
breakfast cereals (Benton & Sargent, 1992; Wyon, Abrahamsson, Jartelius, & Fletcher,
1997; Benton & Parker, 1998; Cueto, Jacoby, & Pollitt, 1998; Smith, Clark, &
Gallagher, 1999; Benton, Slater, & Donohoe, 2001; Wesnes, Pincock, Richardson,
Helm, & Hails, 2003; Nabb & Benton, 2006b; Benton & Jarvis, 2007; Widenhorn-
Müller, Hille, Klenk, & Weiland, 2008) and confectionary snacks (Busch, Taylor,
Kanarek, & Holocomb, 2002; Mahoney, Taylor, & Kanarek, 2007) on neurocognitive
performance. The findings of these studies have generally suggested that carbohydrate
delivery via commercially available breakfast cereals and confectionary snacks can
enhance neurocognitive performance. However, given that the consumption of a
breakfast meal typically delivers a range of nutrients to the body, such studies cannot
reliably ascertain to what extent the glucose contained within such meals has
specifically impacted upon cognition. In addition, many of these studies used a fasting
control condition. Therefore, it may well be that such studies represent a deleterious
30
fasting effect, rather than demonstrating an enhancement effect resulting from meal
ingestion (see Doniger, Simon, & Zivotofsky, 2006; D'Anci, Watts, Kanarek, & Taylor,
2009).
An alternative means of investigating whether glucose delivery via
commercially available foods improves neurocognitive performance is to employ two
treatment conditions, with each treatment being similar in nutritional composition, but
differing in terms of glycaemic index (G.I.). The G.I. is a measure of the effect that
ingested substances have on blood glucose levels. High G.I. foods cause a sharp
increase in blood glucose levels, followed by a sharp decline. Low G.I. foods, however,
result in a smaller but more prolonged rise in blood glucose levels. Two hours following
the consumption of a high G.I. meal, blood glucose levels may be lower than they were
prior to consuming the meal, whereas two hours after consuming a low G.I. meal, blood
glucose levels are typically higher than they were at baseline (Roberts, 2000). A number
of studies have investigated whether performance on a variety of neurocognitive tasks is
improved by the ingestion of meals associated with a) rapid or b) slow release of
glucose into the bloodstream.
Mahoney and colleagues (Mahoney, Taylor, Kanarek, & Samuel, 2005)
investigated the effect of three breakfast treatments on cognitive functioning in children
aged between 6 and 11 years old. The researchers employed a repeated measures design
to test a number of domains of cognitive functioning between one and two hours
following a breakfast treatment comprising either i) low G.I. oatmeal, ii) relatively
higher G.I. cereal or iii) no breakfast. Spatial memory, short-term memory and auditory
attention were demonstrated to be enhanced subsequent to consumption of the low G.I.
oatmeal breakfast, relative to the other breakfast conditions. The authors suggest that
this cognitive improvement may have been due to the low G.I. breakfast treatment
delivering a continued supply of glucose to the bloodstream over a longer period than
31
the other treatments. However, the macronutrient components differed between the two
breakfast meals administered in this study (e.g. protein, fibre, fat, carbohydrate). This is
problematic when trying to determine whether the speed of glucose release specifically
modulated cognitive performance, as opposed to the provision of other nutritional
components of the meal. Interpretation of findings from studies in this area is further
complicated by the fact that the macronutrient content of foods impacts upon the speed
of glucose release into the bloodstream (Nabb & Benton, 2006a). Moreover, given that
blood glucose concentration was not measured in this study, it is difficult to conclude
unequivocally whether an increase in blood glucose was directly responsible for the
cognitive enhancement reported.
A further study has also investigated the influence of low and high G.I. breakfast
meals on attention, working memory and episodic memory in children aged between 6
and 11 years (Ingwersen, Defeyter, Kennedy, Wesnes, & Scholey, 2007). In this study,
ingestion of a high G.I. breakfast meal was associated with a decline in neurocognitive
performance. However, ingestion of a low G.I. breakfast meal significantly reduced this
decline with respect to an accuracy of attention measure and a global episodic memory
score comprising verbal recognition, visual recognition and verbal recall tasks. Similar
to the study by Mahoney and colleagues (2005), these authors also neglected to obtain
measures of blood glucose concentration throughout the testing sessions, and the two
breakfast treatments were not matched for macronutrient composition. Although the
latter limitation is difficult to control when comparing commercially available products,
these two factors make it difficult to conclude whether glucose played a direct or
indirect role in the reported neurocognitive outcomes.
Benton and colleagues (Benton, Maconie, & Williams, 2007) further
investigated the influence of glycaemic load (defined as G.I. x carbohydrate (g)/100) of
breakfast meals on attention and episodic memory performance in 6-7 year old children.
32
The glycaemic load of the breakfast meal ingested was negatively correlated with verbal
episodic memory performance and correlated with the number of attention lapses (i.e. a
lower glycaemic load was associated with better performance). However, the fat content
of the breakfast meal was negatively correlated with sustained attention performance,
which begs the question of whether other macronutrients might be involved in the
reported relationship between glycaemic load and sustained attention. This study also
failed to obtain measures of blood glucose concentration, which does not enable the
efficacy of the glycaemic load variable to be authenticated. It is likely that the three
aforementioned studies (Mahoney et al., 2005; Benton et al., 2007; Ingwersen et al.,
2007) did not measure blood glucose concentration as blood sampling would place too
much of a burden on the young participants in these studies.
In addition to the aforementioned studies which have investigated the role of the
G.I. value of breakfasts in the modulation of neurocognitive performance in children,
several studies have also addressed this question in adults. In line with the findings
reported for the studies in children (above) a breakfast meal with a relatively lower G.I.
was reported to improve verbal episodic memory performance compared to a meal with
a relatively higher G.I. in healthy adults (Benton, Ruffin, Lassel, Nabb, Messaoudi,
Vinoy et al., 2003). A further study revealed that this finding may be more exaggerated
in adults with relatively better glucoregulatory efficiency (Nabb & Benton, 2006a). An
additional study in middle-aged adults found that the ingestion of a simulated low G.I.
treatment (sipping on a glucose drink throughout a testing session) was associated with
superior working memory and selective attention performance relative to a simulated
high G.I. treatment (a single ‗bolus‘ 50 g glucose load) when glucoregulatory efficiency
was controlled for statistically (Nilsson, Radeborg, & Bjorck, 2009). This notion is
further supported by a study in which adults with type 2 diabetes mellitus (who are, by
definition, poor glucoregulators) exhibited superior performance on tests of verbal
33
episodic memory, working memory, executive functioning and selective attention
subsequent to ingestion of a low G.I. breakfast meal relative to a high G.I breakfast
meal (Papanikolaou, Palmer, Binns, Jenkins, & Greenwood, 2006). However, a healthy
control group was not included in this study, so it is not possible to determine whether
the reported observations could also extend to healthy individuals. Finally, a further
study has also reported a beneficial effect of a low G.I. breakfast meal on verbal
episodic memory performance relative to a high G.I. breakfast meal in healthy young
adults (Benton & Nabb, 2004). However, when alcohol intake on the previous evening
was taken into consideration, consumption of lower amounts of alcohol were associated
with better verbal episodic memory performance after a high G.I. meal relative to a low
G.I. meal, whereas the opposite pattern of results was observed for individuals who
consumed comparatively higher quantities of alcohol on the evening prior to testing in
this study. It was concluded by the authors that changes in the insulin response
following alcohol consumption may explain these results (Benton & Nabb, 2004),
suggesting that a complex interaction between glucoregulatory efficiency and the
glycaemic characteristics of the test foods may underlie the observed relationship
between the G.I. of meals and subsequent neurocognitive performance.
From the aforementioned studies in this section, it can be generally concluded
that foods that are associated with a comparatively slower and more prolonged release
of glucose into the bloodstream (i.e. low G.I. foods) enhance neurocognitive
performance relative to high G.I. foods. Attention and episodic memory appear to
particularly benefit from the ingestion of a low G.I. meal. However, it is important to
note that all of the studies reported here were conducted under conditions of relatively
low cognitive demand, with none of the studies mentioned above employing a divided
attention paradigm. Previously in this review, it has been suggested that glucose only
reliably modulates cognitive performance (specifically, verbal episodic memory) in
34
healthy young individuals under conditions of divided attention (see Sünram-Lea et al.,
2002b). Although speculative, it may be that the blood glucose increase resulting from
ingestion of a low G.I. meal would not have been sufficiently high to induce cognitive
enhancement, had participants been required to complete the cognitive tasks
administered in this series of studies under conditions of divided attention. This is
because a low G.I. meal would not bring about a large, acute rise in blood glucose
concentration; the latter is typically observed following ingestion of a high G.I. meal or
a glucose-laden drink. Such a large, acute increase in blood glucose concentration may
well be necessary in order to induce cognitive enhancement under conditions of
increased cognitive demand (including divided attention). This notion will be discussed
further in the following section.
‘Mechanisms of susceptibility’
It has already been discussed throughout this review that divided attention seems
to be an important factor in determining whether the ingestion of oral glucose will be
observed to enhance cognitive performance, particularly in young adults (Sünram-Lea
et al., 2002b). In addition to the notion that cognitive demand modulates the glucose
memory facilitation effect, glucoregulatory efficiency (Craft et al., 1994) and initial
thirst (Scholey, Sünram-Lea, Greer, Elliott, & Kennedy, in press) appear to be
potentially important factors that have been cited in the literature to date. Gibson and
Green (2002) refer to factors which can influence whether foods modulate cognitive
performance as ‗mechanisms of susceptibility‘. Two mechanisms of susceptibility
which have been purported to modulate the glucose memory facilitation effect will now
be summarised: i) cognitive demand, and ii) glucoregulatory efficiency.
35
Divided attention/ cognitive demand
As mentioned above, the glucose memory facilitation effect appears to be only
reliably observed in healthy young adults when the cognitive demand of the task is high
(e.g. Kennedy & Scholey, 2000; Scholey et al., 2001; Sünram-Lea et al., 2002b; Meikle
et al., 2004). Foster and colleagues (1998) were the first to report that the ingestion of
25 g oral glucose enhances verbal episodic memory in healthy young adults under
conditions of divided attention (namely, encoding of a supraspan word list concurrently
with performing sequences of hand movements). A similar procedure has been
associated with verbal episodic memory improvement in subsequent studies (Sünram-
Lea et al., 2001, 2002b, 2002a, 2004). Specifically, in the study by Sünram-Lea and
colleagues (2002b), healthy young adult participants were divided into one of four
secondary task conditions during word list encoding. In the i) ‗hand‘ condition,
participants completed a secondary hand movement task (identical to that employed by
Foster et al., 1998), while in the ii) ‗key‘ condition, participants were required to type a
string of symbols on a computer keyboard during presentation of the word list. In the iii)
‗words‘ condition, participants heard half of the words in the list presented in a male
voice, while the other half were presented in a female voice (participants were
subsequently required to recall the items on the basis of the speaker‘s gender). In the iv)
‗none‘ condition, no secondary task was employed. Participants in the ‗hand‘ and ‗key‘
condition exhibited superior delayed word recall following glucose ingestion, while
participants in the ‗word‘ and ‗none‘ conditions did not demonstrate a glucose memory
facilitation effect. This study provides clear evidence for the notion that glucose only
reliably enhances memory under conditions of increased cognitive demand at encoding.
It is possible that in the ‗word‘ condition, the cognitive demand associated with the
additional task dimension of monitoring the gender of the speaker was not sufficiently
high to induce a glucose enhancement effect.
36
A study conducted by Kennedy and Scholey (2000) provides further evidence
that glucose facilitation of memory in healthy young adults is susceptible to the level of
cognitive demand. The results of this study revealed oral glucose ingestion did not
enhance performance on serial threes (a test of attention and working memory in which
participants are required to count backwards in threes) relative to placebo. However,
performance on the more cognitively demanding serial sevens task (counting backwards
in sevens) was enhanced following glucose ingestion, relative to placebo. A subsequent
study employing a computerised serial sevens task replicated the finding that glucose
facilitates serial sevens performance in healthy young adults (Scholey et al., 2001).
Further, this study integrated a serial sevens control task in which participants were
required to tap the number ‗5‘ four times on a numeric keypad, 20 times per minute (a
task analogous to serial sevens, in that it requires comparable physical effort, but is
much less cognitively demanding). It was reported that the reduction in blood glucose
concentration associated with performance of the more cognitively demanding task
(serial sevens) was greater than that associated with the less cognitively demanding
control task. The findings of Scholey and colleagues (2001) provide further evidence
that is consistent with the notion that glucose is more reliable in facilitating cognitive
performance when the demands of the task are relatively higher. In addition, Meikle and
colleagues (Meikle et al., 2004, 2005) have reported glucose enhancement of verbal
memory only when the task demands are relatively more difficult (i.e. when to-be-
remembered word lists are longer in length or when the individual items contain more
letters). As mentioned previously, the findings of Scholey and colleagues (2009)
provide further support for the notion that the ingestion of oral glucose facilitates the
divided allocation of cognitive resources in healthy young adults.
An interesting theory has emerged as a consequence of this body of research. It
has been suggested that the performance of more cognitively demanding tasks is
37
associated with greater depletion of circulating glucose, and therefore the provision of
additional glucose is useful in ‗topping-up‘ the supply of glucose to the brain (Scholey,
Laing, & Kennedy, 2006). This proposal has been predicated upon several studies in
which the level of circulating glucose has been observed to fall more markedly after the
performance of tasks involving relatively greater cognitive demand (Donohoe &
Benton, 1999c; Scholey et al., 2001; Fairclough & Houston, 2004; Scholey et al., 2006),
and is related to the concept that the brain utilises a considerable amount of energy for
its relative size, while having a low capacity for glucose storage (Peters, Schweiger,
Pellerin, Hubold, Oltmanns, Conrad et al., 2004). The human brain is uniquely large
among primates, and extensive evolutionary changes have been required in a relatively
short period of time to ensure that the human body is able to provide adequate energy to
fuel such a metabolically demanding organ (e.g. reduction in size of the human
gastrointestinal tract and colon to support a high energy, but easily digestible diet; Saris,
Heymsfield, & Evans, 2008). Related to the above, it has already been noted that an
inverted-U dose-response curve underlies the glucose memory facilitation effect
(Parsons & Gold, 1992; Riby, 2004). Although speculative, it may well be that during
the performance of less cognitively demanding tasks, provision of even a small glucose
dose may push the supply of glucose to the brain above the purported optimal level at
which glucose enhancement of cognitive performance is typically observed. However,
from an evolutionary perspective, it makes little sense that an individual should
experience such a large and rapid reduction in circulating glucose as a consequence of
performing a short (albeit demanding) cognitive task, as this could place an individual at
risk of survival (due to relatively reduced glucose availability to the muscles if the
individual was faced with a threatening situation). This reiterates the importance and
ecological relevance of stress hormone mediated glucose release (for a discussion of
sympathetic arousal, glucose release and memory, see below). Alternatively, by contrast
38
to the aforementioned hypothesis that glucose specifically targets the hippocampus in
modulating cognitive performance (Riby & Riby, 2006), the proposition that glucose
only reliably enhances a) memory under conditions of divided attention in healthy
young adults, as well as b) difficult tasks, may constitute evidence that glucose
selectively enhances central executive functioning (Kennedy & Scholey, 2000; see
‗Neurocognitive Mechanisms‘ section, below).
Glucoregulatory efficiency
Impaired glucoregulatory efficiency is typically associated with relatively poor
episodic memory function (e.g. Donohoe & Benton, 2000; Awad et al., 2002; Convit et
al., 2003; Convit, 2005; Dahle et al., 2009; Lamport et al., 2009). As mentioned
previously in this review (see ‗Healthy ageing‘ section, above), several studies have
investigated whether this phenomenon can be reversed via the provision of oral glucose
in older adults. However, fewer studies have investigated the role of glucoregulatory
efficiency in the glucose memory facilitation effect in healthy younger individuals.
Similar to the older adult studies, the findings of such investigations in younger
individuals are equivocal. Some studies have reported that greater enhancement of
memory subsequent to the ingestion of oral glucose is observed in young males who
exhibited relatively poorer glucoregulatory efficiency (Craft et al., 1994; Messier,
Desrochers, & Gagnon, 1999), while others have reported that glucose is relatively
more effective in facilitating cognitive performance in younger adults with better
glucoregulatory efficiency (Meikle et al., 2004). As previously mentioned, this
discrepancy may be due to different methodologies being used between studies to define
‗glucoregulatory efficiency‘. The determination of glucoregulatory efficiency groups on
the basis of a median split may cause individuals with a blood glucose concentration
within the normal range to be somewhat arbitrarily assigned to either the ‗poorer‘ or
39
‗better‘ glucoregulatory group, depending on the glucoregulatory characteristics of the
study sample.
Neurocognitive mechanisms
The specific neurocognitive mechanisms which subserve the glucose memory
facilitation effect presently remain somewhat uncertain. A number of theories relating to
possible neurocognitive mechanisms have been put forward. However, robust evidence
in support of either of these mechanisms has not yet been established in the literature.
Each of these theories will be considered in this section. Much of the work investigating
the specific neurocognitive mechanisms which mediate the glucose memory facilitation
effect have employed animal models, due to the difficulties associated with making
direct interventions in the human central nervous system. Firstly, two prominent
theories pertaining to the anatomical brain regions targeted by glucose in modulating
cognitive performance (namely the hippocampus and the frontal cortex) will be
presented. Secondly, a number of more specific mechanisms that have been proposed in
the literature will be discussed.
Brain regions thought to mediate glucose enhancement of memory
The ‘hippocampus hypothesis’
It is widely accepted that the hippocampus is a key structure mediating episodic
memory functioning (Shastri, 2002). Related to this notion, the hippocampus has been
implicated as being crucially involved in glucose enhancement of memory, given that
episodic memory is the domain of cognition that has been most reliably demonstrated to
benefit from glucose ingestion (Riby, 2004). This supposition has been termed the
‗hippocampus hypothesis‘ (Riby & Riby, 2006).
40
In addition to those studies which have suggested that glucose ingestion most
reliably improves episodic memory performance, other sources of evidence have also
been put forward implicating the hippocampus in the glucose memory facilitation effect.
Firstly, Winocur (1995) employed a conditional discrimination learning task with young
and aged rats following injection of glucose or saline. The conditional discrimination
learning task involves the conditioning of different responses to different stimuli; it is
known to tap the resources of the prefrontal cortex. However, Winocur (1995)
postulated that increasing the delay between stimulus offset and response in this task
also requires involvement of hippocampally-mediated episodic memory. Following a 5
s or 15 s delay between stimulus onset and the time at which rats were able to make a
response, enhanced memory for the stimulus was observed in the aged rats following
glucose injection, relative to injection of saline. However, no memory facilitation was
observed following glucose injection in the absence of a delay between stimulus offset
and response. Given that the no delay condition is postulated to tap the resources of the
prefrontal cortex, whereas the 5 s and 15 s delay conditions are also suggested to
involve the hippocampus, this study suggests that glucose enhancement may be specific
to memory processes which tap the resources of the hippocampus (Winocur, 1995).
Further evidence that the limbic region underpins the glucose memory
facilitation effect is derived from a study which employed the ‗remember-know‘
paradigm subsequent to ingestion of glucose or a placebo treatment (Sünram-Lea et al.,
2008). In this study, healthy young adults completed a recognition memory task, which
involved learning a word list. Ten minutes following encoding of the memory materials,
participants were administered a test list comprising items from the study list as well as
foils, and were required to identify which items had appeared on the study list, and
which had not. For those items that participants identified as having been on the study
list, participants were required to identify whether they ‗remembered‘ the item (i.e.
41
recognition accompanied by recollection of contextual details; analogous to
‗recollection‘), ‗knew‘ the item (i.e. lack of contextual details retained; thought to
reflect ‗familiarity‘ processes) or ‗guessed‘ whether the item had been part of the
original list. Following glucose ingestion, participants were observed to correctly
produce a significantly greater number of ‗remember‘ responses to target items than
participants who were administered a placebo treatment. By contrast, there were no
between group treatment-related differences in ‗know‘ or ‗guess‘ responses. Given that
‗recollection‘ based recognition memory, but not ‗familiarity‘ is thought preferentially
to involve the hippocampus (Aggleton & Brown, 2006), these findings (Sünram-Lea et
al., 2008) further implicate the hippocampus as the brain region that is centrally
involved in mediating the glucose memory enhancement effect.
Additional evidence for hippocampal mediation of the glucose memory
facilitation effect can be drawn from a functional magnetic resonance imaging (fMRI)
study conducted by Stone and colleagues in patients with schizophrenia (Stone,
Thermenos, Tarbox, Poldrack, & Seidman, 2005). The primary finding of this study was
that glucose ingestion was associated with significantly enhanced parahippocampus
activation during verbal encoding, relative to placebo. These results imply that the
medial temporal brain region is crucially involved in subserving the glucose memory
facilitation effect. Further, event-related potentials (ERPs) have also been employed to
address the question of whether glucose specifically targets the hippocampus in
modulating memory performance. In a previous study by Riby and colleagues (Riby,
Sünram-Lea, Graham, Foster, Cooper, Moodie et al., 2008b), participants performed an
oddball task subsequent to the ingestion of oral glucose or placebo, while ERPs were
recorded. A significant treatment effect was observed for the P3b ERP component
(known to reflect memory updating processes; Polich & Criado, 2006): specifically,
glucose administration was associated with reduced P3b amplitude, relative to placebo.
42
However, two ERP components that are associated with attentional processing (P2 and
P3a) were not observed to be modulated by glucose. These findings were interpreted as
demonstrating that glucose enhances memory by decreasing the cognitive resources
required for memory updating (Riby et al., 2008b). P3b is known to be dependent on the
hippocampus, whereas the P2 and P3a components are not, providing further evidence
for the hippocampus hypothesis.
The ‘central executive hypothesis’
Prior to discussing this hypothesis in detail, a brief description of Baddeley and
Hitch‘s working memory framework (Baddeley & Hitch, 1974; Baddeley, 1986; from
which the concept of the central executive is drawn) will be provided. Working memory
was initially envisaged as a three-component system, under the control of a ‗central
executive‘ (which coordinates the functions of two subsidiary ‗slave‘ systems). One of
these slave systems, the ‗phonological loop‘, is responsible for temporarily retaining
verbal memory information, while the visuospatial sketchpad is responsible for
retaining visual and spatial information within working memory (Baddeley, 1986). The
‗central executive‘ is responsible for the attentional control of working memory, with
the primary role of coordinating two or more concurrent tasks (Baddeley, 1996a,
1996b). The initial three-component framework conceptualised working memory
distinctly from long-term memory; as such, the early model (Baddeley & Hitch, 1974)
made no attempt to elucidate the relationship between working memory and long-term
memory. However, more recently, a revision to the original framework has been
postulated in which a direct link has been established between working memory and
long-term memory (Baddeley, 2000). According to the modified working memory
framework, episodic long-term memory is directly linked to the central executive via a
short-term storage system termed the ‗episodic buffer‘ (Baddeley, 2000; see Figure 1.1).
43
In this revised framework, while the central executive is considered to be responsible
for the executive control of working memory, the episodic buffer serves to integrate the
contents of working memory into unitary episodes, and to relay the contents of working
memory to long-term episodic memory for storage (and vice versa for retrieval;
Baddeley, 2000; Repovš & Baddeley, 2006).
Figure 1.1
Baddeley‘s (2000) multi-component working memory framework. This revision of the
model proposes a link between working memory and long-term memory. Further, this
revision incorporates the ‗episodic buffer‘, a short-term storage system lying at the
interface of the central executive and long-term episodic memory. Adapted from
Baddeley (2000).
Although it does have heuristic value, the hippocampus hypothesis does not
account well for studies which have demonstrated glucose enhancement for tasks which
are thought to be mediated independently of the hippocampus. Therefore, it may be that
glucose actually targets more global brain regions in conferring an improvement in
neurocognitive performance. In addition, it has been reported that many of the tasks for
Central
Executive
Visuospatial
Sketchpad
Working
Memory
Visual
Semantics Long-Term
Store
Episodic
Buffer
Episodic
Memory
Phonological
Loop
Language
44
which glucose has been observed to enhance performance rely to some degree on
putatively frontally-mediated ‗central executive‘ function (Kennedy & Scholey, 2000).
The central executive is also crucially important for successfully dividing attention
among concurrently performed tasks (Della Sala, Baddeley, Papagno, & Spinnler,
1995). Moreover, it has been substantially discussed previously in this review that
glucose has only been reliably observed to enhance verbal episodic memory
performance in healthy young adults when target items are encoded under dual task
conditions. On this basis, it has been suggested that a ‗central executive hypothesis‘
may account well for the glucose memory facilitation effect (Kennedy & Scholey,
2000). Further evidence for the frontal/central executive hypothesis can be drawn from
the aforementioned fMRI study conducted by Stone and colleagues (2005), in which a
trend towards greater activation of the dorsolateral prefrontal cortex was reported
subsequent to glucose ingestion (relative to placebo) during verbal encoding. The
central executive hypothesis warrants further attention in future investigations of the
glucose memory facilitation effect, and is a focus of the present thesis.
Specific mechanisms
In addition to those studies which have attempted to explain whether glucose
specifically targets the hippocampus or more global brain regions in enhancing
neurocognitive performance, several studies have considered more specific mechanisms
of glucose action on the central nervous system which could account for the observed
findings pertaining to glucose modulation of memory. Glucose effects on i) cerebral
insulin, ii) acetylcholine (ACh) synthesis, iii) potassium adenosine triphosphate (KATP)
channel function and iv) brain extracellular glucose availability have all been postulated
as potential mediators of the glucose memory enhancement effect. Each of these
theories will now be considered.
45
Insulin
Insulin receptors are densely concentrated in the hippocampus relative to other
brain regions (Unger, McNeill, Moxley, White, Mosi, & Livingston, 1989). Given that
verbal episodic memory is the domain of cognitive performance that has been most
reliably demonstrated to be modulated by glucose ingestion, glucose-mediated insulin
delivery to the hippocampus has been suggested as a candidate mechanism underlying
the glucose memory facilitation effect (Craft et al., 1993; Craft et al., 1994). It has been
proposed that insulin can directly influence memory functioning (Watson & Craft,
2004; Martins, Hone, Foster, Sünram-Lea, Gnjec, Fuller et al., 2006). Specifically,
studies that have involved the intranasal infusion of insulin (i.e. direct delivery of
insulin into the central nervous system) have suggested that insulin administration can
enhance memory performance in the absence of changes in plasma glucose or insulin
(Reger, Watson, Frey, Baker, Cholerton, Keeling et al., 2006; Reger, Watson, Green,
Baker, Cholerton, Fishel et al., 2008; Reger, Watson, Green, Wilkinson, Baker,
Cholerton et al., 2008). Craft and colleagues (1994) observed a gender difference in
glucose facilitation of memory, in that glucose was observed to facilitate episodic
memory in males, but this effect was not observed in female participants (see the
previous section entitled ‗The glucose memory facilitation effect‘). This observation
was attributed by these researchers to the higher rate of insulin induced glucose
utilisation typically observed in males. However, although insulin appears to be an
effective cognitive enhancer in its own right, it is difficult to ascertain reliably whether
insulin effects on the hippocampus mediate the glucose memory facilitation effect. This
is because it is not logistically practicable to conduct studies in humans in which plasma
glucose concentration is increased in the absence of an endogenous rise in blood insulin
levels. Therefore, the hypothesis that insulin mediates the relationship between glucose
ingestion and memory remains rather speculative; indeed, in some respects this may be
46
considered a re-statement of the glucose memory facilitation effect, at least with respect
to the endogenous state.
ACh synthesis
A further proposed mechanism of the glucose memory facilitation effect is that
glucose administration increases the rate of hippocampal acetylcholine (ACh) synthesis.
This line of research originated from evidence that glucose metabolism is involved in
the synthesis of ACh (Messier, 2004). Early animal work reported that administration of
glucose attenuated the amnesic effect of scopolamine injection (Messier et al., 1990;
Durkin, Messier, de Boer, & Westerink, 1992). Further, a sodium-dependent high-
affinity choline uptake assay (Messier et al., 1990) and in vivo microdialysis (Durkin et
al., 1992) suggested that this finding was mediated by increased ACh synthesis.
Ragozzino and colleagues (Ragozzino, Unick, & Gold, 1996) employed an
animal model to systematically investigate memory performance and hippocampal ACh
output (measured via in vivo microdialysis) following administration of either a) saline,
or a glucose dose of b) 100 mg/kg, c) 250 mg/kg or d) 1000 mg/kg. Rats displayed
greater memory, assessed by performance on a maze task, following the 250 mg/kg
glucose dose relative to those rats administered the saline control solution. The activity
associated with performing the maze task increased hippocampal ACh synthesis relative
to during rest. Moreover, ACh output was increased further following the 250 mg/kg
glucose dose, relative to the saline control group, during performance of the maze task.
These findings demonstrate that glucose (250 mg/kg) administered to rats is associated
with a) increased hippocampal ACh output, and b) enhanced memory performance.
Therefore, on the basis of these results, it appears that glucose administration may
facilitate memory by directly increasing hippocampal ACh synthesis in a dose
dependent manner. These results were subsequently extended, in that injecting glucose
47
into the hippocampus unilaterally was observed to increase ACh output from both the
ipsilateral and contralateral hippocampus (Ragozzino, Pal, Unick, Stefani, & Gold,
1998).
In order to further develop an understanding of the relationship between
hippocampal ACh output, glucose and memory, Kopf and colleagues (Kopf,
Buchholzer, Hilgert, Löffelholz, & Klein, 2001) investigated the effect of glucose and
choline (which are precursor metabolites of ACh) on memory performance in a maze
task. First, it was observed that 30 mg/kg glucose injected into the mouse hippocampus
enhanced task performance, relative to injection of saline. Injection of 60 mg/kg choline
chloride had a similar enhancing effect upon performance of the maze task, relative to
saline controls. Furthermore, following the combined administration of 10 mg/kg
glucose and 20 mg/kg choline chloride, memory enhancement was observed, even
though these doses of glucose and choline chloride were not observed to enhance
memory performance when administered independently of one another. 10 mg/kg
glucose also does not typically raise blood glucose levels significantly above baseline.
Therefore, Kopf and colleagues (2001) conclude that the observed memory
enhancement resulted from increased hippocampal ACh synthesis, which was made
possible by the availability of additional glucose - a biosynthetic precursor of ACh. The
suggestion that ACh is a potential mediator of the glucose memory facilitation effect
therefore appears feasible.
KATP channel function
Glucose has also been proposed to possibly influence memory via its effects on
KATP channel regulation. The KATP channel is sensitive to glucose metabolism, in that
glucose causes channel blockade by increasing intra-neuronal ATP levels. In this state,
the neuron becomes depolarised, and therefore mediates neurotransmitter release
48
(Stefani, Nicholson, & Gold, 1999; Stefani & Gold, 2001). In order to test whether this
mechanism may subserve the glucose memory facilitation effect, Stefani and colleagues
(1999), investigated the influence of a) glucose, b) a KATP channel blocker or c) saline
injected into the septum of rats on spatial working memory performance.
Administration of either a) glucose or b) KATP channel blocker enhanced task
performance relative to placebo, and lower doses of a) and b) administered in
combination were also associated with improved task performance (although these
smaller doses did not modulate task performance when administered in isolation). It was
concluded that the similar task performance observed subsequent to both glucose and
KATP channel blocker in this study can be taken as evidence that glucose may modulate
cognitive functioning via its effects on KATP channel function (Stefani et al., 1999). This
finding was replicated in a subsequent study by this same group (Stefani & Gold, 2001).
However, these conclusions should be treated with caution, as these studies do not
directly investigate glucose effects on KATP channel function. The similarity in the
observed findings for both the glucose and the KATP channel blocker conditions might
imply that these two treatments are acting upon a common neurophysiological
mechanism, or they may be exerting a similar outcome via different mechanisms.
Studies that specifically quantify the KATP channel polarity subsequent to glucose
ingestion and investigate subsequent neurocognitive performance may enable these
questions to be addressed further.
Brain glucose availability
A further phenomenon has been observed that potentially provides a
neurological explanation for the glucose memory facilitation effect, involving the
measurement of brain extracellular glucose levels following cognitive testing in rodents.
Traditionally, it has been suggested that glucose transporters maintain brain
49
extracellular glucose levels at a constant rate (McNay & Gold, 1999, 2002). However,
recent evidence has demonstrated that extracellular glucose levels differ between
anatomical brain regions (McNay & Gold, 1999, 2002), and that hippocampal
extracellular glucose levels fluctuate depending on the cognitive demand to which the
limbic region is exposed (McNay, Fries, & Gold, 2000; McNay & Gold, 2002). This
phenomenon raises the possibility that glucose administration increases the localised
availability of brain glucose during conditions of increased hippocampal demand,
during which hippocampal glucose levels may otherwise become depleted. Note that
this neurophysiological observation in rodents is in line with the previously described
phenomenon that systemic plasma glucose levels are more rapidly depleted during tasks
associated with relatively higher cognitive demand in humans (Donohoe & Benton,
1999c; Scholey et al., 2001; Fairclough & Houston, 2004; Scholey et al., 2006).
McNay and colleagues (2000) measured hippocampal extracellular glucose
levels in rats prior to, during and subsequent to one of two spatial working memory
tasks, differing in complexity, that are known to be reliant upon the hippocampus (and
an additional control procedure, in which rats were placed in a box during the testing
period). Thirty minutes prior to behavioural testing, rats were administered a) 250
mg/kg glucose, b) saline or c) no treatment. For rats tested on the more difficult spatial
working memory task that were administered either a) no treatment or b) saline, a fall in
hippocampal glucose levels of 30% and 32% below baseline, respectively, was
observed during the first five minutes of behavioural testing. These sub-baseline glucose
concentrations were then observed throughout the remainder of the test session. By
contrast, rats that completed the less difficult cognitive task did not exhibit this same
degree of depletion in hippocampal glucose levels (i.e. the fall from baseline was 11%
while performing this task for rats that were administered no treatment, and glucose
levels returned to baseline in these rats before the end of the behavioural testing
50
procedure). Further, on the more difficult spatial working memory task, rats that were
administered glucose outperformed those rats that were administered saline or no
treatment. By contrast, there was no difference in performance between the three
treatment groups for those rats that completed the less difficult spatial working memory
task. Together, these results suggest that glucose facilitates memory performance only
on tasks that require greater cognitive demand. This is possibly due to the glucose
treatment replenishing hippocampal extracellular glucose levels which were observed to
become significantly more depleted during performance of the more cognitively
demanding task.
In a subsequent study, McNay and Gold (2001) observed, as expected, that
younger rats outperformed older rats on a spatial working memory task if no treatment
was administered prior to cognitive testing. In accordance with this finding, the deficit
in hippocampal extracellular glucose concentration was greater (and more prolonged) in
aged rats relative to younger rats during task performance. However, no difference in
cognitive performance was observed between young and aged rats when glucose was
administered prior to task performance. Moreover, analogous to the earlier results
reported by McNay and colleagues (2000), blood glucose concentration during testing
was maintained at baseline levels for both groups when the task was performed
subsequent to the delivery of glucose to the bloodstream (McNay & Gold, 2001). This
finding accounts well for the finding that the degree of memory enhancement following
glucose ingestion increases with age (Meikle et al., 2004), and provides sound evidence
for a neurobiological mechanism that may underlie this observation (replenishment of
extracellular hippocampal glucose). Taken together, the results of these two studies
(McNay et al., 2000; McNay & Gold, 2001) imply that a) greater enhancement of
memory subsequent to a glucose load is observed as the task demands increase, and b)
glucose is effective in facilitating memory performance by replenishing the supply of
51
glucose to the hippocampus, which becomes diminished to a greater degree as the
cognitive demand of the task increases.
The emotional memory effect
Emotionally laden material is typically better remembered than neutral stimuli
(Hamann, 2001; LaBar & Cabeza, 2006). Exposure to an emotionally arousing stimulus
leads to the rapid sympathetically mediated release of catecholamines (adrenaline and
noradrenaline) from the adrenal medulla. In addition, a relatively slower stress-related
neuroendocrine mechanism involves the hypothalamic-pituitary-adrenal (HPA) axis
mediated release of glucocorticoids (cortisol in humans; Cahill & McGaugh, 1998;
McGaugh, 2004; LaBar & Cabeza, 2006; van Stegeren, 2008; Wolf, 2008). Both
catecholamines and glucocorticoids stimulate the endogenous liberation of glucose into
the bloodstream, for the inferred purpose of providing the necessary energy to cope with
a stressor (de Kloet, Joëls, & Holsboer, 2005). Adrenaline, noradrenaline and cortisol
are assumed to play a role in subserving memory for emotionally laden material (Cahill
& McGaugh, 1998; McGaugh, 2004; LaBar & Cabeza, 2006; van Stegeren, 2008; Wolf,
2008). However, adrenaline and noradrenaline do not readily cross the blood-brain
barrier (Wenk, 1989; Gold, 1995), and must therefore exert an influence on memory via
auxiliary mechanisms. It has been suggested that adrenaline and cortisol may influence
memory for emotionally laden materials (at least in part) by increasing the supply of
glucose to the brain (Wenk, 1989; Gold, 1995; Brandt, Sünram-Lea, & Qualtrough,
2006). This ‗emotional memory effect‘ may therefore be closely related to the glucose
memory facilitation effect (in that glucose may modulate cognitive performance,
whether it is supplied exogenously or endogenously to the bloodstream).
In accordance with the aforementioned proposal that the emotional memory
effect may be mediated by an increase in the supply of glucose to the brain, several
52
studies have reported that exposure to emotionally arousing stimuli is associated with an
increase in circulating blood glucose concentration. For example, Blake and colleagues
(Blake, Varnhagen, & Parent, 2001) observed that exposure to emotionally arousing
pictures is associated with an increase in circulating blood glucose concentration,
relative to neutral pictures, and that memory for the emotionally arousing pictures was
enhanced, relative to neutral pictures. In addition, Scholey and colleagues (2006) also
reported that exposure to emotionally arousing stimuli (in this case, emotionally
arousing words with a negative valence) led to an increase in blood glucose
concentration. However, in this study, no memory enhancement effect was observed for
the emotionally arousing items, relative to neutral items (Scholey et al., 2006). By
contrast, memory enhancement for emotionally laden pictures in the absence of
observable changes in blood glucose or salivary cortisol concentrations has been
reported (Gore, Krebs, & Parent, 2006). Further, the question of whether oral glucose
ingestion can confer an additional memory enhancement for emotionally laden to-be-
remembered items has also been investigated. In one such study, better memory was
observed for an emotionally arousing narrative, relative to a neutral narrative, and the
emotional narrative was associated with an increase in blood glucose concentration
(Parent, Varnhagen, & Gold, 1999). However, the ingestion of oral glucose was found
to attenuate the emotional enhancement effect in this study (Parent et al., 1999).
Similarly, Brandt and colleagues (2006) reported that recognition memory performance
was superior for negative emotionally laden words, relative to neutral and positive
items, but oral glucose ingestion was not observed to modulate this effect. To
summarise these findings, it appears that memory for emotionally arousing stimuli is
relatively better than memory for neutral stimuli, a phenomenon which may be driven
by increases in circulating glucose concentration. However, the provision of additional
glucose does not further enhance this effect. According to the aforementioned inverted-
53
U dose response relationship pertaining to glucose ingestion and memory performance,
it may be that the provision of additional glucose to the brain, in addition to stress-
hormone mediated increases in circulating glucose, pushes an individual‘s blood
glucose concentration above the optimal range for observing a memory enhancement
effect.
Summary and Conclusions
The modulation of cognitive performance subsequent to the ingestion of oral
glucose is a phenomenon which has now been reliably demonstrated in a) older adults,
b) younger adults (under conditions of divided attention) and c) individuals with clinical
syndromes involving cognitive deficits. Verbal episodic memory is the domain of
cognition that appears to be most amenable to the glucose memory facilitation effect,
possibly suggesting the involvement of the hippocampus in glucose enhancement of
memory. Individual differences in glucoregulatory efficiency may be important in
determining whether an individual is more or less susceptible to experiencing a
cognitive benefit subsequent to glucose ingestion. Further, in healthy young adults,
glucose has only been reliably observed to enhance memory under conditions of
increased cognitive demand, such as dual tasking. This may be related to the notion that
healthy young adults are operating at their ‗cognitive peak‘; therefore, a cognitive
enhancer would only be effective when such individuals face increased cognitive
demands that allow ‗room for improvement‘ (Foster et al., 1998). The role of cognitive
demand in the glucose memory facilitation effect may also implicate the central
executive as being crucially involved in subserving glucose enhancement of memory.
The role of central executive functioning in mediating the glucose memory facilitation
effect was considered in the present thesis.
54
Glucose has been demonstrated to modulate cognitive performance in younger
individuals, including infants and young children. However, only one study has
considered whether glucose is an effective cognitive enhancer in adolescents, with this
study failing to employ an appropriate placebo control condition (Lapp, 1981).
Therefore, the primary aim of the present thesis was to address the question of whether
glucose can be observed to improve verbal episodic memory performance in healthy
adolescents, an important period in context of the ongoing development of the brain
through the teenage years (Giedd, Blumenthal, Jeffries, Castellanos, Liu, Zijdenbos et
al., 1999). The adolescent period is also associated with a higher basal cerebral
metabolic rate relative to adults (Chiron et al., 1992); on this basis it was also of
particular interest to investigate whether the glucose memory facilitation effect can be
extended to individuals in this age range. Much of the work on glucose modulation of
cognitive performance in children has been conducted by investigating task
performance subsequent to ingestion of meals differing with regard to their glycaemic
load. The results of these studies have typically supported the view that a slower and
more prolonged release of glucose into the bloodstream subsequent to a glucose load is
associated with relatively superior neurocognitive performance. However, all of the
studies in this area to date have been conducted under single task conditions, so it is
difficult to infer from these studies whether the low G.I. treatments would also be most
effective when cognitive demand is high. This question was addressed as part of the
present thesis.
A number of specific neurocognitive mechanisms thought to potentially underlie
the glucose memory facilitation effect have been proposed. The most robust of these
theories in terms of empirical evidence is the hypothesis that glucose enhances memory
via its effects on ACh synthesis (Ragozzino et al., 1996; Ragozzino et al., 1998; Kopf et
al., 2001). In addition, it has been reported that glucose administration replenishes the
55
extracellular glucose levels of the rat hippocampus, which become depleted during
performance of demanding tasks (McNay & Gold, 2002). This phenomenon supports
human studies which suggest that plasma glucose becomes depleted to a relatively
greater degree during more demanding cognitive tasks (Donohoe & Benton, 1999c;
Scholey et al., 2006). These studies imply that glucose enhances performance of more
demanding cognitive tasks, as such tasks deplete the supply of glucose to the brain to a
greater degree than relatively less demanding tasks.
It is also worthy of note that glucose-mediated modulation of memory may be
the mechanism by which a memory advantage is observed for to-be-remembered
emotionally laden material, relative to neutral stimuli. It has been noted above that
hormones released in response to an emotionally arousing stimulus (cortisol, adrenaline
and noradrenaline) stimulate glucose release into circulation. Therefore, it may well be
that the memory enhancement that is typically observed for emotionally arousing
material is mediated by glucose, implying that endogenous glucose release can also
improve memory performance. For a conceptual model of the glucose memory
facilitation effect as described in this review, see Figure 1.2.
56
Figure 1.2
A conceptual model of the glucose memory facilitation effect. The ingestion of oral
glucose or acute stress/emotional arousal increases the concentration of circulating
glucose in the periphery, and subsequently, the central nervous system. Via its proposed
effects on a) insulin, b) ACh synthesis and/or c) KATP channel function, glucose
enhances (verbal episodic) memory performance.
In summary, the ingestion of oral glucose is known to enhance cognitive
performance under specific conditions. Glucose has been most reliably associated with
the modulation of verbal episodic memory. In healthy young adults, encoding of
memory materials under conditions of increased cognitive demand appears to be
critical. The present thesis aimed to address the question of whether the glucose
memory facilitation effect can be extended to healthy adolescents. In addition, the
present thesis i) investigated the role of central executive functioning and the
hippocampus in subserving the glucose memory facilitation effect, and ii) further
investigated the influence of several possible modulating factors on the glucose memory
Stress/Arousal
Plasma Glucose
SAM axis
(Adrenaline/
Noradrenaline)
HPA axis
(Cortisol)
Carbohydrate
Ingestion
Central Glucose
Memory
(Verbal
Episodic)
ACh synthesis
Insulin
ATP
57
enhancement effect, including a) task difficulty, b) glucoregulatory efficiency, c) basal
HPA axis function, baseline self-reported stress and anxiety, and d) the emotionality of
the to-be-remembered stimuli.
58
59
Chapter Two
Glucose modulation of verbal episodic
memory in adolescents: Outline of the present thesis
60
As reviewed thoroughly in the previous chapter, there is now substantial
evidence in the literature to suggest that the ingestion of oral glucose is associated with
memory enhancement. Verbal episodic memory is the cognitive domain that has been
most reliably associated with memory enhancement. In addition, the glucose memory
facilitation effect appears to be most reliably demonstrated in healthy young adults
when memory materials are encoded under conditions of divided attention.
The adolescent years represent a very important period in terms of neurological
and cognitive development (Giedd et al., 1999). In addition, the basal cerebral metabolic
rate of glucose (and many other psychopharmacological agents) is higher in adolescents
relative to adults (Chiron et al., 1992). It is therefore crucially important to investigate
whether the glucose memory facilitation effect can be extended to healthy adolescents.
As mentioned in Chapter 1, only one study has previously investigated the relationship
between oral glucose ingestion and subsequent memory performance in adolescents
(Lapp, 1981). This study employed only a fasting control group (i.e. the control group
was not administered an appearance and sweetness matched placebo beverage).
Consequently, the question of whether the glucose memory facilitation effect can be
extended to healthy adolescents needs to be considered further. The primary aim of the
present thesis was therefore to investigate the influence of oral glucose ingestion on
verbal episodic memory performance in healthy adolescents. A number of additional,
more specific research questions, which are outlined herein, were also addressed in the
present thesis.
In Study 1A, the influence of baseline central executive capacity on the glucose
memory facilitation effect was considered. The adolescent period is a very useful age
range in which to consider this issue, given that substantial disparity in executive
capacity is expected in this age group due to the fact that adolescence is an important
time in the context of frontal lobe development (Giedd et al., 1999; Anderson, 2002;
61
Romine & Reynolds, 2005; Whitford, Rennie, Grieve, Clark, Gordon, & Williams,
2007). If the central executive is involved in the mediation of the glucose memory
facilitation effect, it was expected that glucose ingestion would be associated with better
memory improvement for those individuals demonstrating relatively poorer executive
capacity, given that these individuals would have more ‗room for improvement‘ in
terms of cognitive enhancement. Further, Study 1B aimed to extend these findings by
comparing verbal episodic memory performance subsequent to ingestion of a) a low
glycaemic index (G.I.), or b) a high G.I. commercially available breakfast cereal meal.
Data pertaining to baseline central executive capacity was also obtained in this study.
Study 2 continued to investigate the role of central executive capacity as a
potential modulator of the glucose memory facilitation effect. In addition, baseline
memory capacity was tested, to control for individual differences in baseline verbal
episodic memory capacity (a potentially important confounder when investigating the
influence of a nutritional intervention on post-treatment cognitive performance). An
important aspect of Study 2 was also to investigate systematically whether the verbal
encoding of motor sequences performed as a secondary task modulate glucose mediated
verbal episodic memory performance.
Study 3 was the first study of the present thesis to employ a within-subjects
design. Study 3 therefore enabled the influence of glucose ingestion on verbal episodic
memory capacity to be investigated in healthy adolescents, with inter-individual
differences in memory capacity and other baseline attributes being controlled for by the
repeated measures procedure. The use of a within-subjects design also enabled a
measure of glucoregulatory efficiency to be obtained on the glucose testing day for all
participants. Therefore, Study 3 also addressed the question of whether individual
differences in glucoregulatory efficiency modulate susceptibility to the glucose memory
facilitation effect in healthy teenagers.
62
Having already considered the role of the central executive in modulating the
glucose memory facilitation effect (Study 1 and Study 2) in adolescents, Study 4
considered the ‗hippocampus hypothesis‘, which purports that glucose specifically
targets the hippocampus in subserving memory performance (see Chapter 1 for a
detailed discussion of the hippocampus hypothesis). An event-related potential (ERP)
procedure was employed to investigate whether glucose modulates event-related
potential components evoked by the neurocognitive process underlying recollection
(known to be mediated by the hippocampus) and/or familiarity (not thought to be
subserved by the hippocampus).
Study 5 considered whether psychosocial and additional biological variables
related to stress and anxiety can influence the glucose memory facilitation effect in
adolescents. Basal hypothalamic-pituitary-adrenal (HPA) axis function was measured as
a biomarker of stress. It was hypothesised that the HPA axis may be involved in
modulating glucose enhancement of memory, due to the role that the HPA axis plays in
the regulation of blood glucose (itself a modulator of the glucose memory facilitation
effect). A measure of glucose regulation was therefore also obtained, in addition to
subjective measures of baseline adolescent stress and trait anxiety.
Finally, it was an aim of Study 6 to extend the findings of Study 5 by
investigating glucose modulation of emotionally arousing verbal stimuli (which by their
nature already have a memory advantage in the absence of glucose administration) in
individuals differing with regard to a) basal HPA axis function, b) baseline adolescent
stress and trait anxiety, and c) glucoregulatory efficiency. In addition, Study 6 also
aimed to investigate the influence of a) glucose ingestion and b) encoding of the
emotionally arousing items on acute changes in salivary free cortisol (as a biomarker of
HPA axis function) in healthy adolescents.
63
In summary, the empirical work presented here comprehensively addressed the
question of whether oral glucose ingestion modulates verbal episodic memory
performance (for both neutral and emotionally arousing items) in healthy adolescents.
Encoding of to-be-remembered verbal materials took place under conditions of divided
attention. A key focus of the present thesis was to evaluate the integrity of the ‗central
executive hypothesis‘ and the ‗hippocampus hypothesis‘. In addition, the impact of
glucoregulatory efficiency, basal HPA axis function, baseline stress and trait anxiety in
rendering an individual relatively more or less sensitive to glucose modulation of
memory was systematically investigated. Ultimately, the final chapter then draws
conclusions pertaining to i) the influence of oral glucose ingestion on verbal episodic
memory performance in adolescents, ii) the neurocognitive mechanisms which may be
involved in this effect, and iii) whether inter-individual differences in biological and/or
subjective traits can alter ‗susceptibility‘ to the glucose memory facilitation effect.
64
65
Chapter Three
The glucose memory facilitation effect: role of executive load
A paper based on the findings of Study 1B has been published in Nutritional
Neuroscience:
Smith, M. A., & Foster, J. K. (2008). The impact of a high versus a low glycaemic
index breakfast cereal on verbal episodic memory in healthy adolescents. Nutritional
Neuroscience, 11, 219-227.
Chapter 3 could not be included in this digital thesis for copyright reasons.
Please refer to the print copy of the thesis, held in the University Library.
111
Chapter Four
Investigating the influence of executive capacity
and divided attention on the glucose memory facilitation effect
112
Abstract
An aim of the present chapter was to address a potential confound of Study 1, namely
that baseline memory capacity was not controlled for. Therefore, in Study 2,
participants completed an immediate free recall memory test under fasting conditions as
a measure of baseline verbal episodic memory capacity. Participants also undertook a
battery of neurocognitive tests under fasting conditions, in order to further investigate
the potential mediation of the glucose memory facilitation effect by the central
executive. Following this baseline testing, participants were administered either a) a
glucose treatment or b) a placebo treatment, prior to completing a test of verbal episodic
memory concurrently with a secondary hand movement task, analogous to the
methodology of Study 1A. In addition, whether verbal labels were provided for the
secondary task hand movement sequences was manipulated in this study, in order to
investigate whether verbal recoding of the hand movement sequences impacted upon
the effectiveness of glucose ingestion in modulating memory performance. No
difference was observed between the two treatment groups in terms of verbal episodic
memory performance, despite individual differences in baseline memory capacity being
controlled for. Further, executive capacity was not observed to mediate susceptibility
for glucose effects on memory, similar to the findings of Study 1. Taken together, the
present study findings a) do not support the notion of glucose enhancement of memory
in healthy adolescents, b) do not suggest that glucose facilitates verbal rehearsal in
exerting an enhancement effect on verbal episodic memory, and c) further suggest that
the central executive does not mediate the glucose memory facilitation effect as
hypothesised.
113
Introduction
In healthy young adults, glucose has only been demonstrated to reliably enhance
verbal episodic memory performance when word list encoding takes place under
conditions of divided attention (Sünram-Lea et al., 2002b). On this basis, it has been
suggested that the glucose memory facilitation effect is mediated by the central
executive. Further, glucose ingestion has also been observed to improve performance on
tasks of working memory and executive functioning (Benton et al., 1994; Donohoe &
Benton, 1999b; Kennedy & Scholey, 2000). In Study 1A, the influence of executive
capacity on the glucose memory facilitation effect was investigated directly. A
relationship between Stroop performance and glucose ingestion was observed, with
relatively better Stroop performers recalling significantly more items in a test of delayed
verbal memory subsequent to glucose ingestion relative to placebo. This finding
provides some evidence that the central executive may be involved in the mediation of
verbal episodic memory subsequent to glucose ingestion when word list encoding takes
place concurrently with a secondary task. However, the specific nature of this
relationship remains uncertain. Therefore it is of interest to further investigate the
influence of executive capacity on the glucose memory facilitation effect. This question
was addressed in Study 2.
It has now been well established that in healthy young adults, glucose
enhancement of memory is dependent upon increased cognitive demand. Previous
research has demonstrated that oral glucose ingestion improves delayed recall for word
items encoded during performance of a secondary hand movement task or key tapping
task, but no effect of glucose on memory is observed when encoding does not take place
under dual task conditions (Sünram-Lea et al., 2002b). However, in other studies,
whether participants performed a secondary card sorting task at encoding has not been
shown to influence the glucose memory facilitation effect in younger (Riby et al., 2006)
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or older (Riby et al., 2004; Riby et al., 2006) adults. Further research suggests that other
types of cognitive demand may be important in terms of whether glucose is observed to
facilitate memory, such as cognitive load. For example, glucose has been observed to
enhance memory for items of later serial position as list length increases, relative to
placebo (Meikle et al., 2005). The glucose memory enhancement effect has also been
suggested to be reliably observed only under conditions of increased task difficulty. In a
short term recognition memory search task in which participants had to respond as to
whether a target item appeared in a previously presented array, oral glucose was only
found to improve task performance in older adults when the array comprised a greater
number of distractors (Meikle et al., 2004). Moreover, glucose has been observed to
enhance performance, relative to placebo, on a working memory task (Serial Sevens),
but not on the relatively less difficult Serial Threes task (Kennedy & Scholey, 2000).
The mechanism underlying this observation may be related to the observation that blood
glucose concentration declines more rapidly during the Serial Sevens task than a key
pressing control task (Scholey et al., 2001). This finding is similar to a previous study
which observed that blood glucose concentration declines during a demanding
information processing task (Donohoe & Benton, 1999c). Taken together, these studies
suggest that glucose concentration decreases more rapidly with increasing cognitive
demand, and that the ingestion of oral glucose may compensate for this reduction in
available fuel to the brain.
Nevertheless, there appears to be limited consensus across studies with regard to
the types of cognitive demand necessary for glucose facilitation of memory to be
observed. Sünram-Lea and colleagues (2002b) reliably observed the glucose memory
facilitation effect under conditions of divided attention. By contrast, a memory
improvement was not observed subsequent to glucose ingestion when task difficulty
was manipulated by having participants identify target items from distractor items in a
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word recall task, on the basis of the speaker‘s gender. Moreover, as stated above, other
studies have failed to demonstrate the glucose memory facilitation effect in healthy
young adults under conditions of divided attention (e.g. Riby et al., 2006). It would
therefore be of interest to investigate further whether any specific characteristics of the
hand movement task, which is often employed as a secondary task in this area of
research (Foster et al., 1998; Sünram-Lea et al., 2001, 2002b, 2004; Scholey et al.,
2006), may subserve the previous observations from our laboratory that glucose reliably
facilitates memory only under conditions of divided attention at encoding.
Specifically, it has been suggested previously that participants verbally recode hand
movement sequences when performing a motor task (Frencham, Fox, & Maybery,
2004). In previous work by Sünram-Lea and colleagues (Foster et al., 1998; Sünram-
Lea et al., 2001, 2002b, 2004), participants were provided with verbal labels by the
researcher when explaining the secondary task instructions (i.e. ―fist-chop-slap‖; S. I.
Sünram-Lea, personal communication, January 12, 2007). This procedure was not
followed in Study 1 of the present thesis, in that the hand movement sequences were
demonstrated to the participants without the provision of explicit verbal labels. It is
therefore less likely that participants verbally recoded the hand movement sequences in
Study 1 than in previous work by Sünram-Lea and colleagues, which may have reduced
the level of verbal interference exerted by the secondary task on the encoding of the
word list in Study 1. It may well be that glucose targets verbal encoding in improving
verbal episodic memory, a suggestion that accounts well for the lack of memory
enhancement observed subsequent to glucose ingestion in Study 1A, and which
warranted further investigation in the present study.
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Study 2
Aims
The primary aim of the present study was to investigate whether glucose
ingestion exerts an influence on verbal episodic memory in healthy adolescents. An
improvement of the present study design (relative to Study 1) was that baseline verbal
episodic memory was controlled for in Study 2. Further aims of Study 2 were a) to
extend the finding from Study 1A that the glucose memory facilitation effect may be
mediated by executive functioning capacity, and b) to investigate whether the verbal
recoding of the motor movements employed previously as a secondary task in this area
of research (and in Study 1) influences verbal episodic memory performance subsequent
to glucose ingestion.
Hypotheses
It was hypothesised in the present study that oral glucose ingestion would
facilitate verbal episodic memory in healthy adolescent participants, relative to
ingestion of a sweetness matched placebo, and that this effect would be more
pronounced for individuals presented with verbal labels for the hand movement
sequences in the secondary task. It was further hypothesised that the glucose memory
facilitation effect would be observed to be more prevalent in healthy adolescents
demonstrating relatively poorer executive functioning capacity.
Method
Participants
Participants were 90 healthy adolescents (31 males, 59 females), ranging
between 14 and 16 years of age (Mage = 14.8, SDage = 0.6). Participants were recruited
from independent and government secondary schools. There were no significant
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differences between the two treatment groups in terms of age, body mass index (BMI)
and the number of days per week on which breakfast is typically skipped (see Table
4.1). One participant from the glucose treatment group withdrew from the study for
health reasons (the data collected prior to withdrawal were not included in the analysis).
A further participant from the placebo group reported being non-compliant with the
overnight fasting instructions of the study. This participant was also removed from the
data set for all analyses, in order to avoid any potential confounds arising from a
‗second meal effect‘. However, whether this individual was included in the analysis did
not change the results of any of the inferential statistics reported here. Details pertaining
to participant screening and mode of recruitment are identical to those reported in Study
1A.
Table 4.1
Demographic details for the Glucose and Placebo treatment groups.
Glucose Placebo p
Age (years) 14.8 (0.6) 14.8 (0.7) n.s.
BMI (kg/m2) 20.1 (2.7) 20.1 (2.3) n.s.
Average days/week breakfast skipped 0.8 (1.4) 0.8 (1.6) n.s.
Treatment and design
A mixed-model design was employed for the blood glucose and POMS-Bi
analyses, with one between-subjects factor (treatment) and one within-subjects factor
(time). A between-subjects design was employed for the primary memory analyses,
incorporating a single between-subjects factor (treatment). Further, in order to analyse
whether the verbal encoding of the secondary motor sequences impacted upon the
glucose memory facilitation effect, an additional between-subjects factor (verbal labels)
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was included in the analysis. An additional between-subjects factor (baseline memory)
was subsequently added to this analysis to control for the potential confound of baseline
verbal episodic memory capacity on the glucose memory facilitation effect.
Furthermore, in order to analyse the influence of executive capacity on the glucose
memory facilitation effect, an additional between-subjects factor (executive capacity)
was included in subsequent analyses.
The glucose treatment consisted of 25 g ‗Glucodin‘ Glucose Powder (Boots
Healthcare Australia Pty Ltd) dissolved in 300 ml water. The placebo treatment
consisted of five ‗Equal‘ tablets (10% Aspartame, The Merisant Company) dissolved in
300 ml water. It has been demonstrated previously that this quantity of aspartame is
matched for sweetness with 25 g glucose powder when dissolved in 300 ml water
(Sünram-Lea et al., 2008). Participants were randomly assigned to one of these two
treatment groups. The addition of extra sugar or other condiments to these treatments
was not permitted. Participants were required to consume all of the drink that they were
administered.
Materials
Modified Rey Auditory-Verbal Learning Test (RAVLT). The original version of
this task (Rey, 1958; Lezak, 1983) assesses immediate, short delay and long delay free-
recall of a 15-item supraspan word list. This original version comprises five immediate
free-recall trials (List A), followed by immediate free-recall of a second distractor list
(List B). The RAVLT was employed in the present study as a measure of each
participant‘s baseline verbal episodic memory capacity. For the purpose of the present
study, only three immediate recall trials were conducted. The distractor list, as well as
the short and long delay recall phases, was omitted from the test.
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Executive battery. Four tasks designed to tap the resources of the frontal lobes
and central executive were administered as part of the present study, in order to group
participants on the basis of executive capacity. Three of these tasks were employed in
Study 1, while one of these tasks was unique to the present investigation. For Study 2,
the executive battery comprised the Digit Symbol Substitution subtest from the
Wechsler Adult Intelligence Scale Third Edition (WAIS-III; Wechsler, 1997), a
modified version of the Stroop Colour-Word test (Stroop, 1935), a modified version of
the Controlled Oral Word Association Test (COWAT; see Troyer et al., 1997), and the
Elevator Counting with Reversal (ECR) subtest from the Test of Everyday Attention
(TEA; Robertson, Ward, Ridgeway, & Nimmo-Smith, 1994).
The administration of the Digit Symbol Substitution Test, the Stroop Colour-
Word test and the COWAT was identical to the protocol employed for Study 1. The
ECR subtest assesses verbal attention switching and working memory (Strauss et al.,
2006). Participants are required to count a series of tones to determine the ‗floor‘ on
which an ‗elevator‘ stops. The test consists of 10 trials. High pitched tones indicate that
the elevator is about to start going up, and low pitched tones indicate that the elevator is
about to start going down. Middle pitched tones are the tones to be counted, and
indicate a ‗floor‘. Participants must count the middle pitched tones (either forwards or
backwards, depending on whether the sequence of middle pitched tones was preceded
by a high or a low pitched tone). Each trial requires a number of switches in forwards
and backwards counting. Participants are required to respond as to the floor on which
the lift finally stops. A correct response on any given trial is awarded 1 mark; an
incorrect response is awarded 0. The maximum possible score on this test is 10.
Modified California Verbal Learning Test (CVLT). The administration of the
CVLT was identical to that reported in Study 1, except:
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The CVLT word lists were recorded on audiocassette and played, rather
than being read aloud by the researcher (as was the case in Study 1).
Half of the participants from each treatment group were further divided
into two groups on the basis of whether verbal labels were provided in
the instructions for the secondary motor task. In Study 1, the researcher
demonstrated the sequences of hand movements to the participants prior
to the commencement of the task, but no verbal labels (e.g. fist-chop-
slap, backslap-chop-fist), were provided. In Study 2, verbal labels were
provided during demonstration of the secondary motor task to those
participants in the ‗Labels‘ group. Participants in the ‗No Labels‘ group
were provided with a demonstration of the secondary motor task
sequences, however, no verbal labels were provided (i.e. the task
instructions were identical to Study 1).
Bipolar Profile of Mood States (POMS-Bi). The POMS-Bi (McNair, Loor, &
Droppleman, 2003) is a self-report measure of six bipolar mood states. The POMS-Bi
has been employed previously in this area of research (e.g. Scholey & Fowles, 2002;
Benton & Nabb, 2004). The dimensions of mood assessed by this instrument are:
‗composed-anxious‘, ‗agreeable-hostile‘, ‗elated-depressed‘, ‗confident-unsure‘,
‗energetic-tired‘, ‗clearheaded-confused‘. Each factor comprises 12 items (i.e. there are
72 items in total) defined by a single adjective. For each item, participants are required
to indicate how they are feeling right now, on a 4-point scale, with regard to the
adjective presented. Within each factor, six items are positive in polarity, and six items
are negative in polarity. For the purpose of the present investigation, raw scores
obtained for each participant on each factor were converted to standardised scores,
based on high school student norms (McNair et al., 2003). The purpose of converting
raw scores to standardised scores was that this allows for an overall mood score to be
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calculated, and allows a comparison between mood factors. A higher score represents a
more positive feeling of the dimension being measured.
Blood glucose monitoring equipment. Information pertaining to equipment used
for monitoring blood glucose concentration was identical to Study 1.
Procedure
Written informed consent was obtained from participants and their parents.
Participants were instructed not to consume any food or drink, other than water, from
2230 on the evening prior to testing. All test sessions began between 0800 and 0830.
Participants were tested in groups in standard classrooms. The test session commenced
with administration of the modified RAVLT, followed by the executive functioning
battery. The RAVLT and the executive battery were administered at this time to ensure
that participants from both groups completed these tasks under equivalent fasting
conditions. The executive functioning tests were administered in the order in which they
are described in the Materials section (above) for all participants. Following completion
of the executive battery, all participants were weighed and measurements of their height
were obtained. Participants then completed the POMS-Bi and baseline blood glucose
concentrations were measured. Immediately following the measurement of baseline
blood glucose concentration, participants consumed one of the two treatments,
depending on the treatment group to which they had been randomly assigned (glucose,
placebo). Participants were blind as to the contents of the drinks, told only that they
comprised a ―sweet tasting liquid‖. Participants were allowed 10 minutes to consume
their designated treatment. Ten minutes following the completion of treatment
consumption, blood glucose concentrations were measured and participants were
administered the modified POMS-Bi for the second time. Participants then completed
the immediate free-recall trials of the modified CVLT (IFRa trials 1 -5), followed by the
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modified CVLT interference list (IFRb). Motor sequences were performed during
encoding of each CVLT list. Participants were subsequently administered the third
POMS-Bi, and a third measurement of blood glucose concentration was obtained.
Following this, participants completed the short delay recall phases of the CVLT.
Following a short break, the final measurements of blood glucose concentrations were
recorded, and the final POMS-Bi was administered to the participants. The long delay
recall phases of the CVLT were then completed. Following the completion of the testing
procedure, participants were offered a breakfast cereal meal before returning to normal
school classes. The testing procedure is outlined in Table 4.2.
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Table 4.2
The testing procedure followed in Study 2. The time in minutes of each procedure prior
/ subsequent to treatment delivery is displayed in the left column.
t (mins) Procedure
-45 RAVLT & Executive Battery administered
-15 Measurement of height and weight
-10 First blood glucose measurement
First POMS-Bi administration
0 Glucose treatment administered to glucose group
Placebo treatment administered to placebo group
10 Second blood glucose measurement
Second POMS-Bi administration
20 CVLT IFRa Trials 1-5 with secondary motor task
CVLT IFRb with secondary motor task
50 Third blood glucose measurement
Third POMS-Bi administration
60 CVLT SDFR
CVLT SDCR
90 Fourth blood glucose measurement
Fourth POMS-Bi administration
100 CVLT LDFR
CVLT LDCR
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Statistical analysis
Blood glucose values were investigated using a two-way analysis of variance
(ANOVA) with repeated measures on one factor (time of blood sampling). The two
factors were treatment (glucose, placebo) and time (t = -10, 10, 50, 90).
Results on the POMS-Bi scores for each factor (and overall mood) were
analysed using a two-way ANOVA with repeated measures on one factor (time of
POMS-Bi scale administration). The two factors were treatment (glucose, placebo) and
time (t = -10, 10, 50, 90).
Verbal learning was analysed on CVLT IFRa trials 1-5 using a three-way
ANOVA with repeated measures on one factor (IFRa trial). The three factors were
treatment (glucose, placebo), label (labels provided, no labels provided) and trial (1, 2,
3, 4, 5). The ‗label‘ factor was included in this analysis to investigate whether the verbal
encoding of the motor sequences comprising the secondary task influenced performance
on the primary memory task subsequent to glucose ingestion. Modified CVLT delayed
recall results were analysed using a univariate ANOVA with two between-subjects
factors (treatment, label).
To investigate whether baseline verbal memory ability influenced the glucose
memory facilitation effect, a median split was performed on the total score achieved
across the three learning trials of the modified RAVLT. Participants were then assigned
to groups on the basis of baseline verbal memory capacity (low capacity, high capacity).
Using these data, CVLT results were analysed using a three-way ANOVA with three
between-subjects factors (treatment, label, verbal memory capacity).
As in study 1, remembering/forgetting rates throughout the test session on the
CVLT data were also calculated for each participant by subtracting the total score on
SDFR from the total score on IFRa trial 5 (short delay forgetting) and subtracting the
total score on LDFR from the total score on IFRa trial 5 (long delay forgetting). Results
125
were analysed using a three-way ANOVA with repeated measures on one factor
(forgetting index delay; short, long) and two between-subjects factors (treatment;
glucose, placebo and label; labels provided, no labels provided).
In order to investigate the effect of executive capacity on CVLT performance
following oral glucose administration, a median split was performed on the results of
each of the four executive functioning tests. Participants were subsequently assigned to
groups on the basis of capacity for performance on each of the executive functioning
tests (low capacity, high capacity). CVLT results were then analysed using a series of
three-way ANOVAs with three between-subjects factors (treatment, label, executive
capacity).
Results
Blood glucose concentrations
A significant treatment x time interaction effect was observed, F(3, 84) = 28.95,
p < .001, with the effect size being large (partial η2 = .51). Planned comparisons
revealed that blood glucose concentrations were significantly higher for the glucose
group, relative to the placebo group ten minutes, t(86) = 7.98, p < .001, 50 minutes,
t(86) = 6.14, p < .001, and 90 minutes, t(86) = 2.96, p < .01, post-treatment delivery.
Blood glucose concentrations between the glucose and placebo group did not differ at
baseline, t(86) = -0.64, n.s. (see Figure 4.1).
126
4
4.5
5
5.5
6
6.5
7
7.5
-10 10 50 90
Time Pre- / Post Treatment (minutes)
Blo
od
Glu
co
se C
on
cen
trati
on
(mm
ol/
L)
Glucose
Placebo
Figure 4.1
Mean blood glucose concentration for the glucose group and placebo group 10 minutes
prior to treatment delivery (baseline), and 10, 50 and 90 minutes subsequent to
treatment delivery (± S.E.).
In order to investigate whether provision of verbal labels impacted upon blood
glucose concentration, a further treatment x time x label mixed-model analysis was
performed on the blood glucose concentration data at the time-points immediately prior
to (10 minutes post-treatment) and subsequent to (50 minutes post-treatment) memory
encoding. This treatment x time x label interaction was nonsignificant, F(1, 84) < 0.01,
n.s, with the effect size being small (partial η2 = .00). The time x label interaction was
also nonsignificant, F(1, 84) = 0.01, n.s, with the effect size being small (partial η2 =
.00).
POMS-Bi
Analysis of each of the six POMS-Bi factors did not reveal any significant time
x treatment interaction effects. The time x treatment interaction also failed to reach
significance on overall mood. Mood scores were not able to be calculated for three
127
participants, as they did not provide a sufficient number of responses on the POMS-Bi
to calculate mood scores, according to the POMS-Bi manual (McNair et al., 2003).
Modified CVLT
Immediate free recall. The three-way interaction between trial, treatment and
label was nonsignificant on IFRa, F(4, 81) = 1.42, n.s, with the effect size being small
(partial η2 = .07). A significant main effect of trial was observed, F(4, 81) = 262.71, p <
.001, with the effect size being large (partial η2 = .93). Planned comparisons revealed
that the number of items recalled increased significantly between trial 1 and trial 2, p <
.001, trial 2 and trial 3, p < .001, trial 3 and trial 4, p < .001, and trial 4 and trial 5, p <
.001. The treatment x label interaction on the CVLT interference list (IFRb) was
nonsignificant, F (1, 84) = 0.26, n.s, with the effect size being small (partial η2 = .00).
Short delay and long delay recall. One participant from the placebo group
reached ceiling performance on LDFR and LDCR. The treatment x label interaction was
nonsignificant on all CVLT delayed recall phases (see Table 4.3). However, there was a
significant main effect of label on LDCR, in that participants in the group provided with
verbal labels for the secondary motor task recalled significantly more items than those
participants who were not provided with verbal labels for the secondary motor task
(irrespective of treatment), F(1, 84) = 3.99, p < .05, with the effect size being small
(partial η2 = .04).
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Table 4.3
CVLT delayed recall results for the glucose and placebo groups, a) when no verbal labels were provided for the motor sequences within
the secondary task, or b) when verbal labels were provided for the motor sequences within the secondary task. Mean values are displayed,
with standard deviations in parentheses.
No verbal labels provided Verbal labels provided
Modified CVLT delayed recall phase Glucose Placebo Glucose Placebo
Short delay free recall 11.0 (4.2) 10.8 (3.4) 10.9 (4.4) 11.9 (3.6)
Short delay cued recall 12.8 (3.3) 12.2 (2.8) 12.4 (3.7) 13.3 (3.1)
Long delay free recall 11.8 (4.6) 12.2 (3.2) 12.2 (3.4) 13.4 (3.5)
Long delay cued recall* 12.3 (4.4) 12.6 (2.9) 13.3 (3.0) 14.3 (2.7)
Main effect of label: *p < .05.
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In order to control for the possible confounding influence of baseline memory
capacity on CVLT performance subsequent to glucose ingestion, baseline verbal
episodic memory was assessed in this study using a modified version of the RAVLT,
administered prior to treatment ingestion. The total number of items recalled across
three immediate free recall trials of the modified RAVLT was used as an indicator of
baseline verbal episodic memory capacity performance for the purposes of the present
study. A median split was performed on these data to form two groups (‗high‘ and
‗low‘) differing in baseline verbal episodic memory capacity. The treatment x label x
baseline memory interaction was nonsignificant on all four tests of delayed recall.
Nevertheless, as expected the addition of this between-subjects factor into the analysis
yielded a significant main effect of baseline memory on SDFR, F (1, 75) = 16.62, p <
.001 (partial η2 = .18), SDCR, F (1, 75) = 13.58, p < .001 (partial η
2 = .15), LDFR, F (1,
75) = 18.24, p < .001 (partial η2 = .20) and LDCR, F (1, 75) = 15.16, p < .001 (partial η
2
= .17). These significant main effects were due to participants exhibiting superior
baseline verbal episodic memory capacity performing better on CVLT recall,
irrespective of the treatment or verbal label condition to which they were assigned (see
Table 4.4). Five participants failed to complete the modified RAVLT (due to late arrival
at the group testing sessions), and were therefore excluded from this analysis.
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Table 4.4
CVLT delayed recall results for the glucose and placebo groups, for individuals with a) relatively lower baseline verbal episodic memory
capacity and b) relatively higher baseline verbal episodic memory capacity (as evaluated by the RAVLT), separated by verbal label
condition.
Low baseline memory capacity High baseline memory capacity
No verbal labels provided Verbal labels provided No verbal labels provided Verbal labels provided
Modified CVLT recall phase Glucose Placebo Glucose Placebo Glucose Placebo Glucose Placebo
Short delay free recall 9.1 (5.0) 9.6 (3.2) 9.3 (4.3) 9.2 (2.7) 12.1 (0.9) 12.6 (3.5) 12.8 (4.1) 13.4 (3.2)
Short delay cued recall 11.9 (4.2) 11.2 (1.9) 11.2 (3.3) 11.2 (2.1) 13.3 (1.6) 13.8 (3.4) 13.9 (3.7) 14.7 (2.6)
Long delay free recall 10.0 (5.8) 11.0 (2.7) 11.1 (3.1) 11.0 (4.5) 13.3 (1.6) 14.3 (3.4) 13.8 (3.3) 14.9 (1.7)
Long delay cued recall 10.4 (5.4) 11.6 (2.4) 12.6 (3.0) 12.8 (2.8) 13.7 (1.2) 14.3 (3.1) 14.4 (2.8) 15.6 (1.6)
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Remembering/forgetting indices. An analysis of remembering / forgetting rates
revealed a main effect of delay, in that there was a trend of greater recall at the long
delay than the short delay, F(1, 84) = 18.46, p < .001, with the effect size being small
(partial η2 = .18). However, the delay x label x treatment interaction was nonsignificant,
F(1, 84) = 0.18, n.s, with the effect size being small (partial η2 = .00).
Executive battery
There were no significant differences between the two treatment groups in terms
of performance on any of the four executive tasks. Within each of the two treatment
groups, a median split was performed on the total scores for each of the four executive
functioning tasks. This was for the purpose of dividing participants into groups on the
basis of executive capacity. For each CVLT recall phase, the effect of executive
capacity and treatment group on item recall was analysed. However all treatment x label
x executive capacity interactions were found to be nonsignificant (see Table 4.5). Five
participants failed to complete the Digit Symbol Substitution task and Stroop task due to
late arrival at the testing session. Three of these participants also failed to complete the
Phonological Fluency task for this same reason.
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Table 4.5
CVLT delayed recall results for the glucose and placebo groups, for individuals with a) relatively lower executive functioning capacity and
b) relatively higher executive functioning capacity, separated by verbal label condition.
Low executive capacity High executive capacity
No verbal labels provided Verbal labels provided No verbal labels provided Verbal labels provided
CVLT recall phase/executive test Glucose Placebo Glucose Placebo Glucose Placebo Glucose Placebo
SDFR Digit Symbol 9.6 (4.6) 11.1 (2.9) 10.0 (4.5) 12.6 (3.6) 11.8 (2.8) 10.5 (4.1) 13.0 (4.1) 11.8 (3.6)
Stroop 9.2 (4.7) 10.3 (2.2) 9.8 (4.9) 11.7 (3.8) 11.6 (3.1) 11.1 (4.2) 12.4 (3.6) 12.4 (3.4)
Phonemic Fluency 8.8 (5.1) 10.2 (3.3) 9.8 (5.2) 11.1 (3.9) 11.7 (2.6) 12.0 (3.6) 11.8 (3.8) 12.5 (3.4)
TEA Elevator 10.0 (3.2) 10.4 (2.8) 10.1 (4.6) 11.8 (3.6) 11.3 (4.8) 10.9 (3.7) 12.0 (4.1) 12.1 (3.7)
SDCR Digit Symbol 12.0 (3.8) 12.2 (3.5) 11.6 (3.7) 14.2 (3.0) 13.3 (2.5) 12.2 (2.3) 14.5 (3.1) 13.2 (2.9)
Stroop 12.5 (4.0) 11.0 (2.0) 11.3 (4.0) 13.2 (3.4) 12.5 (2.8) 13.0 (3.1) 14.1 (2.8) 14.0 (2.3)
Phonemic Fluency 11.6 (4.5) 11.7 (2.8) 11.6 (4.6) 13.4 (2.8) 13.2 (2.1) 13.2 (2.6) 13.2 (2.8) 13.6 (3.1)
TEA Elevator 12.8 (3.9) 12.0 (2.4) 11.7 (4.0) 13.8 (2.9) 12.7 (3.3) 12.2 (3.0) 13.4 (3.1) 13.8 (2.9)
LDFR Digit Symbol 11.3 (4.2) 12.4 (4.0) 11.7 (3.2) 14.4 (3.3) 11.7 (5.8) 12.2 (2.8) 13.8 (3.6) 13.2 (3.5)
Stroop 11.8 (4.6) 10.8 (2.3) 11.4 (3.4) 13.5 (3.0) 11.1 (5.1) 13.2 (3.6) 13.5 (3.2) 13.8 (4.0)
Phonemic Fluency 10.8 (5.0) 11.8 (3.5) 11.8 (3.8) 11.9 (4.6) 11.9 (4.6) 13.2 (2.7) 12.8 (3.2) 14.5 (2.4)
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TEA Elevator 10.2 (6.7) 11.4 (3.4) 11.1 (3.4) 12.8 (4.1) 12.6 (3.4) 12.5 (3.3) 13.7 (2.9) 14.4 (2.1)
LDCR Digit Symbol 11.8 (4.0) 13.1 (3.6) 12.8 (3.2) 15.4 (2.1) 12.0 (5.4) 12.3 (2.4) 15.0 (2.1) 14.2 (2.6)
Stroop 12.4 (4.4) 11.8 (2.3) 12.4 (3.3) 14.2 (3.0) 11.4 (4.6) 13.2 (3.3) 14.8 (2.0) 15.1 (1.6)
Phonemic Fluency 11.3 (4.7) 12.5 (3.2) 12.7 (3.8) 13.9 (1.6) 12.3 (4.4) 12.8 (2.2) 14.1 (2.2) 15.0 (2.7)
TEA Elevator 10.8 (6.2) 12.2 (2.8) 12.7 (3.5) 14.2 (2.9) 12.9 (3.2) 12.7 (3.0) 14.2 (2.2) 14.7 (2.4)
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Discussion
In the present study, healthy adolescents completed a task of verbal episodic
memory subsequent to ingestion of oral glucose or a placebo under conditions of
divided attention at encoding. Further to the findings of Study 1, a central aim of Study
2 was to investigate whether the glucose memory facilitation effect is mediated by the
central executive. Participants completed a battery of tests of executive functioning
under fasting conditions, in order to determine whether individual differences in
baseline executive capacity influenced memory performance subsequent to glucose
ingestion. Of further interest in the present study was the investigation of whether
previous observations that glucose ingestion is reliably observed to facilitate memory
only under dual task conditions (Sünram-Lea et al., 2002b) is due to verbal interference.
Therefore, half of the participants from each of two treatment groups were provided
with verbal labels for the secondary hand movement task performed during encoding of
a target word list, while the other half of the participants were not provided with verbal
labels.
The primary finding of Study 2 was that, similarly to Study 1A, no difference in
memory performance was observed between adolescents who ingested a glucose drink
and those who consumed the placebo. Glucose ingestion failed to exert an enhancing
effect on verbal episodic memory performance in the present study regardless of
whether verbal labels were provided. This is despite the observation that glucose
ingestion significantly elevated blood glucose concentration relative to the placebo
group. Whether verbal labels were provided to the participants did not impact upon
blood glucose concentration. It is of interest that in the present study, those participants
who were provided with verbal labels for the secondary hand movement task exhibited
significantly better verbal recall performance than the participants who were not
provided with verbal labels, irrespective of treatment group. This finding suggests that
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provision of verbal labels facilitated dual task performance. On the basis of this
observation, it is unlikely that verbal recoding of hand movement sequences interferes
with verbal episodic memory. Therefore, it can reasonably be concluded that in previous
research in which glucose ingestion is observed to facilitate memory during
performance of a secondary motor task (Foster et al., 1998; Sünram-Lea et al., 2001,
2002b, 2004; Scholey et al., 2006), the neurocognitive mechanism by which glucose
exerts an enhancement effect on memory is not directly related to verbal encoding of
target items.
There was a potential confound in the present study regarding the investigation
of whether verbal recoding of hand movement sequences impacts upon the glucose
memory facilitation effect. Namely, some participants who were not provided with
verbal labels may have developed their own labelling system for the hand movement
sequences. The verbalisation of hand movement sequences is a commonly employed
strategy when performing tasks of memory for hand movements (Frencham, Fox, &
Maybery, 2003; Frencham et al., 2004). However, participants were questioned
subsequent to completing the study concerning any strategies employed during the
memory and hand movement tasks, with no participants reporting subjectively that they
had devised their own verbal labels for the hand movement sequences.
A central aim of this thesis is to determine whether the glucose memory
facilitation effect can be extended to healthy adolescents. The findings of Study 1A do
not suggest that the glucose memory facilitation effect is observable in adolescents.
However, it is important to investigate whether confounding factors may have
contributed to the lack of memory improvement observed subsequent to glucose
ingestion in the previous study. Specifically, in Study 2, baseline episodic memory
ability was controlled for by having participants perform an immediate free recall test of
a supraspan word list (RAVLT stimuli) under fasting conditions. While participants
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who demonstrated superior baseline episodic memory performance also performed
better on the CVLT, individual differences in baseline memory capacity did not
differentiate CVLT performance between the glucose and placebo treatment groups.
This suggests that individual differences in baseline memory ability does not account
for the failure to observe the glucose memory facilitation effect in the healthy
adolescent participants in the present study. However, the notion that other inter-
individual differences may contribute to whether glucose is observed to facilitate
memory in healthy adolescents was further investigated, using a within-subjects design,
in Study 3.
A further improvement of Study 2 was that the to-be-remembered word lists
were recorded on audiocassette, rather than being read aloud by the researcher. The
purpose of this amendment to the methodology employed in Study 1 was to better
control the rate at which the items were presented to the participants, and to ensure that
factors associated with stimulus presentation (such as intonation and clarity) were
consistent across all participants. However, as discussed above, this variation in the
study methodology did not contribute to a statistically significant difference in verbal
episodic memory performance between the two treatment groups.
Analogous to Study 1, self-ratings of mood were not found to differ between the
glucose and placebo treatment groups in the present study. In Study 2, a different test of
subjective mood (POMS-Bi) was employed from that administered in Study 1. The
POMS-Bi has been employed in previous studies in this area (Scholey & Fowles, 2002;
Benton & Nabb, 2004). The POMS-Bi was employed in this study, rather than the
Bond-Lader scales used in the previous study, to ensure that the lack of difference in
subjective mood between the glucose and placebo groups reported in the previous study
was not due to insufficient sensitivity in the test instrument. Given previous findings
that glucose ingestion is associated with the relief of tension (Benton & Owens, 1993a)
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and reaction to frustration in children (Benton et al., 1987), it might be expected that
glucose ingestion is associated with changes in subjective mood. Low levels of blood
glucose within the normal range have also been associated with aggressive tendencies
(Donohoe & Benton, 1999a). However, the present study findings were in line with
previous research employing the POMS-Bi that did not observe an effect of glucose
ingestion on mood (Scholey & Fowles, 2002). This last point notwithstanding, ingestion
of a low G.I. breakfast meal has previously been associated with increased self ratings
of energy on the POMS-Bi relative to a high G.I. breakfast meal or fasting (Benton &
Nabb, 2004).
With regard to the hypothesis that the glucose memory facilitation effect is
mediated by the central executive, the present study findings do not suggest that
individual differences in executive capacity significantly influence verbal episodic
memory subsequent to glucose ingestion. In Study 1A, participants who demonstrated
relatively superior performance on the Stroop task recalled more items on the delayed
recall tasks subsequent to glucose ingestion, but not subsequent to placebo. It was an
aim of Study 2 to further investigate the relationship between executive capacity, verbal
episodic memory and glucose ingestion, in order to examine whether individual
differences in executive capacity influence the propensity for glucose enhancement of
memory. Contrary to the findings of Study 1A, Stroop performance was not found to
influence the glucose memory facilitation effect in Study 2. Therefore, the effect related
to the Stroop test observed in Study 1 does not appear to be reliable. Similarly,
performance on the Digit Symbol Substitution and Phonemic Fluency tasks also failed
to influence verbal recall differentially between the glucose and placebo treatment
groups in the current study. An additional test of attentional switching and working
memory (ECR) was incorporated into Study 2. Analogous with the other tests of
executive functioning administered here, differential CVLT performance was not
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observed between the two treatment groups related to ECR performance. On the basis of
this evidence, it is not possible to conclude that the glucose memory facilitation effect is
mediated by the central executive, despite previous research findings reporting
improved performance on tasks of executive functioning subsequent to glucose
ingestion (Benton et al., 1994; Donohoe & Benton, 1999b; Kennedy & Scholey, 2000).
However, a limitation of the present study was that, similar to Study 1A, glucose was
not observed to enhance memory performance, which renders it difficult to investigate
potential neurocognitive mechanisms underlying the glucose memory facilitation effect
in these same individuals. In addition, it may well be that the tasks of executive
functioning that have been employed in Study 1 and Study 2 do not adequately tap the
‗central executive‘ (as conceptualised by Baddeley, 1986), and more specifically, dual
tasking (which is thought to be under the control of the central executive; Della Sala et
al., 1995). Nevertheless, given that the collective findings of Studies 1 and 2 do not
suggest that the central executive is involved in the mediation of the glucose memory
enhancement effect, it seems plausible to investigate empirically whether the glucose
memory facilitation effect is driven by the hippocampus (see Chapter 6).
Summary and Conclusions
The aims of Study 2 were to investigate a) whether the glucose memory
facilitation effect can be extended to adolescents, b) whether glucose exerts an
enhancement effect on verbal episodic memory by facilitating verbal rehearsal, and c)
whether verbal episodic memory improvement subsequent to glucose ingestion is
mediated by the central executive. Oral glucose ingestion was not observed to enhance
verbal episodic memory performance in healthy adolescents under dual task conditions,
regardless of whether verbal labels were provided for the hand movement sequences
comprising the secondary motor task. However, provision of verbal labels was
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associated with greater delayed recall across both treatment conditions, indicating that
verbal recoding of the hand movement sequences does not interfere with encoding of to-
be-remembered verbal items. This finding suggests that glucose does not exert an effect
on verbal episodic memory (as observed in previous studies) by facilitating verbal
rehearsal under conditions of verbal interference, as was hypothesised here. No
relationship was observed in Study 2 between executive capacity, glucose ingestion and
verbal episodic memory performance. It is therefore not possible to conclude, on the
basis of the findings from Studies 1 and 2, that the glucose memory facilitation effect is
mediated by the central executive. However, it is difficult to reach any firm conclusions
regarding the neurocognitive mechanisms underlying the glucose memory facilitation
effect on the basis of the present study findings, given that no effect of oral glucose
ingestion on verbal episodic memory was observed.
The findings of Studies 1A and 2 do not suggest that the glucose memory
facilitation effect is observable in healthy adolescent participants. However, given that
individuals within this age range vary greatly with regard to their degree of cognitive
and neuroanatomical development, and due to the relative sensitivity of the glucose
memory facilitation effect, it seems appropriate to seek to control further for inter-
individual differences in investigating glucose effects on memory in adolescents.
Therefore, Study 3 employed a within-subjects design (in order to maximise control for
individual differences) to investigate whether the glucose memory facilitation effect can
be extended to healthy adolescents.
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141
Chapter Five
Glucose and glucoregulatory influences on memory in healthy adolescents
A paper based on the findings of Study 3 has been published in Biological Psychology:
Smith, M. A., & Foster, J. K. (2008). Glucoregulatory and order effects on verbal
episodic memory in healthy adolescents after oral glucose administration. Biological
Psychology, 79, 209-215.
Chapter 5 could not be included in this digital thesis for copyright reasons.
Please refer to the print copy of the thesis, held in the University Library.
Chapter 6 could not be included in this digital thesis for copyright reasons.
Please refer to the print copy of the thesis, held in the University Library.
195
Chapter Seven
Glucose enhancement of memory: modulation by
adolescent stress, trait anxiety and basal HPA axis function?
A paper based on the findings of Study 5 has been accepted for publication in the
Journal of Psychopharmacology:
Smith, M. A., Hii, H. L., Foster, J. K., & van Eekelen, J. A. M. (in press). Glucose
enhancement of memory is modulated by trait anxiety in healthy adolescent males.
Journal of Psychopharmacology.
Chapter 7 could not be included in this digital thesis for copyright reasons.
Please refer to the print copy of the thesis, held in the University Library.
223
Chapter Eight
Memory for negative emotionally
arousing items after oral glucose ingestion
224
Abstract
In Study 5, the influence of baseline self-reported stress, trait anxiety and basal
hypothalamic-pituitary-adrenal (HPA) axis function on glucose enhancement of
memory was systematically investigated, with trait anxiety being observed to influence
the glucose memory facilitation effect. It is therefore of interest in Study 6 to consider
the role of both ‗trait‘ (i.e. baseline) and ‗state‘ (i.e. acute) affective states on the
glucose memory facilitation effect. In Study 6, healthy adolescent participants attended
two test sessions, separated by an interval of one week. In each session, participants
consumed either a) glucose or b) placebo, prior to encoding of a suprapan word list
under conditions of divided attention. Half of the participants encoded emotionally
arousing words in both sessions, while the other half encoded neutral items. Measures
of baseline stress, trait anxiety and basal HPA axis function were obtained prior to the
test sessions, while measures of salivary free cortisol and mood were taken during the
sessions. Unexpectedly, memory enhancement was not observed a) for the emotional
arousing stimuli or b) subsequent to the ingestion of oral glucose. These observations
were not modulated by a) changes in salivary free cortisol, b) mood or c) either of the
measures of baseline stress, anxiety and HPA axis function. These findings therefore do
not support the glucose memory facilitation effect, nor the observation from Study 5
that trait anxiety modulates the glucose memory facilitation effect. Limitations of Study
6 which may explain the lack of significant effects are discussed.
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Introduction
In the previous chapter, the role of basal HPA axis functioning, subjective stress
and trait anxiety in modulating the glucose memory facilitation effect was investigated.
While basal HPA axis functioning (measured via awakening salivary free cortisol) was
not observed to influence glucose enhancement of memory, trait anxiety was found to
modulate the glucose memory facilitation effect. On the basis of previous evidence that
negative affective states are associated with memory impairment (McEwen & Sapolsky,
1995; Sala et al., 2004), it was suggested that this finding may be related to the notion
that individuals who are not able to perform at their cognitive peak are most amenable
to the glucose memory facilitation effect. However, the relationship between baseline
(‗trait‘) and acute (‗state‘) affective states and their impact upon memory performance
subsequent to the ingestion of oral glucose has been afforded little attention in the
literature. It is therefore of interest to investigate the role of glucose in modulating
memory when an individual‘s acute affective state is manipulated via the presentation of
emotionally arousing versus neutral memory materials.
A number of studies have reported an improvement in memory performance for
emotionally arousing stimuli, for example, recall of emotionally arousing pictures
(Blake et al., 2001) or verbal stimuli (Parent et al., 1999). From an evolutionary
viewpoint, this emotional memory effect may be particularly important in terms of
increasing the saliency of memories for a) experiences in which survival is threatened,
or b) situations of heightened reproductive possibility (Hamann, 2001). The emotional
memory effect is thought to be mediated by the amygdala (McGaugh, 2004) via the
neurohormonal modulation of memory storage in other brain regions including the
hippocampus (Cahill & McGaugh, 1998). It has been further suggested that the
emotional memory effect pertains only to long-term memory recall (Quevedo,
Sant'Anna, Madruga, Lovato, de-Paris, Kapczinski et al., 2003), implicating only those
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brain regions involved in the mediation of long-term memory as relevant in the context
of regulating memory for emotionally arousing stimuli. The activation of the basolateral
amygdala by the stress hormones noradrenaline and cortisol in response to acute
emotional arousal appears to be of importance in terms of the neurohormonal mediation
of emotional memory. The amygdala appears to play a role in tagging the memory trace
as being particularly relevant in order to enhance hippocampal storage of the specific
memory trace (LaBar & Cabeza, 2006; van Stegeren, 2008; Wolf, 2008). The emotional
memory effect appears to persist regardless of the valence (positive or negative) of the
to-be-remembered stimuli. Studies investigating the influence of exposure to
emotionally arousing stimuli on endogenous cortisol levels are currently limited, with
most studies focusing on endogenous cortisol responses to acute psychosocial (e.g.
Kajantie & Phillips, 2006; Smeets, Jelicic, & Merckelbach, 2006), physiological (e.g.
Buchanan, Tranel, & Adolphs, 2006; Schwabe, Bohringer, Chatterjee, & Schachinger,
2008) and naturalistic (e.g. Robinson, Sünram-Lea, Leach, & Owen-Lynch, 2008)
stressors (for a discussion of the theoretical disambiguation of 'stress' and 'emotion' see
Lupien, Maheu, Tu, Fiocco, & Schramek, 2007). It is therefore of interest to investigate
this question in the present study.
As mentioned in Chapter 7, previous studies have investigated whether
emotional memory (i.e. the observation that emotionally laden materials are typically
better remembered than neutral stimuli) can be additionally enhanced by glucose. By
contrast, some studies have reported that the emotional memory effect is in fact
attenuated after oral glucose ingestion in healthy young adults (Parent et al., 1999;
Mohanty & Flint, 2001). Further studies have reported that glucose administration does
not convey any additional memory benefit for emotionally arousing verbal stimuli (Ford
et al., 2002; Brandt et al., 2006), although it was reported by Brandt and colleagues that
items of negative valence were better recollected than neutral or positive items (Brandt
227
et al., 2006). However none of these studies have investigated the role of divided
attention on the emotional memory effect subsequent to oral glucose ingestion. This is
despite previous evidence that glucose only reliably enhances verbal episodic memory
capacity in healthy young adults under conditions of increased cognitive demand at
encoding (Sünram-Lea et al., 2002b; for a detailed discussion see Chapters 1 and 4). It
is therefore of interest in the present study to investigate the combined influence of
glucose ingestion and divided attention on memory for negative emotionally arousing
verbal stimuli in healthy adolescents. It is of further interest in Study 6 to investigate the
influence of basal HPA axis function, self-reported stress and trait anxiety on emotional
memory performance subsequent to oral glucose ingestion, especially given a) the
findings of Study 5 related to modulation of the glucose memory facilitation effect by
trait anxiety, and b) previous reported observations that the emotional memory effect
may be enhanced by negative mood and trait anxiety (Haas & Canli, 2008).
Study 6
Aims
The primary aim of Study 6 was to investigate the influence of oral glucose
ingestion on memory for emotionally arousing verbal stimuli encoded under conditions
of divided attention in healthy adolescent males. A further aim was to investigate
whether acute salivary free cortisol responses to a) glucose and placebo ingestion, and
b) encoding of the emotionally arousing verbal stimuli, would modulate the
relationship between glucose ingestion and memory performance. Additionally, it was
also of interest to consider the role of basal HPA axis function, adolescent stress and
trait anxiety in modulating a) the emotional memory effect subsequent to oral glucose
ingestion, and b) salivary free cortisol levels after encoding of emotionally arousing
verbal stimuli.
228
Hypotheses
It was hypothesised that memory performance would be better for emotionally
arousing relative to neutral items, and that this emotional memory effect would be
exacerbated subsequent to oral glucose ingestion (relative to placebo). This hypothesis
was predicated on previous findings that glucose enhances memory performance in
healthy young individuals when memory materials are encoded under conditions of
divided attention at encoding (Sünram-Lea et al., 2002b; a protocol that was employed
in the present study but not in previous studies investigating glucose modulation of the
emotional memory effect). It was further hypothesised that encoding of the emotionally
arousing stimuli would be associated with an acute increase in salivary free cortisol.
Finally, predicated on the basis of a) previous reports that the emotional enhancement
effect is exacerbated in individuals with relatively high trait anxiety (Haas & Canli,
2008), and b) the findings of Study 5 which suggest that the glucose memory
facilitation effect is modulated by trait anxiety, it was hypothesised that relatively
higher levels of trait anxiety would enhance the glucose memory facilitation effect,
particularly for emotionally arousing stimuli.
Method
Participants
A total of 57 healthy adolescent males, ranging in age between 14 and 17 years
(Mage = 15.5, SDage = 1.0) participated in the present study. Participants were recruited
from secondary schools in Western Australia. Three participants reported non-
compliance with the fasting instructions of the study. These participants were removed
from the data set for all glucose and memory related analyses to avoid any potential
confounds from a ‗second meal effect‘. An additional eight participants attended only
one testing session, and thus were not included in any of the analyses reported here.
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Four further participants exhibited fasting blood glucose concentrations above the
normal range (> 6.1 mmol/L, The Expert Committee on the Diagnosis and
Classification of Diabetes Mellitus, 2003), and were thus also excluded from all
analyses. Therefore, a total of 42 participants were included in the final analyses.
Prior to the commencement of the first testing session, all participants and their
parents completed the screening questionnaire described in Chapter 3. Based on both
parental and participant responses to the screening questionnaire, all participants were
eligible to participate in the study.
Ethics approval for the present study was obtained from the Human Research
Ethics Committee of the University of Western Australia.
Treatment and design
A mixed-model design was employed for the blood glucose analysis, with two
within-subjects factors (treatment, time) and a single between-subjects factor (arousal
condition). A mixed-model design was also employed for the primary memory analyses,
with a single within-subjects factor (treatment) and a single between-subjects factor
(arousal condition). A subsequent mixed-model design incorporated an additional
between-subjects factor (glucoregulatory efficiency). Similarly, mixed-model designs
were also employed to investigate i) baseline self-reported adolescent stress, and ii) trait
anxiety, with the former incorporating an additional between-subjects factor (stress) and
the latter also incorporating an additional between-subjects factor (trait anxiety). A
further mixed-model design comprised an additional between-subjects factor (basal
cortisol).
The glucose and placebo treatments administered in the present study were
identical to those administered in Study 5 (see Chapter 7). Treatment order and arousal
condition were originally approximately counterbalanced. However for the 42
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participants included in the final analyses, treatment order and arousal condition
assignment is displayed in Table 8.1.
Table 8.1
The number of participants assigned to each arousal condition (arousing words or
neutral words) and treatment order (glucose first or placebo first).
Arousal condition/treatment order N
Arousal/glucose first 11
Arousal/placebo first 12
Neutral/glucose first 8
Neutral/placebo first 11
Materials
Saliva sampling equipment and free cortisol analysis. Details pertaining to
saliva sampling and awakening salivary free cortisol quantification are identical to
Study 5. The inter-assay coefficient of variation between the three assays was below
10%. The mean intra-assay coefficient of variation was below 5%.
Adolescent Stress Questionnaire (ASQ). Details pertaining to the ASQ are
identical to those reported in Chapter 7.
State-Trait Anxiety Inventory (STAI). Details pertaining to the STAI are identical
to those reported in the previous chapter.
Memory test. Four different stimulus lists were generated for the purpose of
Study 6. Two of the stimulus lists were for use in the ‗neutral words‘ condition, while
the other two stimulus lists were developed for the ‗arousing words‘ condition. Stimuli
were drawn from the Affective Norms for English Words (ANEW) database (Bradley &
Lang, 1999). This database contains emotional ratings for a large set of English words.
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Items have been rated on a 9-point scale according to valence, arousal and dominance.
For the purposes of generating the stimulus lists for the present study, only male ratings
were used (as no females participated in the present study). The neutral word lists
comprised items from the subset of words in the ANEW with a valence rating between
4 and 7 and an arousal rating of 4 or less. The negative word lists comprised items from
the subset of words in the ANEW with a valence rating of 4 or less, and an arousal
rating of 6 or more. Further, the two neutral lists and the two arousing lists were
matched in terms of valence and arousal. All four lists were matched in terms of
dominance and word frequency.
Analogously with the California Verbal Learning Test (CVLT) and CVLT-II
used in Studies 1, 2, 3 and 5, each list comprised 20 items. Further, the IFR phase
comprised five trials. Words were recorded in a male voice on audiocassette and
presented in each of the five encoding trials at a rate of one item per 2.5 seconds.
Participants were required to write as many of the words as they could remember, in any
order, into a provided booklet after each learning trial. No time limit for recall was
imposed. Following each trial, participants were required to fold the booklet over so that
they were not able to check responses of earlier trials when recalling items. At the same
time that the lists were read aloud, participants were required to perform the secondary
motor task employed in Studies 1, 2, 3 and 5. Similarly to these previous studies of the
present thesis, participants were told that performance on the word recall task and hand
movement task was equally important, and therefore that they should aim to perform
equally well on both tasks. Participants were also told that motor movements were being
recorded by a camcorder so that they could be assessed by the researchers at a later
time. The camcorder was used to induce compliance with task instructions to perform
both tasks equally well, although no such recording actually took place. Analogously
with Studies 3 and 5, a short delay recall phase took place 30 minutes subsequent to the
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commencement of the immediate recall phase, with a long delay recall phase taking
place a further 20 minutes later. In the present study, only free recall was employed for
the delayed recall phases. This is due to the fact that it was not possible to further
categorise the arousing items semantically.
Bipolar Profile of Mood States (POMS-Bi). A description of the POMS-Bi is
provided in Chapter 4. The purpose of incorporating the POMS-Bi in the present study
was to measure the change from baseline on the dimensions of mood and affect
measured by the POMS-Bi subsequent to encoding of the neutral or the emotionally
arousing stimulus lists.
Satiety questionnaire. The three satiety items from the modified Bond Lader
Questionnaire (for a description see Chapter 3) were employed in the present study as a
measure of fluctuations in self-reported satiety at four pre-determined time-points
during the testing sessions.
Blood glucose monitoring equipment. The blood glucose monitoring equipment
used in Study 6 was identical to that described in Chapter 3.
Procedure
Approximately one week prior to the first testing session, written informed
consent was obtained from participants and their parents. At this time, participants were
provided with three Salivette tubes, and were asked to obtain a saliva sample, 10
minutes post-awakening on three separate mornings before the first testing session by
chewing on the Salivette cotton roll for three minutes. Participants were told not to have
anything to eat or drink prior to collecting the samples. They were also asked to take the
samples only on days at which they woke up at their typical time of awakening (i.e. to
avoid collecting the samples on days when they woke considerably earlier or later than
the time that they would normally wake up on a typical school day). Participants were
233
required to record the time at which each sample was taken. Samples collected outside
of the 5-30 minute post-awakening window were excluded from that participant‘s basal
cortisol average. Further, participants were also administered the STAI and ASQ at this
time, for completion prior to the first testing session.
Participants subsequently attended two testing sessions. They were instructed
not to consume any food or drink, other than water, from 10:30 pm on the evening prior
to each of these testing sessions. All test sessions began between 7:00 and 9:15 am.
Participants first completed the POMS-Bi and satiety questionnaire, and baseline blood
glucose concentration was measured. Participants also provided a baseline saliva sample
at this time (participants were required to commence chewing on the cotton roll prior to
the finger prick, in order to minimise the influence of any potential stress/anxiety from
the blood glucose sampling procedure on salivary free cortisol concentration).
Immediately following the measurement of blood glucose concentrations, participants
consumed one of the two treatments. Participants were blind as to the contents of the
drinks, told only that they comprised of a ―sweet tasting liquid‖. Participants were
allowed 10 minutes to consume their designated treatment. Ten minutes following the
completion of treatment consumption, blood glucose concentrations were measured, a
saliva sample was provided and participants were administered the satiety questionnaire
for the second time. Participants then completed the immediate recall trials of the
memory test. Depending on whether participants were assigned to the ‗neutral words‘ or
‗arousing words‘ condition, participants were presented with either one of the neutral
word lists or one of the emotionally arousing word lists. Motor sequences were
performed during encoding of each word list. Participants subsequently completed the
post-encoding POMS-Bi questionnaire. The third satiety questionnaire and a third
measurement of blood glucose concentration was then obtained, and a third saliva
sample was collected. Following this, participants completed the short delay recall
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phase of the memory test. Following a 10 minute break, the final measurement of blood
glucose concentration was recorded, and the final administration of the satiety
questionnaire was given. The long delay recall phase of the memory test was then
completed. Finally, 10 minutes after completion of the long delay recall phase of the
memory test, participants provided a final saliva sample.
A second testing session was conducted exactly one week after the first testing
session. The second testing session was identical to the first testing session, except that
the testing procedure was preceded by a recall test of the items from the first testing
session. Participants were also administered the complementary treatment (glucose or
placebo) and version of the memory test to that administered in the first testing session.
This testing procedure is outlined in Table 8.2.
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Table 8.2
The testing procedure for Study 6. The time in minutes of each procedure
prior/subsequent to treatment delivery is displayed in the left column.
t (mins) Procedure
-15 One-week delayed recall (second testing session only)
-10 First blood glucose measurement
First saliva sample (baseline)
First satiety questionnaire
First POMS-Bi questionnaire
0 Treatment delivery
10 Second blood glucose measurement
Second saliva sample (post-treatment)
Second satiety questionnaire
20
35
Word list encoding (five trials) with secondary motor task
Second POMS-Bi questionnaire
40 Third blood glucose measurement
Third saliva sample (post-encoding)
Third satiety questionnaire
50 Short delay recall
60 Fourth blood glucose measurement
Fourth satiety questionnaire
70
80
Long delay recall
Fourth saliva sample (recovery)
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Statistical analysis
Pearson correlation analyses were employed to investigate the relationship
between mean awakening salivary free cortisol level, ASQ scores and trait anxiety
values.
A treatment (glucose, placebo) x time (-10, 10, 40, 60) x arousal condition
(arousal, neutral) mixed-model analysis of variance (ANOVA) was used to analyse the
blood glucose data, with repeated measures on the treatment and time factors. Similarly,
satiety scores during the test session were also analysed using a treatment (glucose,
placebo) x time (-10, 10, 40, 60) x arousal condition (arousal, neutral) mixed-model
ANOVA, with repeated measures on the treatment and time factors.
‗Change scores‘ were calculated for each factor of the POMS-Bi questionnaire,
by subtracting the baseline score from the post-encoding score. POMS-Bi change scores
were subsequently analysed using a treatment (glucose, placebo) x arousal condition
(arousal, neutral) mixed-model ANOVA, with repeated measures on the treatment
factor. Similarly, the difference between salivary free cortisol values at baseline and a)
post-treatment ingestion, b) post-encoding of the neutral or emotionally arousing
stimuli, and c) 1h post-encoding (recovery) were calculated in order to determine the
change in salivary free cortisol levels across the test session. These values were
analysed using a treatment (glucose, placebo) x time (post-treatment, post-encoding,
recovery) x arousal condition (arousal, neutral) mixed-model ANOVA, with repeated
measures on the treatment and time factors. Further, Pearson correlation analyses were
subsequently employed to investigate the relationship between salivary free cortisol
changes from baseline at the a) post-treatment, b) post-encoding and c) recovery time-
points, and each of the POMS-Bi change scores.
In terms of the memory analyses, a treatment (glucose, placebo) x trial (1, 2, 3,
4, 5) x arousal condition (arousal, neutral) mixed-model ANOVA was employed to
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analyse the immediate recall data, with repeated measures on the treatment and trial
factors. Delayed recall analyses (short delay, long delay) were conducted using
treatment (glucose, placebo) x arousal condition (arousal, neutral) mixed-model
ANOVAs, with repeated measures on the treatment factor. In addition, one-week
delayed recall forgetting indices were calculated by subtracting the number of items
recalled in the one-week delayed recall phase from the long delay recall phase in the
first testing session. These calculations yielded scores that reflect the total number of
items ‗forgotten‘ in the one week-interval between the first and second testing session
for each individual. One-week delayed recall forgetting indices were analysed with a
two-way ANOVA, incorporating treatment (glucose, placebo) and arousal condition
(arousal, neutral) as between-subjects factors.
Similarly to Study 5, a group of relatively ‗better glucoregulators‘ and a group of
relatively ‗poorer glucoregulators‘ was established by calculating the area under the
glucose response curve (AUC) for each participant on the glucose testing day and
performing a median split on these values. The combined influence of treatment, arousal
condition and glucoregulatory efficiency on the memory outcomes was analysed using a
treatment (glucose, placebo) x arousal condition (arousal, neutral) x glucoregulatory
efficiency (better, poorer) mixed-model ANOVA, with repeated measures on the
treatment factor.
Basal HPA axis function, trait anxiety and baseline stress groups were also
established using the procedure outlined in the previous chapter. The combined
influence of treatment, arousal condition and basal HPA axis function on the memory
outcomes was analysed using a treatment (glucose, placebo) x arousal condition
(arousal, neutral) x awakening free cortisol (low, normal, high) mixed-model ANOVA,
with repeated measures on the treatment factor. Likewise, the combined influence of
treatment, arousal condition and baseline stress on the memory outcomes was analysed
238
using a treatment (glucose, placebo) x arousal condition (arousal, neutral) x stress (low,
high) mixed-model ANOVA, with repeated measures on the treatment factor. Similarly,
a treatment (glucose, placebo) x arousal condition (arousal, neutral) x trait anxiety (low,
high) mixed-model ANOVA with repeated measures on the treatment factor, was
employed to investigate the influence of treatment, arousal condition and trait anxiety
on the memory outcomes.
Pearson correlation analyses were subsequently employed to investigate the
relationship between salivary free cortisol changes from baseline at the a) post-
treatment, b) post-encoding and c) recovery time-points, and each of the memory
outcomes. Additionally, Pearson correlation analyses were also conducted between
POMS-Bi changes scores and each of the memory outcomes.
Results
Basal HPA axis function
The mean of the awakening salivary free cortisol values was calculated as a
measure of basal HPA axis function. Mean awakening free cortisol values ranged
between 0.59 μg/dl and 2.08 μg/dl within the present study sample. Correlation analyses
between the mean awakening cortisol level, stress and trait anxiety failed to reveal a
significant relationship between awakening cortisol and the two subjective measures.
Stress and trait anxiety were positively correlated (r = 0.52, p < .001).
Blood glucose concentrations
A significant treatment x time x arousal condition interaction effect was
observed, F(3, 38) = 3.28, p < .05, with a moderate effect size (partial η2 = .21). Planned
comparisons revealed that within the neutral words condition, blood glucose
concentrations were significantly higher subsequent to ingestion of the glucose
239
treatment, relative to the placebo treatment, 10 minutes, t(17) = 5.07, p < .001, and 40
minutes, t(17) = 7.10, p < .001, post-treatment delivery. Within the neutral words
condition, blood glucose concentrations between the glucose and placebo conditions did
not differ at baseline, t(17) = 1.30, n.s. Within the arousing words condition, blood
glucose concentrations were significantly higher subsequent to ingestion of the glucose
treatment, relative to the placebo treatment, 10 minutes, t(23) = 5.28, p < .001, 40
minutes, t(23) = 7.48, p < .001, and 60 minutes, t(23) = 3.58, p < .001 post-treatment
delivery. Within the arousing words condition, blood glucose concentrations between
the glucose and placebo conditions did not differ at baseline, t(23) = 0.96, n.s. Planned
comparisons failed to reveal any significant differences in blood glucose concentration
within each treatment condition between the neutral and arousing words conditions at
any of the four time points (see Figure 8.1).
4
4.5
5
5.5
6
6.5
7
-10 10 40 60
Time Pre-/Post-Treatment (min)
Blo
od
glu
co
se
co
nc
en
tra
tio
n
(mm
ol/L
)
Glucose-Neutral
Placebo-Neutral
Glucose-Arousal
Placebo-Arousal
Figure 8.1
Mean blood glucose concentrations for the four study conditions 10 minutes prior to
treatment delivery (baseline), and 10, 40 and 60 minutes following treatment delivery (±
S.E.).
240
Satiety questionnaire
The treatment x time x arousal condition interaction was nonignificant on the
satiety questionnaire, F (3, 35) = 1.05, n.s, with the effect size being small (partial η2 =
.08). The treatment x time interaction was also nonsignificant on the satiety
questionnaire, F (3, 35) = 0.25, n.s, with the effect size also being small (partial η2 =
.02).
POMS-Bi Questionnaire
‗Change scores‘ were calculated for each of the six POMS-Bi factors by
subtracting the baseline score from the post-encoding score on each factor for all
participants. Analysis of these scores for each of the six POMS-Bi factors did not reveal
any significant treatment x arousal condition interactions.
Salivary free cortisol response
The difference in salivary free cortisol concentrations between baseline and a)
post-treatment ingestion, b) post-encoding of the neutral or emotionally arousing
stimuli, and c) 1h post-encoding (recovery) were calculated for each participant to be
used as indices of changes in cortisol concentration across the testing sessions.
References to cortisol concentrations at each of these time-points reflect these
difference values.
The three-way interaction between time, treatment and arousal condition was
nonsignificant for cortisol response, F(2, 36) = 0.66, n.s, with the effect size being small
(partial η2 = .04). The treatment x time interaction approached significance, F(2, 36) =
2.67, p = 0.08, with the effect size being small (partial η2 = .13). However, all post-hoc
Bonferroni adjusted pairwise comparisons were nonsignificant for this interaction (see
Figure 8.2).
241
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0
Post-Treatment Post-Encoding Recovery
Time of saliva sampling
Sa
liv
ary
fre
e c
ort
iso
l
(dif
fere
nc
e f
rom
ba
se
lin
e;
μg
/dL
)
Glucose-Neutral
Placebo-Neutral
Glucose-Arousal
Placebo-Arousal
Figure 8.2
Differences in salivary free cortisol concentrations between baseline and a) post-
treatment ingestion, b) post-encoding of the neutral or emotionally arousing stimuli, and
c) recovery for the two treatment and two arousal conditions.
Further, correlation analyses between POMS-Bi questionnaire ‗change scores‘
and salivary free cortisol concentrations for the arousal condition on the placebo testing
day revealed a significant negative relationship between post-encoding cortisol
concentration and i) the ‗composed-anxious‘, and ii) the ‗confident-unsure‘ factors of
the POMS-Bi. Moreover, correlation analyses revealed a significant relationship
between recovery cortisol concentration and i) the ‗composed-anxious‘, ii) the
‗confident-unsure‘, and iii) the ‗clearheaded-confused‘ factors of the POMS-Bi on the
placebo testing day for those participants in the arousal condition (see Table 8.3). All
correlation coefficients between POMS-Bi questionnaire ‗change scores‘ and salivary
free cortisol concentrations for the neutral condition were nonsignificant on the placebo
testing day.
242
Table 8.3
Correlations between POMS-Bi questionnaire ‘change scores’ and salivary free
cortisol concentrations for the arousal condition on the placebo testing day.
Post-Treatment Post-Encoding Recovery
Composed-Anxious -0.04 -0.48* -0.47*
Agreeable-Hostile 0.09 -0.30 -0.33
Elated-Depressed 0.12 -0.33 -0.37
Confident-Unsure -0.22 -0.47* -0.49*
Energetic-Tired 0.10 -0.33 -0.38
Clearheaded-Confused -0.09 -0.42 -0.49*
*p < .05.
Memory test
Similarly to Study 5, participants who performed at ceiling (i.e. recalled 100%
of the to-be remembered items) in either the glucose or placebo treatment condition on
any given recall phase of the CVLT-II were excluded from the analyses for that recall
phase.
Immediate recall. The three-way interaction between trial, treatment and arousal
condition was nonsignificant on immediate recall, F(4, 36) = 0.99, n.s, with the effect
size being small (partial η2 = .10). A significant main effect of trial was observed, F(4,
36) = 210.96, p < .001, with the effect size being large (partial η2 = .96). There was a
general trend across both treatment groups of an increase in the number of items
recalled across the five immediate recall trials. Pairwise comparisons revealed that the
number of items recalled increased significantly between trial 1 and trial 2, p < .001,
trial 2 and trial 3, p < .001, trial 3 and trial 4, p < .001, and trial 4 and trial 5, p < .001.
243
Delayed recall. The treatment x arousal condition interaction was nonsignificant
on short delay recall, F(1, 39) = 0.28, n.s, with the effect size being small (partial η2 =
.01). The treatment x arousal condition interaction was also nonsignificant on long delay
recall, F(1, 39) = 0.55, n.s, with the effect size being small (partial η2 = .01). Analysis of
the forgetting indices for the one-week recall phase also yielded a nonsignificant
interaction between treatment and arousal condition, F(3, 36) = 0.55, n.s, with the effect
size being small (partial η2 < .01).
Glucose regulation. A group of relatively ‗better glucoregulators‘ and a group of
relatively ‗poorer glucoregulators‘ were established, using the protocol described in
Chapter 5. The treatment x arousal condition x glucoregulatory efficiency interaction
was nonsignificant for all recall phases of the memory test.
Basal HPA axis function. Participants were initially stratified into three groups
on the basis of mean awakening salivary free cortisol using the procedure described in
the previous chapter (see chapter 7). However, due to there being an insufficient number
of participants in the ‗low‘ awakening free cortisol group, the ‗low‘ and ‗normal‘ groups
were combined for the present study. This resulted in two basal HPA axis function
groups, i) a ‗low/normal‘ group (mean awkening salivary free cortisol ≤ 0.96) and ii) a
‗high‘ group (mean awkening salivary free cortisol > 0.96). Treatment x arousal x
awakening free cortisol interactions were nonsignificant for all recall phases of the
memory test.
ASQ and trait anxiety. Similarly to Study 5, a group of individuals reporting
relatively lower baseline stress and a group of individuals reporting relatively higher
baseline stress were established for analysis by performing a median split on the total
ASQ scores. Likewise, a group of adolescents reporting relatively lower trait anxiety
and a group with relatively higher trait anxiety were established by performing a median
split on the trait anxiety scores.
244
The treatment x stress x arousal condition interaction was nonsignificant for all
recall phases of the memory test. However, a significant treatment x trait anxiety x
arousal condition interaction effect was observed on immediate recall (trial 5), F(1, 38)
= 4.59, p < .05, with the effect size being small (partial η2 = .11). Further, the treatment
x trait anxiety x arousal interaction was also significant on short delay recall F(1, 38) =
5.88, p < .05, with the effect size being small (partial η2 = .13), and on long delay recall
F(1, 38) = 5.65, p < .05, with the effect size also being small (partial η2 = .13). Post-hoc
Bonferroni adjusted pairwise t-tests of each of these significant interaction effects were
nonsignificant.
The two-way interaction between trait anxiety and arousal condition on the
placebo testing day revealed a significant effect on immediate recall (trial 5), F(1, 38) =
10.43, p < .01, with the effect size being moderate (partial η2 = .22). Further, the trait
anxiety x arousal condition interaction was also significant on the placebo testing day
for short delay recall, F(1, 38) = 10.65, p < .01, with the effect size being moderate
(partial η2 = .22), and long delay recall, F(1, 38) = 7.39, p = .01, with the effect size
being small (partial η2 = .16). Post-hoc Bonferroni adjusted pairwise t-tests of each of
these significant interaction effects were nonsignificant.
Acute cortisol response. Correlation analyses failed to reveal a relationship
between a) post-treatment, b) post-encoding and c) recovery cortisol responses and
memory outcomes on the glucose and placebo testing days in the arousal condition.
POMS-Bi. Correlation analyses failed to reveal a relationship between POMS-Bi
changes scores and memory outcomes on the glucose and placebo testing days in the
arousal condition.
245
Discussion
The aim of the present study was to investigate the influence of oral glucose
ingestion on memory for emotionally arousing verbal stimuli encoded under conditions
of divided attention. It was of further interest to investigate whether the acute cortisol
response to encoding of the emotionally arousing stimuli influenced the relationship
between glucose ingestion and memory performance and furthermore, to extend upon
the findings of Study 5 by looking at the role of basal HPA axis function, adolescent
stress and trait anxiety on the glucose memory facilitation effect. In contrast to the
findings of Study 5, a relationship was not observed between trait anxiety and
awakening salivary free cortisol concentration in the present study. However, a
significant positive correlation was observed between baseline adolescent stress and
trait anxiety. As anticipated, blood glucose concentrations were significantly elevated
subsequent to oral glucose ingestion for both glucose conditions, relative to the two
placebo conditions.
The acute salivary free cortisol response during the course of the testing sessions
was not observed to differ significantly between the four study conditions (glucose-
neutral items, placebo-neutral items, glucose-arousing items, placebo-arousing items).
The interaction between treatment condition and the time of cortisol sampling
approached significance. Post-hoc comparisons of this interaction were observed to be
nonsignificant following adjustment for multiple comparisons. However, unadjusted
comparisons (not reported) indicated that the interaction was driven by differences in
salivary free cortisol between the glucose and placebo treatment conditions at
‗recovery‘ (i.e. 1 hour post-encoding), in that a larger decrease in salivary free cortisol
was observed between the baseline and recovery saliva samples subsequent to placebo
ingestion relative to glucose. This may be related to previous observations that HPA
axis activity is stimulated by glucose ingestion (Gibson et al., 1999), especially under
246
conditions of acute stress (Kirschbaum, Gonzalez-Bono, Rohleder, Gessner, Pirke,
Salvador et al., 1997; Gonzalez-Bono et al., 2002).
The relationship between acute, self-reported mood and salivary free cortisol
throughout the placebo testing sessions were investigated for i) the neutral condition,
and ii) the arousal condition. The purpose of this analysis was to confirm that the
biological measure of acute emotional arousal (i.e. salivary free cortisol) corresponded
with a subjective measure of acute emotional arousal (i.e. POMS-Bi scores). This
analysis used data from the placebo condition only to eliminate any confounding
biological influences of glucose ingestion on this relationship. As expected, all
correlations between mood scores and free cortisol concentrations were nonsignificant
for the neutral condition. However, a number of significant relationships were observed
between mood scores and free cortisol concentrations for the arousal condition. On the
‗composed-anxious‘ scale of the POMS-Bi, a significant negative correlation was
observed between the POMS-Bi change score and free cortisol (difference from
baseline) for the arousal condition at the a) post-encoding, and b) recovery time-points.
This relationship suggests that a higher degree of composure is associated with a greater
fall in salivary free cortisol concentration. A similar negative correlation was also
observed at the post-encoding and recovery time-points on the ‗confident-unsure‘ scale
of the POMS-Bi, suggesting that greater confidence is associated with a greater fall in
salivary free cortisol concentration. Further, a significant negative correlation was
observed between the POMS-Bi change score and free cortisol for the arousal condition
at the recovery time-point on the ‗clearheaded-confused‘ scale. This relationship is
indicative of greater ‗clearheadedness‘ being associated with a greater fall in salivary
free cortisol concentration. Taken together, these findings suggest that subjective mood
states are representative of acute cortisol responses to encoding of the emotionally
arousing stimuli.
247
In Study 6, glucose was not observed to modulate memory performance in the
healthy adolescent participants for both the neutral and the emotionally arousing stimuli.
Further, the two emotional arousal conditions were not observed to differentially
influence verbal recall performance. The lack of a significant difference in memory
performance for emotionally arousing and neutral items is somewhat surprising given
previous findings which have supported the notion that memory performance is
typically better for emotionally arousing materials (Parent et al., 1999; Blake et al.,
2001; Hamann, 2001; LaBar & Cabeza, 2006). It is also unexpected that oral glucose
ingestion was not observed to modulate memory performance in the present study,
especially given the results of Study 3 and Study 5, which support the notion that
glucose ingestion improves verbal episodic memory performance in healthy
adolescents. One small difference which could have accounted for this disparity
between the memory outcomes of Studies 3 and 5, and the findings for the neutral
words condition of the present study, is that the present study did not incorporate items
drawn from shared semantic categories. Given that many of the studies investigating
glucose influences on verbal episodic memory have employed the California Verbal
Learning Test (e.g. Foster et al., 1998; Sünram-Lea et al., 2001, 2002b, 2002a, 2004),
which makes use of semantic categories as recall cues, it may well be that this semantic
cueing is somehow important in terms of reliably observing the glucose memory
facilitation effect. Such minor changes to the study methodology may account for
substantial variations in results between studies in this area when taking into
consideration the relative sensitivity of the glucose memory facilitation effect, which
has been alluded to previously in the present thesis. In addition, similarly to Study 5,
basal HPA axis function was not observed to modulate memory performance
subsequent to the ingestion of oral glucose in Study 6.
248
Similarly to Study 5, baseline self-reported adolescent stress was not observed to
influence the glucose memory facilitation effect in the present study. However, the
three-way interaction between treatment, trait anxiety and arousal condition was
significant for immediate recall, short delay recall and long delay recall, although
Bonferroni adjusted pairwise comparisons of these interactions were nonsignificant.
Unadjusted comparisons (not reported) demonstrated that these interactions were driven
largely by individuals who reported relatively lower trait anxiety recalling more
emotionally arousing than neutral items on the placebo testing day. It is somewhat
unexpected that this relationship was observed for the low trait anxiety group, but not
the high trait anxiety group, given previous reports that the emotional enhancement
effect is intensified in individuals with relatively higher trait anxiety (Haas & Canli,
2008). Therefore, the findings of Study 5 related to modulation of the glucose memory
facilitation effect by trait anxiety were not replicated by the neutral words condition in
the present study, possibly related to the lack of semantic cues provided in Study 6, as
suggested previously.
A limitation of Study 6 was that the emotional arousal manipulation was a
between-subjects rather than a repeated measures comparison. It was decided to design
the study in this manner to reduce the burden on the participants, in that participants
would have had to attend four testing sessions if emotional arousal was a repeated
measures factor. It is also likely that this would have contributed to a high participant
dropout rate. However, the mixed-model design that was used may have introduced
additional error. This study design therefore could have contributed to the lack of
emotional memory effect observed in the present study. As alluded to earlier in the
present thesis, both the glucose memory facilitation effect and the emotional memory
effect are relatively sensitive. It would therefore have been most desirable to employ
repeated measures on both the treatment factor and the emotional arousal factor,
249
especially given the potential relative lack of homogeneity regarding baseline memory
capacity and other baseline attributes in adolescents.
In the present study it was expected that encoding of the emotionally arousing
stimuli may have modulated salivary free cortisol concentration. However, this was not
observed to be the case in Study 6. The reason for this lack of modulation of salivary
free cortisol from encoding of emotionally arousing words may be due to a number of
factors. Firstly, although somewhat unlikely, it may be that the HPA axis was
stimulated by encoding of the emotionally arousing stimuli, however this was not
observable via modulations in salivary free cortisol. In this context, it is considered
important in gauging HPA axis function to measure comprehensively a range of HPA
axis mediated hormones and proteins, including adrenocorticotrophin hormone
(ACTH), cortisol binding globulin (CBG) and total plasma cortisol (Kumsta, Entringer,
Hellhammer, & Wüst, 2007; Levine, Zagoory-Sharon, Feldman, Lewis, & Weller,
2007). This is particularly relevant given that numerous genetic and environmental
factors act upon the HPA axis (de Kloet et al., 2005), which means that free cortisol
alone may not be sufficient to determine HPA axis responsiveness to a stressful
challenge. Secondly, previous evidence suggests that psychological stress, such as
exposure to emotionally arousing stimuli, activates the sympathetic-adrenal medullary
(SAM) axis but not the HPA axis. For example, viewing negative emotionally arousing
pictures has been associated with an increase in salivary alpha amylase (sAA), an
enzyme known to mediated by the SAM axis, but not cortisol (van Stegeren, Wolf, &
Kindt, 2008). By contrast, physiological stress induced changes in both cortisol and
sAA (van Stegeren et al., 2008). A limitation of the present study is that no assays for
biomarkers of SAM axis activation were performed, which may have indicated whether
exposure to the emotionally arousing materials encoded by the participants in the
present study induced sympathetic arousal. The collection of heart rate measurements
250
would be one simple technique for obtaining an index of sympathetic arousal. This
methodology has already been employed in some previous investigations of the glucose
memory facilitation effect (Kennedy & Scholey, 2000).
Summary and Conclusions
Glucose was not observed to enhance memory performance for a) emotionally
arousing, or b) neutral items in the present study. Further, basal HPA axis function,
glucoregulatory efficiency and trait anxiety were not observed to influence the
relationship between oral glucose ingestion and verbal episodic memory performance.
Unexpectedly, memory performance was not found to be improved for emotionally
arousing items, and in addition, exposure to emotionally arousing stimuli was not
associated with modulation of salivary free cortisol. Limitations of Study 6 included the
implementation of a mixed-model design with emotional arousal as a between-subjects
factor. This may have influenced the lack of emotional memory findings observed.
Further, a biological measure of SAM axis function would have enabled a conclusion to
be drawn on whether the emotional arousal manipulation was effective in inducing a
sympathetic response to stress. Finally, the present study did not incorporate semantic
cues in the verbal episodic memory test as was the case with studies 1, 2, 3 and 5, which
may have influenced the present study results. Therefore, the findings of Study 6 do not
support the glucose memory facilitation effect or the emotional memory effect in
healthy adolescents. In addition, the finding from Study 5 that trait anxiety mediates the
glucose memory facilitation effect has not been replicated here. However, owing to the
aforementioned limitations of Study 6, the findings of this final study should be treated
with caution.
251
Chapter Nine
General Discussion
252
Introduction
The primary aim of the present thesis was to investigate the influence of oral
glucose ingestion on verbal episodic memory performance in adolescents. This aim was
predicated upon previous research which has demonstrated the enhancing effect of
glucose on verbal episodic memory in healthy elderly (Hall et al., 1989; Manning et al.,
1990; Manning et al., 1992; Parsons & Gold, 1992; Manning et al., 1997; Manning et
al., 1998b; Riby et al., 2004; Riby et al., 2006) and in young adults (Foster et al., 1998;
Sünram-Lea et al., 2001, 2002b, 2002a; Meikle et al., 2004; Sünram-Lea et al., 2004;
Meikle et al., 2005; Riby et al., 2006; Riby et al., 2008a). Additional aims were to
investigate in further detail a number of factors that may potentially modulate an
individual‘s sensitivity to the glucose memory facilitation effect, including inter-
individual differences in executive capacity, glucoregulatory efficiency, basal
hypothalamic-pituitary-adrenal (HPA) axis function, baseline stress and trait anxiety. It
was of further interest to investigate whether the hippocampus specifically subserves the
glucose memory facilitation effect.
Summary and general discussion of key findings
With regard to the primary hypothesis that the glucose memory facilitation
effect can be extended to healthy adolescents, the findings of the first two studies offer
little to support this proposal. Study 2 attempted to control for baseline memory
capacity by employing the Rey Auditory Verbal Learning Test (RAVLT) to enable
baseline memory to be controlled for statistically. Controlling for baseline memory
capacity in this manner did not influence the study outcomes. However, from Study 3
onwards, a repeated measures design was employed. When the full range of individuals‘
cognitive, physiological and personality attributes were controlled for using a repeated
measures methodology (in which each individual served as their own control), glucose
253
enhancement of memory performance was observed in Study 3 (when order effects
were also controlled for statistically; see Smith & Foster, 2008a), Study 4 (in terms of
response times during the recognition memory test; see Smith, Riby, Sunram-Lea, van
Eekelen, & Foster, 2009) and Study 5 (see Smith, Hii, Foster, & van Eekelen, in press).
A significant finding to emerge from Study 1B was that greater remembering
(determined via the calculation of a remembering/forgetting index as a within-subjects
indicator of verbal episodic memory performance) was observed after a long delay for
those participants who consumed a high G.I. breakfast cereal meal, relative to those
participants who consumed a low G.I. meal (Smith & Foster, 2008b). Given that a
difference between these two treatment conditions was not observed at the short delay
recall phase, this finding was attributed to a ‗reminiscence effect‘ (Smith & Vela, 1991).
While ingestion of a high versus a low G.I. breakfast cereal meal did not directly
influence memory recall in Study 1B, this remembering/forgetting effect was thought to
reflect the greater glucose availability subsequent to ingestion of the high G.I. breakfast
cereal, which may be necessary to support verbal episodic memory functioning when
task demands are increased (e.g. when encoding takes place under conditions of divided
attention), as was the case in Study 1B.
Utilisation of a repeated measures design in Study 3 introduced a novel bias into
the study – namely, an order effect. This point notwithstanding, in Study 3, glucose was
observed to benefit short delay cued recall, long delay free recall and long delay cued
recall performance when this order effect was controlled for statistically. A further
benefit of employing a repeated measures design was that it was possible to obtain a
measure of glucoregulatory efficiency (i.e. area under the glucose response curve, AUC)
for all participants. This was not possible for Study 1A and Study 1B, as only ~50% of
the participants in these two studies were administered glucose as part of the testing
procedure. Further analyses of the Study 3 data revealed that the glucose memory
254
facilitation effect was only observed in participants who exhibited relatively better
glucoregulatory efficiency. It remains somewhat uncertain whether a) glucoregulatory
efficiency per se, or rather b) blood glucose concentration being within an optimal range
for memory enhancement in the ‗better glucoregulators‘ group was the more powerful
factor influencing this finding.
Having observed the glucose memory facilitation effect using a repeated
measures design in Study 3 (but not using a between-subjects design in Studies 1 and
2), it was decided that repeated measures should be employed on the ‗treatment‘ factor
for the remainder of the empirical work for the present thesis. While little evidence was
found in support of the hypothesis that the central executive is involved in the mediation
of the glucose memory facilitation effect in the first two studies, Study 4 sought to
further clarify whether glucose specifically targets the hippocampus or more global
brain regions in modulating cognitive performance. The ingestion of oral glucose was
associated with enhancement of event-related potential (ERP) components of i)
recollection (left-parietal old/new effect), and ii) familiarity (mid-frontal old/new effect)
in healthy adolescents. Recollection is known to be mediated by the hippocampus,
whereas familiarity is thought to be subserved by extrahippocampal brain regions (most
notably the perirhinal cortex; Aggleton & Brown, 2006). Therefore, this finding does
not support the purported ‗hippocampus hypothesis‘ pertaining to glucose modulation
of memory (Riby & Riby, 2006). It can therefore be concluded that while Studies 1 and
2 did not support a role for the central executive in mediating the glucose memory
facilitation effect, glucose nevertheless appears to target extrahippocampal brain regions
in subserving neurocognitive performance in healthy adolescents. In addition, Study 4
substantiated the findings of Study 3 whereby the glucose memory facilitation effect is
observable in adolescents, in that faster response times were observed for the
recognition memory task subsequent to oral glucose ingestion (relative to placebo).
255
Once evidence was found to support the notion that the glucose memory
facilitation effect can be extended to healthy adolescents (Study 3 and Study 4), and it
was observed that glucose enhancement of memory is likely mediated by global brain
structures including the hippocampus and extrahippocampal brain regions (Study 4), it
was possible to investigate a number of other factors that potentially modulate an
individual‘s sensitivity to glucose improvement of memory. Given that Study 3 found
evidence that relatively better glucoregulatory efficiency was associated with a memory
benefit subsequent to the ingestion of oral glucose, Study 5 focused on baseline stress
(including subjective baseline stress and trait anxiety measures, as well as basal HPA
axis functioning), which has been associated with the regulation of blood glucose
(Peters et al., 2004; Gibson, 2007; Benedict, Kern, Schmid, Schultes, Born, &
Hallschmid, 2009). Basal HPA axis functioning (salivary free cortisol) and subjective
baseline adolescent stress were not observed to modulate the glucose memory
facilitation effect. However, glucose enhancement of memory was only observed for
those individuals who reported relatively higher trait anxiety. This finding implies that
the glucose memory facilitation effect may be subserved by a related biological
mechanism (e.g. sympathetic adrenal-medullary; SAM; axis function). In addition,
Study 5 also demonstrated that oral glucose ingestion prior to encoding was associated
with greater remembering of a supraspan word list following a one week delay between
encoding and recall.
Finally, in relation to the finding of Study 5 that trait anxiety modulates the
glucose memory facilitation effect, it was suggested that individuals with high trait
anxiety may be relatively more sensitive to emotionally arousing stimuli, potentially
resulting in better memory capacity for arousing items. It was therefore of interest in
Study 6 to further investigate the influence of glucose on memory for emotionally
arousing stimuli. Similarly to Study 5, baseline stress-related subjective and biological
256
measures were obtained, and cortisol responses to a) glucose ingestion and b) exposure
to negative emotionally arousing verbal stimuli were monitored. In Study 6, oral
glucose ingestion failed to improve memory performance for a) neutral, and b)
emotionally arousing stimuli. Further, baseline measures of subjective stress, HPA axis
function and trait anxiety failed to influence memory performance subsequent to oral
glucose ingestion. In addition, there was no effect of encoding the emotionally arousing
stimuli on acute cortisol changes or memory performance for these items. One
potentially important difference between Study 6 and the remainder of the studies
reported here (with the exception of Study 4), was that the earlier studies all employed a
cued recall procedure (in that the verbal stimuli were drawn from shared semantic
categories). This may be important in the context of memory recall for items encoded
subsequent to oral glucose ingestion (for a detailed discussion, see Chapter 8).
Significance of the findings in context of the extant literature
The glucose memory facilitation effect
Glucose enhancement of memory is a robustly observed phenomenon in older
adults (see Chapter 1 for a detailed review). Improvement of verbal episodic memory
has also been observed in younger adults, although a number of factors appear to
modulate this effect in healthy young adults, including whether encoding takes place
under conditions of divided attention (Sünram-Lea et al., 2002b; see also Chapter 1).
The study by Lapp (1981) is the only previous reported observation of glucose
enhancement of memory in adolescents. A limitation of this previous study (Lapp,
1981) was that a fasting control group, rather than a placebo control group, was
implemented. The findings of this study could therefore be attributed to a deleterious
fasting effect in the control group (Doniger et al., 2006) or as a result of the
motivational provision of a ‗reward‘ (a breakfast meal) in the treatment condition. The
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findings of the present thesis therefore contribute greatly to the glucose-memory
literature, by demonstrating reliably that the glucose memory facilitation effect can be
extended to healthy adolescents.
One-week recall
Previous studies have reported that in younger (Sünram-Lea et al., 2002a) and
older (Manning et al., 1992; Manning et al., 1998b) adults, glucose enhances verbal
episodic memory performance when glucose ingestion and item encoding takes place 24
hours prior to memory recall. An aim of the present thesis (Chapter 7) was to extend
these previous findings by investigating verbal episodic memory recall when glucose
ingestion and word list encoding took place one week previously. In Study 5, oral
glucose ingestion was observed to enhance verbal episodic memory free recall
performance after a one week delay, relative to placebo. This finding is in line with
previous observations that glucose is an effective cognitive enhancer after an ‗extra-
long‘ delay (Manning et al., 1992; Manning et al., 1998b; Sünram-Lea et al., 2002a).
Further, the present thesis represents the first observation that glucose can improve
recall performance when recall takes place up to one week post-glucose ingestion and
encoding. Importantly, this finding supports the notion that glucose enhances primarily
memory encoding and/or consolidation, rather than retrieval, as a glucose load
administered one week pre-retrieval would no longer be biologically active, and
therefore would not be able to influence retrieval processes directly.
Glycaemic load
A number of previous studies have suggested that the ingestion of low G.I.
meals (which provide a slower and more prolonged release of glucose into the
bloodstream) are associated with improvements in neurocognitive performance, relative
258
to high G.I. meals (which cause a rapid increase in blood glucose levels, followed by an
equally rapid decline) in children (Mahoney et al., 2005; Benton et al., 2007; Ingwersen
et al., 2007) and adults (Benton et al., 2003; Nabb & Benton, 2006a; Nilsson et al.,
2009). Attention and episodic memory are two domains of cognition that are reliably
improved subsequent to ingestion of a low G.I. meal, relative to a high G.I. meal, across
most of these previous studies. This enhancement effect is likely to be due to the
increased release of glucose into the bloodstream over a long duration (i.e. 2.5 to 3
hours). However, on the basis of previous studies which have demonstrated that
ingestion of a fast-acting glucose laden drink reliably enhances verbal episodic memory
only under conditions of increased cognitive demand (e.g. Sünram-Lea et al., 2002b), it
was hypothesised in Chapter 3 that a high G.I. meal may be most effective in improving
verbal episodic memory performance when memory materials are encoded under
conditions of divided attention. Analysis of remembering/forgetting indices suggested
that subsequent to ingestion of the high G.I. meal, memory performance was indeed
enhanced at the long delay recall phase. This finding suggests that ingestion of high G.I.
meals may be effective in facilitating memory performance when task demands are
high. Further work is required to better understand the nature of the relationship
between ingestion of high G.I. foods and memory encoding under conditions of
increased cognitive demand.
The central executive and hippocampus hypotheses
The neurocognitive mechanisms which subserve the glucose memory facilitation
effect are poorly understood. A dominant theory in the literature is that glucose
enhancement of memory is mediated by the hippocampus (Riby & Riby, 2006), given
that this brain region is intimately involved in episodic memory processes (Shastri,
2002). However, as mentioned in Chapter 1, the ‗hippocampus hypothesis‘ does not
259
account well for studies which have reported that oral glucose ingestion is associated
with enhanced performance on tasks not generally thought to involve mediation by the
hippocampus (e.g. Kennedy & Scholey, 2000). The present thesis therefore sought to
clarify the role of i) the hippocampus, and ii) more global brain regions in meditating
the glucose memory facilitation effect. It was hypothesised in Study 1 and Study 2 that
the glucose memory facilitation effect would be more reliably observed in adolescents
with lower executive functioning capacity, on the basis that (c.f. the hippocampus
hypothesis) if the ‗central executive hypothesis‘ offers a more compelling explanatory
framework, then such individuals would have greater ‗room for improvement‘ in terms
of cognitive performance subsequent to glucose ingestion. However, as mentioned
previously, little evidence was found in Study 1 and Study 2 in terms of the central
executive playing a role in the mediation of the glucose memory facilitation effect. This
point notwithstanding, Study 1 and Study 2 employed a between-subjects design, which
may not be an optimal methodology for observing glucose enhancement of memory in
adolescents. Further, the specific executive function tasks that were used to determine
baseline executive capacity in Study 1 and 2 may have tapped into different elements of
executive functioning (a complex, multi-component entity; see Rabbitt, 1997) than that
component of executive functioning which is critical for effective dual tasking
involving verbal memory and hand movements. It is therefore difficult to conclude
reliably whether the central executive is involved in the mediation of the glucose
memory facilitation effect on the basis of these two studies.
In Study 4, the hippocampus hypothesis was investigated using event-related
potentials (ERPs). ERP methodology has been employed in previous investigations of
the glucose memory facilitation effect (Geisler & Polich, 1994; Knott et al., 2001; Riby
et al., 2008b; de Bruin & Gilsenan, 2009), and is useful for assessing cognitive
performance when overt behavioural responses cannot be reliably obtained. Further, this
260
methodology can offer additional insight into underlying cognitive and neural processes
mediating task performance. A recollection/familiarity recognition memory paradigm
was employed. Given that recollection, but not familiarity is thought to be subserved by
the hippocampus (Brown & Aggleton, 2001; Aggleton & Brown, 2006; Eichenbaum et
al., 2007), it was expected that the ingestion of oral glucose would be associated with
enhanced ERP components of recollection, but not familiarity. This intimation is in line
with the hippocampus hypothesis, and also with a previous behavioural study conducted
by Sünram-Lea and colleagues (2008) which reported that glucose administration
improves recognition memory judgements based on recollection, but not familiarity. In
contrast to the hypothesis that glucose ingestion would selectively enhance ERP
components of recollection, glucose administration was associated with enhanced ERP
components of both recollection and familiarity. On this basis it can be concluded that
glucose does not exclusively target the hippocampus in exerting an influence on
memory performance.
Glucoregulatory efficiency
The findings in the extant literature are equivocal with regard to whether the
glucose memory facilitation effect can be more reliably demonstrated in relatively better
or relatively poorer glucoregulators. In younger individuals, oral glucose ingestion has
been associated with greater memory enhancement in both better (Meikle et al., 2004)
and poorer (Craft et al., 1994; Messier et al., 1999) glucoregulators. In Study 3, the
glucose memory facilitation effect was observed only for those individuals who
exhibited relatively better glucoregulatory efficiency, when order effects were
controlled for statistically. However, glucoregulatory efficiency failed to modulate the
glucose memory facilitation effect in Study 5 and Study 6 (although note that glucose
ingestion was not associated with a memory benefit for neutral or emotional material in
261
Study 6, independent of whether glucoregulatory efficiency was incorporated into the
analysis). It was argued in Chapter 5 that differences exist between studies with regard
to the range of blood glucose values incorporated into each glucoregulatory efficiency
group (which are typically determined by median split or similar method). That is,
participants who are assigned to either the ‗better‘ or ‗poorer‘ glucoregulatory
efficiency group on the basis of their glucoregulatory profile in one study may fulfil the
criteria of the opposite condition in other studies. Therefore, ‗glucoregulatory
efficiency‘ as defined by many studies may in fact merely be a measure of whether the
blood glucose concentration of an individual at the time of memory testing is within the
optimal range to confer an enhancement effect. As mentioned above, the findings of
previous studies (and, indeed, the findings of those studies contained within the present
thesis) relating to glucoregulatory modulation of the glucose memory facilitation effect
are mixed. Therefore, additional work is clearly required to clarify the relationship
between glucoregulatory efficiency, glucose ingestion and memory performance.
Baseline stress
Glucoregulatory abnormalities appear to be intrinsically related to HPA axis
function, in that normal HPA axis function plays an important role in the regulation of
blood glucose (Peters et al., 2004; Benedict et al., 2009). An association has been
demonstrated in the literature between compromised glucoregulatory efficiency and
symptoms of HPA axis dysfunction (Plat et al., 1996; Reynolds et al., 2001; Andrews et
al., 2002; Gibson, 2007). Given the finding that the glucose memory facilitation effect is
modulated by glucoregulatory efficiency in Study 3, and in the young adult literature
(Craft et al., 1994; Messier et al., 1999; Meikle et al., 2004), the present thesis sought to
clarify whether basal HPA axis functioning also modulates glucose enhancement of
memory. In Study 5 and Study 6, basal salivary free cortisol measurements were
262
obtained as a measure of basal HPA axis function, with additional subjective measures
of baseline adolescent stress and trait anxiety also obtained in these two studies. Basal
cortisol and baseline subjective stress were found not to influence the glucose memory
facilitation effect in Study 5 or Study 6. However, Study 5 revealed that oral glucose
ingestion improved memory only in those individuals who reported relatively higher
trait anxiety. The results of Study 6 failed to replicate this finding, although glucose
ingestion was not observed to enhance memory in Study 6 even when no potentially
modulating factors were included in the statistical analyses (possibly due to a number of
limitations that are discussed in the ‗Limitations‘ section, below). The finding that the
glucose memory facilitation effect was modulated by trait anxiety in healthy adolescents
(Study 5) suggests that an alternative physiological mechanism related to baseline
stress/anxiety, possibly the SAM axis, may modulate glucose enhancement of memory.
Glucose and the emotional memory effect
Emotionally arousing stimuli are typically better remembered than neutral
stimuli (Hamann, 2001; LaBar & Cabeza, 2006). Stress hormones, such as adrenaline
and cortisol, have been put forward as potential neuroendocrine mediators of this
emotional memory effect (Wenk, 1989; Gold, 1995; Brandt et al., 2006). These
hormones have been suggested to exert an influence on memory performance via their
role in increasing the level of glucose in the bloodstream following exposure to an
emotionally arousing stimulus. For example, it has been demonstrated that exposure to
emotionally arousing pictures (Blake et al., 2001) or words (Scholey et al., 2006)
increases circulating blood glucose concentration. However, on the basis of previous
studies, glucose administration does not appear to further enhance memory for
emotionally arousing stimuli for which a memory advantage is already evident (Parent
et al., 1999; Ford et al., 2002; Brandt et al., 2006). In the present thesis, the influence of
263
glucose on memory for emotionally arousing stimuli was investigated when memory
materials were encoded under conditions of divided attention (Study 6). This was the
first study to investigate the question of whether glucose administration enhances
memory for emotionally laden material when encoding takes place under dual task
conditions. Given that glucose has only been demonstrated to reliably enhance verbal
episodic memory in healthy young individuals under conditions of increased cognitive
demand (Sünram-Lea et al., 2002b), it was hypothesised that in order for glucose to
exert an influence on emotional memory, item encoding under dual-task conditions may
be crucial. However, in line with previous studies (Parent et al., 1999; Ford et al., 2002;
Brandt et al., 2006), oral glucose ingestion was not observed to enhance emotional
memory in this context here.
Limitations
Several limitations associated with individual studies contained within the
present thesis have been discussed. This section will discuss in further detail some of
the more salient factors, which may have influenced the thesis outcomes as a whole.
The first limitation of the present thesis was that the first two studies employed a
between-subjects design. This choice of study design was based on numerous studies in
the healthy young adult literature which observed glucose improvement of memory
using a between-subjects design (Benton et al., 1994; Foster et al., 1998; Messier et al.,
1998; Sünram-Lea et al., 2001, 2002b, 2002a, 2004). This methodology was also
chosen in order to ensure that the burden on study participants would be minimal.
However, following the first two studies, in which glucose was not observed to
modulate memory in the healthy adolescent participants, it was decided to implement a
within-subjects design for the subsequent studies. This yielded a positive result in terms
of replication of the glucose memory facilitation effect in adolescents, with glucose
264
being observed to significantly modulate memory performance in Study 3 (when an
order effect was controlled for statistically), Study 4 and Study 5. The implementation
of a within-subjects design also enabled more sophisticated measures of glucoregulatory
efficiency (i.e. AUC) to be calculated for every participant. However, for Study 6, it
was decided to use a mixed-model design, with ‗emotional arousal‘ (i.e. whether the
items to be encoded were ‗negatively arousing‘ or ‗neutral‘ in valence) as a between-
subjects factor. Again, this decision was made in order to reduce the burden on the
young study participants, who would have had to attend four testing sessions, each one
week apart, had a within-subjects design been used for Study 6. This is likely to have
led to considerable participant attrition, and therefore would have required a very large
number of participants to be recruited. However, using a between-subjects manipulation
for the emotional arousal variable may have contributed to the lack of emotional
memory effect observed in Study 6, especially given the relative heterogeneity of the
adolescent population from which sampling took place for the present thesis.
Although speculative, it is likely that the adolescent participants recruited for the
present thesis represent a considerably more heterogeneous sample than the participants
recruited for previous young adult studies (which have typically made use of
undergraduate students as research participants; Benton et al., 1994; Parker & Benton,
1995; Foster et al., 1998; Messier et al., 1998; Sünram-Lea et al., 2001, 2002b, 2002a,
2004; Morris, 2008; Sünram-Lea et al., 2008), in terms of baseline memory ability,
socioeconomic status and anticipated educational attainment. Participants were recruited
from a range of private and government schools, representing diverse socioeconomic
backgrounds and anticipated educational attainment (according to numerous statistics
on which secondary school performance is measured in the state of Western Australia).
For this reason, the use of a within-subjects design may have been crucially important in
terms of observing the glucose memory facilitation effect within this thesis, as each
265
participant acted as their own control in this case. For the first two studies in which a
between-subjects design was employed, it could not be determined definitively whether
executive capacity is a relevant modulator of the glucose memory facilitation effect
(especially given the null glucose-memory outcomes of these studies). However, had a
within-subjects design been employed for these two studies, the outcomes may have
been different due to the decreased statistical error associated with the use of a within-
subjects design.
The sample size of the studies within the present thesis, while comparable with
previous studies in the glucose and memory literature, was perhaps not sufficiently large
to conduct further statistical analyses which may have been of interest. For example, it
was not possible due to sample size restrictions to conduct analyses which compared the
influence of glucose ingestion on memory between male and female participants (in
those studies which included both male and female participants). Indeed, the inclusion
of only male participants in Study 5 and Study 6, while important in terms of
eliminating the possible confounds of menstrual cycle and oral contraceptive influences
on HPA axis function in females, limits the generalisability of the Study 5 and Study 6
findings to males only. In addition, for all of the studies other than Study 4, participants
were tested in a small group setting. As discussed in Chapter 3, social loafing (Latané et
al., 1979) may render individuals less inclined to apply maximal effort to the cognitive
tasks in a group testing scenario. Moreover, group testing may be perceived by study
participants as being less confronting than a one-on-one testing session with a
researcher. This may result in a relatively lower degree of stress hormone release, which
has implications for circulating glucose concentration, as discussed previously in the
present thesis.
A further limitation of the present thesis is that glucose influences on verbal
encoding under single-task conditions was not investigated. On the basis of previous
266
reports in healthy young adults that glucose enhances memory only under conditions of
divided attention (Sünram-Lea et al., 2002b), a dual-task paradigm was implemented for
all studies conducted as part of the present thesis (with the exception of Study 4).
However, it would have been of interest to have investigated whether oral glucose
ingestion enhances verbal episodic memory in healthy adolescents under single-task
conditions. In addition, the scope of the present thesis was very narrow, in that the focus
was limited to glucose influences on verbal episodic memory performance. While this
was an intentional decision, on the basis of previous reports that glucose most reliably
enhances verbal episodic memory performance in adults (Riby, 2004), it would of
course have been of interest to address the question of whether glucose administration
can enhance more global cognitive domains in adolescents.
Finally, all of the participants who took part in the studies conducted as part of
the present thesis were healthy adolescents with no relevant health complications (as
assessed by a screening questionnaire). It was important to ensure that all study
participants were healthy in this regard, in order to ensure the reliability of the study
findings. However, the significance of some of the potentially modulating factors that
were investigated in the present thesis, such as glucoregulatory efficiency and HPA axis
function, may have been masked by the decision to focus on healthy adolescents in the
present thesis. Future studies which replicate this work in individuals exhibiting
clinically relevant impairments in glucose regulation and HPA axis functioning may
generate alternative findings to those reported here.
Future research directions
The present thesis has demonstrated that the glucose memory facilitation effect
can be extended to healthy adolescents. However, further work is required to
comprehensively understand the relationship between age, glucose ingestion and
267
cognitive performance. Future work in adolescents should specifically investigate
whether glucose ingestion can improve episodic memory under single task conditions
(as has been reported in older adults) and whether glucose administration can enhance
performance on tests of other forms of memory and further non-memory tasks. In
addition, the respective roles of age and glucoregulatory efficiency need to be further
investigated as potential modulators of the glucose memory facilitation effect. It would
also be of interest to further investigate factors that may influence an individual‘s
susceptibility to glucose enhancement of memory, such as trait anxiety. The role of the
SAM axis in modulating the glucose memory facilitation effect seems an interesting
question that warrants further investigation in future human studies (despite animal
findings which have not supported the hypothesis that glucose influences SAM axis
function; e.g. White & Messier, 1988).
Future work should also focus on further investigating the validity of the
hippocampus hypothesis purported to underlie the glucose memory facilitation effect.
The present thesis found little evidence for the hippocampus hypothesis, with the
findings of Study 4 revealing that glucose appears to target more global brain regions in
modulating memory performance in adolescents. Study 1 and Study 2 investigated a
possible role for the central executive in mediating the glucose memory facilitation
effect; but little support was found for this proposed mechanism. However, as
mentioned above, a between-subjects design was employed in Studies 1 and 2, which
may have compromised the study findings. Further work is therefore required in order
to demonstrate convincingly whether glucose targets specifically the hippocampus, or
more global brain regions (including frontal brain regions which subserve executive
processing). In addition, a focus of future neurobiological research could be to further
investigate the specific cellular mechanisms related to acetylcholine synthesis, the
action of insulin and potassium adenosine triphosphate channel function, which have
268
been purported as potential molecular mediators of the glucose memory facilitation
effect. The question of which of these specific neurobiological mechanisms may best
account for the phenomenon that oral glucose ingestion enhances cognitive performance
was beyond the scope of the present thesis. Nevertheless, this is a very worthwhile
question to be addressed in future animal studies of the glucose memory facilitation
effect.
Summary and Conclusions
The present thesis sought to investigate the glucose memory facilitation effect in
healthy adolescents. The primary conclusion that can be drawn from the overall thesis
findings is that oral glucose ingestion enhances verbal episodic memory performance in
healthy adolescent humans, when memory materials are encoded under conditions of
divided attention. This finding is in line with similar previous findings in young adults
(Foster et al., 1998; Sünram-Lea et al., 2001, 2002b, 2002a, 2004), and supports earlier
work that glucose is an effective cognitive enhancer in elderly humans (Hall et al.,
1989; Manning et al., 1990; Manning et al., 1992; Parsons & Gold, 1992; Manning et
al., 1997; Manning et al., 1998b; Riby et al., 2004; Riby et al., 2006) and individuals
with cognitive deficits (Craft et al., 1992; Manning et al., 1998a; Pettersen & Skelton,
2000; Stone et al., 2003; Riby et al., 2009). In addition, glucose enhancement of
memory in adolescents may be modulated by glucoregulatory efficiency. However, it
has been argued that measures of ‗glucoregulatory efficiency‘ that have been typically
employed in this area of research to date may better reflect whether the observed blood
glucose concentration subsequent to a glucose load is within the optimal range for
exerting a cognitive benefit. Individuals reporting relatively higher trait anxiety appear
more likely to exhibit verbal episodic memory enhancement subsequent to oral glucose
ingestion, a finding which suggests that biological mechanisms underlying trait anxiety
269
(such as SAM axis functioning) may be intimately involved in the glucose memory
facilitation effect.
Figure 9.1 displays the theoretical model of the glucose memory facilitation
effect that was introduced in Chapter 1. Contributions of the present thesis to this
conceptual model are outlined in the figure in bold text. The revised model incorporates
the novel finding from the present thesis that the glucose memory facilitation effect can
be extended to healthy adolescents. Further, the extended model proposes that
glucoregulatory efficiency and trait anxiety may modulate glucose enhancement of
memory, and suggests that glucose targets hippocampal and extrahippocampal brain
regions in modulating memory performance.
270
Figure 9.1
An extended version of the conceptual model of the glucose memory facilitation effect
that was presented in Chapter 1. Modifications to this model on the basis of the present
thesis are displayed in bold text. The glucose memory facilitation effect can be extended
to adolescents (Studies 3, 4, 5), an effect that appears to be modulated by trait anxiety
(Study 5). Inter-individual differences in glucoregulatory efficiency may also influence
this relationship (Study 3). In mediating memory performance in adolescents, glucose
appears to target both hippocampal and extrahippocampal brain regions (Study 4).
To summarise, the present thesis represents the first observation that oral
glucose ingestion can enhance memory performance in healthy adolescents. A number
of potential modulators of this effect have been investigated as part of this work, with
glucoregulatory efficiency and trait anxiety implicated as relevant to the glucose
memory facilitation effect. In addition, the present thesis has supported previous work
suggesting that glucose enhances performance on non-hippocampal tasks (e.g. Hall et
al., 1989; Benton, 1990; Kennedy & Scholey, 2000; Scholey et al., 2001; Scholey et al.,
Stress/Arousal
Carbohydrate
Ingestion
Plasma Glucose
SAM axis
(Adrenaline/
Noradrenaline)
HPA axis
(Cortisol)
Central Glucose
(hippocampus +
more global brain
regions)
Memory
(Verbal
Episodic)
in adults &
adolescents
ACh synthesis
Insulin
ATP
Glucoregulatory Efficiency
Depends
on trait
anxiety
271
2009), in that ERP findings supported the notion that glucose targets both hippocampal
and non-hippocampal brain regions in improving cognitive performance. Possible
limitations of the studies (most notably that some variables were manipulated in a
between-subjects fashion for some of the studies) may have compromised the findings
related to the investigations of a) the central executive as a potential mediator of the
glucose memory enhancement effect, and b) glucose influences on the emotional
memory effect. Nevertheless, the outcomes of the present thesis are of substantial
importance in context of better understanding i) the age groups which are likely to
experience a neurocognitive benefit as a result of oral glucose ingestion, and ii) factors
which may influence the glucose memory facilitation effect, particularly in healthy
adolescents.
272
273
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