glucose modulation of verbal episodic memory in adolescents · glucose modulation of verbal...

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


Results ............................................................................................................ 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


Materials ................................................................................................. 146

Modified California Verbal Learning Test-II (CVLT-II) ............... 146

Modified Bond-Lader Questionnaire .............................................. 147

Blood glucose monitoring equipment ............................................. 147

Procedure ................................................................................................ 148


Results ............................................................................................................ 152


Bond-Lader Scale ................................................................................... 152

Modified CVLT-II .................................................................................. 153


ix

Delayed recall. ................................................................................ 153

Treatment x treatment order interactions. ....................................... 154

Glucose regulation .......................................................................... 156

Discussion .............................................................................................................. 160


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


Materials ................................................................................................. 177

Recognition memory task. .............................................................. 177


Procedure ................................................................................................ 179

EEG recording and data reduction ......................................................... 180


Results ............................................................................................................ 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


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


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


Procedure ................................................................................................ 203


Results ............................................................................................................ 209

xi

Basal HPA axis function ........................................................................ 209


Bond-Lader Scale ................................................................................... 210

Modified CVLT-II .................................................................................. 210


Delayed recall ................................................................................. 211


Basal HPA axis function ................................................................. 213

ASQ and trait anxiety ..................................................................... 213

Discussion .............................................................................................................. 216


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


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


Procedure ................................................................................................ 232


Results ............................................................................................................ 238

Basal HPA axis function ........................................................................ 238


Satiety questionnaire .............................................................................. 240

POMS-Bi Questionnaire......................................................................... 240

Salivary free cortisol response ............................................................... 240

Memory test ............................................................................................ 242

Immediate recall ............................................................................. 242

Delayed recall ................................................................................. 243


Basal HPA axis function ................................................................. 243

ASQ and trait anxiety ..................................................................... 243

Acute cortisol response ................................................................... 244

POMS-Bi ........................................................................................ 244

Discussion.............................................................................................................. 245


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


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) 17-48 300 mg/kg No Between e




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).


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.

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.

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)

114

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).

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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

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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)


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)


133

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)


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

135

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).


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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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.

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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:


enhancement of memory is modulated by trait anxiety in healthy adolescent males.

Journal of Psychopharmacology.

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

226

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

237

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.

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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.

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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.

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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,

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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

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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).


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.

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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

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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

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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

257

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.


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.


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.

273

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