Sweet memories

Michael A. Smith looks at glucose effects on human memory performance

Glucose is the brain’s primary fuel, but what is the effect of manipulating blood glucose on human memory performance? There is now a large body of evidence suggesting that under certain conditions, increased levels of glucose in the blood can acutely enhance performance in some domains of memory and cognition more generally. Conversely, cognitive impairment has been detected in individuals with disorders that involve glycaemic dysregulation, such as diabetes. This cognitive dysfunction has potential lifestyle implications for individuals living with diabetes

Back in 2001 Professor Andrew Scholey wrote a piece for The Psychologist on the beneficial effects of glucose and oxygen for human cognitive performance (see tinyurl.com/scholey). At the time, I was still a year away from starting my undergraduate degree in psychology, and five years off commencing my PhD on the influence of oral glucose ingestion on memory performance in adolescents. I hadn’t even considered the idea of studying psychology at university, let alone considered the notion that a substance as ubiquitous as glucose could impact profoundly on cognitive performance! Since Scholey’s article relating to these two ‘fuels for thought’, the literature reporting beneficial effects of oxygen has stagnated somewhat. However, there is now a large body of literature relating to what is often referred to as the ‘glucose memory facilitation effect’. We have developed a reasonably good understanding of the conditions under which glucose ingestion reliably enhances memory performance, and the mechanisms by which glucose influences neurocognitive functioning.

The ‘glucose memory facilitation effect’
The enhancing effects of glucose on human memory have been investigated since the 1980s. As the brain’s primary fuel, it makes perfect sense that glucose should be intimately involved in mediating cognitive performance. Glucose appears to influence memory performance in an ‘inverted-U’ dose-dependent fashion, with memory modulation being most amenable following a glucose dose of approximately 25–50g (pure powdered glucose, which is typically dissolved in water). This is approximately equivalent to the sugar content of a standard-sized chocolate bar. Early studies found that the ingestion of a glucose solution resulted in superior episodic memory performance relative to a sweetness matched placebo.

However, while early studies
found support for the ‘glucose memory facilitation effect’, the most robust findings emerged only in the elderly and individuals with memory deficits. This suggested that glucose effects on memory performance are observed only in individuals who are not functioning at their ‘cognitive peak’, in whom there is substantial ‘room for improvement’ (Smith, Riby et al., 2011). A further feature of these early studies was that while most investigations observed a glucose-enhancing effect for verbal episodic memory (typically involving encoding and recall of a word list), studies that investigated the influence of oral glucose on other cognitive domains reported more equivocal effects. This led some authors (e.g. Riby & Riby, 2006) to question whether the cognitive-enhancement effects of glucose are mediated by the hippocampus, a brain region that is intimately involved in subserving verbal episodic memory performance.

In the late 1990s and early 2000s  Professor Jonathan Foster, later my PhD supervisor, together with his colleague Dr Sandra Sünram-Lea, developed a novel paradigm for investigating the influence of glucose on verbal episodic memory performance in healthy young adults, ensuring that these healthy young individuals at the prime of their cognitive capacity would not be able to operate at their cognitive optimum. Following glucose ingestion, healthy young adults encoded verbally presented word lists, while concurrently performing hand movement sequences as a distractor task (participants were asked to focus attention equally on both memorising the word list and performing the hand movements). Repeated replications have demonstrated that glucose reliably enhances memory recall when word lists are encoded under such dual-task conditions (Foster et al., 1998; Sünram-Lea et al., 2001, 2002). Foster and Sünram-Lea conclude, on the basis of these findings, that glucose enhances verbal episodic memory performance in healthy young adults only under conditions of divided attention (whereby even individuals at a stage of the lifespan associated with optimal cognitive performance capabilities are not able to perform at their cognitive peak due to competing cognitive demands from the dual-task paradigm). Converging evidence from a range of more recent studies demonstrates that glucose is an effective cognitive enhancer in healthy young adults under conditions of increased task demand, irrespective of whether the primary task is a memory task or a task designed to assess non-memory domains of cognition (Kennedy & Scholey, 2000; Scholey et al., 2001; Scholey et al., 2009).

Taking on the teenagers
Much of my own research in this area has investigated whether the ‘glucose memory facilitation effect’ extends to healthy adolescents. The original rationale for this programme of work was pragmatic, rather than theoretically driven. I had been awarded funding to undertake a PhD in the School of Paediatrics and Child Health at the University of Western Australia, and thus needed to develop a project proposal that included research in children. While there is some evidence that the glucose memory facilitation effect is observable in infants (Horne et al., 2006), studies investigating the effect in children and adolescents were limited at that time.

While the decision to focus on adolescents began as a pragmatic one, a theoretically driven rationale soon emerged. I was surprised to discover that the rate of breakfast skipping in adolescents was very high (daily breakfast consumption has been estimated at less than 40 per cent in boys and less than 30 per cent in girls: Timlin et al., 2008; although rates may have since improved somewhat as a result of the increasing prevalence and popularity of school breakfast clubs). It struck me that there was a real issue here: if teenagers were attending school without having eaten breakfast, then surely their brains would not be in a condition to operate optimally in terms of facilitating learning. This was a concept that we set out to test.

In 2008 we published the first paper to suggest that the ‘glucose memory facilitation effect’ could be extended to adolescents (Smith & Foster, 2008a). Adolescents were administered a glucose drink, or an artificial sweetener (aspartame) placebo drink early in the morning, following an overnight fast. They then encoded a verbally presented word list while simultaneously performing hand-movement sequences, followed by immediate and delayed recall phases. Glucose enhancement of memory was observed at the ‘long delay’ recall phases, 20–40 minutes after encoding. Further analyses of these data revealed that the effect was observed only in participants with better glucoregulatory efficiency (i.e. those individuals in whom blood glucose levels returned to baseline more quickly). Interestingly, this finding suggests that having elevated blood glucose for an extended period may be detrimental to cognitive performance.

In a subsequent study (Smith, Hii et al., 2011) we found further evidence for the glucose memory facilitation effect in a sample of adolescent males, and additionally observed that glucose only enhanced memory performance in individuals with relatively high self-reported levels of trait anxiety. Intriguingly, those adolescents with high trait anxiety exhibited substantially poorer verbal episodic memory capacity in the placebo condition, but glucose enhanced memory recall in these individuals to a comparable level of performance to those with lower levels of trait anxiety. We concluded that this could be another example of glucose-mediated memory enhancement under conditions whereby there is substantial ‘room for improvement’, as it is reasonably well established that anxiety is associated with memory impairment. A further noteworthy finding from this study was that we additionally tested word recall one week post-encoding (i.e. glucose was administered prior to encoding, but not retrieval). Interestingly, the glucose memory facilitation effect persisted after a one-week delay, suggesting that glucose enhanced memory encoding to the extent that items were better remembered after a one-week delay, relative to placebo.

Given that our rationale for the programme of work investigating the glucose memory facilitation effect in adolescents was that adolescents frequently skip breakfast, we also investigated glucose effects on memory when glucose was delivered under more ecologically valid conditions; specifically, via a breakfast meal. In one study (Smith & Foster, 2008b), we administered either a low or a high glycaemic index (G.I.) meal to adolescents, before they completed a verbal episodic memory task under dual-task conditions (as above, encoding took place concurrently with a secondary hand-movement task). High G.I. foods (such as cornflakes or a bagel) are associated with a very rapid increase in blood glucose during the approximately 30 minutes following meal ingestion, followed by an equally rapid decline (as a result of the insulin rebound effect, blood glucose can actually fall below baseline during the one- to two-hour period following ingestion of a high G.I. meal). By contrast, low G.I. foods (such as porridge) are associated with a less pronounced, but more prolonged, increase in blood glucose, relative to ingestion of a high G.I. meal (see Figure 1).

Previous studies in children, adolescents and young adults have suggested that low G.I. foods are associated with enhanced performance on various cognitive tasks (Benton et al., 2003; Ingwersen et al., 2007; Mahoney et al., 2005). However, in the memory component of each of these studies, encoding took place under conditions of relatively low cognitive demand. In our study, we hypothesised that the high G.I. meal would be associated with enhanced memory performance relative to the low G.I. condition, given the relatively increased energy resources required for encoding under dual-task conditions. This is precisely what we found in this study, with enhanced recall being observed subsequent to a high G.I meal (cornflakes with semi-skimmed milk), relative to a low G.I. meal (bran with semi-skimmed milk).

While this finding is commensurate with other findings in this area suggesting that relative to a placebo drink (G.I. = 0), a glucose drink (G.I. = 100, the highest possible G.I.) is associated with improvements in verbal episodic memory when memory materials are encoded under dual-task conditions, it is somewhat problematic from an advocacy point of view. This is because many high G.I. breakfast cereals deliver comparatively high levels of sugar, and due to the adverse health effects of sugary diets, it would be inappropriate to suggest that breakfast meals high in sugar would be routinely appropriate. Indeed, research that has supported beneficial effects of low G.I. breakfast meals on attention suggests that the sustained attentional demands required for a morning of learning at school may require a more prolonged release of glucose into the bloodstream – conditions that would be subserved by a low G.I. breakfast meal. These findings do nevertheless demonstrate that when task demands are exceptionally high, the additional glucose supply to the blood stream delivered by a high G.I. meal may enhance task performance.

Mechanisms of action
So how does glucose actually work to improve human cognitive performance? Animal studies have shed some light on the specific neuroanatomical pathways, suggesting that (i) the observed glucose effects may in fact be due to the actions of insulin (the hippocampus in particular is densely populated with insulin receptors), (ii) glucose increases the synthesis of specific neurotransmitters, including hippocampal synthesis of acetylcholine, and (iii) glucose mediates adenosine triphosphate–sensitive potassium channel regulation, enabling neurotransmitter release under conditions of increased glucose metabolism (Smith, Riby et al., 2011).

In addition to this animal work, several studies have attempted to ascertain the validity of the aforementioned ‘hippocampus hypothesis’ (i.e. the notion that glucose specifically targets the hippocampus in mediating memory). Neuroimaging studies in humans have largely refuted this idea. While there have been some reports of glucose-mediated increases in hippocampal activity during memory tasks (Parent et al., 2011), other studies have suggested a role for brain regions that are not traditionally associated with episodic memory functioning. Following glucose administration, increased right ventrolateral prefrontal cortex activity administration has been detected during dual-tasking in older adults (Gagnon et al., 2012). This finding implies that glucose enhancement of verbal episodic memory under conditions of divided attention could be subserved via augmented prefrontal activity. In addition, during a recognition memory task preceded by oral glucose ingestion, we have observed enhanced event-related potential (ERP) components that are associated with both hippocampally mediated and non-hippocampally mediated cognitive processes (Smith et al., 2009). Taken together, these studies implicate not only the hippocampus, but also other more global brain regions as being intimately involved in the glucose memory facilitation effect.

When regulation goes wrong
Given that relatively small, acutely administered glucose doses can have such a drastic influence on brain physiology, which in turn results in observable cognitive benefits, we might also expect more prolonged modulation of cognitive functioning in individuals with chronically high blood glucose. Indeed, cognitive deficits have been observed in disorders involving dysregulated glucose metabolism, such as Type 2 diabetes. Type 2 diabetes is a condition whereby either (i) insufficient insulin is produced to metabolise the amount of circulating blood glucose, or (ii) the actions of insulin in metabolising blood glucose aren’t effective (a condition known as insulin resistance). Both of these physiological pathways result in chronically high blood glucose if the condition is untreated (usually via lifestyle interventions such as dietary modification and exercise in the first instance). It is now well established that this chronic illness is associated with cognitive complications, again most notably in the domain of verbal episodic memory (Jones et al., 2014).

It is interesting to note that verbal episodic memory may be the domain of cognition that is most affected by Type 2 diabetes, given that this is also the cognitive domain arguably most amenable to the aforementioned glucose memory facilitation effect. However, an alternative explanation is that the greater number of reported observations in this domain is a mere reflection of the relatively greater interrogation of verbal episodic memory effects as such tests are easy to administer. Indeed, other cognitive deficits, such as slower processing speed and executive dysfunction have been reported in individuals with Type 2 diabetes (Yeung et al., 2009). Work by our current Northumbria University PhD student Nicola Jones is investigating memory for more complex visual stimuli in older adults with Type 2 diabetes, and is employing the use of EEG to investigate potential neurocognitive deficits that may be underpinning observed cognitive impairment in this population.

Together with my Northumbria University colleague Dr Leigh Riby, recent work in our laboratory has been concerned with investigating performance on relatively demanding cognitive tasks in older adults with Type 2 diabetes. Specifically, a recently completed study funded by Diabetes UK (Smith et al., 2014) has considered whether such cognitive deficits may underlie problems with functional living and postural stability (e.g. maintaining balance and walking while talking). We observed a decrease in instrumental functional living capacity (i.e. activities that are not strictly necessary for fundamental functioning, but that facilitate independent living in the community, such as using the telephone and managing one’s own finances) in older adults with Type 2 diabetes relative to age-matched controls. In addition, most robust cognitive effects in terms of cognitive impairment in the older adults with Type 2 diabetes were observed on the more demanding attentional control and executive functioning tasks. Further, we found that older adults with Type 2 diabetes were relatively poorer at maintaining balance when they were required to stand on the spot concurrently with a secondary task (counting backwards in threes). While this finding could be suggestive of more global dual-tasking deficits in older adults with Type 2 diabetes, an interesting extended explanation of this result is that problems with dividing attention between two concurrent tasks (such as walking while talking or trying to retain information in working memory) could partially account for a relatively higher frequency of falls in older adults with Type 2 diabetes. The higher frequency of falls reported by this population is typically attributed to such complications of diabetes as peripheral neuropathy (causing sensory loss to the limbs) and macrovascular problems (affecting blood flow to the extremities). However, our findings suggest that cognitive complications leading to reduced balance could play a role in mediating the prevalence of falls in older adults with Type 2 diabetes, and this finding warrants attention in future research.

Conclusions
Over the past decade and a half, we’ve come a long way in better understanding the ‘glucose memory facilitation effect’. In healthy young individuals, oral glucose ingestion only reliably enhances memory performance under conditions of increased cognitive demand. Glucose is known to most robustly influence memory performance when individuals are not operating at their cognitive peak, in situations where the ‘room for improvement’ is at its greatest, such as in individuals with greater levels of anxiety. Further, Type 2 diabetes is associated with chronic memory impairment. Both the glucose-enhancement effects and Type 2 diabetes appear to be most amenable to modulation of verbal episodic memory over other cognitive domains, but ample evidence suggests that it may be the degree of cognitive demand, rather than the cognitive domain per se, that dictates whether the effect will be observed.

Michael A. Smith
is Senior Lecturer in Psychobiology and Health Psychology, Northumbria University
[email protected]

References

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