The impact of flavonoids on memory: physiological and molecular considerations

Emerging evidence suggests that a group of dietary-derived phytochemicals known as flavonoids are able to induce improvements in memory acquisition, consolidation, storage and retrieval. These low molecular weight polyphenols are widespread in the human diet, are absorbed to only a limited degree and localise in the brain at low concentration. However, they have been found to be highly effective in reversing age-related declines in memory via their ability to interact with the cellular and molecular architecture of the brain responsible for memory. These interactions include an ability to activate signalling pathways, critical in controlling synaptic plasticity, and a potential to induce vascular effects capable of causing new nerve cell growth in the hippocampus. Their ability to activate the extracellular signal-regulated kinase (ERK1/2) and the protein kinase B (PKB/Akt) signalling pathways, leading to the activation of the cAMP response element-binding protein (CREB), a transcription factor responsible for increasing the expression of a number of neurotrophins important in de. ning memory, will be discussed. How these effects lead to improvements in memory through induction of synapse growth and connectivity, increases in dendritic spine density and the functional integration of old and new neurons will be illustrated. The overall goal of this critical review is to emphasize future areas of investigation as well as to highlight these dietary agents as promising candidates for the design of memory-enhancing drugs with relevance to normal and pathological brain ageing (161 references).

Food for thought: the role of dietary flavonoids in enhancing human memory, learning and neuro-cognitive performance

Emerging evidence suggests that dietary-derived flavonoids have the potential to improve human memory and neuro-cognitive performance via their ability to protect vulnerable neurons, enhance existing neuronal function and stimulate neuronal regeneration. Long-term potentiation (LTP) is widely considered to be one of the major mechanisms underlying memory acquisition, consolidation and storage in the brain and is known to be controlled at the molecular level by the activation of a number of neuronal signalling pathways. These pathways include the phosphatidylinositol-3 kinase/protein kinase B/Akt (Akt), protein kinase C, protein kinase A, Ca-calmodulin kinase and mitogen-activated protein kinase pathways. Growing evidence suggests that flavonoids exert effects on LTP, and consequently memory and cognitive performance, through their interactions with these signalling pathways. Of particular interest is the ability of flavonoids to activate the extracellular signal-regulated kinase and the Akt signalling pathways leading to the activation of the cAMP-response element-binding protein, a transcription factor responsible for increasing the expression of a number of neurotrophins important in LTP and long-term memory. One such neurotrophin is brain-derived neurotrophic factor, which is known to be crucial in controlling synapse growth, in promoting an increase in dendritic spine density and in enhancing synaptic receptor density. The present review explores the potential of flavonoids and their metabolite forms to promote memory and learning through their interactions with neuronal signalling pathways pivotal in controlling LTP and memory in human subjects.

Differential cognitive effects of Ginkgo biloba after acute and chronic treatment in healthy young volunteers

Acute doses of Ginkgo biloba have been shown to improve attention and memory in young, healthy participants, but there has been a lack of investigation into possible effects on executive function. In addition, only one study has investigated the effects of chronic treatment in young volunteers. This study was conducted to compare the effects of ginkgo after acute and chronic treatment on tests of attention, memory and executive function in healthy university students. Using a placebo-controlled double-blind design, in experiment 1, 52 students were randomly allocated to receive a single dose of ginkgo (120 mg, n=26) or placebo (n=26), and were tested 4h later. In experiment 2, 40 students were randomly allocated to receive ginkgo (120 mg/day; n=20) or placebo (n=20) for a 6-week period and were tested at baseline and after 6 weeks of treatment. In both experiments, participants underwent tests of sustained attention, episodic and working memory, mental flexibility and planning, and completed mood rating scales. The acute dose of ginkgo significantly improved performance on the sustained-attention task and pattern-recognition memory task; however, there were no effects on working memory, planning, mental flexibility or mood. After 6 weeks of treatment, there were no significant effects of ginkgo on mood or any of the cognitive tests. In line with the literature, after acute administration ginkgo improved performance in tests of attention and memory. However, there were no effects after 6 weeks, suggesting that tolerance develops to the effects in young, healthy participants.

Blueberry-induced changes in spatial working memory correlate with changes in hippocampal CREB phosphorylation and brain-derived neurotrophic factor (BDNF) levels

Phytochemical-rich foods have been shown to be effective at reversing age-related deficits in memory in both animals and humans. We show that a supplementation with a blueberry diet (2% w/w) for 12 weeks improves the performance of aged animals in spatial working memory tasks. This improvement emerged within 3 weeks and persisted for the remainder of the testing period. Memory performance correlated well with the activation of cAMP-response element-binding protein (CREB) and increases in both pro- and mature levels of brain-derived neurotrophic factor (BDNF) in the hippocampus. Changes in CREB and BDNF in aged and blueberry-supplemented animals were accompanied by increases in the phosphorylation state of extracellular signal-related kinase (ERK1/2), rather than that of calcium calmodulin kinase (CaMKII and CaMKIV) or protein kinase A. Furthermore, age and blueberry supplementation were linked to changes in the activation state of Akt, mTOR, and the levels of Arc/Arg3.1 in the hippocampus, suggesting that pathways involved in de novo protein synthesis may be involved. Although causal relationships cannot be made among supplementation, behavior, and biochemical parameters, the measurement of anthocyanins and flavanols in the brain following blueberry supplementation may indicate that changes in spatial working memory in aged animals are linked to the effects of flavonoids on the ERK-CREB-BDNF pathway. (c) 2008 Elsevier Inc. All Fights reserved.

Effects of divided attention and speeded responding on implicit and explicit retrieval of artificial grammar knowledge

The artificial grammar (AG) learning literature (see, e.g., Mathews et al., 1989; Reber, 1967) has relied heavily on a single measure of implicitly acquired knowledge. Recent work comparing this measure (string classification) with a more indirect measure in which participants make liking ratings of novel stimuli (e.g., Manza & Bornstein, 1995; Newell & Bright, 2001) has shown that string classification (which we argue can be thought of as an explicit, rather than an implicit, measure of memory) gives rise to more explicit knowledge of the grammatical structure in learning strings and is more resilient to changes in surface features and processing between encoding and retrieval. We report data from two experiments that extend these findings. In Experiment 1, we showed that a divided attention manipulation (at retrieval) interfered with explicit retrieval of AG knowledge but did not interfere with implicit retrieval. In Experiment 2, we showed that forcing participants to respond within a very tight deadline resulted in the same asymmetric interference pattern between the tasks. In both experiments, we also showed that the type of information being retrieved influenced whether interference was observed. The results are discussed in terms of the relatively automatic nature of implicit retrieval and also with respect to the differences between analytic and nonanalytic processing (Whittlesea Price, 2001).

Input and output modality effects in immediate serial recall

In immediate recall tasks, visual recency is substantially enhanced when output interference is low (Cowan, Saults, Elliott, & Moreno, 2002; Craik, 1969) whereas auditory recency remains high even under conditions of high output interference. Ibis auditory advantage has been interpreted in terms of auditory resistance to output interference (e.g., Neath & Surprenant, 2003). In this study the auditory-visual difference at low output interference re-emerged when ceiling effects were accounted for, but only with spoken output. With written responding the auditory advantage remained significantly larger with high than with low output interference. These new data suggest that both superior auditory encoding and modality-specific output interference contribute to the classic auditory-visual modality effect.

Irrelevant sound effects amongst younger and older adults: objective findings and subjective insights

Two experiments examine the effects of extraneous speech and nonspeech noise on a visual short-term memory task administered to younger and older adults. Experiment 1 confirms an earlier report that playing task-irrelevant speech is no more distracting for older adults than for younger adults (Rouleau T Belleville, 1996), indicating that "irrelevant sound effects" in short-term memory operate in a different manner to recalling targets in the presence of competing speech (Tun, O'Kane, T Wingfield, 2002). Experiment 2 extends this result to nonspeech noise and demonstrates that the result cannot be ascribed to hearing difficulties amongst the older age group, although the data also show that older adults rated the noise as less annoying and uncomfortable than younger adults. Implications for theories of the irrelevant sound effect, and for cognitive ageing, are discussed.

Phonological similarity effects without a phonological store: an individual differences model

The feature model of immediate memory (Nairne, 1990) is applied to an experiment testing individual differences in phonological confusions amongst a group (N=100) of participants performing a verbal memory test. By simulating the performance of an equivalent number of “pseudo-participants” the model fits both the mean performance and the variability within the group. Experimental data show that high-performing individuals are significantly more likely to demonstrate phonological confusions than low performance individuals and this is also true of the model, despite the model’s lack of either an explicit phonological store or a performance-linked strategy shift away from phonological storage. It is concluded that a dedicated phonological store is not necessary to explain the basic phonological confusion effect, and the reduction in such an effect can also be explained without requiring a change in encoding or rehearsal strategy or the deployment of a different storage buffer.

Empirical impact of cache effects for vision system design

Computer vision applications generally split their problem into multiple simpler tasks. Likewise research often combines algorithms into systems for evaluation purposes. Frameworks for modular vision provide interfaces and mechanisms for algorithm combination and network transparency. However, these don’t provide interfaces efficiently utilising the slow memory in modern PCs. We investigate quantitatively how system performance varies with different patterns of memory usage by the framework for an example vision system.

Speech perception and phonological short-term memory capacity in language impairment: preliminary evidence from adolescents with specific language impairment (SLI) and autism spectrum disorders (ASD)

Background: The cognitive bases of language impairment in specific language impairment (SLI) and autism spectrum disorders (ASD) were investigated in a novel non-word comparison task which manipulated phonological short-term memory (PSTM) and speech perception, both implicated in poor non-word repetition. Aims: This study aimed to investigate the contributions of PSTM and speech perception in non-word processing and whether individuals with SLI and ASD plus language impairment (ALI) show similar or different patterns of deficit in these cognitive processes. Method & Procedures: Three groups of adolescents (aged 14–17 years), 14 with SLI, 16 with ALI, and 17 age and non-verbal IQ matched typically developing (TD) controls, made speeded discriminations between non-word pairs. Stimuli varied in PSTM load (two- or four-syllables) and speech perception load (mismatches on a word-initial or word-medial segment). Outcomes & Results: Reaction times showed effects of both non-word length and mismatch position and these factors interacted: four-syllable and word-initial mismatch stimuli resulted in the slowest decisions. Individuals with language impairment showed the same pattern of performance as those with typical development in the reaction time data. A marginal interaction between group and item length was driven by the SLI and ALI groups being less accurate with long items than short ones, a difference not found in the TD group. Conclusions & Implications: Non-word discrimination suggests that there are similarities and differences between adolescents with SLI and ALI and their TD peers. Reaction times appear to be affected by increasing PSTM and speech perception loads in a similar way. However, there was some, albeit weaker, evidence that adolescents with SLI and ALI are less accurate than TD individuals, with both showing an effect of PSTM load. This may indicate, at some level, the processing substrate supporting both PSTM and speech perception is intact in adolescents with SLI and ALI, but also in both there may be impaired access to PSTM resources.

Potential health effects of Champagne wine consumption

Epidemiological studies have suggested an inverse correlation between red wine consumption and the incidence of cardiovascular and neurodegenerative disorders. Although white wines are generally low in polyphenol content as compared to red wines, champagne has been shown to contain relatively high amounts of phenolic acids that may exert protective cellular actions in vivo. In this study, we have investigated the potential cardioprotective and neuroprotective effects of champagne. Our data suggest that a daily moderate consumption of champagne may improve vascular performance via the delivery of phenolic constituents capable of improving NO bioavailability and the modulation of metalloproteinase. Moreover, champagne intervention significantly increased spatial working memory in aged animals, whilst no improvement was observed in the presence of alcohol. Together, these data indicate that polyphenols present in champagne may induce cardioprotective and neuroprotective effects, delaying the onset of degenerative disorders.

Blueberry supplementation induces spatial memory improvements and region-specific regulation of hippocampal BDNF mRNA expression in young rats

Rationale: Flavonoid-rich foods have been shown to be able to reverse age-related cognitive deficits in memory and learning in both animals and humans. However, to date, there have been only a limited number of studies investigating the effects of flavonoid-rich foods on cognition in young/healthy animals. Objectives: The aim of this study was to investigate the effects of a blueberry-rich diet in young animals using a spatial working memory paradigm, the delayed non-match task, using an eight-arm radial maze. Furthermore, the mechanisms underlying such behavioural effects were investigated. Results: We show that a 7-week supplementation with a blueberry diet (2 % w/w) improves the spatial memory performance of young rats (2 months old). Blueberry-fed animals also exhibited a faster rate of learning compared to those on the control diet. These behavioural outputs were accompanied by the activation of extracellular signal-related kinase (ERK1/2), increases in total cAMP-response element binding protein (CREB) and elevated levels of pro- and mature brain-derived neurotrophic factor (BDNF) in the hippocampus. Changes in hippocampal CREB correlated well with memory performance. Further regional analysis of BDNF gene expression in the hippocampus revealed a specific increase in BDNF mRNA in the dentate gyrus and CA1 areas of hippocampi of blueberry-fed animals. Conclusions: The present study suggests that consumption of flavonoid-rich blueberries has a positive impact on spatial learning performance in young healthy animals, and these improvements are linked to the activation of ERK–CREB– BDNF pathway in the hippocampus.

Does high-frequency repetitive transcranial magnetic stimulation produce residual and/or cumulative effects within an experimental session?

A common procedure for studying the effects on cognition of repetitive transcranial magnetic stimulation (rTMS) is to deliver rTMS concurrent with task performance, and to compare task performance on these trials versus on trials without rTMS. Recent evidence that TMS can have effects on neural activity that persist longer than the experimental session itself, however, raise questions about the assumption of the transient nature of rTMS that underlies many concurrent (or "online") rTMS designs. To our knowledge, there have been no studies in the cognitive domain examining whether the application of brief trains of rTMS during specific epochs of a complex task may have effects that spill over into subsequent task epochs, and perhaps into subsequent trials. We looked for possible immediate spill-over and longer-term cumulative effects of rTMS in data from two studies of visual short-term delayed recognition. In 54 subjects, 10-Hz rTMS trains were applied to five different brain regions during the 3-s delay period of a spatial task, and in a second group of 15 subjects, electroencephalography (EEG) was recorded while 10-Hz rTMS was applied to two brain areas during the 3-s delay period of both spatial and object tasks. No evidence for immediate effects was found in the comparison of the memory probe-evoked response on trials that were vs. were not preceded by delay-period rTMS. No evidence for cumulative effects was found in analyses of behavioral performance, and of EEG signal, as a function of task block. The implications of these findings, and their relation to the broader literature on acute vs. long-lasting effects of rTMS, are considered.

Epoch-specific functional networks involved in working memory

Working memory (WM) is not a unitary construct. There are distinct processes involved in encoding information, maintaining it on-line, and using it to guide responses. The anatomical configurations of these processes are more accurately analyzed as functionally connected networks than collections of individual regions. In the current study we analyzed event-related functional magnetic resonance imaging (fMRI) data from a Sternberg Item Recognition Paradigm WM task using a multivariate analysis method that allowed the linking of functional networks to temporally-separated WM epochs. The length of the delay epochs was varied to optimize isolation of the hemodynamic response (HDR) for each task epoch. All extracted functional networks displayed statistically significant sensitivity to delay length. Novel information extracted from these networks that was not apparent in the univariate analysis of these data included involvement of the hippocampus in encoding/probe, and decreases in BOLD signal in the superior temporal gyrus (STG), along with default-mode regions, during encoding/delay. The bilateral hippocampal activity during encoding/delay fits with theoretical models of WM in which memoranda held across the short term are activated long-term memory representations. The BOLD signal decreases in the STG were unexpected, and may reflect repetition suppression effects invoked by internal repetition of letter stimuli. Thus, analysis methods focusing on how network dynamics relate to experimental conditions allowed extraction of novel information not apparent in univariate analyses, and are particularly recommended for WM experiments for which task epochs cannot be randomized.

Dietary levels of pure flavonoids improve spatial memory performance and increase hippocampal brain-derived neurotrophic factor.

Evidence suggests that flavonoid-rich foods are capable of inducing improvements in memory and cognition in animals and humans. However, there is a lack of clarity concerning whether flavonoids are the causal agents in inducing such behavioral responses. Here we show that supplementation with pure anthocyanins or pure flavanols for 6 weeks, at levels similar to that found in blueberry (2% w/w), results in an enhancement of spatial memory in 18 month old rats. Pure flavanols and pure anthocyanins were observed to induce significant improvements in spatial working memory (p = 0.002 and p = 0.006 respectively), to a similar extent to that following blueberry supplementation (p = 0.002). These behavioral changes were paralleled by increases in hippocampal brain-derived neurotrophic factor (R = 0.46, p<0.01), suggesting a common mechanism for the enhancement of memory. However, unlike protein levels of BDNF, the regional enhancement of BDNF mRNA expression in the hippocampus appeared to be predominantly enhanced by anthocyanins. Our data support the claim that flavonoids are likely causal agents in mediating the cognitive effects of flavonoid-rich foods.