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.

The impact of flavonoids on spatial memory in rodents: from behaviour to underlying hippocampal mechanisms

Emerging evidence suggests that a group of dietary-derived phytochemicals known as flavonoids are able to induce improvements in memory, learning and cognition. Flavonoids have been shown to modulate critical neuronal signalling pathways involved in processes of memory, and therefore are likely to affect synaptic plasticity and long-term potentiation mechanisms, widely considered to provide a basis for memory. Animal dietary supplementation studies have further shown that flavonoid-rich foods are able to reverse age-related spatial memory and spatial learning impairments. A more accurate understanding of how a particular spatial memory task works and of which aspects of memory and learning can be assessed in each case, are necessary for a correct interpretation of data relating to diet-cognition experiments. Further understanding of how specific behavioural tasks relate to the functioning of hippocampal circuitry during learning processes might be also elucidative of the specific observed memory improvements. The overall goal of this review is to give an overview of how the hippocampal circuitry operates as a memory system during behavioural tasks, which we believe will provide a new insight into the underlying mechanisms of the action of flavonoids on cognition.

Learning and memory in holocaust survivors with posttraumatic stress disorder

Background: Impairments in explicit memory have been observed in Holocaust survivors with posttraumatic stress disorder. Methods: To evaluate which memory components are preferentially affected, the California Verbal Learning Test was administered to Holocaust survivors with (n = 36) and without (n = 26) posttraumatic stress disorder, and subjects not exposed to the Holocaust (n = 40). Results: Posttraumatic stress disorder subjects showed impairments in learning and short-term and delayed retention compared to nonexposed subjects; survivors without posttraumatic stress disorder did not. Impairments in learning, but not retention, were retained after controlling fir intelligence quotient. Older age was associated with poorer learning and memory performance in the posttraumatic stress disorder group only. Conclusions: The most robust impairment observed in posttraumatic stress disorder was in verbal learning, which may be a risk factor for or consequence of chronic posttraumatic stress disorder. The negative association between performance and age may reflect accelerated cognitive decline in posttraumatic stress disorder.

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.

Steady-spectrum contexts and perceptual compensation for reverberation in speech identification

Perceptual compensation for reverberation was measured by embedding test words in contexts that were either spoken phrases or processed versions of this speech. The processing gave steady-spectrum contexts with no changes in the shape of the short-term spectral envelope over time, but with fluctuations in the temporal envelope. Test words were from a continuum between "sir" and "stir." When the amount of reverberation in test words was increased, to a level above the amount in the context, they sounded more like "sir." However, when the amount of reverberation in the context was also increased, to the level present in the test word, there was perceptual compensation in some conditions so that test words sounded more like "stir" again. Experiments here found compensation with speech contexts and with some steady-spectrum contexts, indicating that fluctuations in the context's temporal envelope can be sufficient for compensation. Other results suggest that the effectiveness of speech contexts is partly due to the narrow-band "frequency-channels" of the auditory periphery, where temporal-envelope fluctuations can be more pronounced than they are in the sound's broadband temporal envelope. Further results indicate that for compensation to influence speech, the context needs to be in a broad range of frequency channels. (c) 2007 Acoustical Society of America.

Perceptual compensation for reverberation in speech identification: effects of single-band, multiple-band and wideband noise contexts

Perceptual effects of room reverberation on a "sir" or "stir" test-word can be observed when the level of reverberation in the word is increased, while the reverberation in a surrounding 'context I utterance remains at a minimal level. The result is that listeners make more "sit" identifications. When the context's reverberation is also increased, to approach the level in the test word, extrinsic perceptual compensation is observed, so that the number of listeners' "sir" identifications reduces to a value similar to that found with minimal reverberation. Thus far, compensation effects have only been observed with speech or speech-like contexts in which the short-term spectrum changes as the speaker's articulators move. The results reported here show that some noise contexts with static short-term spectra can also give rise to compensation. From these experiments it would appear that compensation requires a context with a temporal envelope that fluctuates to some extent, so that parts of it resemble offsets. These findings are consistent with a rather general kind of perceptual compensation mechanism; one that is informed by the 'tails' that reverberation adds at offsets. Other results reported here show that narrow-band contexts do not bring about compensation, even when their temporal-envelopes are the same as those of the more effective wideband contexts. These results suggest that compensation is confined to the frequency range occupied by the context, and that in a wideband sound it might operate in a 'band by band' manner.

Perceptual compensation for effects of reverberation in speech identification

Listeners were asked to identify modified recordings of the words "sir" and "stir," which were spoken by an adult male British-English speaker. Steps along a continuum between the words were obtained by a pointwise interpolation of their temporal-envelopes. These test words were embedded in a longer "context" utterance, and played with different amounts of reverberation. Increasing only the test-word's reverberation shifts the listener's category boundary so that more "sir"-identifications are made. This effect reduces when the context's reverberation is also increased, indicating perceptual compensation that is informed by the context. Experiment I finds that compensation is more prominent in rapid speech, that it varies between rooms, that it is more prominent when the test-word's reverberation is high, and that it increases with the context's reverberation. Further experiments show that compensation persists when the room is switched between the context and the test word, when presentation is monaural, and when the context is reversed. However, compensation reduces when the context's reverberation pattern is reversed, as well as when noise-versions of the context are used. "Tails" that reverberation introduces at the ends of sounds and at spectral transitions may inform the compensation mechanism about the amount of reflected sound in the signal. (c) 2005 Acoustical Society of America.

Perceptual compensation for effects of echo and of reverberation on speech identification

In an ideal "reverberant" room, the energy of the impulse responses decays smoothly, at a constant rate of dB/s, so that gradually-decaying tails are added at the ends of sounds. Conversely, a single echo gives a flat energy-decay up to the echo's arrival time, which then drops abruptly, so that sounds with only echoes lack the decaying-tail feature of reverberation. The perceptual effects of these types of reflection pattern were measured with test-words from a continuum of steps between "sir" and "stir", which were each embedded in a carrier phrase. When the proportion of reflected sound in test-words is increased, to a level above the amount in the carrier, the test words sound more like "sir". However, when the proportion of reflected sound in the carrier is also increased, to match the amount in the test word, there can be a perceptual compensation where test words sound more like "stir" again. A reference condition used real-room reverberation from recordings at different source to receiver distances. In a synthetic-reverberation condition, the reflection pattern was from a "colorless" impulse response, comprising exponentially-decaying reflections that were spaced at intervals. In a synthetic-echo condition, the reflection pattern was obtained from the synthetic reverberation by removing the intervals between reflections before delaying the resulting cluster relative to the direct sound. Compensation occurred in the reference condition and in different types of synthetic reverberation, but not in synthetic-echo conditions. This result indicates that the presence of tails from reverberation informs the compensation mechanism.

Redintegration and lexicality effects in children: do they depend upon the demands of the memory task?

The effect of long-term knowledge upon performance in short-term memory tasks was examined for children from 5 to 10 years of age. The emergence of a lexicality effect, in which familiar words were recalled more accurately than unfamiliar words, was found to depend upon the nature of the memory task. Lexicality effects were interpreted as reflecting the use of redintegration, or reconstruction processes, in short-term memory. Redintegration increased with age for tasks requiring spoken item recall and decreased with age when position information but not naming was required. In a second experiment, redintegration was found in a recognition task when some of the foils rhymed with the target. Older children were able to profit from a rhyming foil, whereas younger children were confused by it, suggesting that the older children make use of sublexical phonological information in reconstructing the target. It was proposed that redintegrative processes in their mature form support the reconstruction of detailed phonological knowledge of words.

Systematic distortions of perceptual stability investigated using immersive virtual reality

Using an immersive virtual reality system, we measured the ability of observers to detect the rotation of an object when its movement was yoked to the observer's own translation. Most subjects had a large bias such that a static object appeared to rotate away from them as they moved. Thresholds for detecting target rotation were similar to those for an equivalent speed discrimination task carried out by static observers, suggesting that visual discrimination is the predominant limiting factor in detecting target rotation. Adding a stable visual reference frame almost eliminated the bias. Varying the viewing distance of the target had little effect, consistent with observers underestimating distance walked. However, accuracy of walking to a briefly presented visual target was high and not consistent with an underestimation of distance walked. We discuss implications for theories of a task-independent representation of visual space. © 2005 Elsevier Ltd. All rights reserved.

Neural mechanisms of visual object priming: evidence for perceptual and semantic distinctions in fusiform cortex

Previous functional imaging studies have shown that facilitated processing of a visual object on repeated, relative to initial, presentation (i.e., repetition priming) is associated with reductions in neural activity in multiple regions, including fusiforin/lateral occipital cortex. Moreover, activity reductions have been found, at diminished levels, when a different exemplar of an object is presented on repetition. In one previous study, the magnitude of diminished priming across exemplars was greater in the right relative to the left fusiform, suggesting greater exemplar specificity in the right. Another previous study, however, observed fusiform lateralization modulated by object viewpoint, but not object exemplar. The present fMRI study sought to determine whether the result of differential fusiform responses for perceptually different exemplars could be replicated. Furthermore, the role of the left fusiform cortex in object recognition was investigated via the inclusion of a lexical/semantic manipulation. Right fusiform cortex showed a significantly greater effect of exemplar change than left fusiform, replicating the previous result of exemplar-specific fusiform lateralization. Right fusiform and lateral occipital cortex were not differentially engaged by the lexical/semantic manipulation, suggesting that their role in visual object recognition is predominantly in the. C visual discrimination of specific objects. Activation in left fusiform cortex, but not left lateral occipital cortex, was modulated by both exemplar change and lexical/semantic manipulation, with further analysis suggesting a posterior-to-anterior progression between regions involved in processing visuoperceptual and lexical/semantic information about objects. The results are consistent with the view that the right fusiform plays a greater role in processing specific visual form information about objects, whereas the left fusiform is also involved in lexical/semantic processing. (C) 2003 Elsevier Science (USA). All rights reserved.

The effect of learning condition on perceptual anticipation, awareness, and visual search

The efficacy of explicit and implicit learning paradigms was examined during the very early stages of learning the perceptual-motor anticipation task of predicting ball direction from temporally occluded footage of soccer penalty kicks. In addition, the effect of instructional condition on point-of-gaze during learning was examined. A significant improvement in horizontal prediction accuracy was observed in the explicit learning group; however, similar improvement was evident in a placebo group who watched footage of soccer matches. Only the explicit learning intervention resulted in changes in eye movement behaviour and increased awareness of relevant postural cues. Results are discussed in terms of methodological and practical issues regarding the employment of implicit perceptual training interventions. (c) 2005 Elsevier B.V. All rights reserved.

fMRI delineation of working memory for emotional prosody in the brain: commonalities with the lexico-semantic emotion network

Decoding emotional prosody is crucial for successful social interactions, and continuous monitoring of emotional intent via prosody requires working memory. It has been proposed by Ross and others that emotional prosody cognitions in the right hemisphere are organized in an analogous fashion to propositional language functions in the left hemisphere. This study aimed to test the applicability of this model in the context of prefrontal cortex working memory functions. BOLD response data were therefore collected during performance of two emotional working memory tasks by participants undergoing fMRI. In the prosody task, participants identified the emotion conveyed in pre-recorded sentences, and working memory load was manipulated in the style of an N-back task. In the matched lexico-semantic task, participants identified the emotion conveyed by sentence content. Block-design neuroimaging data were analyzed parametrically with SPM5. At first, working memory for emotional prosody appeared to be right-lateralized in the PFC, however, further analyses revealed that it shared much bilateral prefrontal functional neuroanatomy with working memory for lexico-semantic emotion. Supplementary separate analyses of males and females suggested that these language functions were less bilateral in females, but their inclusion did not alter the direction of laterality. It is concluded that Ross et al.'s model is not applicable to prefrontal cortex working memory functions, that evidence that working memory cannot be subdivided in prefrontal cortex according to material type is increased, and that incidental working memory demands may explain the frontal lobe involvement in emotional prosody comprehension as revealed by neuroimaging studies. (c) 2007 Elsevier Inc. All rights reserved.

Saccadic eye movements as an index of perceptual decision-making

One of the most common decisions we make is the one about where to move our eyes next. Here we examine the impact that processing the evidence supporting competing options has on saccade programming. Participants were asked to saccade to one of two possible visual targets indicated by a cloud of moving dots. We varied the evidence which supported saccade target choice by manipulating the proportion of dots moving towards one target or the other. The task was found to become easier as the evidence supporting target choice increased. This was reflected in an increase in percent correct and a decrease in saccade latency. The trajectory and landing position of saccades were found to deviate away from the non-selected target reflecting the choice of the target and the inhibition of the non-target. The extent of the deviation was found to increase with amount of sensory evidence supporting target choice. This shows that decision-making processes involved in saccade target choice have an impact on the spatial control of a saccade. This would seem to extend the notion of the processes involved in the control of saccade metrics beyond a competition between visual stimuli to one also reflecting a competition between options.