Enhancing Human Cognition with Cocoa Flavonoids
Valentina Socci
Daniela Tempesta
Giovambattista Desideri
Luigi De Gennaro
Michele Ferrara- 1Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
- 2Department of Life, Health and Environmental Sciences, University of L’Aquila, L’Aquila, Italy
- 3Department of Psychology, “Sapienza” University of Rome, Rome, Italy
Enhancing cognitive abilities has become a fascinating scientific challenge, recently driven by the interest in preventing age-related cognitive decline and sustaining normal cognitive performance in response to cognitively demanding environments. In recent years, cocoa and cocoa-derived products, as a rich source of flavonoids, mainly the flavanols sub-class, have been clearly shown to exert cardiovascular benefits. More recently, neuromodulation and neuroprotective actions have been also suggested. Here, we discuss human studies specifically aimed at investigating the effects of acute and chronic administration of cocoa flavanols on different cognitive domains, such as executive functions, attention and memory. Through a variety of direct and indirect biological actions, in part still speculative, cocoa and cocoa-derived food have been suggested to possess the potential to counteract cognitive decline and sustain cognitive abilities, particularly among patients at risk. Although still at a preliminary stage, research investigating the relations between cocoa and cognition shows dose-dependent improvements in general cognition, attention, processing speed, and working memory. Moreover, cocoa flavanols administration could also enhance normal cognitive functioning and exert a protective role on cognitive performance and cardiovascular function specifically impaired by sleep loss, in healthy subjects. Together, these findings converge at pointing to cocoa as a new interesting nutraceutical tool to protect human cognition and counteract different types of cognitive decline, thus encouraging further investigations. Future research should include complex experimental designs combining neuroimaging techniques with physiological and behavioral measures to better elucidate cocoa neuromodulatory properties and directly compare immediate versus long-lasting cognitive effects.
Introduction
With the increase in general population aging, age-related cognitive decline has progressively become a major public health issue. Consequently, enhancing cognitive resources came to be a priority scientific challenge, mainly driven by the need to detect preventive agents for cognitive decline and dementia. At the same time, immediate cognitive enhancement is often desirable in cognitively demanding environments. Stimulants such as caffeine are indeed commonly used to sustain cognitive performance during periods of fatigue and prolonged wakefulness (1).
In the last years, the field of nutraceuticals and functional food has developed along with the interest in the potential modulatory effects of food constituents on human health. In this context, there has been increasing interest in the biological effects of flavonoids, a class of polyphenolic compounds, as potential nutraceuticals with several beneficial biological actions, including cardioprotection, neuroprotection, and neuromodulation. Particularly, cocoa bean has been recognized as a rich source of flavonoids, mainly the flavanols subclass in the form of epicatechin and catechin (2).
Chocolate also contains other functional ingredients, such as the methylxanthine caffeine and theobromine, with the potential to influence neurocognitive function. However, relative to total flavanols content, caffeine and theobromine concentrations in cocoa and chocolate have been considered lower than those required to exert significant pharmacological actions (3).
Epidemiologic studies suggest that a regular intake of flavonoids could be associated with better cognitive function (4), decreased risk of dementia (5) and cognitive decline (6), lower prevalence of cognitive impairment (7), better cognitive evolution over a 10-year period (8), and better dose-dependent cognitive performance in normal aging (9).
The specific mechanisms of action of flavonoids responsible for cognitive protection and modulation are not entirely elucidated. Nevertheless, increasing evidence supports the notion that cocoa and chocolate consumption provides several health benefits, including neurocognitive enhancement and neuroprotective effects. In this brief review, we discuss human studies specifically aimed at investigating the effects of acute and chronic administration of cocoa flavanols on cognition.
Enhancing Cognition with Cocoa Flavonoids: Direct Versus Indirect Mechanisms of Action
The beneficial effects of polyphenolic compounds have been first attributed to their ability to exert antioxidant actions (10). However, due to the very low concentration of flavonoids detectable in the brain, it is unlikely that direct antioxidant action can entirely account for cognitive effects in vivo. Instead, flavonoids’ neurobiological effects are now believed to be mediated by a range of actions involving the ability to protect vulnerable neurons, enhance neuronal function, and stimulate regeneration via interaction with neuronal intracellular signaling pathways involved in neuronal survival and differentiation, long-term potentiation (LTP), and memory (11).
Flavonoids can counteract neuronal injury underlying neurodegenerative diseases such as Parkinson and Alzheimer diseases through their interaction with signaling proteins important in the pro-survival pathways (12). Interestingly, flavonoids and their metabolites cross the blood–brain barrier and have been localized in the brain, particularly in areas crucial for learning and memory such as hippocampus, cerebral cortex, cerebellum, and striatum (13–15). These structures are particularly vulnerable to the effects of aging and neurodegeneration, suggesting that flavonoids could exert direct neuroprotective effects (16). Direct interactions within several cellular signaling pathways have been described, such as mitogen-activated protein kinase, extracellular signal-regulated kinase, and phosphoinositide 3-kinase (PI3-kinase/Akt) signaling cascades (17), that are crucially involved in triggering gene expression and protein synthesis for LTP (18). In memory-related areas such as the hippocampus, flavonoids promote the expression of brain-derived neurotrophic factor (BDNF), that is crucial to adult neurogenesis, synaptic growth, and neuronal survival (19). Increasing evidence from animal models indicates that flavonoids can promote cognitive benefits through their ability to directly interact with the cellular and molecular architecture involved in memory function (2, 11, 12). To date, however, it is still not entirely clear whether and to what extent these direct biological actions also extend to the human brain.
Flavonoids could also display their neurocognitive effects indirectly, through their capability of inducing cardiovascular actions. In this regard, cardiovascular benefits of cocoa and chocolate consumption are now well established and include endothelium-dependent vasodilation, which contributes to the maintenance of normal blood flow, reduced platelet aggregation, and blood pressure improvement (20–26).
Importantly, flavanols such as epicatechin can improve endothelial function by increasing the nitric oxide (NO) bioavailability, a key regulator of vascular function, leading to improvements in vascular tone and blood pressure regulation (27, 28). These peripheral vascular changes may also extend to brain perfusion, leading to a more efficient cerebrovascular coupling during neuronal activation, which is considered crucial for the functional and structural integrity of the brain. Moreover, as increased cerebrovascular function promotes adult neurogenesis in the hippocampus (29), flavonoid-mediated vascular changes could be additionally relevant for memory function.
Coherently, increasing evidence highlights the potential of cocoa flavanols to influence cognitive abilities interacting with the cerebrovascular system. Flavanol-rich cocoa has been shown to significantly increase cerebral blood flow (CBF) 1–2 h post-intervention in humans (30–32), suggesting that flavanols’ indirect, vasodilatatory actions could account for acute cognitive enhancement following a single administration (16). Conversely, cognitive benefits associated with long-term flavonoids intake are more likely to involve morphological changes induced by direct actions on neuronal signaling. However, indirect mechanisms of action can also contribute to long-term neuroprotective effects, as increases in NO levels can further impact on brain vascularization over time by promoting angiogenesis, thus resulting in better cerebrovascular communication.
Effects of Cocoa Flavanols Daily Intake on Cognition: Evidence from Chronic Investigations
In line with the evidence suggesting a favorable association between flavonoids’ regular consumption and cognitive performance in elderly subjects (33), chronic and sub-chronic cognitive effects of cocoa flavanols administration have been addressed in normal aging and clinical populations (see Table 1).
Table 1. Summary of the studies examining the effects of daily administration of cocoa flavanols on cognitive performance.
In this respect, the daily consumption of flavanol-rich cocoa drink has been showed to positively affect cognition, leading to improvements in cognitive performance both in older adults with early memory decline (36) and in cognitively intact elderly subjects (39). Specifically, compared to the low-flavanol condition (48 mg), the chronic administration of intermediate (520 mg) and high (993 mg) cocoa flavanols content over an 8-week period was associated to improvements in processing speed, executive function, and working memory in subjects with mild cognitive impairment. At higher cocoa flavanols concentrations, significant improvements were also evident in a verbal fluency task. Interestingly, such cognitive beneficial effects were paralleled by improvements in blood pressure and insulin resistance, suggesting a role of endothelial function and glucose sensitivity in modulating cognitive function in these patients (36). More recently, similar findings were replicated in healthy aged participants. Subjects in the intermediate and high cocoa flavanols groups, after a daily consumption over an 8-week period, showed better performance in several cognitive domains compared to those in the low-flavanol group (39).
By contrast, in healthy older adults a 6-week cocoa flavanols intervention showed no significant effects on cognitive and cardiovascular outcomes (34). In this study, however, participants were administered chocolate bar or beverage containing 397 or 357 mg flavanols, respectively; insufficient flavanols content may therefore account for the negative finding.
In middle-aged (40–65) subjects, Camfield et al. (35) investigated the chronic (30-day intake) neurocognitive effects of 250 and 500 mg cocoa flavanols administration using a spatial working memory task and steady-state visually evoked potentials (SSVEP). Compared to placebo, participants receiving cocoa flavanols treatment showed changes in SSVEP average amplitude and phase across several posterior parietal and centro-frontal sites that indicated an increased neural efficiency in response to the working memory task. Hence, cocoa flavanols long-term intake could effectively improve cognition trough increased neural efficiency, although, in this healthy population, the observed changes in brain activation were not paralleled by concomitant improvements in spatial working memory accuracy. Similarly, a sub-chronic (5 days) daily intake of 172 mg cocoa flavanols was associated, in healthy young subjects, to increased blood oxygenation level-dependent signal in various brain regions in response to an attention switching task, without any behavioral effect (31).
It has been proposed that cocoa long-term cognitive protection could particularly affect populations at risk. In this regard, Sorond et al. (37) evaluated the effect of flavanol-rich cocoa on neurovascular coupling in older subjects with vascular risk factors. In patients with impaired cerebrovascular coupling at baseline, cocoa administration was associated with improvements in cerebrovascular function both acutely and after a 30-day period. Moreover, chronic flavanols intake also resulted in improvements in cognitive flexibility. Conversely, no significant effects of cocoa administration on neurovascular coupling and cognitive performance were observed in those with intact cerebrovascular functions (37).
Besides improving CBF and CBF velocity after daily intake (41, 42), cocoa flavanols could also specifically affect cerebral blood volume in memory-related brain areas (38). Using high-resolution functional magnetic resonance imaging, a 3-month intervention with 900-mg cocoa flavanols resulted in increased cerebral blood volume in the dentate gyrus of the hippocampus, a structure particularly affected by aging and potentially implicated in memory decline. Moreover, the increase in cerebral blood volume was highly correlated with improvements in performance in a dentate gyrus-dependent memory task. Cocoa flavanols regular intake could therefore improve human dentate gyrus function through global increase in blood flow or a more selective increase in capillary density.
More recently, Neshatdoust et al. (40) investigated the link between cognitive performance and BDNF serum levels in older participants following cocoa flavanols chronic administration over 12 weeks. Results showed that, in comparison to a low-flavanol control (23 mg total flavanols), the daily intake of a high-flavanol cocoa drink (494 mg total flavanols) was associated with higher BDNF serum levels and improvements in global cognition scores. Therefore, changes in serum BDNF levels induced by cocoa flavanols could additionally underpin the beneficial effect of chronic cocoa flavanols intake on cognitive functions.
Collectively, these findings seem to support quite consolidated epidemiological evidence indicating that regular cocoa flavanols intake possesses the potential to protect human cognition, particularly in aged populations (33). As suggested (43), cocoa flavanols long-term beneficial effects on cognition could also possibly explain the correlation between country levels of chocolate consumption and Nobel Prizes per capita.
Acute Effects of Cocoa Flavanols Intake on Cognition
Only few randomized controlled trials have investigated the possibility that human cognitive function may be improved following acute cocoa consumption, within 6 h post-ingestion (see Table 2).
Table 2. Summary of the studies examining the effects of acute administration of cocoa flavanols on cognitive performance.
In a double-blind crossover study, 30 healthy adults were administered chocolate drinks containing 520 and 994 mg flavanols and 46 mg matched control, with a 3-day washout between sessions (44). Cognitive assessment, designed to be cognitively fatiguing, consisted in a 10-min task battery administered in six consecutive repetitions, including a serial subtraction task and a rapid visual information processing task. Results showed that, compared to control, both 520 and 994 mg cocoa flavanols doses significantly improved working memory performance on serial subtractions.
Using a similar acute intervention, Field et al. (45) found that 2 ho after a 773-mg cocoa flavanols supplementation, young participants showed enhanced performance on the accuracy measure of a spatial working memory task, as well as performance improvements on a choice reaction time task. Also, visual function was improved, with better visual contrast sensitivity and time to detect motion direction (45).
By contrast, Pase et al. (46) failed to demonstrate any acute effect of 500 mg cocoa flavanols administration on cognition in older adults. Cognitive assessment included measures of memory and attention. However, as a limitation, participants had a standardized lunch break before testing session; it is therefore possible that flavonoids effects were masked by post-prandial factors (46).
Immediate cognitive enhancement induced by high-flavanol cocoa is generally supposed to be mediated by the capability of their metabolites to promote crucial changes in peripheral and central blood flow. Some investigations therefore included behavioral and cardiovascular measures to explore the association between acute post-intervention cognitive enhancement and changes in peripheral and central blood perfusion. In this respect, Massee et al. (47) showed improvements in a serial subtraction task after the acute administration, in healthy subjects, of a cocoa bar containing 250 mg of flavanols. However, this study failed to demonstrate significant concomitant cardiovascular improvements after treatment. Conversely, a pilot study in healthy young participants showed that a single higher dose of flavanol-rich cocoa (516 mg) caused a significant global increase in CBF 2 h post-treatment (31). This result suggests an increased brain perfusion mediated by NO-dependent vasodilation, after cocoa consumption (31, 49).
In line with this result, in a recent near-infrared spectroscopy study, the administration of 903 mg cocoa flavanols increased cerebral oxygenation during the Stroop task performance in comparison to placebo, again suggesting increased NO-mediated vasodilation. Conversely, cocoa flavanols had no acute effects on serum BDNF levels (48). Therefore, these data support the idea that flavanols-induced acute changes in brain perfusion could underpin immediate cognitive-enhancing effects. However, the increased cerebral blood oxygenation was not paralleled by concomitant effects on cognitive performance (48). The young age of participants may have contributed to the lack of behavioral effects. This could be particularly relevant in this study, as participant performed a very short, relatively simple cognitive task. Since cocoa has been shown to affect cognitive performance in healthy individuals undergoing sustained effortful cognitive processing (44), these results open the possibility that, at least in healthy young adults, a high level of cognitive demand is needed to uncover the subtle immediate behavioral effects of flavonoids.
Accordingly, it could be argued that flavanols may be more effective in sustaining performance in highly demanding contexts or in presence of impaired physiological functions (e.g., cardiovascular risk factors). In this respect, we recently evaluated, in healthy young subjects, the effects of acute flavanol-rich chocolate administration on cardiovascular and cognitive function known to be specifically impaired by lack of sleep (27, 28). To this purpose, participants underwent two baseline sessions, performed after undisturbed nocturnal sleep, and two experimental sessions, after one night of total sleep deprivation. Subjects were randomly assigned to consume, 90 min before each testing session, flavonoid-rich dark chocolate (520 mg total flavanols) or flavonoid-poor chocolate (88.5 mg total flavanols). Cognitive assessment included the Psychomotor Vigilance Task, as a measure of behavioral alertness, and a 2-back working memory task. A single flavanol-rich cocoa administration was effective at counteracting the vascular impairment observed after a night of total sleep deprivation. Moreover, in the female subsample, cocoa flavanols also counteracted cognitive impairment specifically induced by sleep loss, leading to improvements in the accuracy measure of the working memory task. This result supports the idea of a specific effectiveness of cocoa flavanols in sustaining higher order cognitive performance during sustained effortful processing in healthy individuals. Interestingly, in the whole sample higher flow-mediated dilation levels, indicative of improved endothelial function, were related to better performance accuracy. Thus, although direct CBF measurements were not included, the results indicate that a single flavanol-rich chocolate administration could exert beneficial effects on cognitive performance through the capability to induce acute changes in peripheral and central blood flow via NO-dependent vasodilation.
Altogether, investigations on acute cognitive-enhancing effects of cocoa flavanols support the effectiveness of cocoa at sustaining cognitive performance, although with mixed results. Quantity and bioavailability of the consumed cocoa flavanols, together with the length and cognitive load of the cognitive assessment, represent crucial factors that may significantly impact on the experimental outcomes.
Conclusion
In recent years, in the context of an increased interest in the modulatory effects of food constituents on human health, cocoa flavanols have been suggested to display a variety of beneficial biological actions, including neuroprotection and cognitive modulation.
At present, the limited number of studies investigating cocoa flavanols intake and cognitive performance has produced mixed results. Indeed, physiological responses to flavonoid supplementation such as vasodilation, both at peripheral and central levels, have been consistently replicated; conversely, cognitive findings are not as unequivocal. When trying to account for such discrepancies, several methodological differences should be considered in dose, form, and timeframe of the cocoa flavanols administration, as well as in length and cognitive load of the experimental tasks. All these variables could have a remarkable impact on physiological and behavioral results and are likely to partly explain discrepancies among results.
Nevertheless, the evidence accumulated so far suggests that cocoa flavanols administration can be effective at sustaining cognitive performance, leading to improvements in measures of general cognition, attention, processing speed and memory. Beneficial cognitive effects of regular flavanols intake, particularly in patients at risk, are presumably mediated by direct neuroprotective actions as well as improvements in cerebrovascular and metabolic functions. Furthermore, acute administration of cocoa flavanols could result in immediate cognitive-enhancing effect, sustaining performance particularly in cognitively demanding conditions, including fatigue and sleep loss.
Altogether, research on the effects of cocoa and chocolate on human cognition, although at its preliminary stage, converges at pointing to cocoa as a new interesting nutraceutical tool to protect human cognition and counteract different types of cognitive decline, thus encouraging further investigations. Future research should be addressed to the identification of sensitive experimental measures capable of detecting flavanol-induced subtle changes in cognitive performance. Moreover, the characterization of appropriate dose, timing, and form of flavanols intervention required to reach beneficial effects in different populations, as well as the inclusion of fully matched placebo controls, are needed. Undefined remain also the effects of both acute and chronic administration of cocoa flavanols on chronic sleep deprivation and shift work, situations that may have a pronounced clinical impact. To elucidate immediate and long-term neuromodulatory properties of cocoa, future investigations should be ideally designed to include neuroimaging techniques in conjunction with cognitive and physiological measures.
Author Contributions
VS wrote the manuscript. VS and MF conceived and organized the structure of the review. DT contributed to write the first draft of the manuscript. DT, GD, LG, and MF contributed to the critical revision of the paper and approved the final manuscript for the publication.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Abbreviations
BOLD, blood oxygenation level-dependent; BDNF, brain-derived neurotrophic factor; CBF, cerebral blood flow; ERK, extracellular signal-regulated kinase; LTP, long-term potentiation; MAPK, mitogen-activated protein kinase; NIRS, near-infrared spectroscopy; NO, nitric oxide; PI3-kinase/Akt, phosphoinositide 3-kinase; SSVEP, steady-state visually evoked potentials.
References
1. Wesensten NJ, Killgore WD, Balkin TJ. Performance and alertness effects of caffeine, dextroamphetamine, and modafinil during sleep deprivation. J Sleep Res (2005) 14:255–66. doi:10.1111/j.1365-2869.2005.00468.x
2. Williams RJ, Spencer JP. Flavonoids, cognition, and dementia: actions, mechanisms, and potential therapeutic utility for Alzheimer disease. Free Radic Biol Med (2012) 52:35–45. doi:10.1016/j.freeradbiomed.2011.09.010
3. Benton D, Donohoe RT. The effects of nutrients on mood. Public Health Nutr (1999) 2:403–9. doi:10.1017/S1368980099000555
4. Crichton GE, Elias MF, Alkerwi A. Chocolate intake is associated with better cognitive function: the Maine-Syracuse Longitudinal Study. Appetite (2016) 100:126–32. doi:10.1016/j.appet.2016.02.010
5. Commenges D, Scotet V, Renaud S, Jacqmin-Gadda H, BarbergerGateau P, Dartigues JF. Intake of flavonoids and risk of dementia. Eur J Epidemiol (2000) 16:357–63. doi:10.1023/A:1007614613771
6. Moreira A, Diógenes MJ, de Mendonça A, Lunet N, Barros H. Chocolate consumption is associated with a lower risk of cognitive decline. J Alzheimers Dis (2016) 53:85–93. doi:10.3233/JAD-160142
7. Kuriyama S, Hozaka A, Ohmori K, Shimazu T, Matsui T, Ebihara S, et al. Green tea consumption and cognitive function: a cross-sectional study from the Tsurugaya project. Am J Clin Nutr (2006) 83:355–61.
8. Letenneur L, Proust-Lima C, Le Gouge A, Dartigues JF, BarbergerGateau P. Flavonoid intake and cognitive decline over a 10-year period. Am J Epidemiol (2007) 165:1364–71. doi:10.1093/aje/kwm036
9. Nurk E, Refsum H, Drevon CA, Tell GS, Nygaard HA, Engedal K, et al. Intake of flavonoid-rich wine, tea, and chocolate by elderly men and women is associated with better cognitive test performance. J Nutr (2009) 139:120–7. doi:10.3945/jn.108.095182
10. Rice-Evans CA, Miller NJ, Paganga G. Structure-antioxidant activity relationships of flavonoids and phenolic acids. Free Radic Biol Med (1996) 20:933–56. doi:10.1016/0891-5849(95)02227-9
11. Spencer JP. Food for thought: the role of dietary flavonoids in enhancing human memory, learning and neuro-cognitive performance. Proc Nutr Soc (2008) 67:238–52. doi:10.1017/S0029665108007088
12. Spencer JP. Flavonoids and brain health: multiple effects underpinned by common mechanisms. Genes Nutr (2009) 4:243–50. doi:10.1007/s12263-009-0136-3
13. Datla KP, Christidou M, Widmer WW, Rooprai HK, Dexter DT. Tissue distribution and neuroprotective effects of citrus flavonoid tangeretin in a rat model of Parkinson’s disease. Neuroreport (2001) 12:3871–5. doi:10.1097/00001756-200112040-00053
14. Passamonti S, Vrhovsek U, Vanzo A, Mattivi F. Fast access of some grape pigments to the brain. J Agric Food Chem (2005) 53:7029–34. doi:10.1021/jf050565k
15. Milbury PE, Kalt W. Xenobiotic metabolism and berry flavonoid transport across the blood-brain barrier. J Agric Food Chem (2010) 58:3950–6. doi:10.1021/jf903529m
16. Nehlig A. The neuroprotective effects of cocoa flavanol and its influence on cognitive performance. Br J Clin Pharmacol (2013) 75:716–27. doi:10.1111/j.1365-2125.2012.04378.x
17. Sokolov AN, Pavlova MA, Klosterhalfen S, Enck S. Chocolate and the brain: neurobiological impact of cocoa flavanols on cognition and behavior. Neurosci Biobehav Rev (2013) 37:2445–53. doi:10.1016/j.neubiorev.2013.06.013
18. Kelleher RJ, Govindarajan A, Jung HY, Kang H, Tonegawa S. Translational control by MAPK signaling in long-term synaptic plasticity and memory. Cell (2004) 116:467–79. doi:10.1016/S0092-8674(04)00115-1
19. Valente T, Hidalgo J, Bolea I, Ramirez B, Anglés N, Reguant J, et al. A diet enriched in polyphenols and polyunsaturated fatty acids, LMN diet, induces neurogenesis in the subven-tricular zone and hippocampus of adult mouse brain. J Alzheimer Dis (2009) 18:849–65. doi:10.3233/JAD-2009-1188
20. Flammer AJ, Hermann F, Sudano I, Spieker L, Hermann M, Cooper KA, et al. Dark chocolate improves coronary vasomotion and reduces platelet reactivity. Circulation (2007) 116:2376–82. doi:10.1161/CIRCULATIONAHA.107.713867
21. Grassi D, Lippi C, Necozione S, Desideri G, Ferri C. Short-term administration of dark chocolate is followed by a significant increase in insulin sensitivity and a decrease in blood pressure in healthy persons. Am J Clin Nutr (2005) 81:611–4.
22. Grassi D, Necozione S, Lippi C, Croce G, Valeri L, Pasqualetti P, et al. Cocoa reduces blood pressure and insulin resistance and improves endothelium-dependent vasodilation in hypertensives. Hypertension (2005) 46:398–405. doi:10.1161/01.HYP.0000174990.46027.70
23. Grassi D, Desideri G, Necozione S, Lippi C, Casale R, Properzi G, et al. Blood pressure is reduced and insulin sensitivity increased in glucose-intolerant, hypertensive subjects after 15 days of consuming high-polyphenol dark chocolate. J Nutr (2008) 138:1671–6.
24. Grassi D, Desideri G, Ferri C. Protective effects of dark chocolate on endothelial function and diabetes. Curr Opin Clin Nutr Metab Care (2013) 16:662–8. doi:10.1097/MCO.0b013e3283659a51
25. Grassi D, Desideri G, Necozione S, Di Giosia P, Barnabei R, Allegaert L, et al. Cocoa consumption dose-dependently improves flow-mediated dilation and arterial stiffness decreasing blood pressure in healthy individuals. J Hypertens (2015) 33:294–303. doi:10.1097/HJH.0000000000000412
26. Shrime MG, Bauer SR, McDonald AC, Chowdhury NH, Coltart CE, Ding EL. Flavonoid-rich cocoa consumption affects multiple cardiovascular risk factors in a meta-analysis of short-term studies. J Nutr (2011) 141:1982–8. doi:10.3945/jn.111.145482
27. Grassi D, Ferri C, Desideri G. Brain protection and cognitive function: cocoa flavonoids as nutraceuticals. Curr Pharm Des (2016) 22:145–51. doi:10.2174/1381612822666151112145730
28. Grassi D, Socci V, Tempesta D, Ferri C, De Gennaro L, Desideri G, et al. Flavanol-rich chocolate acutely improves arterial function and working memory performance counteracting the effects of sleep deprivation in healthy individuals. J Hypertens (2016) 34:1298–308. doi:10.1097/HJH.0000000000000926
29. Gage FH. Mammalian neural stem cells. Science (2000) 287:1433–8. doi:10.1126/science.287.5457.1433
30. Richelle M, Tavazzi I, Enslen M, Offord EA. Plasma kinetics in man of epicatechin from black chocolate. Eur J Clin Nutr (1999) 53:22–6. doi:10.1038/sj.ejcn.1600673
31. Francis ST, Head K, Morris PG, Macdonald IA. The effect of flavanol-rich cocoa on the fMRI response to a cognitive task in healthy young people. J Cardiovasc Pharmacol (2006) 47:S215–20. doi:10.1097/00005344-200606001-00018
32. Lamport DJ, Pal D, Moutsiana C, Field DT, Williams CM, Spencer JP, et al. The effect of flavanol-rich cocoa on cerebral perfusion in healthy older adults during conscious resting state: a placebo controlled, crossover, acute trial. Psychopharmacology (2015) 232:3227–34. doi:10.1007/s00213-015-3972-4
33. Vauzour D. Dietary polyphenols as modulators of brain functions: biological actions and molecular mechanisms underpinning their beneficial effects. Oxid Med Cell Longev (2012) 2012:914273. doi:10.1155/2012/914273
34. Crews WD, Harrison DW, Wright JW. A double-blind, placebo-controlled, randomized trial of the effects of dark chocolate and cocoa on variables associated with neuropsychological functioning and cardiovascular health: clinical findings from a sample of healthy, cognitively intact older adults. Am J Clin Nutr (2008) 87:872–80.
35. Camfield DA, Scholey A, Pipingas A, Silberstein R, Kras M, Nolidin K, et al. Steady state visually evoked potential (SSVEP) topography changes associated with cocoa flavanol consumption. Physiol Behav (2012) 105:948–57. doi:10.1016/j.physbeh.2011.11.013
36. Desideri G, Kwik-Uribe C, Grassi D, Necozione S, Ghiadoni L, Mastroiacovo D, et al. Benefits in cognitive function, blood pressure, and insulin resistance through cocoa flavanol consumption in elderly subjects with mild cognitive impairment: the Cocoa, Cognition, and Aging (CoCoA) Study. Hypertension (2012) 60:794–801. doi:10.1161/HYPERTENSIONAHA.112.193060
37. Sorond FA, Hurwitz S, Salat DH, Greve DN, Fisher ND. Neurovascular coupling, cerebral white matter integrity, and response to cocoa in older people. Neurology (2013) 81:904–9. doi:10.1212/WNL.0b013e3182a351aa
38. Brickman AM, Khan UA, Provenzano FA, Yeung LK, Suzuki W, Schroeter H, et al. Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults. Nat Neurosci (2014) 17:1798–803. doi:10.1038/nn.3850
39. Mastroiacovo D, Kwik-Uribe C, Grassi D, Necozione S, Raffaele A, Pistacchio L, et al. Cocoa flavanol consumption improves cognitive function, blood pressure control, and metabolic profile in elderly subjects: the Cocoa, Cognition, and Aging (CoCoA) Study—a randomized controlled trial. Am J Clin Nutr (2015) 101:538–48. doi:10.3945/ajcn.114.092189
40. Neshatdoust S, Saunders C, Castle SM, Vauzour D, Williams C, Butler L, et al. High-flavonoid intake induces cognitive improvements linked to changes in serum brain-derived neurotrophic factor: two randomised, controlled trials. Nutr Healthy Aging (2016) 24:81–93. doi:10.3233/NHA-1615
41. Sorond FA, Lipsitz LA, Hollenberg NK, Fisher ND. Cerebral blood flow response to flavanol-rich cocoa in healthy elderly humans. Neuropsychiatr Dis Treat (2008) 4:433–40. doi:10.1016/j.cortex.2006.01.003
42. Sorond FA, Hollenberg NK, Panych LP, Fisher ND. Brain blood flow and velocity: correlations between magnetic resonance imaging and transcranial Doppler sonography. J Ultrasound Med (2010) 29:1017–22. doi:10.7863/jum.2010.29.7.1017
43. Messerli FH. Chocolate consumption, cognitive function, and Nobel laureates. N Engl J Med (2012) 367:1562–4. doi:10.1056/NEJMon1211064
44. Scholey AB, French SJ, Morris PJ, Kennedy DO, Milne AL, Haskell CF. Consumption of cocoa flavanols results in acute improvements in mood and cognitive performance during sustained mental effort. J Psychopharmacol (2010) 24:1505–14. doi:10.1177/0269881109106923
45. Field DT, Williams CM, Butler LT. Consumption of cocoa flavanols results in an acute improvement in visual and cognitive functions. Physiol Behav (2011) 103:255–60. doi:10.1016/j.physbeh.2011.02.013
46. Pase MP, Scholey AB, Pipingas A, Kras M, Nolidin K, Gibbs A, et al. Cocoa polyphenols enhance positive mood states but not cognitive performance: a randomized, placebo-controlled trial. J Psychopharmacol (2013) 27:451–8. doi:10.1177/0269881112473791
47. Massee LA, Ried K, Pase M, Travica N, Yoganathan J, Scholey A, et al. The acute and sub-chronic effects of cocoa flavanols on mood, cognitive and cardiovascular health in young healthy adults: a randomized, controlled trial. Front Pharmacol (2015) 6:93. doi:10.3389/fphar.2015.00093
48. Decroix L, Tonoli C, Soares DD, Tagougui S, Heyman E, Meeusen R. Acute cocoa flavanol improves cerebral oxygenation without enhancing executive function at rest or after exercise. Appl Physiol Nutr Metab (2016) 41:1225–32. doi:10.1139/apnm-2016-0245
Keywords: chocolate, flavanols, neuroprotection, cognitive function, cardiovascular function
Citation: Socci V, Tempesta D, Desideri G, De Gennaro L and Ferrara M (2017) Enhancing Human Cognition with Cocoa Flavonoids. Front. Nutr. 4:19. doi: 10.3389/fnut.2017.00019
Received: 01 March 2017; Accepted: 27 April 2017;
Published: 16 May 2017
Edited by:
Mauro Serafini, University of Teramo, ItalyReviewed by:
Andrea Enzo Scaramuzza, Istituti Ospitalieri di Cremona, ItalyAlberto Finamore, Council for Agricultural Research and Economics-Food and Nutrition Research Center, Italy
Copyright: © 2017 Socci, Tempesta, Desideri, De Gennaro and Ferrara. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Michele Ferrara, michele.ferrara@univaq.it