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Chocolate and The Brain PDF
Chocolate and The Brain PDF
Review
a r t i c l e i n f o a b s t r a c t
Article history: Cocoa products and chocolate have recently been recognized as a rich source of flavonoids, mainly fla-
Received 18 February 2013 vanols, potent antioxidant and anti-inflammatory agents with established benefits for cardiovascular
Received in revised form 17 June 2013 health but largely unproven effects on neurocognition and behavior. In this review, we focus on neuro-
Accepted 18 June 2013
modulatory and neuroprotective actions of cocoa flavanols in humans. The absorbed flavonoids penetrate
and accumulate in the brain regions involved in learning and memory, especially the hippocampus. The
Keywords:
neurobiological actions of flavanols are believed to occur in two major ways: (i) via direct interactions
Cocoa flavanols
with cellular cascades yielding expression of neuroprotective and neuromodulatory proteins that pro-
Chocolate
Antioxidant
mote neurogenesis, neuronal function and brain connectivity, and (ii) via blood-flow improvement and
Anti-inflammatory angiogenesis in the brain and sensory systems. Protective effects of long-term flavanol consumption
Neurogenesis on neurocognition and behavior, including age- and disease-related cognitive decline, were shown in
Angiogenesis animal models of normal aging, dementia, and stroke. A few human observational and intervention stud-
Age- and disease-related decline ies appear to corroborate these findings. Evidence on more immediate action of cocoa flavanols remains
Neurocognition limited and inconclusive, but warrants further research. As an outline for future research on cocoa flavanol
Neuromodulation impact on human cognition, mood, and behavior, we underscore combination of functional neuroimaging
Neuroprotection
with cognitive and behavioral measures of performance.
© 2013 Published by Elsevier Ltd.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2445
2. Cocoa flavanols in the brain signaling cascades . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2446
3. Neuroprotective action of cocoa flavanols in aging and neurological disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2447
3.1. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2447
3.2. Human population studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2448
3.3. Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2448
4. Neuromodulation of cognition, mood, learning, and memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2449
4.1. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2449
4.2. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2449
5. Concluding remarks and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2450
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2452
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2452
1. Introduction
other natural product but chocolate has ever been viewed as having enzymatic activity (Stevenson and Hurst, 2007; Mann et al., 2009).
a positive effect on a wide variety of health conditions ranging from Flavanols occur in high concentrations in beverages such as green
intestinal and female complaints, fever, and cardiovascular dis- tea and red wine, fruits and berries (e.g., apple skin, grapes, pears,
eases to promotion of strength before military and sexual conquests blueberry), vegetables (tomatoes, soy, and olives), and, especially,
(Wilson, 2010; Wolfe and Shazzie, 2005). Reports on chocolate’s cocoa (Manach et al., 2004; Neveu et al., 2010; Scalbert et al.,
health benefits are dated back as far as Aztec and Maya medical 2011; Sies et al., 2012). The flavonoid contents in cocoa prod-
practice (e.g., Hurst et al., 2002) and ever since, anecdotal evidence ucts and chocolate differ substantially depending on the cocoa
has been abundant on chocolate effects on health. Only by the end variety (in some beans, amounting up to 20%), geographic origin,
of the 20th century, however, claims on supposed health benefits cultivating, agricultural and postharvest practices, and manufac-
of chocolate have increasingly drawn a scientific interest in cocoa turing (Wollgast and Anklam, 2000; Niemenak et al., 2006). In the
products and chocolate, which eventually resulted in an approval Dutch population, chocolate contributes to about 20% of the total
by the European Food Safety Agency (EFSA, 2012) of a health claim flavonoid intake in adults, with an even higher percentage in chil-
for dark chocolate with high flavanol content as to its impact on dren (Arts et al., 1999). In American diet, chocolate represents the
“maintenance of normal endothelium-dependent vasodilation”. third top source of antioxidants after fruits and vegetables (255,
Most studies so far have been conducted on the effects of 233, and 104 mg/day, respectively; Vinson et al., 2006). Also in the
chocolate intake on the cardiovascular system, skin, cholesterol French adult population with the total daily dietary polyphenol
concentrations, and the release of neurotransmitters anandamide intake of 1.2 g, including 99 mg catechins, cocoa products account
and serotonin, and on the health-related properties of high- for the third major source of epicatechin (17%) after green tea (28%)
quality dark chocolate, containing the stimulants theobromine and apples (24%; Pérez-Jiménez et al., 2011). Yet human and animal
and caffeine (Lamuela-Raventós et al., 2005; Katz et al., 2011). studies on neuroprotective properties of flavonoids, especially in
Dark chocolate also comprises high concentrations of flavanols (a preventing cognitive decline, have mostly examined plant-derived
flavonoid subgroup, mainly epicatechin; Whiting, 2001) known as substances other than cocoa flavanols (e.g., Macready et al., 2009).
potent antioxidative agents. While some work has been done on Flavonoid-rich pine extracts such as Gingko biloba are reported to
the influence of theobromine and caffeine on mood and cognition delay the onset of memory loss, dementia, and Alzheimer’s disease
(e.g., Smit and Rogers, 2000; Smit et al., 2004; Smit and Blackburn, (Weinmann et al., 2010), but the evidence remains controversial
2005; Nehlig, 2010), the impact of cocoa flavanols on human cog- (Birks and Grimley Evans, 2009).
nitive and affective function, executive control and behavior has Animal studies show that flavanols and their metabolites can
yet to be determined. In accord with accumulating evidence for cross the blood–brain barrier, inducing beneficial effects on the
enhancing effects of chocolate consumption on cognitive function, brain tissue and function (angio- and neurogenesis, changes in neu-
Messerli (2012) reports, as an occasional note, a strong positive ron morphology) and stimulating widespread blood circulation in
correlation between chocolate intake per capita and the number of the brain (Vauzour et al., 2008). The most common flavanol found in
Nobel laureates in various countries. cocoa, epicatechin (Whiting, 2001), is rapidly absorbed in humans
In contrast to potential effects on cognition and behavior, and is detectable in blood plasma already 30 min after intake. The
evidence-based benefits of cocoa and chocolate consumption epicatechin levels peak 2–3 h after intake, exhibiting a strong posi-
for cardiovascular system are well established and include tive correlation with the dose of ingested chocolate (Richelle et al.,
endothelium-dependent vasodilation recently found to contribute 1999), and return to baseline by 6–8 h after consumption. The pos-
to normal blood flow (Engler et al., 2004; Hooper et al., 2012; sibility of flavanols and metabolites to penetrate and accumulate
Kay et al., 2006; Grassi et al., 2005, 2008). Cardiovascular health in the brain regions mainly related to learning and memory, sug-
has been closely linked to cognitive performance (e.g., DeCarli, gests they may exert a direct positive impact on the brain, including
2012). Animal studies have shown that the absorbed flavonoids cognition and neuroprotection (Nehlig, 2013).
directly interact with a number of cellular and molecular targets in Neurobiological impact of flavanols on the brain, learning, mem-
the brain, exerting pronounced antioxidative effects and improv- ory, and cognition are believed to occur in two major ways (Fig. 1).
ing brain tissue and function in the regions mainly implicated First, flavonoids can specifically interact within a number of cellu-
in learning, memory, and cognition (Andrés-Lacueva et al., 2005; lar signaling pathways, primarily with mitogen-activated protein
Passamonti et al., 2005; Vauzour et al., 2008). This suggests a poten- (MAPK), extracellular-signal-regulated (ERK) and phosphoinosi-
tial neuromodulatory and neuroprotective role for cocoa flavanols tide 3-kinase (PI3-kinase/Akt) signaling cascades. These cascades
and their significance for cognitive and affective function, execu- trigger gene expression and protein synthesis for maintaining
tive control and behavior. However, only few human studies so long-term potentiation (LTP) and establishing long-term memo-
far have specifically addressed neurobiological, cognitive, affective ries (Kelleher et al., 2004). Flavonoids modulate the transcription
and behavioral effects of flavanol-rich cocoa products. The present factors engaged in signal transduction through protein-kinase inhi-
review focuses on analysis of the existing evidence on potential bition (Goyarzu et al., 2004), and promote the expression of brain
neuromodulatory and neuroprotective actions of cocoa flavanols derived neurotrophic factor (BDNF) that is critical for neurogen-
in humans. Our analysis highlights further ways in investigation of esis, also in adult animals, synaptic growth and neuron survival,
the impact of flavanol-rich cocoa products on neurocognition and especially in the learning- and memory-related brain regions such
behavior. as the hippocampus and subventricular zone (Kim et al., 2006;
Valente et al., 2009). Second, flavonoids facilitate production of
2. Cocoa flavanols in the brain signaling cascades the signaling molecule nitric oxide, which inhibits the incidence
of atheromatous plaque adhesion molecules causing inflammation
The flavanol monoisomers epicatechin and catechin are (Gonzalez-Gallego et al., 2007), and importantly, improves vascu-
the predominant flavonoid compounds in cocoa, with the lar endothelial function by relaxing the smooth muscle tissue of
2-phenyl-3,4-dihydro-2H-chromen-3-ol as underlying skeleton. blood vessels (e.g., Heiss et al., 2003; Schroeter et al., 2006). In this
These monomers represent the base molecules for concatenated way, flavanol-rich cocoa can impose vasodilation in a nitric oxide-
oligomers, the proanthocyanidins. Antioxidant properties of fla- dependent way both at the cardiovascular and peripheral levels.
vanols are chemically mediated through oxidation of two aromatic This in turn results in enhanced cerebral blood flow and blood
hydroxyl groups to a quinone (Bors and Michel, 2002). In addi- perfusion throughout the central and peripheral nervous system
tion, flavanols foster antioxidant system through modulation of (Fisher et al., 2003, 2006; Hollenberg et al., 2009), affording better
A.N. Sokolov et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 2445–2453 2447
(2007), however, administered a polyphenol-rich omega-3 fatty intake from multiple food items including chocolate (assessed once
acid diet of Greenland Eskimos to another type of Tg mice (another as the study begun) was associated with both better cognitive
animal model of Alzheimer’s disease), and did not find any diet performance at baseline and better evolution of performance over
benefits, except for several behavioral measures such as open field time. The most positive evolution was found in participants in
activity and maze entries. In both studies, Tg mice were similar, the two highest quartiles of flavonoid intake compared to those
with Arendash et al. (2007) using a second-generation cross of the in the lowest quartile. After 10-year follow-up, participants with
Tg2576 and the 6.2 lines that carried an additional mutation in the the lowest flavonoid intake had lost on average 2.1 points on the
presenilin gene 1, PS1. The distinct outcomes were likely due to the Mini-Mental State Examination, compared to the 1.2-point loss in
difference in either diets or study protocols to which the mice were participants of the highest quartile. The study raises the possibility
exposed. of an association between dietary flavonoid intake and cognitive
In an animal model of stroke, Shah et al. (2010) administered aging.
orally mice with 5, 15, or 30 mg/kg epicatechin 90 min before
middle cerebral artery occlusion. Epicatechin-treated mice, com-
pared to the control group, exhibited significantly smaller lesion 3.3. Clinical studies
volumes and improved neurological scores. Mice that were post-
treated with 30 mg/kg of epicatechin at 3.5 h after the occlusion The known benefits of flavonoids for vascular health (Ried et al.,
had also significantly smaller infarct volumes and improved neu- 2012) may represent a promising approach in treating cerebrovas-
rological scores. Villarreal-Calderon et al. (2010) reported that a cular disorders and protecting cognitive and functional behavior
treatment with dark chocolate prevents the inflammation of the in the elderly. Age- and disease-related disturbances in cerebral
vagus nerve resulting from a 16-month exposure of mice to the blood flow are thought to be commonly accompanied by cognitive
polluted air of Mexico City. Mice exposed to polluted air had a and behavioral decline. Dietary high-flavanol cocoa intake is asso-
significant imbalance in genes coding for antioxidant defenses, ciated with an increased cerebral blood flow velocity in the middle
apoptosis and neurodegeneration at the level of the dorsal vagal cerebral artery, suggesting a promising role for high-flavanol cocoa
complex and this imbalance was mitigated by chocolate adminis- consumption in the treatment of cerebrovascular ischemic syn-
tration. dromes such as dementia and stroke. For instance, Sorond et al.
(2008) report that following two weeks of high-flavanol cocoa
3.2. Human population studies intake, in 34 healthy elderly volunteers (aged 72 ± 6 years; 16
males), mean blood flow velocity in the middle cerebral artery mea-
Observational human population studies on neuroprotective sured by transcranial Doppler ultrasound significantly increases by
and neuromodulatory action of flavonoids, including high-flavanol 8% at one week and 10% at two weeks.
cocoa, have often been poorly controlled, whereas prospective lon- Potent antioxidative and anti-inflammatory properties of
gitudinal studies remain laborious and costly. To date, therefore, flavonoids have been proposed to play a role in preventing mild
evidence for beneficial neuroprotective and anti-inflammatory cognitive impairment, a precursor of dementia, and Alzheimer’s
effects of cocoa flavanols on cognitive and behavioral decline in disease. In Alzheimer’s disease, an increased production and accre-
aging and neurological disease is rather limited. In a prospective tion of A-peptides activates microglia, resulting in release of
study of a large sample of men aged 69–89 years (Kalmijn et al., inflammatory mediators that further enhance A production, giv-
1997), risk of cognitive decline (assessed by the Mini-Mental State ing rise to neuronal dysfunction and cellular death. While -
Examination) tended to inversely relate to flavonoid intake, though and ␥-secretase facilitate A production, ␣-secretase inhibits it.
no association was found between the risk of cognitive decline Recent work in cultured human neuroblastoma cells shows that
and vitamin C- or E-intake served as the antioxidant reference to low concentrations of nitric oxide up-regulate the expression of ␣-
flavonoids. In a cross-sectional study of the elderly Norwegian pop- secretase and down-regulate that of -secretase. This suggests the
ulation, Nurk et al. (2009) investigated the association between cerebrovascular nitric oxide might inhibit A production (McCarty,
cognitive performance and flavonoid intake from chocolate, wine, 2006; Pak et al., 2005). Cocoa flavanols, especially epicatechin, act
and tea. Participants aged 70–74 years (n = 2031; 55% females) com- directly on the endothelium of brain vessels, stimulating activity of
pleted a comprehensive cognitive test battery consisting of the the endothelial nitric oxide synthase that in turn induces vasodila-
Kendrick Object Learning Test, Trail Making Test (part A), versions tion and improves cerebrovascular perfusion (Fisher et al., 2006;
of the Digit Symbol Test, Block Design, Mini-Mental State Exami- Schroeter et al., 2006; Patel et al., 2008). So far, there does not
nation, and Controlled Oral Word Association Test. Habitual food seem to be any proven association between intake of antioxidants
intake was assessed by a self-reported food frequency question- and vitamins and Alzheimer’s disease (see Luchsinger and Mayeux,
naire. Chocolate, wine, or tea consumers yielded significantly better 2004 for review), however, several studies did report a diminished
mean test scores and lower prevalence of poor cognitive perfor- cerebral blood flow in dementia patients (Ruitenberg et al., 2005;
mance. Those consuming all three items had the best test scores Nagahama et al., 2003). Cerebrovascular atrophy is also known to
and the lowest risk for poor test performance. The association lead to mild cognitive impairment and subsequently to Alzheimer’s
between intake of the foods and cognition were dose-dependent, disease. It is therefore conceivable that beneficial properties of
with sharp improvements at intakes of ∼10 g/day chocolate and cocoa flavanols may slow down the transition from mild cogni-
∼75–100 ml/day wine, and a linear improvement for tea intake. tive impairment to Alzheimer’s disease (Nagahama et al., 2003).
The effect was most pronounced for wine and modestly weaker Commenges et al. (2000) conducted a clinical trial with 1367 par-
for chocolate intake. It appears that in the elderly, a diet high in ticipants aged over 65 years, 66 from which developed dementia.
some flavonoid-rich foods is associated with better performance in The relative risk of developing dementia adjusted for age for the two
several cognitive abilities in a dose-dependent manner. highest consumptions of flavonoids was 0.55 (95% confidence inter-
Participants of a prospective 10-year Personnes Agées Quid val, 0.34–0.90). After further adjustment for sex, education level,
(PAQUID) study (n = 1640; aged ≥65 years, free from dementia) weight and vitamin C intake, the relative risk decreased to 0.49 (95%
underwent testing of cognitive function at four consecutive time confidence interval, 0.26–0.92). Thus, it appears that antioxidant
points (Letenneur et al., 2007). At each visit, the cognitive functions flavonoid intake is inversely related to the risk of dementia. How-
were assessed by test battery including Mini-Mental State Exami- ever, in this study flavonoids came mainly from fruits, vegetables,
nation, Benton’s Visual Retention Test, and “Isaacs” Set. Flavonoid wine and tea rather than cocoa.
A.N. Sokolov et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 2445–2453 2449
Most recently, Desideri et al. (2012) studied 90 elderly individ- 4. Neuromodulation of cognition, mood, learning, and
uals with mild cognitive impairment (mean age, 71 years; 43 males) memory
who consumed once daily for eight weeks a drink containing either
∼990 mg (high), ∼520 mg (moderate), or ∼45 mg (low-flavanol) 4.1. Animal studies
of cocoa flavanols. Cognitive function was assessed by the Mini-
Mental State Examination, Trail Making Test A and B, and verbal Flavonoids are believed to trigger expression of neuromodula-
fluency test. At the end of the follow-up period, Mini-Mental State tory proteins in the brain regions implicated in learning, memory,
Examination scores were similar in the treatment groups. In the and cognition, suggesting cocoa flavanols can exhibit immediate
high- and moderate-flavanol compared to the low-flavanol groups, and short-term action on neurocognition, mood, and behavior. Sur-
time required to complete both Trail Making Tests was significantly prisingly, only a few animal studies have addressed these issues.
lower. Verbal fluency score was significantly better in the high- Mice treated with one of the major chocolate flavanols, epicat-
compared to low-flavanol group. The high- and moderate-flavanol echin, at the dose of 500 g/g (daily supply of 2.5 mg) showed
groups also exhibited decreased insulin resistance, blood pressure, pronounced angiogenesis in the hippocampus (van Praag et al.,
and lipid peroxidation. This appears to be the first dietary inter- 2007). Epicatechin treatment combined with exercise (running
vention study to demonstrate the efficacy of regular consumption a wheel) improved retention of spatial memory and increased
of cocoa flavanols for improving cognitive function in the elderly dendritic spine density in the dentate gyrus of the hippocam-
with mild cognitive impairment. pus. Moreover, epicatechin treatment facilitated gene expression
The ability of flavonoids to improve and maintain vascular associated with learning in the hippocampus but did not affect hip-
function offers a further possibility to investigate the relation- pocampal adult neurogenesis. Yamada et al. (2009) compared the
ship between cocoa flavanol intake and neuronal and functional effects of short-term versus long-term (two-week) oral administra-
loss after stroke (for recent animal data, see, e.g., Shah et al., tion of cocoa mass in large amounts (100 mg/100 g body weight) in
2010; Section 3.1). In the meta-analysis of three human stud- the rat elevated T-maze test, an animal model of anxiety. Short-
ies comprising 114,009 participants, Buitrago-Lopez et al. (2011) term administration significantly abolished avoidance behavior
reported a 29% reduction of stroke risk in high chocolate con- during immediate test performance, suggesting a reduced fear con-
sumers compared to low consumers. Buijsse et al. (2010) found ditioning. Long-term administration enhanced brain concentration
an even stronger inverse correlation between chocolate consump- of emotion-related neurotransmitter serotonin and its turnover.
tion and stroke risk than for myocardial infarction. Rautiainen et al. The findings indicate short-term cocoa intake shows an anxio-
(2012) examined the association between the total antioxidant lytic effect, whereas long-term intake affects brain monoamine
capacity (including fruits, vegetables, tea, coffee, and chocolate) metabolism. This suggests flavanol impacts on the amygdala under-
and stroke risk in women, aged 49 to 83 years, from the Swedish pinning regulation of anxiety and encoding of affective valence (e.g.,
Mammography cohort. The study included 5680 women with Morrison and Salzman, 2010). Flavanol action therefore may occur
and 31,035 women without a history of cardiovascular disease. in the brain regions outside the hippocampus and subventricular
Diet was assessed with a self-reported food frequency ques- zone, in which it has already been established.
tionnaire, and dietary total antioxidant capacity calculated using
oxygen radical absorbance capacity values. Stroke cases were 4.2. Human studies
subdivided into cerebral infarctions, hemorrhagic and unspeci-
fied strokes. Using multivariate analyses with hazard ratios, the In humans, several studies have aimed to identify immediate
dietary antioxidant capacity was found to be inversely associated and short-term action of cocoa flavanols on mood and cognitive
with total stroke in disease-free women (17% risk reduction) and performance with as yet inconclusive outcome. Crews et al. (2008)
hemorrhagic stroke in women with disease history (45% risk reduc- had healthy older adults (n = 101; 41 males; age, ≥60 years) to
tion). consume daily for 6 weeks either a 37-g bar of dark chocolate
In Parkinson’s disease, abnormal action of the neuromodula- and 8 ounces (237 ml) of artificially sweetened cocoa beverage or
tor adenosine, which fails to suppress unwanted motor activity similar placebo products. Participants underwent hematological,
in the basal ganglia via striatopallidal neurons, has been linked to blood pressure, and pulse rate measurements, and accomplished
impaired motor function (Jankovic, 2008). Adenosine antagonists, several cognitive tests: Selective Reminding, Wechsler Memory
including caffeine and chocolate, have therefore been consid- Scale-III Faces I and Faces II subtests, Trail Making Test, Stroop Test,
ered for ameliorating parkinsonian motor dysfunction. Parkinson’s Wechsler Adult Intelligence Scale-III Digit Symbol-Coding subtest,
patients do report an increased chocolate consumption, indepen- and General Activation subscale of the Activation-Deactivation
dent of concomitant depressive symptoms (Wolz et al., 2009). Adjective Check List (A-DACL). The only effect observed was a
However, in an investigator-blinded, placebo-controlled, crossover significantly higher, compared to the placebo group, pulse rate,
trial in 26 patients with moderate Parkinson’s disease (Wolz et al., with no effects found on blood pressure, hematological, and cogni-
2012), a single acute dose of dark chocolate failed to improve tive variables. In a randomized, double-blind, controlled, balanced,
motor function (assessed by Unified Parkinson’s Disease Rating three period crossover study, 30 healthy young adults (mean
Scale motor score) over white flavanol-free white chocolate. The age, 22 years; 13 males) consumed high-flavanol (520 mg and
outcome might likely be due to lacking patient blindfolding, the 994 mg) cocoa drinks and a matched control drink, with a three-day
dose of chocolate used, its flavanol content, and the time frame of washout between drinks (Scholey et al., 2010). Over a 1 h testing
treatment. period, participants repeatedly performed 10-min cycles of a Cogni-
To the most part, the neuroprotective potential described above tive Demand Battery (two serial subtraction tasks, Serial Threes and
is attributable to cocoa and chocolate flavanols rather than other Serial Sevens), a Rapid Visual Information Processing (RVIP) task,
ingredients such as caffeine that has been widely implicated in and a “mental fatigue” scale. High-flavanol cocoa intake improved
counteracting age- and disease-related cognitive decline such as Serial Threes performance. The 994-mg beverage yielded speeded
in Alzheimer’s and Parkinson’s disease (Costa et al., 2010; Santos RVIP responses, but also more errors during Serial Sevens. Only the
et al., 2010). Unlike in coffee, tea and soft drinks, the caffeine (and 520-mg beverage attenuated self-reported “mental fatigue”. This
theobromine) concentration in chocolate and cocoa products is is the first report on immediate improvements of cognitive func-
much lower than that of flavanols to account for potential effects tion following high-flavanol cocoa consumption in healthy young
of chocolate (Benton, 2004). adults.
2450 A.N. Sokolov et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 2445–2453
Fig. 3. Topographic differences in the average steady state visually evoked potentials SSVEP amplitudes at baseline and retest for a spatial working memory task (encoding,
hold interval, and retrieval) in the low, medium and high cocoa flavanol (CF) groups. Warm and cool colors show SSVP amplitude decreases and increases, respectively,
post-treatment compared to baseline. (For interpretation of the references to color in the figures throughout the article, please consult the web version of this article.)
From Camfield et al., 2012. Steady state visually evoked potential (SSVEP) topography changes associated with cocoa flavanol consumption. Physiology and Behavior 105,
948–57. Copyright © 2011 Elsevier Inc. with permission of Elsevier Ltd.
food matrix, or food composition, in which cocoa flavonoids appear DeCarli, C., 2012. Cerebrovascular disease: assessing the brain as an end-organ of
in food (e.g., Lamuela-Raventós et al., 2005; Manach et al., 2004). vascular disease. Nat. Rev. Cardiol. 9, 435–436.
Desideri, G., Kwik-Uribe, C., Grassi, D., Necozione, S., Ghiadoni, L., Mastroiacovo, D.,
For example, ingestion of 100 g dark chocolate along with 200 ml Raffaele, A., Ferri, L., Bocale, R., Lechiara, M.C., Marini, C., Ferri, C., 2012. Benefits in
milk results in a substantial reduction of both total antioxidant cognitive function, blood pressure, and insulin resistance through cocoa flavanol
capacity and (-)epicatechin content of human plasma, compared consumption in elderly subjects with mild cognitive impairment: the Cocoa,
Cognition, and Aging (CoCoA) study. Hypertension 60, 794–801.
to ingestion of 100 g pure dark chocolate, and the reduction is even EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA), 2012. Scientific
greater after ingestion of 200 g milk chocolate (Serafini et al., 2003). Opinion on the substantiation of a health claim related to cocoa flavanols and
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