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It has been proposed that green tea extract may have a beneficial impact on cognitive functioning, suggesting promising clinical implications. However, the neural mechanisms underlying this putative cognitive enhancing effect of green tea extract still remain unknown. This study investigates whether the intake of green tea extract modulates effective brain connectivity during working memory processing and whether connectivity parameters are related to task performance. Using a double-blind, counterbalanced, within-subject design, 12 healthy volunteers received a milk whey-based soft drink containing 27.5 g of green tea extract or a milk whey-based soft drink without green tea as control substance while undergoing functional magnetic resonance imaging. Working memory effect on effective connectivity between frontal and parietal brain regions was evaluated using dynamic causal modeling. Green tea extract increased the working memory induced modulation of connectivity from the right superior parietal lobule to the middle frontal gyrus. Notably, the magnitude of green tea induced increase in parieto-frontal connectivity positively correlated with improvement in task performance. Our findings provide first evidence for the putative beneficial effect of green tea on cognitive functioning, in particular, on working memory processing at the neural system level by suggesting changes in short-term plasticity of parieto-frontal brain connections. Modeling effective connectivity among frontal and parietal brain regions during working memory processing might help to assess the efficacy of green tea for the treatment of cognitive impairments in psychiatric disorders such as dementia.
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Green tea extract enhances parieto-frontal connectivity
during working memory processing
André Schmidt &Felix Hammann &Bettina Wölnerhanssen &
Anne Christin Meyer-Gerspach &rgen Drewe &
Christoph Beglinger &Stefan Borgwardt
Received: 7 January 2014 / Accepted: 26 February 2014
#The Author(s) 2014. This article is published with open access at
Rationale It has been proposed that green tea extract may
have a beneficial impact on cognitive functioning, suggesting
promising clinical implications. However, the neural mecha-
nisms underlying this putative cognitive enhancing effect of
green tea extract still remain unknown.
Objectives This study investigates whether the intake of green
tea extract modulates effective brain connectivity during
working memory processing and whether connectivity param-
eters are related to task performance.
Material and methods Using a double-blind, counterbalanced,
within-subject design, 12 healthy volunteers received a milk
whey-based soft drink containing 27.5 g of green tea extract or
a milk whey-based soft drink without green tea as control sub-
stance while undergoing functional magnetic resonance imaging.
Working memory effect on effective connectivity between fron-
tal and parietal brain regions was evaluated using dynamic causal
Results Green tea extract increased the working memory in-
duced modulation of connectivity from the right superior
parietal lobule to the middle frontal gyrus. Notably, the
magnitude of green tea induced increase in parieto-frontal
connectivity positively correlated with improvement in task
Conclusions Our findings provide first evidence for the puta-
tive beneficial effect of green tea on cognitive functioning, in
particular, on working memory processing at the neural sys-
tem level by suggesting changes in short-term plasticity of
parieto-frontal brain connections. Modeling effective connec-
tivity among frontal and parietal brain regions during working
memory processing might help to assess the efficacy of green
tea for the treatment of cognitive impairments in psychiatric
disorders such as dementia.
Keywords Cognition .Working m em or y .Green tea extract .
Brain activity .Effective connectivity .Dynamic causal
Recent research indicates that green tea extract or its main
ingredients has a beneficial impact on cognitive functioning in
humans. For instance, it has been demonstrated that the con-
sumption of green tea improved memory and attention in
subjects with mild cognitive impairments (Park et al. 2011)
and that the consumption of flavonoid-rich foods such as
green tea reduced beta-amyloid-mediated cognitive impair-
ments in Alzheimer transgenic mice, suggesting a potential
therapeutic utility in dementia (Rezai-Zadeh et al. 2008;
Williams and Spencer 2012). Furthermore, higher consump-
tion of green tea has also been associated with a lower prev-
alence of cognitive impairments in older adults (Kuriyama
et al. 2006). Comparable results were obtained in another study
investigating the association between green tea consumption
and cognition in 2,501 people aged over 55 years by showing
that the intake of green tea was significantly related to a lower
A. Schmidt :S. Borgwardt (*)
Department of Psychiatry (UPK), University of Basel, Wilhelm
Klein Str. 27, 4012 Basel, Switzerland
A. Schmidt :S. Borgwardt
Medical Image Analysis Center, Schanzenstrasse 55, 4031 Basel,
F. Hammann :B. Wölnerhanssen :A. C. Meyer-Gerspach :
J. Drewe :C. Beglinger
Department of Gastroenterology, University Hospital Basel,
4031 Basel, Switzerland
S. Borgwardt
Department of Psychosis Studies, Institute of Psychiatry, Kings
College London, London, UK
DOI 10.1007/s00213-014-3526-1
prevalence of cognitive impairments (Ng et al. 2008). In addi-
tion to preventing cognitive decline, green tea consumption
might even lead to better cognitive performances in
community-living older adults (Feng et al. 2010), which may
indicate a cognitive enhancing effect in healthy subjects.
More recently, a study used functional magnetic resonance
imaging (fMRI) to investigate whether this beneficial impact
of green tea on cognition could be related to altered brain
activity in regions crucially engaged during higher-order cog-
nitive functioning (Borgwardt et al. 2012). They demonstrated
relatively increased brain activation in fronto-parietal regions,
most pronounced in the right frontal cortex after the adminis-
tration of green tea extract during working memory (WM)
processing as assessed by the N-back task (Borgwardt et al.
2012). These data suggest that green tea extract may modulate
brain activity in key areas for mediating WM processing in the
human brain such as the dorsolateral prefrontal cortex
(Goldman-Rakic 1996). However, successful WM processing
during the N-back task requires a functional coupling of
parietal and frontal brain regions as shown by functional
(Owen et al. 2005; Rottschy et al. 2012) and effective con-
nectivity studies (Deserno et al. 2012;Maetal.2011). It has
been suggested that effective connectivity from the parietal
cortex to the frontal cortex may contribute to the encoding of
incoming stimuli (Ma et al. 2011), while the connections from
the frontal to the parietal cortex likely mediate the updating of
rules (e.g., 2-back condition; Gazzaley et al. 2004;Sauseng
et al. 2005). Therefore, it is conceivable that the increased
frontal activity during WM processing after green tea admin-
istration (Borgwardt et al. 2012) may have resulted from a
change in functional couplingconnectivity from the parietal to
the frontal cortex.
We thus explored in the current study whether the ad-
ministration of green tea extract changed brain connectivity
between the frontal and parietal cortex during WM process-
ing. In particular, we applied dynamic causal modeling
(DCM; Friston et al. 2003) to fMRI data from 12 healthy
subjects receiving green tea extract and a control beverage
while performing a N-back WM task. DCM can explicitly
evaluate the directional modulation effects of contextual
experimental conditions (e.g. the 2-back condition) on ef-
fective connectivity and has been successfully used to de-
tect pharmacological manipulations from fMRI data
(Grefkes et al. 2010; Schmidt et al. 2013b). Furthermore,
we tested whether the effect of green tea on the WM-
induced modulation of connectivity was related to its effect
on the task performance. Given the important functional
coupling between parietal and frontal brain regions during
the N-back task (Owen et al. 2005; Rottschy et al. 2012),
and that the intake of green tea extract increases prefrontal
activity (Borgwardt et al. 2012), we hypothesized that green
tea extract would enhance effective connectivity from the
parietal to the frontal cortex.
Material and methods
In total, 12 healthy right-handed male completed the study
(mean age 24.1 years; standard deviation 2.6). All participants
were nonsmokers. Participants were told to abstain from any
substance use for the duration of the study, and from the intake
of alcohol, caffeine, green tea products, and citrus juices for 24
and 12 h before each study day, respectively. At the start of the
study, a urine sample was collected for screening for amphet-
amines, benzodiazepines, cocaine, methamphetamine, opi-
ates, and THC using immunometric assay kits. None of the
participants were tested positive on any of the sessions. Par-
ticipants were carefully screened using a semistructured clin-
ical interview to exclude psychiatric or physical illness or a
family history of psychiatric illness. The local State Ethical
Committee (Ethikkommission Beider Basel) approved the
study and all participants gave their informed written consent
after the study procedure had been explained to them in detail.
The study was registered with (identifier:
Experimental design
A double-blind, vehicle-controlled, and within-subject
design with randomized order of substance administra-
tion using an established protocol was conducted over
four sessions (Bhattacharyya et al. 2012; Borgwardt et al.
2008). Participants received either 250 or 500 ml milk
whey-based soft drink containing 13.75 and 27.5 g of
green tea extract, respectively (Rivella, Rothrist, Switzer-
land), or a milk whey-based soft drink without green tea
extract as control condition. Each participant was
scanned four times with a 1-week interval between scans.
Before each scanning session, participants swallowed a
feeding tube for application of the test solutions. The
doses of 250 (that were diluted to 500 ml to control for
volume effects) and 500 ml were selected to produce an
effect on regional brain functioning without provoking
any toxic, psychiatric or physical symptoms, which
might have confounded interpretation of the fMRI data
and caused difficulties for participants to tolerate the
procedure. As the intragastric administration bypassed
the sensory systems, volunteers were prevented from
guessing which treatment they were being given. An
intravenous line was inserted in the nondominant arm
of each participant at the start of the testing session to
monitor substance whole-blood levels. All participants
were physically examined before testing and their heart
rate and blood pressure were assessed in 5-min intervals
throughout the 1-h session.
Composition of test drinks
Rivella is a commercially available carbonated soft drink on
the basis of milk whey. In 1999, a new flavor with a 0.05 %
addition of standardized green tea extract was introduced. The
control drink is most similar to the drink of interest, apart from
the green tea extract, differs primarily in its lower carbohy-
drate content (2.5 g/100 ml difference). In detail, the test drink
contains the following ingredients: water, milk whey 35 %,
lactic acid, carbon dioxide, calcium cyclamate, acesulfame K,
and the following minerals: sodium 130 mg/l, potassium
450 mg/l, magnesium 35 mg/l, calcium 165 mg/l, and chloride
330 mg/l. Additionally, it contains the following ingredients:
green tea extract 0.05 %, ascorbic acid 120 mg/l, pyridoxine
30 mg/l, and fructose 25 g/l. Green tea extract is prepared from
the dried green leaves of Camellia sinensis with a drug:extract
ratio of 5.5:1, 47.552.5 % m/m polyphenols [high-pressure
liquid chromatography (HPLC)], 5.010.0 % m/m caffeine
(HPLC), 0.31.2 % m/m theobromine (HPLC), and 1.0
3.0 % m/m theanine (HPLC). One gram of extract corre-
sponds to 5.5 g of green tea leaves. To equalize carbohydrate,
the control treatments were supplemented with 6.25 or 12.5 g
of sucrose for 250 and 500 ml, respectively. To additionally
blind volunteers to treatments, 250 ml treatments and controls
were diluted to 500 ml with 250 ml of uncarbonated spring
mineral water. This preparatory step also ensures equivalent
rates of gastric emptying. Treatments were heated to room
temperature and freed from carbon dioxide by stirring.
fMRI paradigm: N-back task
A rapid, mixed trial, event-related fMRI design was used with
jittered interstimulus intervals incorporating random event
presentation to optimize statistical efficiency (Ettinger et al.
2011). During the N-back task (Broome et al. 2009), all
subjects saw series of letters with an interstimulus interval of
2 s. Each stimulus was presented for 1 s. During a baseline (0-
back) condition, subjects were required to press the button
with the right hand when the letter Xappeared. During 1-
back and 2-back conditions, participants were instructed to
press the button if the currently presented letter was the same
as that presented 1 (1-back condition) or 2 trials beforehand
(2-back condition). The three conditions were presented in ten
alternating 30 s blocks (2×1-back, 3×2-back and 5×0-back)
matched for the number of target letters per block (i.e., 2 or 3),
in a pseudo-random order.
Image acquisition and analysis
fMRI was performed on a 3T scanner (Siemens Magnetom
Verio, Siemens Healthcare, Erlangen, Germany) using an
echo planar sequence with a repetition time of 2.5 s, echo
time of 28 ms, matrix 76×76, 126 volumes and 38 slices with
0.5 mm interslice gap, providing a resolution of 3× 3 × 3 mm
and a field of view 228× 228 mm
. We analyzed fMRI data
using SPM8 ( All volumes
were realigned to correct for head movements, mean adjusted
by proportional scaling, normalized into standard stereotactic
space (Montreal Neurological Institute), and smoothed using a
8 mm full-width at half-maximum Gaussian kernel. We con-
volved the onset times for each condition (0-back, 1-back, and
2-back) with a canonical haemodynamic response function.
Serial correlations were removed using a first-order
autoregressive model and a high-pass filter (128 s) was ap-
plied to remove low-frequency noise. Six movement parame-
ters were also entered as nuisance covariates to control for
movement. We focused our analysis on the 2-back >0-back
contrast (main effect of task) to capture the highest possible
WM load during the N-back task according to previous N-
back fMRI studies (Deserno et al. 2012; Schmidt et al. 2013b).
Differences in local brain activity between the different
treatment conditions have previously been reported
(Borgwardt et al. 2012); here, we extended this study by
conducting an effective connectivity analysis using DCM
(Friston et al. 2003), which was restricted to the bilateral
superior parietal lobule (SPL) and middle frontal gyrus
(MFG). As this previous analysis revealed significant differ-
ences in fronto-parietal activity especially between the 500 ml
doses (Borgwardt et al. 2012), we restricted our connectivity
analysis to these two conditions only. The selection of our
ROIs were based on the following evidences: (a) the previ-
ously published 2-back >0-back contrast of this data (Fig. 1a;
Borgwardt et al. 2012), (b) the previous functional connectiv-
ity studies emphasizing the importance of fronto-parietal cou-
pling for WM (Gazzaley et al. 2004; Sauseng et al. 2005), and
(c) the previous DCM studies of WM (Deserno et al. 2012;
Schmidt et al. 2013b). The treatment-specific fronto-parietal
network was detected using an anatomical mask taken from
the Automated Talairach atlas in the WFU Pick Atlas toolbox
(Tzourio-Mazoyer et al. 2002) consisting of the bilateral SPL
and MFG. Statistical significance was assessed at the cluster
level using the nonstationary random field theory (Hayasaka
et al. 2004). The first step of this cluster-level inference
strategy consisted of identifying spatially contiguous voxels
at a threshold of p< 0.001, without correction (cluster-forming
threshold; Petersson et al. 1999). Finally, a familywise error
(FWE)-corrected cluster-extent threshold of p< 0.05 was de-
fined to infer statistical significance.
Effective connectivity analysis: DCM
DCM10 (revision number 4290) as implemented in SPM8
was used to analyze effective fronto-parietal connectivity
during WM processing. In DCM for fMRI, the dynamics of
the neural states underlying regional BOLD response are
modeled by a bilinear differential equation that describes
how the neural states change as a function of endogenous
interregional connections, modulatory effects on these con-
nections, and driving inputs (Friston et al. 2003; Stephan et al.
2007). The endogenous connections represent coupling
strengths in the absence of inputs to the system (task-
independent), while the modulatory effects represent
context-specific and additive changes in coupling (task-
induced alterations in connectivity). The modeled neuronal
dynamics is then related to the measured blood oxygen level-
dependent (BOLD) signal using a hemodynamic forward
model (Stephan et al. 2007). Here, we explicitly examined
how the coupling strengths between frontal and parietal re-
gions are changed by the 2-back condition (modulatory
Model design and time series extraction
Across all models tested, we assumed the same network
layout of connections between right and left SPL and MFG.
Specifically, SPL and MFG were reciprocally connected
Fig. 1 a Local maxima with the bilateral superior parietal lobule and
middle frontal gyri induced by the main effect of task (2-back >0-back
contrast) after the administration of green extract or the of the control
substance (FWE cluster level corrected at p<0.05).bModel space tested
in this study. 1right SPL, 2left SPL, 3right MFG, and 4left MFG. In
particular, we contrasted models in which the 2-back WM condition was
allowed to modulate, within both hemispheres: (F1) the parieto-frontal
connections, (F2) the fronto-parietal connections, or (F3)both.These
three intrahemispheric options were crossed with four possibilities which
interhemispheric connections might be modulated by the 2-back WM
condition, i.e., (a) none (first column of Fig. 1b), (b) the interhemispheric
connections between parietal areas (second column of Fig. 1b), (c)the
interhemispheric connections between frontal areas (third column of
Fig. 1b), or (d) both (fourth column of Fig. 1b). As a result, our model
space consisted of 12 alternative models, each of which was fitted to the
data from each individual subject
within both hemispheres, with additional interhemispheric
connections between all regions. Similar to a recent DCM
study of WM (Ma et al. 2011), the visual input (driving)
entered the SPL bilaterally (Baizer et al. 1991; Nakashita
et al. 2008). Starting from this basic layout, a factorial struc-
tured model space was derived by considering where the
modulatory effect of the 2-back WM condition might be
expressed within both hemispheres (for a graphical summary
of the model design see Fig. 1b). Subject-specific regional
time series from the SPL and MFG were extracted from
spherical volumes of interest with 12 mm in diameter that
were centered on the condition maxima of the 2-back >0-back
contrast within the anatomical mask taken from the Automat-
ed Talairach atlas in the WFU Pick Atlas toolbox (Tzourio-
Mazoyer et al. 2002) using the first eigenvariate of voxels
above a subject-specific F-threshold of p<0.001 uncorrected.
When a subject had no voxel above threshold at the group
maxima (Fig. 1a, Table 1), we selected the nearest supra-
threshold voxel within the mask. One subject revealed no
activated voxels under these criteria and was therefore exclud-
ed from the connectivity analysis.
Bayesian model selection and Bayesian model averaging
Bayesian model selection (BMS) was used to determine the
most plausible neurophysiological network given the data as
expressed by a series of competing DCMs. BMS rests on
comparing the (log) evidence of a predefined set of models
(the model space). The model evidence is the probability of
observing the empirical data, given a model, and represents a
principled measure of model quality, derived from probability
theory (Penny et al. 2004). We used a random-effects BMS
approach for group studies, which is capable of quantifying
the degree of heterogeneity in a population while being ex-
tremely robust to potential outliers (Stephan et al. 2009b).
This method considers the model as a random variable and
estimates the parameters of a Dirichlet distribution, which
describes the probabilities of all models considered. One
common way to summarize the results of random effects
BMS is to report the exceedance probability (EP) of each
model, i.e., the probability that this model is more likely than
any other of the models tested, given the group data (Stephan
et al. 2009b). Given that different models may be found to be
optimal across treatments and statistical comparison of model
parameter estimates is only valid if those estimates stem from
the same model, Bayesian model averaging (BMA) has been
recommended as standard approach for clinical DCM studies
(Seghier et al. 2010; Stephan et al. 2010). BMA averages
posterior parameter estimates over models, weighted by the
posterior model probabilities (Penny et al. 2010). Thus,
models with a low posterior probability contribute little to
the estimation of the marginal posterior.
Statistic of DCM parameters
Following BMA, we used the resulting posterior means from
the averaged DCM for examining between-treatment differ-
ences. In this paper, we focused on WM-induced changes in
connectivity. Thus, we tested for group differences in the
modulatory effects only. We then used a paired ttest, testing
which of the connectivity parameters differed across the
500 ml treatments.
Statistics of WM performances
Beyond previous analyses of reaction times and number of
errors (Borgwardt et al. 2012), WM performances were ob-
jectively quantified using signal detection theory using the
formula d=z(Hits)z(FA), where FA reflects false alarms
(Macmillan and Creelman 1991). Hit and false alarm rates of
zero or one were adjusted as previously described (Macmillan
and Kaplan 1985). Paired ttest was used to assess between-
treatment differences in WM performances.
Working memory performance
There was a strong trend toward a significantly improved task
performance as expressed by the sensitivity index dafter
consumption of green tea extract [mean (SD): 3.23 (0.42)]
compared with the control drink [mean (SD): 2.84 (0.45);
t(11)=2.041; p=0.066; Fig. 2].
Bayesian model selection
We first used Bayesian model selection (BMS) to compare the
model evidence for the three families of models with either
bidirectional, forward, or backward modulation of prefrontal
Ta b l e 1 MNI coordinates (x,y,z) of the treatment maxima during working memory processing
Left MFG Right MFG Left SPL Right SPL
Green tea extract (50, 22,34) (cluster size: 1199) (52, 26, 34) (cluster size: 740) (30, 62, 48) (cluster size: 895) (32, 58, 54) (cluster size: 910)
Sham condition (36, 4, 64) (cluster size: 220) (26, 14, 50)(cluster size: 215) (34, 54, 56) (cluster size: 255) (28, 60, 50) (cluster size: 188)
Reported activations survive FWE correction at p<0.05 at peak and cluster level
parietal connections. BMS revealed that the family with WM-
induced modulation of both forward and backward modula-
tion of prefrontalparietal connections (F1) was superior to
the other families in the green tea (EP 63 %) and control
condition (EP 66 %). Single model inference showed that
model 12 emerged as the most likely model in the green tea
(EP 45 %) and control condition (EP 49 %). These BMS
results across both treatment conditions are summarized in
Fig. 3.
Effective connectivity results
Statistical analysis of treatment differences in connection
strengths concerned the posterior means of coupling esti-
mates, following BMA over all 12 models. Thus, in our
analysis of effective connectivity, we were able to test for
between-treatment differences in eight parameters describing
the modulation of fronto-parietal connections, within and
across hemispheres, induced by the 2-back WM condition.
Paired ttest results for all connection are summarized in
Tab le 2. A significantly increased WM-induced modulation
of connectivity from the right SPL to the right MFG was
found in the green tea condition compared with the control
beverage [t(10)=2.53; p=0.030; not corrected for multiple
comparisons; Fig. 4].
Importantly, we found a significant positive correlation
between the effect of green tea on task performance and right
SPLright MFG connectivity (r=0.637, p=0.035; Fig. 5).
In the present study we investigated the neural mechanisms
underlying the putative beneficial impact on green tea extract
on cognitive functioning. In particular, we explored by apply-
ing DCM to fMRI data whether green tea extract altered the
WM-induced modulation of interregional effective connectiv-
ity between the parietal and frontal cortex. The main findings
are that green tea extract increased the WM-induced modula-
tion of connectivity from the right superior parietal lobule to
the middle frontal gyrus. Furthermore, this effect of green tea
on parieto-frontal connectivity positively correlated with its
effect on task performance, suggesting a neural mechanism
for the positive effect of green tea consumption on cognitive
functioning at the system network level. Our finding of in-
creased parieto-frontal coupling during WM processing in-
duced by green tea might also explain the recently reported
increase in prefrontal brain activity after green tea administra-
tion (Borgwardt et al. 2012). Thus, these studies together
indicate that green tea extract might modulate WM processing
by increasing prefrontal brain activity as a result of enhanced
bottom-up connectivity from the parietal cortex.
Comparing competing models against the same data, we
found that the family of models considering a bidirectional
WM-induced modulation of connectivity between the parietal
and frontal cortex had fitted the data of all participants best
irrespective of treatments. This result supports previous func-
tional connectivity studies emphasizing the importance of
fronto-parietal connections for WM (Owen et al. 2005;
Rottschy et al. 2012). The N-back task requires different
cognitive processes including a continuous encoding of in-
coming visual letters and rule updating. Connections from the
parietal to the frontal cortex (bottom-up) may contribute to the
encoding of incoming stimuli (Ma et al. 2011), while the
connections from the frontal to the parietal cortex (topdown)
likely mediate the updating of rules (Gazzaley et al. 2004;
Sauseng et al. 2005). Under this perspective, we may specu-
late that our result of enhanced parieto-frontal connectivity
induced by green tea intake may indicate an improvement in
stimuli encoding during the N-back task.
Plasticity-dependent mechanism underlying the effect
of green tea on cognitive functioning
Green tea mainly consists of polyphenols, particularly cate-
chins such as ()-epigallocatechin gallate (EGCG), caffeine,
and theanine, as well a lot of additional ingredients. In the
following, we show that these different substances share an
overlap in activity of at least one biochemical pathway, the N-
methyl-D-aspartate receptor (NMDAR) pathway, suggesting a
plasticity-dependent mechanism that may link the cognitive
effects of green tea from the micro- to the macro-level.
Studies in rodents support the idea of improved WM after
green tea administration via catechin-induced promotion of
antioxidative activity (Kaur et al. 2008). In accordance, pre-
vious studies proposed that EGCG mediates its protective
effect on cognitive functioning through antioxidant and iron-
Fig. 2 Mean of sensitivity indexes (d) ± SE during working memory
processing for both treatment conditions. (Asterisk) indicates a between-
treatment difference at p=0.066
chelating properties and modulation of cell-signaling and cell
survival pathways (Mandel and Youdim 2004; Weinreb et al.
2004). In other words, EGCG appears to reduce oxidative
stress (OS)-induced neurotoxicity as expressed by the gener-
ation of reactive oxygen species (ROS) generation. ROS
generation is critically mediated by NMDAR-dependent flow
of Ca
ions into neurons (Lafon-Cazal et al. 1993;Schanne
et al. 1979). Treatment with green tea catechins as potent
natural antioxidants completely normalized the response to
activation of NMDAR by bath application of NMDA in the
mouse brain, suggesting the involvement of OS in abnormal
NMDAR-induced plasticity (Chepkova et al. 2013). Further-
more, EGCG promotes neural plasticity in the mouse
hippocampus (Xie et al. 2008) and a facilitation of Ca
dependent glutamate release in rats (Chou et al. 2007). In
Alzheimer disease, oligomeric Aβattenuates NMDAR-
mediated Ca
influx associated with an increase in ROS
production (He et al. 2011). Furthermore, amyloid protein
impairs synaptic plasticity by modulating an NMDA-type
glutamate receptor-dependent signaling pathway (Shankar
et al. 2007;Snyderetal.2005). Specifically, amyloid-b (Ab)
protein dimers isolated directly from Alzheimersbrainsdis-
rupt synaptic plasticity and memory via inhibition of long-
term potentiation and an enhancement of long-term depres-
sion (Shankar et al. 2008), both of which are critically medi-
ated by NMDARs (Bliss and Collingridge 1993; Malenka and
Fig. 3 Bayesian model selection (BMS) results on family level (upper column) and single model level (lower column) over both treatment conditions
separately. BMS results are reported in terms of exceedance probabilities
Ta b l e 2 Paired ttest results for
the between-treatment compari-
son of connectivity estimates
(modulatory effects of 2-back
WM condition)
Difference does not survive
Bonferroni correction for multiple
differences mean
error mean
tValue Significance
Left to right parietal connectivity 0.00 0.37 0.11 0.02 p=0.987
Left parieto-frontal connectivity 0.01 0.22 0.07 0.09 p=0.923
Right to left parietal connectivity 0.14 0.50 0.15 0.96 p=0.360
Right parieto-frontal connectivity 0.20 0.26 0.08 2.53 p=0.030*
Left fronto-parietal connectivity 0.05 0.37 0.11 0.45 p=0.665
Left to right frontal connectivity 0.22 0.56 0.17 1.31 p=0.219
Right fronto-parietal connectivity 0.08 0.51 0.15 0.54 p=0.598
Right to left frontal connectivity 0.08 0.15 0.05 1.78 p=0.106
Nicoll 1993; Paoletti et al. 2013). Remarkably, EGCG de-
creases Aβlevels and plaques in mice, reduced Aβmediated
cognitive impairment and modulates tau pathology in
Alzheimer transgenic mice (Lee et al. 2009; Rezai-Zadeh
et al. 2005,2008), as well as prevents Aβ-induced mitochon-
drial dysfunction, impairment of NMDA Ca
influx and ROS
production (He et al. 2011). In addition to tea catechins,
theanine, which is an amino acid uniquely found in tea leaf,
may also possess neuroprotective effect (Nathan et al. 2006),
probably by its antagonistic effect on ionotropic glutamate
receptor subtypes, such as NMDARs (Kakuda 2011). More-
over, the beneficial effects of caffeine on stress-induced mem-
ory disturbance are mimicked by antagonists of adenosine
A2a receptors, likely mediated by its ability to control gluta-
matergic transmission, especially NMDAR-dependent plas-
ticity (Cunha and Agostinho 2010). Taken together, these
studies suggest that green tea extract or its ingredients coun-
teracts the OS-induced impairments in cognitive functioning
via its effect on NMDAR-dependent synaptic plasticity.
In this study, we examined, at the network connectivity
level, whether green tea intake altered the short-term plasticity
of interregional connections between the frontal and the pari-
etal cortex during WM processing by using DCM. DCM is a
generic Bayesian system identification technique that allows
inferring on NMDA-dependent synaptic plasticity by comput-
ing the dynamics of interacting neural macro-systems (Friston
et al. 2003; Stephan et al. 2006,2009a). Previous studies
demonstrated the sensitivity of DCM for NMDAR stimulation
(Moran et al. 2011) and that blocking of the NMDAR leaded to
altered synaptic plasticity of the bottom-up connectivity from
left primary auditory cortex to superior temporal gyrus during
an auditory oddball task (Schmidt et al. 2013a). Thus, we
propose that our result of an enhanced parieto-frontal connec-
tivity during WM processing induced by green tea intake might
reflect a green tea-induced modulation of NMDAR-dependent
synaptic plasticity, suggesting a mechanism at the network
level for the cognitive effect of green tea consumption.
There are some limitations to be considered in the present
study. In contrast to the imaging results, we observed no
significant effect of green tea consumption on task perfor-
mances. However, we found a strong trend toward improved
performance, suggesting that our study sample was too small
to achieve differences on behavioural parameters. This suits
with evidence that fMRI data on small subject numbers are
relatively robust (Friston et al. 1999), while behavioral index-
es are typically underpowered and could be confounded by
many personal attributes that cannot be clearly assigned to the
cognition required for adequate task performance (Wilkinson
and Halligan 2004). A further caveat is that there is a differ-
ence between using a soft drink containing green tea and a
pure green tea extract. Oral ingestion of pure green tea extract
would have avoided any cross effects or effects of other
components as caffeine that may be involved in the positive
effect of green tea extract on cognitive performance.
The present study shows that green tea extract enhances
functional connectivity from the parietal to the frontal cortex
during WM processing in healthy controls. Interestingly, this
effect on effective connectivity was related to the green tea
induced improvement in cognitive performance. Our findings
Fig. 4 The modulatory effect of the 2-back WM condition on the
connection from the right SPL to the right MFG in the sham condition
and after the administration of green tea extract. The yaxis denotes the
average over all subjects and all 12 DCMs (using BMA) with regard to
the posterior mean (1/s) of the modulatory effect; this encodes changes in
connection strength induced by the 2-back WM condition. Significant
between-treatment differences at (asterisk)p<0.05. Error bars represent
standard deviations derived from Bayesian parameter averages
Fig. 5 Significant positive correlation between the effect of green tea on
task performance and SPLMFG connectivity (green tea minus control
substance; r=0.64, p<0.05). That is, the stronger the increase in SPL
MFG connectivity induced by green tea, the higher the improvement in
the task performance compared with the control drink
provide first insights into the neural effect of green tea on WM
processing at the neural network level, suggesting a mecha-
nism on short-term plasticity of interregional brain connec-
tions. Our findings further suggest that the assessment of
effective connectivity among frontal and parietal brain regions
during working memory processing may provide a promising
tool to assess the efficacy of green tea or other compounds for
the treatment of cognitive impairments in psychiatric disor-
ders such as dementia.
Acknowledgments This study was supported by grants from the
Rivella. All authors have agreed to its submission in this form and we
do not have any conflict of interests that might be interpreted as influenc-
ing its content. The sponsor of the study had no role in study design,
collection, analysis, interpretation of data, writing of this report, and in the
decision to submit the paper for publication. We would like to acknowl-
edge the infrastructural support of the Medical Image Analysis Centre,
University Hospital Basel.
Open Access This article is distributed under the terms of the Creative
Commons Attribution License which permits any use, distribution, and
reproduction in any medium, provided the original author(s) and the
source are credited.
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... Nine of 26 studies were classified as good-quality studies according to the Quality Assessment Tool for Neuroimaging Methodology in Individual Studies criteria [27][28][29][30][31][32][33][34][35] (see S3 in supplementary material and individual summary tables, right columns), 14 were categorized as fair-quality studies, [36][37][38][39][40][41][42][43][44][45][46][47][48][49] and three studies [50][51][52] were classified as poor-quality studies. ...
... Regarding general study methodology, nine studies were classified as good quality according to NHBIH Quality Assessment Tool for Controlled Intervention Studies criteria [27][28][29]31,33,40,41,47,50,51 For the completeness of the review, the findings of all studies are presented in brief, however with a greater focus on good-quality studies. ...
... Twenty of the identified studies were conducted in healthy individuals [32][33][34][35][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53] with individual group sizes of n = 4-47 and mean age ranges of 20-33 years (see Tables 2-4). The methodological quality was "fair" (scores ≥50%) in 13 of these studies, good (scores ≥75%) in four studies and poor (scores<50%) in three studies (Tables 2-4). ...
Background: Developing treatments for cognitive impairment is key to improving the functioning of people with mood disorders. Neuroimaging may assist in identifying brain-based efficacy markers. This systematic review and position paper by the International Society for Bipolar Disorders Targeting Cognition Task Force examines the evidence from neuroimaging studies of pro-cognitive interventions. Methods: We included magnetic resonance imaging (MRI) studies of candidate interventions in people with mood disorders or healthy individuals, following the procedures of the Preferred Reporting Items for Systematic reviews and Meta-Analysis 2020 statement. Searches were conducted on PubMed/MEDLINE, PsycInfo, EMBASE, Cochrane Library and from inception to 30th April 2021. Two independent authors reviewed the studies using the National Heart, Lung, Blood Institutes of Health Quality Assessment Tool for Controlled Intervention Studies and quality of neuroimaging methodology assessment checklist. Results: We identified 26 studies (N=702). Six investigated cognitive remediation or pharmacological treatments in mood disorders (N=190). In healthy individuals, 14 studies investigated pharmacological interventions (N=319), two cognitive training (N=73) and four neuromodulatory treatments (N=120). Methodologies were mostly rated as 'fair'. 77% studies investigated effects with task-based fMRI. Findings varied but most consistently involved treatment-associated cognitive control network (CCN) activity increases with cognitive improvements, or CCN activity decreases with no cognitive change, and increased functional connectivity. In mood disorders, treatment-related default mode network suppression occurred. Conclusions: Modulation of CCN and DMN activity is a putative efficacy biomarker. Methodological recommendations are to pre-declare intended analyses and use task-based fMRI, paradigms probing the CCN, longitudinal assessments, mock scanning and out-of-scanner tests.
... To date, anti-obesity, cardiovascular protective, immunomodulatory, anti-inflammatory, antiviral, and other beneficial effects have been reported following polyphenol intake. 1 In recent years, studies have investigated the effects of polyphenols as a countermeasure against the decline in brain function and stress associated with aging, which has become a social problem. For example, cocoa, 2,3 grapes, 4 Ginkgo biloba extract, 5 and tea 6 have been suggested to improve the performance of cognitive tasks, improve mood, and reduce vascular endothelial function deterioration associated with stress in healthy humans. ...
... Various reports have been published regarding the reduction of mental fatigue caused by polyphenols. Cacao flavanols, 2,29 matcha, 6,30 and purple grape 31 have been reported to reduce reaction time and mental fatigue in acute food responses in brain function tests. These responses may be a common effect of easily absorbable polyphenols. ...
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The antioxidant properties of polyphenols, which are found in most plants, have been shown to be useful for maintaining health, including enhancing brain function and alleviating stress. We aimed to investigate the effect of a single intake of taxifolin-containing foods on cognitive task performance and whole blood gene expression in healthy young adults. This study was a randomized, placebo-controlled, double-blind, crossover trial in which healthy young adults were administered a single dose of either a placebo or food containing taxifolin. Cognitive tests (serial 3s, serial 7s, and rapid visual information processing) to examine brain activity and visual analog scale questionnaires to analyze mental fatigue were applied. The set of tests was repeated four times. The findings showed that taxifolin intake improved calculation abilities and reduced mental fatigue. An analysis of whole blood gene expression before and after the test revealed that the expression of foreign substance removal-related genes increased following the ingestion of taxifolin and that most differentially expressed genes were enriched in granulocytes. Taxifolin intake was shown to affect the brain activity of healthy young adults and demonstrated an antifatigue effect, thereby reducing subjective fatigue. A single intake of taxifolin may enhance the removal of foreign substances by strengthening the innate immune system and suppressing the occurrence of injury.
... supplemented with green tea extract [166,167], but failed to match their whey control drink for caffeine. Two studies also demonstrated cerebral blood flow and electroencephalogram (EEG) effects of single doses of the tea polyphenol EGCG [122,168], but in the absence of any cognitive performance effects. ...
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The plant defence compound caffeine is widely consumed as a performance enhancer in a sporting context, with potential benefits expected in both physiological and psychological terms. However, although caffeine modestly but consistently improves alertness and fatigue, its effects on mental performance are largely restricted to improved attention or concentration. It has no consistent effect within other cognitive domains that are important to sporting performance, including working memory, executive function and long-term memory. Although caffeine’s central nervous system effects are often attributed to blockade of the receptors for the inhibitory neuromodulator adenosine, it also inhibits a number of enzymes involved both in neurotransmission and in cellular homeostasis and signal propagation. Furthermore, it modulates the pharmacokinetics of other endogenous and exogenous bioactive molecules, in part via interactions with shared cytochrome P450 enzymes. Caffeine therefore enjoys interactive relationships with a wide range of bioactive medicinal and dietary compounds, potentially broadening, increasing, decreasing, or modulating the time course of their functional effects, or vice versa. This narrative review explores the mechanisms of action and efficacy of caffeine and the potential for combinations of caffeine and other dietary compounds to exert psychological effects in excess of those expected following caffeine alone. The review focusses on, and indeed restricted its untargeted search to, the most commonly consumed sources of caffeine: products derived from caffeine-synthesising plants that give us tea (Camellia sinensis), coffee (Coffea genus), cocoa (Theabroma cacao) and guaraná (Paullinia cupana), plus multi-component energy drinks and shots. This literature suggests relevant benefits to mental performance that exceed those associated with caffeine for multi-ingredient energy drinks/shots and several low-caffeine extracts, including high-flavanol cocoa and guarana. However, there is a general lack of research conducted in such a way as to disentangle the relative contributions of the component parts of these products.
... This enhancement was accompanied by an increase in brain theta waves in multiple brain areas (the temporal, frontal, parietal, and occipital areas), which has been related to improved cognitive alertness (Park et al. 2011). Magnetic resonance imaging has also shown changes in short-term plasticity in parietal-frontal brain synergies, accompanied by increased working memory processing in a population that had experimentally consumed a whey-based soft drink containing green tea extract (Schmidt et al. 2014). The results obtained in another study performed in healthy women showed a positive modulation of reading span performance, observed 24 hours after the administration of a single dose of 5.4 g of green tea extract (with at least 45% epigallocatechin gallate) in women from 50 to 63 years of age. ...
Substances with modulatory capabilities on certain aspects of human cognition have been revered as nootropics from the dawn of time. The plant kingdom provides most of the currently available nootropics of natural origin. Here, in this systematic review, we aim to provide state-of-the-art information regarding proven and unproven effects of plant-derived nootropics (PDNs) on human cognition in conditions of health and disease. Six independent searches, one for each neurocognitive domain (NCD), were performed in parallel using three independent scientific library databases: PubMed, Cochrane and Scopus. Only scientific studies and systematic reviews with humans published between January 2000 and November 2021 were reviewed, and 256 papers were included. Ginkgo biloba was the most relevant nootropic regarding perceptual and motor functions. Bacopa monnieri improves language, learning and memory. Withania somnifera (Ashwagandha) modulates anxiety and social-related cognitions. Caffeine enhances attention and executive functions. Together, the results from the compiled studies highlight the nootropic effects and the inconsistencies regarding PDNs that require further research. Supplemental data for this article is available online at
Low mental energy can contribute to decreased productivity, altered life balance, decreased physical performance, and ultimately affect quality of life. As such, there is a great demand for food and beverage products that positively impact mental energy. Numerous products claim to alter mental energy making continued review of the scientific evidence critical. The objective of this study was to conduct a scoping review of randomized controlled trials to evaluate the effect of 18 dietary ingredients on mental energy outcomes in adults without severe disease. Methods: A literature search, completed using PubMed, resulted in the identification of 2261 articles, 190 of which met eligibility from initial abstract review. Full-text review was completed on the 190 studies which resulted in 101 articles that fully met eligibility for inclusion in this study. The search strategy for two ingredients did not yield any eligible studies, leaving studies for 16 ingredients that were extracted and summarized by reported significantly improved outcomes for cognition, mood and perceived feelings, and sleep assessments. The preliminary results for several dietary ingredients directionally suggested a mental energy benefit (≥20% of outcomes), including ashwagandha, chamomile, dark chocolate, ginseng, green tea, lavender, lion's mane mushroom, maca, tart cherries, turmeric, and valerian root. The results of this scoping review suggest that of the 16 dietary ingredients reviewed, 11 may be promising for further exploration on their potential benefits in supporting mental energy. Given consumer demand and market growth for food and beverage products that positively impact mental energy; continued efforts in assessment method alignment and additional evaluation in well-designed trials is warranted. KEY TEACHING POINTSOf the 16 dietary ingredients reviewed, 11 (ashwagandha, chamomile, dark chocolate, ginseng, green tea, lavender, lion's mane mushroom, maca, melatonin foods, turmeric, and valerian root) may be promising for further exploration on their potential mental energy benefits.Dark chocolate, ginseng, ashwagandha, and lion's mane mushroom were the most promising ingredients for further evaluation in the cognition domain of the ingredients evaluated.Turmeric, maca, lavendar, and ashwagandha were the most promising ingredients for further evaluation in the mood and perceived feelings domain of the ingredients evaluated.Ashwagandha, chamomile, green tea, melatonin foods, valerian root were the most promising ingredients for further evaluation in the sleep domain of the ingredients evaluated.Additional, well-designed, consistent, clinical trials and systematic reviews are warranted as the challenge of heterogeneity in mental energy study design remains.
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Alzheimer's disease (AD) is the leading cause of dementia, an estimated 5 million people in the US suffer at a cost of more than $70 billion per year. The main theories on the causes of AD include amyloid-beta (Aβ), tauopathy, inflammation and oxidative stress. The purpose of writing this review article is to look at the various types of natural antioxidants and the mechanism of action of each against AD therapy. Method: this article reviews antioxidants to activity of action againts AD. The following databases were searched from their inception: Google scholar, Science direct, PubMed. The document relevant analyzed and included in the review. Therefore, this paper mainly focuses on the recent developments of common used antioxidant therapies for AD. Results: Alzheimer's disease correlates with free radicals which can be minimized by consuming natural antioxidants from foods such as vitamins C and E, carotenoids (β-carotene and astaxanthin), Flavonoids, Green tea, Huperzine, Ginko biloba, Centella asiatica, Curcumin, Melissa officinalis, Polygala tenuifolia, Salvia miltiorrhiza bung and Withaniasomnifera (L), with a variety of different mechanisms of action for each of these types of natural antioxidants. Conclusion: The therapeutic potential of AD in natural antioxidants plays an important role in prevention and treatment INTRODUCTION Alzheimer's disease is a degenerative brain disease and the most common cause of dementia 1. The number of the disease is projected to reach 106.8 million worldwide by the year 2050, therefore, the disease is a growing public health concern with major socioeconomic burden 2. The risk of AD varies from 12% to 19% for women over the age of 65 years and 6% to 10% for men 3 and rises exponentially with age, such that up to 47% of individuals over the age of 80 develop AD 4. Dementia is a syndrome, a group of symptoms that has a number of causes. The characteristic symptoms of dementia are difficulties with memory, language, problem-solving and other cognitive skills that affect a person's ability to perform everyday activities. These difficulties occur because nerve cells (neurons) in parts of the brain involved in cognitive function have been damaged or destroyed.
Aging is inevitable; however, bioactives are naturally present in several plants and their products have been reported to provide remarkable protection against age-induced complications and enhance healthspan as well as lifespan due to their potent health promontory effects. Tea catechins are flavonoids, occurring largely in tea plants (Camellia sinensis). An array of studies has reported that catechins possess strong anti-cancer, anti-diabetic, cognition improving, and coronary vascular impairments preventive effects. The present chapter describes the antioxidant and anti-inflammatory potentials of tea catechins involved in the prevention of aging and age-related pathological events to explore the possibility of developing plant-origin drugs to promote healthy aging.
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Background: Numerous benefits of green tea have been reported. However, the effects of green tea on cognitive function remain disputable and the mechanism is still unclear. Objective: To investigate the relationship of green tea consumption with cognitive function and related blood biomarkers among Chinese middle-aged and elderly people. Methods: A total of 264 participants aged 50–70 years old were enrolled from Zhongnan Hospital of Wuhan University. They were interviewed about green tea consumption patterns and underwent neuropsychological tests covering five main cognitive domains to assess cognition including Montreal Cognitive Assessment (MoCA) and the other 10 scales. Then we detected serum oxidative stress biomarkers including Superoxide Dismutase (SOD), Malondialdehyde (MDA), Glutathione Peroxidase (GPx), Glutathione Reductase (GR), and Alzheimer’s disease (AD) markers including β-amyloid (Aβ) 40 , Aβ 42 , and phosphorylated tau-181 (pTau 181 ). Results: In the tea-consuming group, the MoCA scores ( P = 0.000), Hopkins Verbal Learning Test (HVLT) immediate recall ( P = 0.012) and delayed recall ( P = 0.013) were significantly higher while Trail Making Test-B ( P = 0.005) and Victoria Stroop test interference ( P = 0.000) were lower. In terms of oxidative stress markers, the tea-consuming group had lower serum MDA levels ( P = 0.002) and higher serum SOD ( P = 0.005) and GPx ( P = 0.007) levels. In terms of AD markers, serum pTau 181 (P < 0.000), Aβ 42 ( P = 0.019) and total Aβ levels ( P = 0.034) but not serum Aβ 40 levels, were lower in the tea-consuming group. In the logistic regression analysis, there was a significant negative correlation between green tea consumption and cognitive impairment (OR = 0.26, 95 % CI 0.13 0.52 for high group). Conclusion: Regular green tea consumption is associated with better cognitive function among Chinese middle-aged and elderly people, mainly reflected in memory and executive function. It may achieve protective effects by reducing AD-related pathology and improving anti-oxidative stress capacity and higher levels of tea consumption have a stronger protective effect.
Human and animal studies have shown that casein peptide (casein hydrolysate) has positive effects on cognitive function. This double-blind randomized controlled study aimed to investigate whether single ingestion of casein peptide could affect cognitive function (executive function) and cognitive neural activity in healthy older adults. We assigned 47 participants to one of the three dietary supplements as follows: casein peptide (TMP, n = 15), casein (TMC, n = 16), and indigestible dextrin (TMF, n = 16). Dietary supplements were ingested 30 min before starting the experiment; moreover, neural activity while performing the task-switching reaction time (SWT) trial was assessed through functional magnetic resonance imaging (fMRI). Additionally, we used a visual analog scale (VAS) test to assess the pre- and post-test feeling and mood. Regarding the parameters of the SWT trial, there were no significant among-group differences in the reaction time, accuracy rate, and %SwitchCost. Contrastingly, the fMRI experiment revealed among-group differences in the main effects in the medial frontal gyrus, Supplementary motor cortex (SMC), posterior cingulate gyrus (PCg), and amygdala (Amyg). Specifically, there was a significant decrease in the neural activities in the SMC and PCg in the TMP group than in the other two groups. Moreover, there was a significant increase in the neural activity in the Amyg in the TMP group compared with the TMF, but not the TMC, group. Furthermore, the VAS score was significantly higher in the TMP group than in the other two groups. There were no recorded adverse outcomes. Our findings suggested that TMP ingestion by older adults could temporarily suppress complementary neural activity in specific brain regions involved in executive functions, as well as default mode network activity, which could improve cognitive neural activities.
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Over the last 2 decades, a large number of neurophysiological and neuroimaging studies of patients with schizophrenia have furnished in vivo evidence for dysconnectivity, ie, abnormal functional integration of brain processes. While the evidence for dysconnectivity in schizophrenia is strong, its etiology, pathophysiological mechanisms, and significance for clinical symptoms are unclear. First, dysconnectivity could result from aberrant wiring of connections during development, from aberrant synaptic plasticity, or from both. Second, it is not clear how schizophrenic symptoms can be understood mechanistically as a consequence of dysconnectivity. Third, if dysconnectivity is the primary pathophysiology, and not just an epiphenomenon, then it should provide a mechanistic explanation for known empirical facts about schizophrenia. This article addresses these 3 issues in the framework of the dysconnection hypothesis. This theory postulates that the core pathology in schizophrenia resides in aberrant N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic plasticity due to abnormal regulation of NMDARs by neuromodulatory transmitters like dopamine, serotonin, or acetylcholine. We argue that this neurobiological mechanism can explain failures of self-monitoring, leading to a mechanistic explanation for first-rank symptoms as pathognomonic features of schizophrenia, and may provide a basis for future diagnostic classifications with physiologically defined patient subgroups. Finally, we test the explanatory power of our theory against a list of empirical facts about schizophrenia.
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L-theanine (N-ethyl-L-glutamine) or theanine is a major amino acid uniquely found in green tea. L-theanine has been historically reported as a relaxing agent, prompting scientific research on its pharmacology. Animal neurochemistry studies suggest that L-theanine increases brain serotonin, dopamine, GABA levels and has micromolar affinities for AMPA, Kainate and NMDA receptors. In addition has been shown to exert neuroprotective effects in animal models possibly through its antagonistic effects on group 1 metabotrophic glutamate receptors. Behavioural studies in animals suggest improvement in learning and memory. Overall, L-theanine displays a neuropharmacology suggestive of a possible neuroprotective and cognitive enhancing agent and warrants further investigation in animals and humans.
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Importance: Brain imaging studies have identified robust changes in brain structure and function during the development of psychosis, but the contribution of abnormal brain connectivity to the onset of psychosis is unclear. Furthermore, antipsychotic treatment can modulate brain activity and functional connectivity during cognitive tasks. Objectives: To investigate whether dysfunctional brain connectivity during working memory (WM) predates the onset of psychosis and whether connectivity parameters are related to antipsychotic treatment. Design: Dynamic causal modeling study of functional magnetic resonance imaging data. Setting: Participants were recruited from the specialized clinic for the early detection of psychosis at the Department of Psychiatry, University of Basel, Basel, Switzerland. Participants: Seventeen participants with an at-risk mental state (mean [SD] age, 25.24 [6.3] years), 21 individuals with first-episode psychosis (mean [SD] age, 28.57 [7.2] years), and 20 healthy controls (mean [SD] age, 26.5 [4] years). Main outcome and measure: Functional magnetic resonance imaging data were recorded while participants performed an N-back WM task. Functional interactions among brain regions involved in WM, in particular between frontal and parietal brain regions, were characterized using dynamic causal modeling. Bayesian model selection was performed to evaluate the likelihood of alternative WM network architectures across groups, whereas bayesian model averaging was used to examine group differences in connection strengths. Results: We observed a progressive reduction in WM-induced modulation of connectivity from the middle frontal gyrus to the superior parietal lobule in the right hemisphere in healthy controls, at-risk mental state participants, and first-episode psychosis patients. Notably, the abnormal modulation of connectivity in first-episode psychosis patients was normalized by treatment with antipsychotics. Conclusions and relevance: Our findings suggest that the vulnerability to psychosis is associated with a progressive failure of functional integration of brain regions involved in WM processes, including visual encoding and rule updating, and that treatment with antipsychotics may have the potential to counteract this.
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NMDA receptors (NMDARs) are glutamate-gated ion channels and are crucial for neuronal communication. NMDARs form tetrameric complexes that consist of several homologous subunits. The subunit composition of NMDARs is plastic, resulting in a large number of receptor subtypes. As each receptor subtype has distinct biophysical, pharmacological and signalling properties, there is great interest in determining whether individual subtypes carry out specific functions in the CNS in both normal and pathological conditions. Here, we review the effects of subunit composition on NMDAR properties, synaptic plasticity and cellular mechanisms implicated in neuropsychiatric disorders. Understanding the rules and roles of NMDAR diversity could provide new therapeutic strategies against dysfunctions of glutamatergic transmission.
Neurodegeneration in Parkinson's, Alzheimer's, and other neurodegenerative diseases seems to be multifactorial, in that a complex set of toxic reactions including inflammation, glutamatergic neurotoxicity, increases in iron and nitric oxide, depletion of endogenous antioxidants, reduced expression of trophic factors, dysfunction of the ubiquitin-proteasome system, and expression of proapoptotic proteins leads to the demise of neurons. Thus, the fundamental objective in neurodegeneration and neuroprotection research is to determine which of these factors constitutes the primary event, the sequence in which these events occur, and whether they act in concurrence in the pathogenic process, This has led to the current notion that drugs directed against a single target will be ineffective and rather a single drug or cocktail of drugs with pluripharmacological properties may be more suitable. Green tea catechin polyphenols, formerly thought to be simple radical scavengers, are now considered to invoke a spectrum of cellular mechanisms of action related to their neuroprotective activity. These include pharmacological activities like iron chelation, scavenging of radicals, activation of survival genes and cell signaling pathways, and regulation of mitochondrial function and possibly of the ubiquitin-proteasome system. As a consequence these compounds are receiving significant attention as therapeutic cytoprotective agents for the treatment of neurodegenerative and other diseases.