Beruflich Dokumente
Kultur Dokumente
Neuroscience Research
journal homepage: www.elsevier.com/locate/neures
a r t i c l e
i n f o
Article history:
Received 25 October 2014
Accepted 2 December 2014
Available online 31 December 2014
Keywords:
Glucose metabolism
Memory
Language
Connectivity
Graph analysis
Reserve effect
a b s t r a c t
Education involves learning new information and acquiring cognitive skills. These require various cognitive processes including learning, memory, and language. Since cognitive processes activate associated
brain areas, we proposed that the brains of elderly people with longer education periods would show
traces of repeated activation as increased synaptic connectivity and capillary in brain areas involved in
learning, memory, and language. Utilizing positron emission topography (PET), this study examined the
effect of education in the human brain utilizing the regional cerebral glucose metabolism rates (rCMRglcs). 26 elderly women with high-level education (HEG) and 26 with low-level education (LEG) were
compared with regard to their regional brain activation and association between the regions. Further,
graphical theoretical analysis using rCMRglcs was applied to examine differences in the functional network properties of the brain. The results showed that the HEG had higher rCMRglc in the ventral cerebral
regions that are mainly involved in memory, language, and neurogenesis, while the LEG had higher rCMRglc in apical areas of the cerebrum mainly involved in motor and somatosensory functions. Functional
connectivity investigated with graph theoretical analysis illustrated that the brain of the HEG compared
to those of the LEG were overall more efcient, more resilient, and characterized by small-worldness.
This may be one of the brains mechanisms mediating the reserve effects found in people with higher
education.
2014 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.
1. Introduction
Education in schools involves systematic learning in an environment conducive to learning new information and academic skills.
It involves repetitive learning of various cognitive functions and
skills such as memory, language, mathematics, and logic. This process usually takes place from childhood to early adulthood when
brain plasticity is the greatest. On the other hand, training involves
specic physical or mental repetitive learning aimed at improving
ones capability, productivity and performance (Neubauer and Fink,
2009; Ericsson and Ward, 2007). Physical or job training is usually narrower in extent and shorter in duration compared to school
education. Learning, whether by training or school education, is a
process that modies the brain through experiences. Therefore, it
can be postulated that school education will result in changes in the
broader brain regions involved in memory, language, mathematics,
and logic. However, training will likely be followed by change in a
limited brain region involved in the specic skill or job that was
trained.
Numerous studies have investigated how experiences an animal
has modify its brain. Diamond and her colleagues (1988) were one
of the rst teams to nd experimental evidence where experience
changes the brain at various levels. They analyzed the brains of rats
bred in enriched environments (EE) and those bred in impoverished environments (IE) over many years. The results showed that
there were differences in the thickness of the cortex, the size of the
http://dx.doi.org/10.1016/j.neures.2014.12.009
0168-0102/ 2014 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.
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Table 1
The demographics and mean scores of Korean Dementia Rating Scales for the two education groups.
HEG (n = 26)
Age
Years of formal education
Total scores of K-DRS
LEG (n = 26)
Mean
SD
Mean
SD
69.88
14
135.92
4.95
2
4.53
71
4.62
128.15
5.17
1.72
7.16
0.79
18.13
4.67
0.430
<0.001
<0.001
status. Twenty-six members were age-matched into each education group (two sample independence t-test of the mean age,
t = 0.79, p > 0.43). The high-education group (HEG) members had
more than 12 years of education, while those in the low education
group (LEG) had less than 6 years of schooling (Table 1).
Occupational history did not differ signicantly between the
two education groups. The majority of subjects were full-time
housewives both in the HEG (18/26) and the LEG (11/26). Those
who had jobs in the HEG were teachers, pharmacists, and secretaries, while those in the LEG were hair dressers, vendors, and retail
store clerks. All women were the primary individuals responsible
for the household duties. The limited social activity of women in
the sample was very similar to those of their peers within the time
period the subjects graduated from school (1940s1960s). In addition, as women with lower socioeconomic status (SES), heavily
represented in the LEG, tended to work for a living compared to
those with higher SES who were mostly full-time housewives, the
analysis of previous occupation were deemed inappropriate in this
sample, and were excluded from the main analyses.
This study was approved by the Seoul National University institutional Review Board (SNUIRB). All subjects were informed of the
study procedure and the PET scan. Informed consent forms were
signed by all participants of the study.
2.2. PET imaging
PET scans were taken by a Philips Allegro PET scanner
(Philips Electronics, New York) with an intrinsic full-widthat-half-maximum (FWHM) resolution of 5.2 mm. Before F18uoro-2-deoxyglucose (FDG) administration, a transmission scan
was performed for 5 min with a Ge-68 rod source to correct for attenuation. PET Images were reconstructed using a 3D
RAMLA algorithm and displayed in a 128 128 matrix (pixel size
2 mm 2 mm 2 mm). Images were simultaneously collected for
90 continuous planes at 2 mm thickness. PET scanning continued
for 10 min in three-dimensional mode 40 min after an intravenous
injection of 5 MBq/kg FDG in the resting state with open-eyes,
non-pegged ears, and no intended thought in a dark and quiet environment. The environment was such that the elderly subjects did
not suffer any stress from closed space.
2.3. Image analysis
Processing and statistical analyses of the PET images were performed using Statistical Parametric Mapping 2 (SPM2; Members &
Collaborators of the Wellcome Trust Centre for Neuroimaging, UCL,
UK) implanted in Matlab (Mathworks Inc., Sherborn, Natick, MA).
Prior to the statistical analysis, all images were spatially normalized
in the MNI standard template to remove inter-subject anatomical
variations. The spatially normalized images were smoothed by convolution using an isotropic Gaussian kernel with a 16 mm FWHM.
The statistical analysis data were the relative glucose metabolic
rates, which are the regional glucose metabolic values of voxels
divided by the whole brain glucose metabolic value and multiplied
by a scale factor of 50 (Brett, 1999).
Occipital lobe
43 Calcarine cortex-L
44 Calcarine cortex-R
45 Cuneus-L
49 Superior occipital
gyrus-L
50 Superior occipital
gyrus-R
51 Middle occipital
gyrus-L
52 Middle occipital
gyrus-R
53 Inferior occipital
gyrus-L
54 Inferior occipital
gyrus-R
55 Fusiform gyrus-L
Temporal lobe
80 Heschl gyrus-L
81 Heschl gyrus-R
82 Superior temporal
gyrus-L
83 Superior temporal
gyrus-R
84 Superior temporal
pole-L
85 Superior temporal
pole-R
86 Middle temporal
gyrus-L
87 Middle temporal
gyrus-R
88 Middle temporal
pole-L
89 Middle temporal
pole-R
90 Inferior temporal
gyrus-L
91 Inferior temporal
gyrus-R
Cerebellum
56 Fusiform gyrus-R
92 Cerebellum-L
Parietal lobe
93 Cerebellum-R
57 Postcentral gyrus-L
94 Vermis
58 Postcentral gyrus-R
Brain stem
59 Superior parietal
gyrus-L
60 Superior parietal
gyrus-R
61 Inferior parietal
gyrus-L
62 Inferior parietal
gyrus-R
63 Supramarginal gyrus-L
64 Supramarginal gyrus-R
95 Midbrain
46 Cuneus-R
47 Lingual gyrus-L
48 Lingual gyrus-R
65 Angular gyrus-L
66 Angular gyrus-R
96 Pons
97 Medulla
67 Precuneus-L
68 Precuneus-R
69 Paracentral lobule-L
70 Paracentral lobule-R
Basal ganglia and
diencephalon
71 Caudate-L
72 Caudate-R
73 Putaman-L
74 Putaman-R
75 Pallidum-L
76 Pallidum-R
77 Thalamus-L
78 Thalamus-R
79 Hypothalamus
53
d1
jN j =
/ i ij
n1
iN
1
1 2ti
Ci =
,
n
n
ki (ki1 )
iN
iN
iN
d
jN j =
/ i ij
n1
54
The algorithm based on weighted matrix is not considerably different from that based on the binary matrix, except for matrix entries
and the denition of path length. The weighted characteristic path
length is dened as
1
Lw =
n
iN
dw
jN,j =
/ i ij
n1
u,vg w
2.6.1.2. Regional network measures. In order to examine the network of the two education groups on local scale, local clustering
a fraction of triangles around individual nodes was calculated
as the measure of segregation, while local betweenness centrality
as a measure of centrality of the local networks. Since comparing every network density for the regional measures results in
a large number of comparisons (number of densities number
of ROIs), the areas under a curve (AUC) of the regional network
measures were compared. For this purpose, the curves extracted
from thresholding across the density ranges (0.10:0.02:0.40)
were used. Each of these curves depicts the changes in a specic network measure for each group as a function of network
density. The areas were normalized for between-group comparison since the coefcients of the two groups were signicantly
different.
1
wuv
ij
3. Results
3.1. Mean comparison of the rCMRglc between the two education
groups in 97 ROIs
The ROIs where the mean rCMRglc of the HEG was signicantly higher than that of the LEG (nonparametric permutation test
(MannWhitney), p < 0.05, one-tailed) are shown in Table 3 and the
Table 3
The ROIs where a rCMRglc of the HEG is signicantly higher than that of the LEG (permutation test, p < 0.05, one-tailed).
Region
HEG
rCMRglc (mean) SD
75.92
76.10
80.09
71.64
78.80
72.75
62.83
59.95
77.83
73.57
79.80
83.46
70.14
65.33
64.04
70.00
60.57
83.29
69.11
78.52
73.04
80.43
61.69
60.58
78.10
57.42
74.22
79.22
2.08
2.22
2.17
2.40
2.34
2.71
2.42
3.23
2.73
2.25
2.60
3.04
2.24
2.77
2.36
3.33
2.63
2.76
3.69
2.07
2.68
2.44
3.76
2.39
2.69
2.75
2.90
2.61
LEG
rCMRglc (mean) SD
74.29
74.20
78.08
69.06
77.08
70.52
60.75
56.93
76.24
72.14
78.31
81.18
68.79
63.47
62.08
68.05
58.90
80.90
67.19
77.03
71.82
78.60
59.31
58.92
77.23
56.17
73.32
78.44
2.68
1.96
3.26
2.82
2.20
3.11
2.87
3.88
2.38
2.96
2.53
4.62
2.15
2.87
3.12
4.32
3.18
4.30
3.89
2.64
2.31
3.31
4.14
3.42
2.74
2.59
3.39
2.69
p
<0.0005*
<0.0005*
<0.0005*
0.001
0.001
0.002
0.002
0.002
0.002
0.003
0.003
0.004
0.004
0.006
0.006
0.006
0.006
0.008
0.010
0.015
0.016
0.018
0.019
0.021
0.023
0.025
0.028
0.044
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Table 4
The ROIs where a rCMRglc of the LEG is signicantly higher than that of the HEG (permutation test, p < 0.05, one-tailed).
Region
HEG
rCMRglc (mean) SD
82.02
77.42
87.80
82.10
80.57
79.17
81.49
87.05
76.62
3.43
2.78
2.35
5.06
3.78
2.30
3.33
2.69
2.12
LEG
rCMRglc (mean) SD
85.66
78.82
89.71
85.78
83.54
80.59
83.84
88.86
77.49
4.12
2.37
2.60
4.93
4.78
2.64
3.97
3.88
2.32
p
<0.0005*
0.004
0.005
0.005
0.006
0.013
0.013
0.023
0.044
ROIs where the mean rCMRglc of the LEG was signicantly higher
than that of the HEG are shown in Table 4 (see Table 2 for ROIs).
For reference, the voxels where the mean rCMRglc of the HEG
and that of the LEG were signicantly different were examined
at each lobe over the whole-brain. The statistical parametric map
(two-sample t-test) is shown in Fig. 1. The mean rCMRglc of the HEG
located in the ventral cerebral regions and the subcortex were signicantly higher than that of the LEG. On the other hand, the mean
rCMRglc of the LEG located in the apical regions of the cerebral
cortex was signicantly higher than that of the HEG.
3.2. A graph theoretical analysis
3.2.1. Measures based on binary matrix
The correlation (association) matrices, the binary (adjacency)
matrices, and the brain connectivity maps (excluding cerebellum,
brain stem, and hypothalamus) generated at a minimum density
(0.10) for each group are shown in Fig. 2. The brain connectivity
was visualized with the BrainNet Viewer (Xia et al., 2013). The correlation coefcients of the LEG were generally higher than those
of the HEG (Fig. 2I). The brains of the HEG members had longer
connections that are mediated by hubs-nodes located at temporal
areas and render information ow among remote areas. Its connectivity was comparatively uniform over the whole brain, while that
of the LEG were characterized by locally clustered network with
scanty long connections (Fig. 2III).
Between-group differences in global network measures on
networks thresholded at a range of densities (0.10:0.02:0.40) were
investigated. Compared with the LEG, the HEG network showed
larger global efciency at every density and showed signicant difference in the 0.140.34 density range. Compared with the LEG,
the HEG network showed larger normalized clustering coefcient
(Gamma) and smaller normalized path length (Lambda) at every
density. Lambda showed signicant differences in the 0.200.32
density ranges between the two education groups. This pattern led
to larger small-world indices (Sigma) in the HEG network at every
density and showed signicantly larger small-world indices in the
0.100.20 and 0.240.28 density ranges (permutation test, p < 0.05)
(Fig. 3).
In order to analyze the network behavior in response to random
attacks, the size of the largest remaining component in response
to successive node removal, in random order, was calculated at
the minimum density (0.1). The remaining largest component size
change of the network as a function of randomly removed node
Fig. 1. The voxels that showed signicant difference in the mean rCMRglc of the HEG and that of the LEG are illustrated in colors (overlaid on a single T1 image template of
SPM2). Arabic numbers above the images indicate MNI template z-coordinates (p < 0.001, uncorrected).
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Fig. 2. Correlation matrices, binary matrices, and brain connectivity maps thresholded at the minimum density (0.10). (I) Correlation (association) matrix for the HEG and
the LEG; the color-bar shows the strength of the connection. (II) Binary (adjacency) matrix for the HEG and the LEG; red color represents connection existence. (III) The brain
connectivity for the HEG and LEG. Each number in the horizontal and vertical axes indicates the ROIs. See Table 2 for the name of ROI corresponding to each number in this
gure.
fractions is shown in Fig. 4 (left). In most of the removed node fractions, the remaining largest component size of the HEG network
was larger compared to LEG, and in some the differences were signicant. The same procedure analyzed the network behaviors in
response to targeted attacks, but removed the nodes in decreasing
nodal betweenness centrality order. The HEG network was more
robust to targeted attacks compared to the LEG network and the
difference reached signicance at a few attacked node fractions
(permutation test, p < 0.05) (Fig. 4, right).
The identied HEG hubs were the bilateral olfactory cortices,
the left hippocampus, the left parahippocampus, the left amygdala,
and the midbrain. The LEG hubs were the left pallidum, the right
superior temporal pole, and the pons.
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Fig. 3. Global network measures as a function of network density. Global efciency, Gamma (=C/Crand : normalized clustering), Lambda (=L/Lrand : normalized path length),
and Sigma (=Gamma/Lamda: small-world index) based on binary adjacent matrix. The + sign indicates that between-group difference is signicant at the density (p < 0.05,
permutation test). Note the signicantly higher global efciency and small-worldness of the HEG.
betweenness centrality than the LEG were the right insula, the left
hippocampus, the right angular gyrus, and the left caudate. The
inverse was the right Inferior frontal orbital gyrus, the left putamen,
and the left pallidum (Fig. 5II).
Fig. 4. Between-group differences in network resilience to random attack and targeted attack. Changes in the size of the largest component of the networks after random
attack (left) and targeted attack (right). The + sign indicates between-group difference is signicant at the removed node fraction (p < 0.05, permutation test).
58
Fig. 5. Between-group difference in AUC (area under a curve) of normalized local network measures. (I) Between-group difference in AUC of normalized local clustering.
(II) Between-group difference in AUC of normalized local betweenness centrality. Vertical coordinates larger than 0 indicate LEG > HEG. Each number in the horizontal axes
indicates the ROIs. The + sign indicates that between-group difference was signicant at the region (permutation test, p < 0.05). See Table 2 for the ROI corresponding to each
number in this gure.
(HEG) with some bias to the left (Fig. 1 and Table 3). Those of the
apical part of the cerebral cortex that involve the pre- and the postcentral areas as well as the adjacent precuneus were signicantly
higher in elderly women with lower education (LEG) (Fig. 1 and
Table 4). Consistent with the cerebral asymmetry theories (Hines,
1987), the HEG members tended to show higher metabolism in the
left side of the brain than the LEG members, although this was not as
great as the disparity between the inferior versus superior regions
(Tables 3 and 4 and Fig. 1).
The two education groups also differed signicantly in the functional connectivity of the brain regions. We found that the brain
network of the HEG members had better balance between integration (Lambda and Global efciency) and segregation (Gamma)
resulting in greater small-worldness (Sigman; Watts and Strogatz,
1998.) This means there were more functionally segregated ROIs
with a robust number of integrating links in the HEG. The HEG also
demonstrated greater resilience both to random attacks and targeted attacks (Fig. 4) and larger global efciency (Fig. 3) based on
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Fig. 6. Global efciency, Gamma, Lambda, and Sigma values of the HEG and the LEG based on weighted connection matrices (permutation test, p < 0.05). The * sign indicates
the signicance of between-group difference.
binary matrices. To our knowledge, this is the rst study to investigate the effects of education on functional connectivity of the brain
regions.
Consistent with the principle of brain plasticity, the regions that
showed higher activation in the HEG were found mostly in association cortices that are involved in memory and language processing.
The medial temporal areas, such as the hippocampus complex, are
well known for their roles in declarative memory while the caudate is one of the major sites of procedural memory (Squire, 2004).
The key language and auditory sites in the left cerebral cortex also
showed signicantly higher activation in the HEG. While the left
inferior frontal regions of the cerebrum has long been recognize
as the center for spoken language production, the left fusiform
gyrus has been found to be associated with orthographic processing
in written language (Tsapkini and Rapp, 2010). These results are
consistent with the fact that people with higher education are
more likely to utilize language skills both in spoken and written
forms. Supporting this notion is the signicantly higher activation in insula, and temporal pole by the HEG. These areas along
with the inferior frontal regions have been associated with complex sentence processing and semantics such as metaphors (Rapp
et al., 2004; Diaz and Hogstrom, 2011), gurativeness (Schmidt and
Seger, 2009; Diaz and Hogstrom, 2011), and abstraction (Jefferies
et al., 2009). In addition, insular is not only an integral component
of the central auditory nervous system, but also a vital relay station
in auditory perception. Bilateral damage to this region results in
total auditory agnosia (Bamiou et al., 2003).
In this context, a higher activation of the apical regions of
the cerebral cortex like the supplementary motor area, the precentral gyrus, the paracentral lobule, and the postcentral gyrus,
suggests that motor and somatosensory functions have been utilized heavily in elderly subjects with low education who could have
been more frequently involved in activities that require physical
labor. It is possible that the LEG members would have developed
better motor skills and physical awareness than those of the HEG
members.
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5. Conclusion
Years of formal education affected the regional metabolism and
the connectivity of the regions in elderly women. To our knowledge, this is the rst study to investigate the effects of education on
resting-state regional brain metabolism and its functional connectivity. For women with higher education, the increased metabolism
was observed in the ventral parts of the cerebral cortex that are
associated with memory, language, and brain plasticity. On the
other hand, for women who received minimal education, regional
brain metabolism was increased in the apical parts of the cortex,
which are mainly involved in motor action and somatic senses.
These ndings are consistent with the notion that higher education
promotes learning, memory, and language skills. They also suggest
that people with more education would have greater brain plasticity, which would be critically important for the reserve of the
brain. Findings from the graph theoretical analyses provide further
evidence that longer education enables greater resilience and efciency in the brain. Our ndings have implications on the neural
reserve in the development of Alzheimers dementia; i.e., how education might moderate the effect of neuropathology in Alzheimers
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