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Learning to read alters cortico-subcortical cross-talk in the visual system of illiterates

  • Iswar Saran Degree College, University of Allahabad

Abstract and Figures

Learning to read is known to result in a reorganization of the developing cerebral cortex. In this longitudinal resting-state functional magnetic resonance imaging study in illiterate adults, we show that only 6 months of literacy training can lead to neuroplastic changes in the mature brain. We observed that literacy-induced neuroplasticity is not confined to the cortex but increases the functional connectivity between the occipital lobe and subcortical areas in the midbrain and the thalamus. Individual rates of connectivity increase were significantly related to the individual decoding skill gains. These findings crucially complement current neurobiological concepts of normal and impaired literacy acquisition.
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Learning to read alters cortico-subcortical cross-talk in
the visual system of illiterates
Michael A. Skeide,
* Uttam Kumar,
Ramesh K. Mishra,
Viveka N. Tripathi,
Anupam Guleria,
Jay P. Singh,
Frank Eisner,
Falk Huettig
Learning to read is known to result in a reorganization of the developing cerebral cortex. In this longitudinal
resting-state functional magnetic resonance imaging study in illiterate adults, we show that only 6 months of
literacy training can lead to neuroplastic changes in the mature brain. We observed that literacy-induced neu-
roplasticity is not confined to the cortex but increases the functional connectivity between the occipital lobe
and subcortical areas in the midbrain and the thalamus. Individual rates of connectivity increase were signifi-
cantly related to the individual decoding skill gains. These findings crucially complement current neuro-
biological concepts of normal and impaired literacy acquisition.
Learning to read is a profound cultural experience requiring systematic
instruction and intensive practice over months or years (1). Yet, hemo-
dynamic brain activity induced by perceiving printed words changes after
only a few weeks of training letter-sound links (2). Enhanced functional
selectivity to print emerges in parts of the visual system, that is, the bilateral
occipital cortices (3), and in a multimodal symbol processing region lo-
cated in the left temporo-occipital fusiform cortex (2,4,5). These findings
have revealed the important insight that literacy-related learning triggers
cognitive adaptation mechanisms manifesting themselves in increased
blood oxygen leveldependent (BOLD) responses during print processing
tasks (6,7). However, it remains elusive whether reading acquisition
also leads to an intrinsic functional reorganization of neural circuits.
Here, we used resting-state functional magnetic resonance imaging
(fMRI) as a measure of spontaneous neuronal activity to capture the
impact of reading acquisition on the functional connectome (8). In
a controlled longitudinal intervention study, we taught 21 illiterate
Hindi-speaking adults how to read Devanagari script for 6 months. The
goal was to compare the changes in resting-state fMRI data before and
after learning of the sample taught to read with those of a sample of nine
Hindi-speaking illiterates who did not undergo such instruction. Partici-
pants were recruited from the same societal community in two villages of a
rural area near the city of Lucknow in North India and matched for the
most relevant cognitive, demographic, and socioeconomic variables.
Given that becoming literate goes along with widely distributed
modulations of cortical responses to print, we assumed that the effects
of our intervention could be best captured with a two-step procedure.
First, we performed an unbiased network centrality analysis to explore
functional connectivity between each voxel and all other voxels of the
brain without predefining seed regions. The cluster of the most strongly
connected voxels was then used as a post hoc seed region to identify the
specific network driving the global change in functional connectivity.
Behavioral effects of practicing Devanagari script on letter
knowledge and word-reading skills
The behavioral effectiveness of the literacy instruction was reflected in
significant group (reading-trained individuals versus untrained illiter-
ates) by time (before versus after intervention) interactions of letter
knowledge [F
= 17.80, P< 0.001, h
of variance (ANOVA)] and word reading (F
=15.96,P< 0.001, h
0.36; 2 × 2 mixed ANOVA). Both interactions were driven by signif-
icant improvements of the trained group (letter knowledge: z=4.20,
P< 0.001, r=0.65;wordreading:z= 3.83, P< 0.001, r= 0.59; Wilcoxon
signed-rank tests) that were not observed in the untrained group (letter
knowledge: z=0.41,P=0.684;wordreading:z=0.37,P=0.715;Wilcoxon
signed-rank tests) (Table 1).
Resting-state network centrality changes in the bilateral
pulvinar nuclei and the right superior colliculus
Initially, we investigated in a voxel-wise fashion at the whole-brain level
whether the experience of becoming literate modifies network nodes of
spontaneous hemodynamic activity. Therefore, we comparedtraining-
relateddifferences in the degree centrality of BOLD signals between the
groups (9). A significant group by time interaction (t
= 4.17, P<
0.005, corrected for cluster size) was found in a single coherent cluster
(k= 35 voxels; voxel size 3 × 3 × 3 mm
) extending from the right
superior colliculus of the brainstem [MNI (Montreal Neurological In-
stitute) coordinates: +6, 30, 3] to the bilateral pulvinar nuclei of the
thalamus (MNI coordinates: +6, 18, 3; 6, 21, 3) (Fig. 1). This
interaction was characterized by a significant mean degree centrality
increase in the trained group (t
=8.55,P< 0.001, d=1.31;pairedttest)
that did not appear in the untrained group, which remained at the base-
line level (t
= 0.14, P= 0.893; paired ttest) (Fig. 1). To establish the
reliability of the training-induced increase in subcortical network cen-
trality, we performed a confirmatory leave-one-out cross-validation analy-
sis. A linear binary support vector machine classification revealed that
the experimental and control groups are not statistically distinguishable
before the training (accuracy, 54.76%; P=0.272),butdoshowastatisti-
cally significant difference after the training (accuracy, 76.98%; P= 0.017).
Increasing temporal coupling of spontaneous BOLD activity
in the subcortical visual nuclei and the visual cortex
The cluster obtained from the degree centrality analysis was then used
as a seed region in a voxel-wise functional connectivity analysis (10).
Department of Neuropsychology, Max Planck Institute for Human Cognitive and
Brain Sciences, Stephanstrasse 1a, 04103 Leipzig, Germany.
Centre of Biomedical
Research, Raibareli Road, 226014 Lucknow, Uttar Pradesh, India.
University of Hyder-
abad, Prof. C.R. Rao Road, Gachibowli, 500046 Hyderabad, Telangana, India.
for Behavioural and Cognitive Sciences, University of Allahabad, University Road, Old
Katra, 211002 Allahabad, Uttar Pradesh, India.
Department of Psychology, University
of Allahabad, 211002 Allahabad, Uttar Pradesh, India.
Donders Institute, Radboud
University, Montessorilaan 3, 6525 HR Nijmegen, Netherlands.
Psychology of
Language Department, Max Planck Institute for Psycholinguistics, Wundtlaan 1,
6525 XD Nijmegen, Netherlands.
*Corresponding author. Email:
Skeide et al., Sci. Adv. 2017; 3: e1602612 24 May 2017 1of7
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Table 1. Participant demographic information and behavioral performance.
Trained group Untrained group Group difference
n21 9
Age (years) 31.57 ± 4.90* 31.78 ± 5.47* z= 0.21, P= 0.837
Gender (female/male) 20/1 8/1
Monthly income (Rupees) 2313.50 ± 629.15* 2500 ± 433.01* z= 0.96, P= 0.375
Literate family members 2.95 ± 1.54* 2.86 ± 1.46* z=0,P=1
Raven test 13.29 ± 2.67*
11.67 ± 2.60*
z= 1.42, P= 0.164
Letter knowledge pretest 10.38 ± 12.50*
7.22 ± 10.12*
z= 0.98, P= 0.341
Letter knowledge posttest 33.81 ± 7.11*
5.44 ± 9.84*
z= 4.21, P< 0.001
Word reading pretest 0.57 ± 1.57*
1.56 ± 2.65*
z= 1.41, P= 0.301
Word reading posttest 7.10 ± 8.53*
1.56 ± 2.35*
z= 2.61, P= 0.009
Days between tests 189.76 ± 22.74* 171.22 ± 63.85* z= 1.31, P= 0.193
*Mean ± SD. Raven test raw scores (maximum 60 points). Raw scores.
Fig. 1. Learning to read modifies subcortical network centrality. Whole-brain degree centrality map thresholded at z= 2.58 (P< 0.005, corrected for cluster size) with
corresponding color bar indicating the range of zscores. The effect of literacy instruction is depicted as a group (reading-trained individuals versus untrained illiterates) by
time (before versus after intervention) interaction. The significant cluster stretches from the right superior colliculus of the brainstem (MNI coordinates: +6, 30, 3) to the
bilateral pulvinar nuclei of the thalamus (MNI coordinates: +6, 18, 3; 6, 21, 3). The box plot resolves the interaction by separately showing the individual mean z
values for each factor level. Mean degree centrality values of the untrained group did not differ significantly from zero (time 1: t
= 1.76, P= 0.116; time 2: t
= 1.10, P=
0.302; one-sample ttests).
Skeide et al., Sci. Adv. 2017; 3: e1602612 24 May 2017 2of7
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more strongly coupled to those of the right superior colliculus and the
bilateral pulvinar nuclei as a consequence of learning to read. A signif-
icant group by time interaction (t
= 4.45, P< 0.005, corrected for
cluster size) emerged as a single coherent cluster in the areas V1, V2,
V3, and V4 of the right occipital cortex (k= 48 voxels; voxel size 3 × 3 ×
; MNI coordinates: +24, 81, +15; +24, 93, +12; +33, 90, +3)
(Fig. 2). The cortico-subcortical mean functional connectivity got sig-
nificantly stronger in the group that took part in the reading program
(z=3.77,P< 0.001, r= 0.58; Wilcoxon signed-rank test) but not in
the group that remained illiterate (z= 0.77, P= 0.441; Wilcoxon
signed-rank test).
Stronger functional coactivation in the early visual pathway
and the individual gain in letter and word knowledge
Finally, we wanted to find out whether there was a relation between
the detected neural alterations and the behavioral improvements at
the individual level. To this end, we derived an index for the growth
of brain-functional connectivity [correlation coefficient of the BOLD
time courses of each of the two regions of interest (ROIs) after minus
before the intervention] and two indices for the increase of literacy
(letter knowledge/word-reading skills after minus before the inter-
vention). Individual slopes of cortico-subcortical connectivity were
significantly associated with improvement in letter knowledge (r=
0.40, P= 0.014; one-sided Pearsons correlation) and with improvement
in word-reading ability (r=0.38,P= 0.018; one-sided Spearmansrank
We used resting-state fMRI to examine the specific effects of learning
Devanagari script on the functional connectome of illiterate Hindi-
speaking Indian adults within the framework of a controlled longitu-
dinal design. Network centrality of spontaneous hemodynamic activity
significantly increased with training in the bilateral pulvinar nuclei
of the thalamus and the right superior colliculus of the brainstem.
Fig. 2. Learning to read strengthens cortico-subcortical functional connectivity. (A) Voxel-wise functional connectivity map derived from seeding in the significant
degree centrality cluster. The image is thresholded at z= 2.58 (P< 0.005, corrected for cluster size). The color bar indicates the range of zscores. Becoming literate goes
along with increased coupling of BOLD signal time courses between mesencephalic/diencephalic visual nuclei and a single cluster spanning the areas V1, V2, V3, and V4
of the right occipital cortex (MNI coordinates: +24, 81, +15; +24, 93, +12; +33, 90, +3). (B) The group (reading-trained individuals versus untrained illiterates) by time
(before versus after intervention) interaction becomes evident from the box plot, indicating that the functional connectivity is strongly and specifically enhanced in the
group that underwent reading instruction. (C) Line graphs depicting the coefficients of the correlations between the hemodynamic time series separately for each
individual subject, each group, and each time. (D) Mean time series of the BOLD signal for each group and each time.
Skeide et al., Sci. Adv. 2017; 3: e1602612 24 May 2017 3of7
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Moreover, BOLD signal time courses of these subcortical structures
were significantly more strongly coupled with the areas V1 to V4 of
the right occipital cortex after acquiring basic literacy skills. Individ-
ual gains in intrinsic functional connectivity turned out to be signif-
icantly associated with individual gains in letter identification and
word-reading skills.
Currently existing neurobiological models of reading assume that
literacy boosts low-level hemodynamic responses to complex visual
objects in areas V1 to V4 of the occipital cortex (6). Here, we provide
the first evidence for functional neuroplasticity in mesencephalic and
diencephalic nuclei upstream of V1 as a consequence of reading ac-
quisition. These results call for a reconceptualization of the neural basis
of reading by expanding the experimental perspective from one focused
solely on the cortex to one that also includes the subcortical areas asso-
ciated with oculomotor control and selective visuospatial attention.
Nonhuman primate experiments on visual motion perception sug-
gest that the superior colliculi support the initiation of saccadic eye
movements (11). Accordingly, the observed increase in connectomic
centrality of the right superior colliculus in the course of literacy
training might reflect the fine-tuning of oculomotor activity necessary
for guiding fixations through printed text. An explanation for the
effect in the bilateral pulvinar nuclei can be derived from numerous
studies in humans highlighting the central role of these thalamic
structures for selectively allocating attentional resources to visual
stimuli (1216). This is in line with several independent studies sug-
gesting a causal role of visuospatial attention skills for reading acqui-
sition. Namely, it has been repeatedly shown in preliterate children
that visuospatial skills predict reading outcome (17,18). Moreover,
there is evidence that reading abilities can be improved by training
with an action video game that challenges visual attention (19).
If interpreted in light of recent nonhuman primate work, enhanced
functional connectivity between the subcortical nuclei and the right oc-
cipital cortex detected after reading intervention indicates that the pul-
vinar is involved in synchronizing information transmission across the
visual cortex (20,21). Signal exchange between these structures is hy-
pothesized to be located anatomically along the long-distance white
matter fiber tract that directly connects them (22,23).
Literacy-driven functional modulations of the right occipital cortex
were not restricted to V1 and V2, as one would expect for alphabetic
writing systems (24), but extended into V3 and V4. This might be ex-
plained by the nature of the Devanagari script, which is visually more
complex than alphabetic writing systems. Devanagari is written from
left to right and used for over 100 languages other than Hindi (for
example, Bengali, Nepali, and Tibetan) and by hundreds of millions
of people. It is an alpha-syllabic writing system comprising the so-
called aksharas that represent sound simultaneously at the syllable
and phoneme level. Vowels and consonants are, thus, not ordered
sequentially as independent letter units inwords. Devanagari is similar
to alphabetic writing systems in that symbols mostly convey a words
phonology (that is, distinct units that correspond to individual pho-
nemesratherthansyllablesorwords). However, Devanagari is also sim-
ilar to logographic writing systems (for example, Japanese, Chinese) in
that it also consists of visually complex symbols that are larger than pho-
nological units and that are indivisibleinthatsomeofthecomponent
parts (for example, diacritic signs) cannot stand alone. In line with our
finding in Devanagari, fMRI effects in V3 and V4 during print process-
ing are known from Chinese readers (25). Right-lateralized manifesta-
tions of functional plasticity in the occipital cortex after training
reading-related decoding skills have been repeatedly found especially
in comparable samples of illiterate adults reaching modest performance
levels but remain to be illuminated in future studies (3,4).
Previous task-based fMRI experiments have associated the process
of learning to read with increasing BOLD responses in the so-called
visual word form area(VWFA) of the left temporo-occipital fusiform
cortex (2,4). We hypothesize that the high visual processing demands
arising from the complex visuospatial arrangement of Devanagari
characters might have induced a strong training effect in low-level vi-
sual areas (26), and that the potentially more subtle effect of symbolic
learning in the VWFA would not reach statistical significance. Follow-
up studies combining event-related fMRI paradigms with resting-state
fMRI are necessary to confirm this hypothesis. However, we did not
expect to be able to identify the VWFA when seeding in subcortical
nuclei of the visual pathway to examine their resting-state functional
connectivity. The VWFA has been shown repeatedly to be functionally
connected to the dorsal attention network and not to lower-level visual
areas when examining BOLD signals at the low-frequency sampling
range covered in resting-state fMRI (27,28).
Recent cross-sectional MRI studies on adults and school-age chil-
dren have reinvigorated the long-standing view that functional deficits
and structural disruptions of the thalamus might play a role in devel-
opmental dyslexia, the most common learning disorder characterized
by severe difficulties in learning how to read and spell (2932). Our
results indicate that the functional connectivity profile of the thalamus
can change substantially even after 6 months of reading instruction in
adulthood. Hence, beginning readers appear to train their subcortical
sensory and attentional systems intensively. Therefore, one of the core
challenges for the field is to determine whether thalamic abnormalities
are a potential causal factor for developmental dyslexia or just a con-
sequence of the impoverished reading experience of dyslexic individ-
uals. Recent behavioral work suggests that visual motion processing
skills are causally related to literacy acquisition. Specifically, dyslexic
individuals perform such tasks more poorly than age-matched and
reading levelmatched controls (33,34). This could mean that a disrup-
tion of the underlying neural pathway connecting the lateral geniculate
nucleus of the thalamus with V5 might be a contributing cause of dys-
lexia. Whether a similar role can be ascribed to the pathway connecting
the pulvinar nuclei of the thalamus with the occipital cortex must be
determined in follow-up studies. In particular, longitudinal studies
following preschool children are needed to disentangle physiological
causes from consequences arising from impaired literacy acquisition
in scripts carrying both alphabetic and logographic features (35).
Learning-induced changes in coupling of spontaneous functional
responses support the encoding or consolidation of novel experiences
(3638). Specifically, increased connectivity of functionally distinct
areas might reflect the synchronization of excitability states of different
neuronal populations (39). Future work on animal models combining
resting-state fMRI and electrophysiological recordings is needed to
confirm this hypothesis.
Note that the size of the sample investigated, though comparable
to recent fMRI studies of literacy acquisition (4), is nevertheless small.
Another limitation is that the training effects of the intervention
group were compared with a passive, but not an active, control group.
Accordingly, it remains to be shown whether the results reported here
are literacy-specific or a general effect of visual training involving in-
tricate symbols.
In conclusion, we have shown that only 6 months of learning to
read leads to massive macroscopic functional reorganization processes
in the mature human brain. When becoming literate in adulthood,
Skeide et al., Sci. Adv. 2017; 3: e1602612 24 May 2017 4of7
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spontaneous hemodynamic activity of mesencephalic and diencephalic
nuclei is strongly coupled with hemodynamic activity of the occipital
cortex. These findings crucially c omplement current neural concepts of
readingbysuggestingthatliteracyexperience reshapes the earliest visual
computation centers even before reaching the primary visual cortex. It
a consequence of the reduced literacy experience of dyslexic individuals
or a potential cause of their disorder.
Participants were recruited from two villages near the city of Lucknow
in the northern Indian state of Uttar Pradesh as part of a study that
was approved by the ethics committee of the Center of Biomedical
Research, Lucknow. After giving informed consent, 51 healthy right-
handed human volunteers without a known history of psychiatric dis-
ease or neurological condition took part in the reading training and in
the resting-state fMRI experiment. For unknown reasons, 18 partici-
pants did not complete the scanning sessions and were therefore ex-
cluded from further analysis (see Demographic and behavioral data
for more details). Three additional participants were disregarded be-
cause their fMRI data did not pass our quality control procedure (see
MRI datafor more details). Accordingly, 30 participants (mean age,
31.63 years; two males; Table 1) were included in the final behavioral
and neural analyses. At the beginning of the study, all of them self-
reported that they were never taught how to read, spell, or write and
never attended school. Subsequently, they were first assessed for their
actual letter (akshara) knowledge and word-reading skills (Table 1) and
then underwent MRI scanning. Not one of them was able to read more
than eight simple words at the beginning of the study. The participants
were randomly assigned either to the group that received reading
instruction (n= 28 at the beginning of the study; n=21includedin
the final analysis) or to the group that did not receive any instruction
(n= 23 at the beginning of the study; n= 9 included in the final analysis).
Final sample sizes were similar to recent fMRI studies of literacy acqui-
sition (4). Group assignment was based on the following order: The first
subject was assigned to the training group, the next subject to the con-
trol group, the third subject to the training group, and so on. For orga-
nizational reasons, all investigators knew the group allocation during
acquisition and analysis of the data. The instructor was a professional
teacher who followed the locally established method of reading
instruction. During the first month of instruction, reading and writing
of the 46 primary Devanagari characters were taught simultaneously.
Thepracticeofaksharas was followed by the practice of two-syllable
words. Approximately 200 words were taught in the first month. Dur-
ing the second month, participants were taught to read and write simple
sentences containing mostly two-syllable words. In the third month of
instruction, the participants started to learn three-syllable words and
continued to practice reading and writing of simple sentences. For
the remaining 3 months of the program, more complex words and
some basic grammar rules were taught. For example, the participants
learned about the differences between nouns, pronouns, verbs, pro-
verbs, and adjectives and also about basic rules of tense and gender.
At the end of the study, that is, approximately 6 months later (mean
gap, 184 days), participants were first scanned and then tested again
on the same day for their akshara letter knowledge and word-reading
skills. The pretest items (used before the intervention) and posttest items
(used after the intervention) were identical. We cannot exclude the pos-
sibility that the participantsas a side effect of literacywere more fre-
quently exposed to complex pictures (for example, in magazines).
Demographic and behavioral data
Participants were matched for age, gender, handedness, income, num-
ber of literate family members, and nonsymbolic intelligence (Table 1).
Each variable revealed a significant result either in a Kolmogorov-
Smirnov test or in a Shapiro-Wilk test for normality of distribution,
so that nonparametric Mann-Whitney Utests were run to compare
the groups. No significant differences were found for any of the varia-
bles (all z< 1; Table 1). The 18 excluded participants who did not
complete the scanning sessions were significantly younger (z=2.97,
P= 0.003; Mann-Whitney Utest), performed significantly better in
the test of nonsymbolic intelligence (z=2.17,P= 0.030; Mann-
Whitney Utest), and had significantly fewer literate family members
(z=2.54,P= 0.011; Mann-Whitney Utest) compared to the included
30 participants who completed the sessions. The groups showed no
significant difference either in letter knowledge (z=0.47,P= 0.638;
Mann-Whitney Utest) or word-reading (z= 0.62, P= 0.538; Mann-
Whitney Utest) ability at the beginning of the study (see below for
details regarding these measures). Information on age, income, and
number of literate family members was obtained by personal interview.
Right-handedness was also verified in an interview by asking the parti-
cipants which hand they used for common activities (for example,
drawing). Ravens Progressive Matrices were administered to test for
nonverbal abilities.
Two measures of literacy were taken, namely, letter identification
(knowledge of the 46 primary Devanagari characters) and word-
reading ability (knowledge of 86 words of varying syllabic complexity).
The effects of literacy instruction on behavioral performance were sta-
tistically evaluated using SPSS (
spss/) to calculate a 2 × 2 mixed-design ANOVA with time [test
performance before the (non-)intervention versus test performance
after the (non-)intervention] as a within-subjects factor and group (il-
literates who underwent intervention versus illiterates who did not
undergo intervention) as a between-subjects factor. ANOVA is an appro-
priate test here because it has been repeatedly demonstrated to yield valid
results independent of the assumption of normality of data distribution
(40,41), which was violated here according to the Kolmogorov-Smirnov
and Shapiro-Wilk tests. Post hoc, nonparametric Wilcoxon signed-rank
tests were run to compute within-subjectlevel changes in performance.
MRI data
MRI examination was conducted with a 3.0-Tesla Siemens MAGNETOM
Skyra (Siemens AG) whole-body magnetic resonance scanner using a
64radio frequencychannel head coil.
For anatomical localization, T1-weighted three-dimensional
magnetization-prepared rapid-acquisition gradient echo images were
acquired using a pulse sequence with repetition time (TR) = 1.690 ms,
echo time (TE) = 2.60 ms, inversion time (TI) = 1.100 ms, field of view
(FOV) = 256 × 256, matrix size = 256 × 256 × 192, and voxel size = 1.0 ×
1.0 × 1.0 mm
For resting-state fMRI (eyes closed, no active stimulation, and no
explicit task), 150 T2*-weighted gradient echo echo-planar imaging
volumes covering 38 slices were collected by applying a pulse sequence
with TR = 2.400 ms, TE = 30 ms, FOV = 224 × 224, matrix size = 64 ×
The T1 images were visually inspected for artifacts and then segmen-
ted into gray matter, white matter, and cerebrospinal fluid using the
Skeide et al., Sci. Adv. 2017; 3: e1602612 24 May 2017 5of7
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DARTEL algorithm (42) implemented in SPM8 (
spm/software/spm8/). These segmentations served to create individual
tissue masks and a sample-specific template in MNI space.
The fMRI data were preprocessed using the SPM8 software package
( and the DPARSF toolbox
( First, the first four volumes of each scan were dis-
carded to allow for signal equilibration. Second, the images were slice
timecorrected by interpolation and resampling to the slice at the mid
time point of each TR. Third, the images were motion-corrected by
realigning them to the first acquired volume. Fourth, additional motion
correction was carried out by regressing out three translational and
three rotational motion parameters of each volume and its preceding
volume as well as the square of each of these values (43). Mean signals
of the white matter and the cerebrospinal fluid and linear and quadratic
trends were also included in this model to control for physiological
noise induced by respiration and pulsating veins. Fifth, each time series
was temporally bandpass-filtered (0.01 to 0.1 Hz) using an ideal rectan-
gular filter. Sixth, the images were resampled to a spatial resolution of
3.0 × 3.0 × 3.0 mm
and normalized to the sample-specific template in
MNI space. Finally, the images were spatially smoothed with a 4-mm
full width at half maximum Gaussian kernel, resulting in an
average smoothness of 7.0 × 6.9 × 7.0 mm
To account for the confounding effect of residual head motion, we
calculated the framewise displacement (FD) of each individual time
series following the approach introduced by Power et al.(44). Of 33
data sets, 30 did not exceed a single-volume threshold of 0.5981 at
both acquisition time points when determining the 100 volumes with
the lowest FD values. The three data sets violating this criterion were
removed fromthe further analyses. The mean FD of the least motion-
distorted 100 volumes included in the final analyses was as low as
0.1036 (SD, 0.0443) for the first time point and 0.1193 (SD, 0.0600)
for the second time point. Of 6000 volumes, 5394 revealed an FD < 0.2.
Whole-brain functional connectivity was computed using the de-
gree centrality algorithm developed by Zuo et al.(9), which quantifies
connectivity by counting the number of correlations of each voxel with
all voxels at a threshold of r> 0.25 and then assigns this number as a
centrality value to each voxel. This analysis was carried out in MNI
space using a group-average gray matter mask of 67.441 voxels. The
resulting degree centrality images were Fishersr-to-ztransformed
and then statistically analyzed in the framework of the flexible factorial
design implemented in SPM8 running a 2 × 2 mixed-design ANOVA
with time [test performance before the (non-)intervention versus test
performance after the (non-)intervention] as a within-subjects factor
and group (illiterates who underwent intervention versus illiterates
who did not undergo intervention) as a between-subjects factor. Mean
FD values did not differ significantly within groups between time
points (trained individuals: z=0.92,P= 0.357; untrained illiterates:
z= 0.53, P= 0.594; Wilcoxon signed-rank tests) and also not between
groups (time point 1: z= 0.11, P= 0.934; time point 2: z=1.15,P=
0.263; Mann-Whitney Utests) but were nevertheless entered as a nui-
sance covariate of interest into the ANOVA to remove any potential
relations between residual head motion and the effects of interest (45).
When testing for statistical significance, signal variance of the two
groups was not assumed to be equal because group sizes were different.
Accordingly, Pvalues were Greenhouse-Geissercorrected to account
for potential nonsphericity of the data. Clusters, that is, connected vox-
els sharing at least a corner (26 voxels), were multiple-comparison
corrected by combining a type I error threshold of P< 0.005 with a
spatial extent threshold of P< 0.05. The latter threshold was
determined by running 10,000 iterations of a Monte Carlo simulation
as implemented in the AlphaSim tool (,
which revealed a minimum cluster size cutoff of k= 35 voxels (for
the 67.441 gray matter voxels). Note that the size and the smoothness
of the image were determined with SPM8 rather than AlphaSim to
avoid overestimating the level of significance (46). Individual mean z
values of the significant clusters were extracted with the REX toolbox
across the factor levels with SPSS to resolve the effects characterizing
the interaction. A confirmatory leave-one-out cross-validation analysis
was carried out by training a linear support vector machine classifier
(with the goal of distinguishing group membership before and after the
training) first on a random subject before quantifying its performance
on the remaining data sets. In accordance with the number of subjects
in the sample, this procedure was repeated 30 times, each time with a
new assignment of subjects and leaving aside each of the already given
observations. Classification performance was estimated by averaging
the indices obtained on the different repetitions. Statistical significance
was determined nonparametrically by running 10,000 iterations of a
permutation test.
The seed-based voxel-wise functional connectivity analysis (10)w
carried out by extracting the individual means of the BOLD signal time
series from the significant cluster identified with the degree centrality
approach and then calculating their brain-wide correlation maps,
which were finally Fishersr-to-ztransformed. The procedure of
statistical testing was identical to the procedure applied to the degree
centrality maps.
Anatomical identification of all significant clusters was based on the
Harvard-Oxford Subcortical Structural Atlas and the Juelich Histological
Atlas implemented in FSL (47).
Seed-based ROI-wise functional connectivity analyses (10)wererun
by extracting the individual means of the BOLD signal time series from
the two significant clusters obtained from the previous analyses and by
correlating them with each other. Subsequently, the individual correla-
tion coefficients of the BOLD time courses of each of the two ROIs ob-
tained before the (non-)intervention were subtracted from the
coefficients obtained after the (non-)intervention. In addition, the indi-
vidual letter identification and word-reading test scores, respectively,
acquired before the (non-)intervention were subtracted from the scores
obtained after the (non-)intervention. The resulting index of increase of
functional connectivity was correlated separately with the index of in-
crease of letter identification skills (normally distributed data; Pearsons
product-moment correlation coefficient) and the index of increase of
word-reading performance (not normally distributed data; Spearmans
rank correlation coefficient) in SPSS. One-sided Pvalues are reported
because the analyses were carried out under the a priori assumption
that better literacy skills would go along with stronger functional
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Acknowledgments: F.H. would like to thank A. Cutler. Funding: This project was funded by
the Max Planck Society. Author contributions: F.H. designed the research; U.K., R.K.M., V.N.T.,
A.G., and J.P.S. recruited the participants and collected data; M.A.S. performed the analyses;
and M.A.S., F.E., and F.H. wrote the paper. Competing interests: The authors declare that they
have no competing interests. Data and materials availability: All data needed to evaluate
the conclusions in the paper are present in the paper. Additional data related to this paper may
be requested from F.H.
Submitted 22 October 2016
Accepted 23 March 2017
Published 24 May 2017
Citation: M. A. Skeide, U. Kumar, R. K. Mishra, V. N. Tripathi, A. Guleria, J. P. Singh, F. Eisner,
F. Huettig, Learning to read alters cortico-subcortical cross-talk in the visual system of
illiterates. Sci. Adv. 3, e1602612 (2017).
Skeide et al., Sci. Adv. 2017; 3: e1602612 24 May 2017 7of7
on May 25, 2017 from
doi: 10.1126/sciadv.1602612
2017, 3:.Sci Adv
Huettig (May 24, 2017)
Tripathi, Anupam Guleria, Jay P. Singh, Frank Eisner and Falk
Michael A. Skeide, Uttam Kumar, Ramesh K. Mishra, Viveka N.
visual system of illiterates
Learning to read alters cortico-subcortical cross-talk in the
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... Learning to read may result in brain network reorganization (Houde et al., 2010;Martin et al., 2015). In one restingstate functional magnetic resonance imaging (fMRI) study of illiterate adults, Skeide et al. (2017) observed that a 6-month literacy intervention altered the cortico-subcortical crosstalk in the visual system of illiterate individuals. Some studies, including studies based on comparisons between children and adults (Koyama et al., 2020), literacy training studies (Alcauter et al., 2017;Hancock et al., 2017;Koyama et al., 2020;Mohammadi et al., 2020), and child development studies, (Alcauter et al., 2017) also found that cortico-subcortical alterations play an important role at the early stage of learning to read. ...
... The thalamo-occipital circuit is an important visuospatial pathway and involves visual processing and visual pathway reorganization in early reading (Muller-Axt et al., 2017;Skeide et al., 2017;Tschentscher et al., 2019), and its damage can cause blindsight and developmental dyslexia (Rima and Schmid, 2020). Fronto-striatal connectivity is a critical Frontiers in Neuroscience 02 ...
... The second pathway we found was the thalamo-occipital visual pathway formed by the functional connectivity between the right thalamus and right superior occipital gyrus. This was consistent with a previous study that trained illiterate individuals to be literate and found that training improved the degree of the thalamic activity and the strength of its connection to the occipital lobe (Skeide et al., 2017). In addition, we further investigated the predictive relationship between reading ability and the thalamo-occipital pathway and found that the predictive effect of reading on the thalamo-occipital pathway was unidirectional in both beginning and intermediate readers, and the predictive effect decreased gradually with reading ability. ...
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... To provide a first exploration , we focus only on education in this paper but encourage future authors to focus on other dimensions of SEP (see also the Discussion).A large body of research explored how education acts as an important determinant of health. At the individual level, education leads to lasting cognitive changes, which enhances the ability for abstract thinking, sense of personal control, and motivation to solve problems and plan for the future (Kandel, 2007;van der Pol, 2011;Skeide et al., 2017;Heckman, Humphries, and Veramendi, 2017). Consequently, more educated individuals are better at identifying health risks and adapt their behaviour to minimise exposure to health hazards and pursue better health (Baker, 2014). ...
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... While it is undeniable that learning to read induces widespread changes in the visual system, both in the cortex and even in its functional connections to subcortical regions (Dehaene et al., 2015;Skeide et al., 2017), this in no way proves that visual factors do not cause reading problems; if reading development so greatly affects the visual system, this only further emphasizes how heavily reading relies on this system. In fact, it is already well-established that specific reading problems can appear after damage to the visual system (Adler, 1944(Adler, , 1950Sparr et al., 1991). ...
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... In addition to the above cortical structures, we also found subcortical regions modestly related to early RfP including ventral DC, thalamus and putamen regions. A previous study has also found that literacy-induced neuroplasticity improves functional connectivity between the occipital cortex and subcortical regions in the midbrain and the thalamus, which is not just restricted to the cortex, after half-a-year of literacy training in adults (Skeide et al., 2017). Analysis across multiple cohorts has also indicated that patients with attention disorder have decreased subcortical regions including the caudate and putamen, as well as whole ICV (Hoogman et al., 2017). ...
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... As vOT becomes more specialized for reading, children become increasingly automatic in their word identification. The majority of the previous studies demonstrating links between reading proficiency and vOT specialization have focused on cross-sectional comparisons (e.g., Carreiras et al., 2009;Church et al., 2008;Dehaene et al., 2010;Turkeltaub et al., 2003)-or lower-level reading skills (Ben-Shachar et al., 2011;Maurer et al., 2006Maurer et al., , 2011Skeide et al., 2017). Our findings are important because they demonstrate that variable and individually determined increased fluency demands modulate the specialization of vOT for reading only after word identification proficiency is achieved. ...
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Developmental dyslexia is a neurodevelopmental disorder characterized by an unexpected impairment in literacy acquisition leading to specific poor academic achievement and possible secondary symptoms. The multi-level framework of developmental dyslexia considers five levels of a causal pathway on which a given genotype is expressed and hierarchically transmitted from one level to the next under the increasing influence of individual learning-relevant traits and environmental factors moderated by cultural conditions. These levels are the neurobiological, the information processing and the skill level (prerequisites and acquisition of literacy skills), the academic achievement level and the level of secondary effects. Various risk factors are present at each level within the assumed causal pathway and can increase the likelihood of exhibiting developmental dyslexia. Transition from one level to the next is neither unidirectional nor inevitable. This fact has direct implications for prevention and intervention which can mitigate transitions from one level to the next. In this paper, various evidence-based theories and findings regarding deficits at different levels are placed in the proposed framework. In addition, the moderating effect of cultural impact at and between information processing and skill levels are further elaborated based on a review of findings regarding influences of different writing systems and orthographies. These differences impose culture-specific demands for literacy-specific cognitive procedures, influencing both literacy acquisition and the manifestation of developmental dyslexia.
According to established cognitive neuroscience knowledge based on studies on disabled and typically developing readers, reading is based on a dual-stream model in which a phonological-dorsal stream (left temporo-parietal and inferior frontal areas) processes unfamiliar words and pseudowords, whereas an orthographic-ventral stream (left occipito-temporal and inferior frontal areas) processes known words. However, correlational neuroimaging, causal longitudinal, training, and pharmacological studies have suggested the critical role of visuo-spatial attention in reading development. In a double blind, crossover within-subjects experiment, we manipulated the neuromodulatory effect of a short-term bilateral stimulation of posterior parietal cortex (PPC) by using active and sham tRNS during reading tasks in a large sample of young adults. In contrast to the dual-stream model predicting either no effect or a selective effect on the stimulated phonological-dorsal stream (as well as to a general multisensory effect on both reading streams), we found that only word-reading performance improved after active bilateral PPC tRNS. These findings demonstrate a direct neural connectivity between the PPC, controlling visuo-spatial attention, and the ventral stream for visual word recognition. These results support a neurobiological model of reading where performance of the orthographic-ventral stream is boosted by an efficient deployment of visuo-spatial attention from bilateral PPC stimulation.
In this handbook, the world's leading researchers answer fundamental questions about dyslexia and dyscalculia based on authoritative reviews of the scientific literature. It provides an overview from the basic science foundations to best practice in schooling and educational policy, covering research topics ranging from genes, environments, and cognition to prevention, intervention and educational practice. With clear explanations of scientific concepts, research methods, statistical models and technical terms within a cross-cultural perspective, this book will be a go-to reference for researchers, instructors, students, policymakers, educators, teachers, therapists, psychologists, physicians and those affected by learning difficulties.
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Significance Functional MRI (fMRI) is 25 years old, yet surprisingly its most common statistical methods have not been validated using real data. Here, we used resting-state fMRI data from 499 healthy controls to conduct 3 million task group analyses. Using this null data with different experimental designs, we estimate the incidence of significant results. In theory, we should find 5% false positives (for a significance threshold of 5%), but instead we found that the most common software packages for fMRI analysis (SPM, FSL, AFNI) can result in false-positive rates of up to 70%. These results question the validity of a number of fMRI studies and may have a large impact on the interpretation of weakly significant neuroimaging results.
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Background: It is well established that phonological awareness, print knowledge and rapid naming predict later reading difficulties. However, additional auditory, visual and motor difficulties have also been observed in dyslexic children. It is examined to what extent these difficulties can be used to predict later literacy difficulties. Method: An unselected sample of 267 children at school entry completed a wide battery of tasks associated with dyslexia. Their reading was tested 2, 3 and 4 years later and poor readers were identified (n = 42). Logistic regression and multiple case study approaches were used to examine the predictive validity of different tasks. Results: As expected, print knowledge, verbal short-term memory, phonological awareness and rapid naming were good predictors of later poor reading. Deficits in visual search and in auditory processing were also present in a large minority of the poor readers. Almost all poor readers showed deficits in at least one area at school entry, but there was no single deficit that characterised the majority of poor readers. Conclusions: Results are in line with Pennington's () multiple deficits view of dyslexia. They indicate that the causes of poor reading outcome are multiple, interacting and probabilistic, rather than deterministic.
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Unlabelled: The pulvinar is the largest nucleus in the primate thalamus and contains extensive, reciprocal connections with visual cortex. Although the anatomical and functional organization of the pulvinar has been extensively studied in old and new world monkeys, little is known about the organization of the human pulvinar. Using high-resolution functional magnetic resonance imaging at 3 T, we identified two visual field maps within the ventral pulvinar, referred to as vPul1 and vPul2. Both maps contain an inversion of contralateral visual space with the upper visual field represented ventrally and the lower visual field represented dorsally. vPul1 and vPul2 border each other at the vertical meridian and share a representation of foveal space with iso-eccentricity lines extending across areal borders. Additional, coarse representations of contralateral visual space were identified within ventral medial and dorsal lateral portions of the pulvinar. Connectivity analyses on functional and diffusion imaging data revealed a strong distinction in thalamocortical connectivity between the dorsal and ventral pulvinar. The two maps in the ventral pulvinar were most strongly connected with early and extrastriate visual areas. Given the shared eccentricity representation and similarity in cortical connectivity, we propose that these two maps form a distinct visual field map cluster and perform related functions. The dorsal pulvinar was most strongly connected with parietal and frontal areas. The functional and anatomical organization observed within the human pulvinar was similar to the organization of the pulvinar in other primate species. Significance statement: The anatomical organization and basic response properties of the visual pulvinar have been extensively studied in nonhuman primates. Yet, relatively little is known about the functional and anatomical organization of the human pulvinar. Using neuroimaging, we found multiple representations of visual space within the ventral human pulvinar and extensive topographically organized connectivity with visual cortex. This organization is similar to other nonhuman primates and provides additional support that the general organization of the pulvinar is consistent across the primate phylogenetic tree. These results suggest that the human pulvinar, like other primates, is well positioned to regulate corticocortical communication.
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The neural basis of specific reading disability (SRD) remains only partly understood. A dozen studies have used voxel-based morphometry (VBM) to investigate gray matter volume (GMV) differences between SRD and control children, however, recent meta-analyses suggest that few regions are consistent across studies. We used data collected across three countries (France, Poland, and Germany) with the aim of both increasing sample size (236 SRD and controls) to obtain a clearer picture of group differences, and of further assessing the consistency of the findings across languages. VBM analysis reveals a significant group difference in a single cluster in the left thalamus. Furthermore, we observe correlations between reading accuracy and GMV in the left supramarginal gyrus and in the left cerebellum, in controls only. Most strikingly, we fail to replicate all the group differences in GMV reported in previous studies, despite the superior statistical power. The main limitation of this study is the heterogeneity of the sample drawn from different countries (i.e., speaking languages with varying orthographic transparencies) and selected based on different assessment batteries. Nevertheless, analyses within each country support the conclusions of the cross-linguistic analysis. Explanations for the discrepancy between the present and previous studies may include: (1) the limited suitability of VBM to reveal the subtle brain disruptions underlying SRD; (2) insufficient correction for multiple statistical tests and flexibility in data analysis, and (3) publication bias in favor of positive results. Thus the study echoes widespread concerns about the risk of false-positive results inherent to small-scale VBM studies. Hum Brain Mapp 36:1741–1754, 2015.
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Recent years have seen the publication of a range of new theories suggesting that the basis of dyslexia might be sensory dysfunction. In this Opinion article, the evidence for and against several prominent sensory theories of dyslexia is closely scrutinized. Contrary to the causal claims being made, my analysis suggests that many proposed sensory deficits might result from the effects of reduced reading experience on the dyslexic brain. I therefore suggest that longitudinal studies of sensory processing, beginning in infancy, are required to successfully identify the neural basis of developmental dyslexia. Such studies could have a powerful impact on remediation.
Diversity is the basis of fitness selection. Although the genome of an individual is considered to be largely stable, there is theoretical and experimental evidence - both in model organisms and in humans - that genetic mosaicism is the rule rather than the exception. The continuous generation of cell variants, their interactions and selective pressures lead to life-long tissue dynamics. Individuals may thus enjoy 'clonal health', defined as a clonal composition that supports healthy morphology and physiology, or suffer from clonal configurations that promote disease, such as cancer. The contribution of mosaicism to these processes starts during embryonic development. In this Opinion article, we argue that the road to cancer might begin during these early stages.
Although impaired auditory–phonological processing is the most popular explanation of developmental dyslexia (DD), the literature shows that the combination of several causes rather than a single factor contributes to DD. Functioning of the visual magnocellular–dorsal (MD) pathway, which plays a key role in motion perception, is a much debated, but heavily suspected factor contributing to DD. Here, we employ a comprehensive approach that incorporates all the accepted methods required to test the relationship between the MD pathway dysfunction and DD. The results of 4 experiments show that (1) Motion perception is impaired in children with dyslexia in comparison both with age-match and with reading-level controls; (2) pre-reading visual motion perception—independently from auditory–phonological skill—predicts future reading development, and (3) targeted MD trainings—not involving any auditory–phonological stimulation—leads to improved reading skill in children and adults with DD. Our findings demonstrate, for the first time, a causal relationship between MD deficits and DD, virtually closing a 30-year long debate. Since MD dysfunction can be diagnosed much earlier than reading and language disorders, our findings pave the way for low resource-intensive, early prevention programs that could drastically reduce the incidence of DD.
The human pulvinar is the largest thalamic area in terms of size and cortical connectivity. Although much is known about regional pulvinar structural anatomy, relatively little is known about pulvinar functional anatomy in humans. Cooccurrence of experimentally induced brain activity is a traditional metric used to establish interregional brain connectivity and forms the foundation of functional neuroimaging connectivity analyses. Because functional neuroimaging studies report task-related coactivations within a standardized space, meta-analysis of many whole-brain studies can define the brain's interregional coactivation across many tasks. Such an analysis can also detect and define variations in functional coactivations within a particular region. Here we use coactivation profiles reported in ∼ 7,700 functional neuroimaging studies to parcellate and define the pulvinar's functional anatomy. Parcellation of the pulvinar's coactivation profile identified five clusters per pulvinar of distinct functional coactivation. These clusters showed a high degree of symmetry across hemispheres and correspondence with the human pulvinar's cytoarchitecture. We investigated the functional coactivation profiles of each resultant pulvinar cluster with meta-analytic methods. By referencing existent neuroimaging and lesion-deficit literature, these profiles make a case for regional pulvinar specialization within the larger human attention-controlling network. Reference to this literature also informs specific hypotheses that can be tested in subsequent studies in healthy and clinical populations. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
The acquisition of literacy transforms the human brain. By reviewing studies of illiterate subjects, we propose specific hypotheses on how the functions of core brain systems are partially reoriented or 'recycled' when learning to read. Literacy acquisition improves early visual processing and reorganizes the ventral occipito-temporal pathway: responses to written characters are increased in the left occipito-temporal sulcus, whereas responses to faces shift towards the right hemisphere. Literacy also modifies phonological coding and strengthens the functional and anatomical link between phonemic and graphemic representations. Literacy acquisition therefore provides a remarkable example of how the brain reorganizes to accommodate a novel cultural skill.