RESEARCH ARTICLE

Mathematical learning deficits originate in

early childhood from atypical development of
a frontoparietal brain network
Ulrike Kuhl ID1,2, Sarah Sobotta1, Legascreen Consortium¶, Michael A. Skeide ID1*

1 Research Group Learning in Early Childhood, Max Planck Institute for Human Cognitive and Brain
Sciences, Leipzig, Germany, 2 Machine Learning Group, Faculty of Technology, Bielefeld University,
Bielefeld, Germany

a1111111111 ¶ Membership of the Legascreen Consortium is provided in the Acknowledgments.

a1111111111 * skeidelab@gmail.com
a1111111111
a1111111111
a1111111111
Abstract
Mathematical
AU : Pleaseconfirmthatallheadinglevelsarerepresentedcorrectly:
learning deficits are defined as a neurodevelopmental disorder (dyscalculia)
in the International Classification of Diseases. It is not known, however, how such deficits
OPEN ACCESS emerge in the course of early brain development. Here, we conducted functional and struc-
Citation: Kuhl U, Sobotta S, Legascreen tural magnetic resonance imaging (MRI) experiments in 3- to 6-year-old children without for-
Consortium, Skeide MA (2021) Mathematical mal mathematical learning experience. We followed this sample until the age of 7 to 9 years,
learning deficits originate in early childhood from identified individuals who developed deficits, and matched them to a typically developing
atypical development of a frontoparietal brain
control group using comprehensive behavioral assessments. Multivariate pattern classifica-
network. PLoS Biol 19(9): e3001407. https://doi.
org/10.1371/journal.pbio.3001407 tion distinguished future cases from controls with up to 87% accuracy based on the regional
functional activity of the right posterior parietal cortex (PPC), the network-level functional
Academic Editor: Andreas Nieder, Universität
Tübingen, GERMANY activity of the right dorsolateral prefrontal cortex (DLPFC), and the effective functional and
structural connectivity of these regions. Our results indicate that mathematical learning defi-
Received: February 15, 2021
cits originate from atypical development of a frontoparietal network that is already detectable
Accepted: September 6, 2021
in early childhood.
Published: September 30, 2021

Copyright: © 2021 Kuhl et al. This is an open

access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original Introduction
author and source are credited. Developmental learning disorder with impairment in mathematics (ICD-11 6A03.2 https://
Data Availability Statement: All relevant data are icd.who.int, hereafter: dyscalculia) occurs in as much as 3% to 7% of the population [1].
within the paper and its Supporting Information Affected individuals suffer from devastating consequences for educational opportunity, psy-
files. chosocial well-being, mental health, and professional achievement [2,3].
Funding: This work was supported by a grant of Like other developmental disorders such as attention-deficit/hyperactivity disorder and
the Max Planck Society and the Fraunhofer Society autism spectrum disorder, dyscalculia is classified as a neurodevelopmental disorder. Previous
(M.FE.A.NEPF0001), by funding for the project ITS. work in 11- to 12-year-old children identified hemodynamic underactivations of parietal and
ML as part of the ICT 2020 Program financed by
prefrontal cortices during numerosity comparison as the functional neural correlates of dyscal-
the Federal Ministry of Education and Research
Germany (BMBF), by the Project Management
culia [4]. Additional observation and intervention studies and meta-analyses in children con-
Agency of the German Aerospace Center (DLR) (U. sistently identified these regions as a canonical mathematical information processing network
K.), and by a grant of the German Research connected by the superior longitudinal fasciculus (SLF) [5–8].

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PLOS BIOLOGY Early childhood sources of math deficits in the developing brain

Foundation (Heisenberg Program Grant awarded to Compared to other neurodevelopmental learning disorders, like dyslexia, the brain basis of
M.A.S.). The funders had no role in study design, dyscalculia is still strongly understudied [9]. In particular, the current lack of longitudinal
data collection and analysis, decision to publish, or
studies following children before they undergo mathematical instruction limits our under-
preparation of the manuscript.
standing of the actual developmental origins of dyscalculia. Such preinstruction studies are
Competing interests: The authors have declared considered as the gold standard approach to disentangle potential predispositions for develop-
that no competing interests exist.
ing a learning disorder from the qualitatively and quantitatively different learning experience
Abbreviations: AUCSF,:cerebrospinal fluid; DLPFC, that affected individuals have [10].
Anabbreviationlisthasbeencompiledforthoseusedthroughoutthetext:Pleaseverifythatallentriesarecorrect:
dorsolateral prefrontal cortex; FWHM, full width at In the present study, a sample of 3- to 6-year-old children without formal mathematical
half maximum; GM, gray matter; IQ, intelligence
learning experience underwent functional and structural magnetic resonance imaging (MRI)
quotient; LQ, laterality quotient; MNI, Montreal
Neurological Institute; MRI, magnetic resonance and was then followed until the age of 7 to 9 years (second grade in school) when they were
imaging; PC, precuneus; PPC, posterior parietal comprehensively assessed for mathematical and other cognitive abilities. We identified 15 chil-
cortex; ROI, region of interest; SD, standard dren who developed dyscalculia according to an operational definition (1 standard deviation
deviation; SLF, superior longitudinal fasciculus; [SD] below the math performance of a reference population). These children were matched to
WISC-IV, Wechsler Intelligence Scale for Children;
15 typically developing children to minimize differences in age, sex, handedness, maternal
WM, white matter.
education, language ability, nonverbal intelligence quotient (IAU Q), and
: PleasenotethatIQhasbeendefinedasin
verbal short-term mem-
ory. A priori power analyses based on effect sizes of previously published studies revealed
power levels of 0.96 to 0.99 for our sample.
Our starting point was to explore group differences in spontaneous resting-state hemody-
namic activity at the regional level (amplitude of low-frequency fluctuations and regional
homogeneity) and at the network level (degree centrality). Although the consistent results
reported in the literature allowed us to generate anatomically specific hypotheses, we did not
initially constrain our analysis to predefined regions of interest. Instead, to account for the
lack of groundwork on the specific population of young unschooled children, we conducted
anatomically unbiased whole-brain analyses. To maximize the sensitivity and specificity of the
group classification, we ran multivariate pattern analyses following a searchlight-based
approach. Post hoc, we also examined whether the classification results were driven by a par-
ticular component of mathematical cognition (visuospatial numerosity detection and calcula-
tion problem solving). The next step was an effective functional connectivity (Granger
causality) analysis designed to find out whether causal interactions between nodes of the math-
ematical processing network differed between children who developed dyscalculia and typical
controls. Finally, based on diffusion-weighted MRI data, we also reconstructed white matter
(WM) fiber pathways connecting these nodes and tested for group differences in streamline
density.
Following the available results for older children already suffering from dyscalculia, we
expected significant functional and structural differences compared to controls in the canoni-
cal mathematical processing network comprising parietal and prefrontal cortices and their
structural connection via the SLF.

Results
A priori power analyses
The statistical power of our resting-state fMRI analysis was estimated based on a previous
study comparing 7- to 11-year-old schoolchildren with dyscalculia (n = 15) with typical con-
trols (n = 16) [11]. In this study, differences with respect to the coupling of hemodynamic acti-
vation time courses revealed a large effect size (Cohen’s d = 1.44) in the right posterior parietal
cortex (PPC). According to an a priori power analysis based on the difference between 2 inde-
pendent means, these effects can be replicated at a power level of 0.96 assuming a corrected
threshold of P < 0.05 in the present sample of children with dyscalculia (n = 15) and typical
controls (n = 15).

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PLOS BIOLOGY Early childhood sources of math deficits in the developing brain

Table 1. Sample characteristics.

Dyscalculia group Control group Comparison9
1
Age 4 y 11 m ± 8 m 5y0m±9m d = 0.24 | P = 0.699
(mean ± SD2 | min–max) 3 y 11 m–6 y 1 m 3 y 11 m–6 y 0 m
Sex (male | female) 4 | 11 6|9 d = 0.69 | P = 0.699
Handedness (LQ3 mean ± SD | right | ambidextrous | left) 71 ± 35 65 ± 40 d = 0.04 | P = 0.899
14 | 0 | 1 13 | 1 | 1
Maternal education4 4.47 ± 1.19 4.27 ± 1.39 d = 0.20 | P = 0.591
(mean ± SD | min–max) 3–6 3–7
Language ability5 56.13 ± 24.17 57.07 ± 5.74 d = 0.24 | P = 0.517
(mean ± SD | min–max) 0–100 49–68
Nonverbal IQ6 96.73 ± 10.44 98.87 ± 11.91 d = 0.19 | P = 0.606
(mean ± SD | min–max) 76–111 81–125
Verbal short-term memory7 9.13 ± 2.30 8.80 ± 2.24 d = 0.24 | P = 0.525
(mean ± SD | min–max) 6–15 6–13
Math ability8 9.40 ± 4.78 67.93 ± 26.45
(mean ± SD | min–max) 1–16 31–99
1
Age in years (y) and months (m) at which children underwent MRI.
2
Standard deviation.
3
LQ (custom version of the Edinburgh Handedness Inventory adapted for children).
4
Combined score of mother’s school education (4-point scale: no degree: 0 points; German “Abitur” (high school diploma/A level): 3 points) and vocational
qualification (5-point scale: no qualification: 0 points; German “Habilitation” (postdoctoral academic qualification): 4 points) (self-designed custom questionnaire).
5
Standard scores (T) with mean and SD = 50 ± 10 (German sentence comprehension test for children (TSVK)).
6
Standard scores with mean and SD = 100 ± 15 (WPPSI-III).
7
Raw scores of a number sequence recall task, sequence length increases every 3 items from 2 to maximally 9 until all 3 items of a length are recalled incorrectly,
children receive a point for each correctly recalled number sequence (K-ABC).
8
Percentile ranks (HRT); group comparison statistic not reported to avoid circularity.
9
Effect size (Cohen’s d) | P value (categorical data: FAU
isher: exact
PleasenotethatasperPLOSstyle;
test, normally distributed continuous data: Student t test, not normally distributed continuous data:
testsshouldnotbeinpossessiveform:
Wilcoxon signed-rank test).
HAU
RT, Heidelberg
: AbbreviationlistshavebeencompiledforthoseusedthroughoutTables1
calculation test; IQ, intelligence quotient; K-ABC, Kaufman Assessment
4:Pleaseverifythatallentriesarecorrect:
Battery for Children; LQ, laterality quotient; MRI, magnetic resonance
imaging; WPPSI-III, Wechsler Preschool and Primary Scale of Intelligence.

https://doi.org/10.1371/journal.pbio.3001407.t001

We conducted a similar a priori power analysis for our diffusion-weighted MRI analysis
based on a previous study comparing 8- to 11-year-old schoolchildren with dyscalculia
(n = 15) with typical controls (n = 15) [12]. The effect size of the reported differences in WM
connectivity of the right SLF was large (Cohen’s d = 1.50). In the current sample, this effect
can be replicated at a power level of 0.99 given a corrected threshold of P < 0.05.

Sample characteristics
Children who developed dyscalculia did not differ from typically developing matched controls
in terms of age, sex, handedness, maternal education, language ability, nonverbal IQ, and verbal
short-term memory (all d < 0.69, all P > 0.517, assessed at baseline in kindergarten). However,
the math ability of children who developed dyscalculia was significantly lower compared to typi-
cal controls (visuospatial numerosity detection: d = 2.85; calculation problem solving: d = 2.29;
all P < 0.001, assessed at follow-up in school). All sample characteristics are specified in Table 1.

Regional functional activity

As a first step, we explored at the whole-brain level whether regional hemodynamic activity in
children who went on to develop dyscalculia differed from typically developing children. Our

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PLOS BIOLOGY Early childhood sources of math deficits in the developing brain

Fig 1. Regional functional classification results. The color bar indicates the peak accuracy for the classification of children with dyscalculia
versus typical controls (P < 0.001, corrected by permutation testing) based on the amplitude of low-frequency fluctuations and the regional
homogeneity of the signals. The numerical data used in this figure are included in S1 Data.
https://doi.org/10.1371/journal.pbio.3001407.g001

classifier was able to significantly distinguish between the groups based on the amplitude of
low-frequency fluctuations and the regional homogeneity of the signals. Peak classification
accuracy for the amplitude of low-frequency fluctuations was 86.67% in the right PPC and
80% in the right precuneus (PC) (P < 0.001, corrected by permutation testing) (Fig 1A,
Table 2). Peak classification accuracy for regional homogeneity was 86.67% in the right PC
and the left dorsolateral prefrontal cortex (DLPFC), 83.34% in the right and left PPC and the
left DLPFC, and 76.67% in the left frontal pole (P < 0.001, corrected by permutation testing)
(Fig 1B, Table 2).

Network-level functional connectivity

Our next step was to explore whether also the network-level hemodynamic activity of the
future dyscalculia group differed from controls. To this end, we examined the functional
connectivity between each voxel and all other voxels of the brain without predefining seed
regions by computing whole-brain degree centrality maps. These maps revealed a peak
classification accuracy of 86.67% in the right orbitofrontal cortex and 83.34% in the right
DLPFC, the left PC and the right cuneus (P < 0.001, corrected by permutation testing)
(Fig 2, Table 3).

Table 2. Regional functional classification results.

Amplitude of low-frequency fluctuations
Size (voxels) Size (mm3) Peak accuracy (%) Sensitivity at peak Specificity at peak MNI coordinates xyz Anatomical location
25 900 86.67 86.67 86.67 +30 −54 +44 PPC
27 972 80.00 73.34 86.67 +12 −63 +46 PC
Regional homogeneity
Size (voxels) Size (mm3) Peak accuracy (%) Sensitivity at peak Specificity at peak MNI coordinates xyz Anatomical location
40 1,440 86.67 86.67 86.67 +12 −51 +45 PC
32 1,152 86.67 86.67 86.67 −24 +12 +41 DLPFC
29 1,044 83.34 80.00 86.67 +30 −45 +46 PPC
29 1,044 83.34 80.00 86.67 −17 −62 +42 PPC
27 972 83.34 80.00 86.67 −45 +24 +25 DLPFC
22 792 76.67 66.67 86.67 −27 +54 −02 Frontal pole

DLPFC, dorsolateral prefrontal cortex; MNI, Montreal Neurological Institute; PC, precuneus; PPC, posterior parietal cortex.

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PLOS BIOLOGY Early childhood sources of math deficits in the developing brain

Fig 2. Network-level functional classification results. The color bar indicates the peak accuracy for the classification
of children with dyscalculia versus typical controls (P < 0.001, corrected by permutation testing) based on whole-brain
functional connectivity (degree centrality). The numerical data used in this figure are included in S2 Data.
https://doi.org/10.1371/journal.pbio.3001407.g002

Functional dissociation of cognitive components

The test used to determine dyscalculia combines 2 fundamental components of mathematical
cognition, namely, visuospatial numerosity detection and calculation problem solving.
Accordingly, we wanted to find out whether the reported classification results were driven by
region-specific associations with a particular component. Following a recent meta-analysis of
mathematical processing in children, we focused on the cluster in the right PPC, a region that
was most strongly associated with numerosity, and on the clusters in the left and right DLPFC,
a region that was most strongly associated with calculation [5]. We found that a significantly
higher proportion of variance in visuospatial numerosity detection (R2 = 0.20) compared to
calculation problem solving (R2 = 0.05) was explained by the amplitude of low-frequency fluc-
tuations of the right PPC (Cohen’s d = 0.90, P = 0.015, family-wise error corrected), but not by
the regional homogeneity of the right PPC (Cohen’s d = 0.67, P = 0.061, family-wise error cor-
rected). Additionally, a significantly higher proportion of variance in calculation problem solv-
ing (R2 = 0.64) compared to visuospatial numerosity detection (R2 = 0.57) was explained by
the degree centrality of the right DLPFC (Cohen’s d = 0.49, P = 0.017, family-wise error cor-
rected), but not by the regional homogeneity of the left DLPFC (Cohen’s d = 0.26, P = 0.306).

Effective functional connectivity

Building on these results, we also investigated whether the causal interaction between the PPC
and the DLPFC differed between future dyscalculics and typical controls. To this end, we com-
pared Granger causality indices quantifying the linear directional influence of one hemody-
namic time series onto the other. Compared to children who developed dyscalculia, control
children showed a significantly stronger influence of the right PPC on the right DLPFC (pair

Table 3. Network-level functional classification results.

Size (voxels) Size (mm3) Peak accuracy (%) Sensitivity at peak Specificity at peak MNI coordinates xyz Anatomical location
31 1,116 86.67 93.34 80.00 +03 +24 −18 Orbitofrontal cortex
68 2,448 83.34 80.00 86.67 +45 +27 +30 DLPFC
46 1,656 83.34 93.34 73.34 −15 −57 +25 PC
44 1,586 83.34 86.67 80.00 +18 −72 +30 Cuneus

DLPFC, dorsolateral prefrontal cortex; MNI, Montreal Neurological Institute; PC, precuneus.

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PLOS BIOLOGY Early childhood sources of math deficits in the developing brain

Fig 3. Effective connectivity differences. Granger causality indices for pairs of regions of interest derived from (A) the regional
homogeneity of the left PPC and the left DLPFC, (B) the amplitude of low-frequency fluctuations of the right PPC and the degree centrality
of the right DLPFC, and (C) the regional homogeneity of the right PPC and the degree centrality of the right DLPFC. Arrows indicate the
direction of the influence of one hemodynamic time series onto the other. Vertical lines at the top and the bottom of the bars depict the SD.
Horizontal lines within the bars represent the group median. Dots denote single cases that are more than 1.5 SDs away from the group
mean. Asterisks indicate significant differences between children with dyscalculia and controls at a threshold of P < 0.05 (family-wise error
corrected). The numerical data used in this figure are included in S3 Data. DAU
LPFC,: AbbreviationlistshavebeencompiledforthoseusedthroughoutFigs3and4
dorsolateral prefrontal cortex; PPC, posterior parietal
cortex.
https://doi.org/10.1371/journal.pbio.3001407.g003

of clusters derived from the regional homogeneity of the right PPC and the degree centrality of
the right DLPFC: Cohen’s d = 1.41, P = 0.004, family-wise error corrected; pair of clusters
derived from the amplitude of low-frequency fluctuations of the right PPC and the degree cen-
trality of the right DLPFC: Cohen’s d = 1.11, P = 0.030, family-wise error corrected) and partly
also in the opposite direction (PPC cluster derived from regional homogeneity: Cohen’s
d = 1.35, P = 0.013, family-wise error corrected; PPC cluster derived from the amplitude of
low-frequency fluctuations: Cohen’s d = 0.85, P = 0.186, family-wise error corrected). No sig-
nificant differences in both directions were observed for the clusters derived from the regional
homogeneity of the left PPC and the left DLPFC (all Cohen’s d < 0.26) (Fig 3).

Structural connectivity
Finally, we examined differences in structural connectivity within the right SLF, the WM fiber
tract connecting the PPC and the DLPFC [6]. In this analysis, we focused on a streamline den-
sity index since our searchlight-based multivariate pattern analysis approach required a three-
dimensional tract reconstruction as a search space. The classification of children that devel-
oped dyscalculia versus typically developing children yielded a peak accuracy of 77.78% when
seeding from the PPC cluster derived from the amplitude of low-frequency fluctuations and a
peak accuracy of 81.48% when seeding from the PPC cluster derived from regional homogene-
ity (all P < 0.001, corrected by permutation testing) (Fig 4, Table 4).

Discussion
In this study, we investigated the neurodevelopmental predisposition for dyscalculia using
functional and structural MRI data of 3- to 6-year-old children without formal mathematical

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PLOS BIOLOGY Early childhood sources of math deficits in the developing brain

Fig 4. Structural connectivity classification results. The color bar indicates the peak accuracy for the classification of
children with dyscalculia versus typical controls (P < 0.001, corrected by permutation testing) based on the structural
connectivity (streamline density) of the right SLF connecting the right PPC and the right DLPFC. The numerical data
used in this figure are included in S4 Data. DLPFC, dorsolateral prefrontal cortex; PPC, posterior parietal cortex; SLF,
superior longitudinal fasciculus.
https://doi.org/10.1371/journal.pbio.3001407.g004

learning experience who either went on to develop the disorder or not. These 2 groups were
significantly differentiated based on the regional functional activity of the right PPC, the net-
work-level functional activity of the right DLPFC, and the effective functional and structural
WM connectivity of both regions.

Role of the frontoparietal system for typical and atypical mathematical

learning
Right PPC dysfunction is a prime candidate for dyscalculia since this region is known to
underlie visuospatial numerosity detection in early childhood and possibly already in infancy
[13–15]. Our data confirm this notion and provide evidence for a dissociation between the
prediction of numerosity detection skills from parietal cortex activity and the prediction of cal-
culation problem solving skills from prefrontal cortex activity. This dissociation is supported

Table 4. Structural connectivity classification results.

Streamline density of the SLF1
Size (voxels) Size (mm3) Peak accuracy (%) Sensitivity at peak Specificity at peak MNI coordinates xyz Anatomical location
46 46 77.78 86.67 66.67 +25 −15 +37 SLF
Streamline density of the SLF2
Size (voxels) Size (mm3) Peak accuracy (%) Sensitivity at peak Specificity at peak MNI coordinates xyz Anatomical location
10 10 81.48 86.67 75.00 +18 −17 +34 SLF
17 17 77.67 93.34 58.34 +35 −14 +26 SLF
1
Cluster derived from the amplitude of low-frequency fluctuations.
2
Cluster derived from regional homogeneity.
MNI, Montreal Neurological Institute; SLF, superior longitudinal fasciculus.

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PLOS BIOLOGY Early childhood sources of math deficits in the developing brain

by single-cell recordings in nonhuman primates showing that parietal neurons respond signifi-
cantly earlier to numerosity than prefrontal neurons [16,17]. Accordingly, the prefrontal cor-
tex is thought to receive numerosity information from the parietal cortex for further goal-
directed processing [16,17]. Our effective connectivity results suggest that a reduction of this
parietal-to-frontal numerosity information transfer is a central neurobiological predisposition
for developing dyscalculia. At the same time, our data indicate that, to a lesser degree, the fron-
tal-to-parietal retrieval of this information also seems to be hampered in children that are pre-
disposed for dyscalculia. While these interpretations remain to be verified in a task-based
fMRI experiment, they provide a plausible possible explanation for the hallmark behavioral
feature that individuals with dyscalculia need much more time than unaffected individuals to
solve mathematical problems. Alternatively, it is also possible that the observed effects could
be due to group differences in attention or working memory, cognitive systems that are also
implemented in parietal and prefrontal cortices [18,19]. In this case, follow-up task-based
fMRI studies are necessary to determine whether number-specific or domain-general attention
and working memory systems are affected in dyscalculia.
A central portion of the SLF, the structural backbone of frontotemporal signal transfer,
revealed streamline density differences between future dyscalculics and controls. This observa-
tion is in line with a study that found an association between the fractional anisotropy of a cen-
tral part of this fiber tract and calculation problem solving in 10- to 15-year-old children [6].
Future longitudinal work in even younger children will have to clarify whether these structural
connectivity differences precede the reported functional connectivity differences or vice versa.

Right hemisphere lateralization of neurodevelopmental differences in

dyscalculia
A recent meta-analysis revealed that children with a mean age of 9 years show a right-lateral-
ized parietal cortex response when solving numerosity tasks and a left-lateralized parietal cor-
tex response when solving calculation tasks [5]. The right parietal cortex differences we found
fit into this picture given that the 3- to 6-year-old children studied here have at best vestigial
calculation experience. A meta-analysis in adults suggests that brain responses during numer-
osity and calculation tasks become bilaterally distributed over parietal and prefrontal cortices
toward adulthood [20]. A possible explanation for this developmental expansion to the left
parietal cortex could be that adults rely on verbalized numerosity fact retrieval, a strategy that
may still be developing in children. Verbal numerosity processing in the left parietal cortex
thus may not be a predisposition for dyscalculia, but a consequence of deficient nonverbal
numerosity processing. A long-term longitudinal study would be necessary to corroborate this
hypothesis.

Predictive performance in comparison to behavioral screening benchmarks

With a peak classification accuracy of 87%, the best MRI-based early predictors of dyscalculia
reported in this study outperformed the best behavioral early screening tools currently avail-
able for which accuracy rates of 76% to 79% are documented [21]. This result is remarkable
when contrasting the short acquisition time of the resting-state fMRI scan used in our study (3
minutes and 24 seconds) with typical behavioral test durations of 30 to 40 minutes. Further-
more, our MRI-based approach in principle works for children as young as 3 years, whereas
current behavioral test instruments can only be used a few months before school at 5 to 6 years
of age.

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PLOS BIOLOGY Early childhood sources of math deficits in the developing brain

Operational definition of dyscalculia and group matching for cognitive

skills
It must be noted that the operational definition of dyscalculia used here (1 SD below the math
performance of a reference population) is more lenient than the definitions used in the DSM-5
(1.5 SDs) and the ICD-11 (2 SDs). Nevertheless, we assume that this diagnostic discrepancy
does not compromise the generalizability of the present findings to more severely affected
individuals. The rationale for this assumption is that there is a large body of genetic, neural,
and behavioral evidence suggesting that dyscalculia forms the lower end of a continuum of
math ability rather than a qualitatively distinct ability profile [22,23]. That being said, since
math ability was assessed only once at the end of second grade in school, we could not ensure
the persistence of math difficulties and thus not exclude an inflated false-positive rate.
While the 2 groups were matched for cognitive skills based on behavioral assessment data
collected at a preschool age, we acknowledge that the 2 groups might not be balanced anymore
in second grade with respect to language ability, nonverbal IQ, and verbal short-term memory.
Nevertheless, the currently available literature suggests that possible differences between
affected and typically developing children can be expected to reach small or at best moderate
effect sizes [23].

Statistical power
It is important to point out that published effect sizes of neuroimaging data tend to be overesti-
mated. This limitation also applies to the 2 studies included in the power analysis conducted
for the present study. Therefore, we have to acknowledge that the large power levels reported
here might have been overestimated. In any case, we cannot assume that the present study is
sufficiently powered to also detect moderate or small effects. Additionally, our power analysis
is based on a univariate statistical framework that can only indirectly inform but not fully cap-
ture the complex multivariate pattern analyses conducted here.

Conclusions
The present study identified a neurobiological early childhood predisposition for dyscalculia
characterized by altered spontaneous activity, functional interaction, and structural connectiv-
ity of a frontoparietal network in the developing brain.

Methods
Participants
Participants were recruited between 2012 and 2013 from the Leipzig metropolitan area as part
of a larger study (82 children) focusing on developmental learning disorders. Participants were
partially preselected by specifying children with a familial risk for learning difficulties as the
main target group during recruitment. An initial screening revealed 54 children who did not
have a history of neurological, psychiatric, hearing or vision disorders, that they were native
German monolingual speakers, and that they did not yet receive math instruction. In this con-
text, it has to be noted that in many European countries, including Germany, typical state kin-
dergartens are not part of the school system and do not provide formal math education. MRI
data recording and behavioral testing took place between 2013 and 2014 at a kindergarten age
of 3 to 6 years. Follow-up math assessment was conducted between 2017 and 2018 at the end
of second grade in school when the children were 7 to 9 years old. All parents gave written
informed consent, and all children gave verbal informed assent to participate. The study was

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PLOS BIOLOGY Early childhood sources of math deficits in the developing brain

approved by the Ethics Committee of the University of Leipzig, Germany (approval number
320-11-26092011).

Operational definition of developmental dyscalculia

Dyscalculia was operationally defined at the end of second grade based on a standardized and
age-normed mathematical ability test. Children were assigned to the dyscalculia group
(n = 15) if they performed equal to or below the 16th percentile rank of the reference popula-
tion performance (equivalent to 1 SD below the mean of the normal distribution or a T-score
of 40). These 15 children were matched to a control group of 15 children who performed equal
to or above the 30th percentile rank in the math test, but did not differ in terms of age, sex,
handedness, maternal education, nonverbal IQ, and verbal short-term memory. The matching
was done with R–3.6.3 (https://www.r-project.org) by randomly sampling groups of 15 control
children from a pool of 39 possible candidates 500 times, generating 500 unique matchings.
For each of these random matchings, statistical differences between the dyscalculia group and
the prospective control group with respect to the abovementioned covariates were assessed.
The matching that most effectively minimized differences between groups (i.e., maximized the
P values of the statistical comparisons) was selected to derive the control group. None of the
participants in the final sample scored below 70 in a nonverbal IQ test (as required by the
ICD-11) or received a diagnosis of developmental dyslexia or attention deficit hyperactivity
disorder (according to parental questionnaires).
A priori power analyses were based on the framework of the difference between 2 indepen-
dent means implemented in the software package G� Power (http://www.gpower.hhu.de). The
effect sizes of the previous studies used for these power analyses were derived by z-transform-
ing the reported peak t-statistics for particular regions of interest and use the resulting z-scores
to compute Cohen’s d based on the formula described in [24].

Standardized behavioral testing

Handedness was assessed with a customized version of the Edinburgh Handedness Inventory
that was adapted for children. The participants were asked to perform or simulate everyday
activities with their hands so that we were able to calculate a laterality quotient (LQ). Right-
handedness was defined as LQ > +48, left-handedness as LQ � –28, and ambidexterity as –
28 < LQ � +48.
Maternal education was assessed with an in-house questionnaire and defined as the sum of
school education and professional education. School education was quantified on a scale from
0 to 3 (0 = no school graduation, 1 = graduation after 9 years (German “Hauptschulabs-
chluss”), 2 = graduation after 10 years (German “Mittlere Reife”), and 3 = high school gradua-
tion). Higher education was quantified on a scale from 0 to 4 (0 = no professional degree,
1 = vocational degree, 2 = university of applied sciences degree, 3 = college graduate, and
4 = graduate degree).
To derive a nonverbal IQ score, we used the perceptual reasoning subscale of the Wechsler
Intelligence Scale for Children (WISC-IV) (https://www.testzentrale.de/shop/wechsler-
intelligence-scale-for-children-fourth-edition.htmlAU). : PleasenotethattheprovidedURLisnotvalid=acces
Mathematical ability was assessed using the Heidelberg calculation test (https://www.
testzentrale.de/shop/heidelberger-rechentest.html). This comprehensive tool consists of 11
subtests covering addition, subtraction, multiplication, division, symbolic and nonsymbolic
numerosity comparison, numerosity estimation, numerical sequencing, and counting. Correct
answers were added together and transformed into a percentile rank based on age norms for a
full scale of total mathematical ability comprising 2 subscales: visuospatial numerosity

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PLOS BIOLOGY Early childhood sources of math deficits in the developing brain

detection (including symbolic and nonsymbolic numerosity comparison, numerosity estima-

tion, numerical sequencing, and counting) and calculation problem solving (including addi-
tion, subtraction, multiplication, and division).
Handedness and intelligence were assessed individually in a single session in a small child
laboratory room. Mathematical ability was assessed as a group test (max. 15 children) in a sep-
arate session in a larger seminar room. In each sample, these data were acquired by max. 3 dif-
ferent research assistants that were thoroughly familiarized with the testing procedure
beforehand. Before collecting the data, each assistant passed 3 supervised practice sessions
with children that were not enrolled in the current study.

Magnetic resonance imaging

MRI data were acquired on a 3T Trio scanner (Siemens, Erlangen, Germany) with a 12-chan-
nel head coil. T1-weighted MP2RAGE images were recorded with the parameters TR = 5,000
ms, TE = 2.82 ms, TI = 700 ms, matrix size: 250 × 219 × 188 and 2 different voxel sizes (10
cases / 10 controls: 1.3 × 1.3 × 1.3 mm; 5 cases / 5 controls: 1.0 × 1.0 × 1.0 mm). T2� -weighted
EPI images (100 resting-state fMRI volumes) were recorded with the parameters TR = 2,000
ms, TE = 30 ms, voxel size 3 × 3 × 3.9 mm, matrix size: 192 × 192 × 111. Diffusion-weighted
EPI images (60 diffusion-encoding directions) were acquired with the parameters TR = 8,000
ms, TE = 83 ms, voxel size 1.9 × 1.9 × 1.9 mm, matrix size: 192 × 192 × 111. Participants under-
went an extensive training session in a mock scanner prior to the actual scanning session. Dur-
ing the 30-minute training, children received continuous real-time feedback regarding their
head motion via a motion sensor system.

T1-weighted data processing

T1-weighted MP2RAGE images were first visually inspected to ensure that the data were not
corrupted by imaging artifacts including diffuse image noise along the phase encoding direc-
tion, ghosting, or Gibbs artifacts. Subsequently, images were skull-stripped and aligned with a
template derived from a reference sample of 4.5- to 8.5-year-old children (http://www.bic.mni.
mcgill.ca/ServicesAtlases/NIHPD-obj1) with an isotropic resolution of 1.0 mm in Montreal
Neurological Institute (MNI) space using Freesurfer Version 5.3.0 (http://surfer.nmr.mgh.
harvard.edu). We then normalized the images to an age-specific template in MNI space that
we directly derived from the present sample using Advanced Normalization Tools Version
2.2.0 (http://picsl.upenn.edu/software/ants). Due to the differences with respect to the original
voxel sizes, the T1 data were only used for normalizing the fMRI data and not for morphomet-
ric analyses. All anatomical locations were identified with the Harvard–Oxford Cortical Struc-
tural Atlas implemented in FSL 5.0.9 (https://fsl.fmrib.ox.ac.uk).

T2� -weighted resting-state fMRI data processing

T2� -weighted resting-state fMRI data were preprocessed using FSL 5.0.9 and MATLAB
R2017b (https://www.mathworks.com). After removing the first 4 volumes of each scan, data
were slice-time corrected. Head motion was quantified by framewise displacement (the sum of
rotational and translational rigid body realignment parameters from one volume to the next)
[25]. To account for head motion, volumes with a framewise displacement >0.5 mm were
removed from further analysis. The number of volumes remaining did not differ significantly
between the dyscalculia group (mean: 83, SD: 17) and the control group (mean: 88, SD: 10)
(Cohen’s d = 0.10, P = 0.574).
Partial volume maps for gray matter (GAU M), white
: PleasenotethattheabbreviationGMhasbeenintroducedfor
matter (WM), and cerebrospinal fluid
(CSF) were generated from the segmented MNI T1 data (FSL FAST). WM and CSF masks

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PLOS BIOLOGY Early childhood sources of math deficits in the developing brain

were thresholded at 80% tissue probability, before rigid alignment to individual resting-state
fMRI space. To further control for head motion as well as scanner-related and physiological
noise, 5 principal components from WM and CSF were regressed out together with the 6 line-
arly detrended motion parameters [26]. Residual data were band-pass filtered at 0.01 to 0.1 Hz
and spatially smoothed with a 6-mm full width at half maximum (FAU WHM): PleasenotethatFWHMhasbeend
kernel, leading to
an effective smoothness of around 8 to 9 mm.
In the final step, we computed regional homogeneity values, the fractional amplitude of
low-frequency fluctuations and degree centrality at the whole-brain level [27–29]. Regional
homogeneity quantifies the coherence of hemodynamic time series within a confined
neighborhood of voxels. Specifically, it is defined as Kendall’s coefficient of concordance
[30] of a given voxel with the voxels within its immediate vicinity. The index may range
from 0 to 1, with higher values indicating that the time series of the examined neighbor-
hood of voxels is temporally more homogeneous. The fractional amplitude of low-fre-
quency fluctuations corresponds to the ratio (i.e., the contribution) of the low-frequency
amplitude (i.e., 0.01 to 0.08 Hz) to the amplitude to the entire frequency range (i.e., 0 to
0.25 Hz) [30]. To obtain the fractional amplitude of low-frequency fluctuations for a given
voxel, the frequency spectrum of the preprocessed data is determined first and then the
sum of the amplitude across the whole frequency spectrum along with the amplitude over
the low-frequency range are computed before the ratio is taken in the final step. Regional
homogeneity and the fractional amplitude of low-frequency fluctuations were computed
with the DPARSF toolbox (http://rfmri.org/DPARSF) in SPM version 12.7219 (https://
www.fil.ion.ucl.ac.uk/spm/ software/spm12/). Degree centrality quantifies the similarity of
the hemodynamic time series within a voxel to the time series of all other voxels across the
whole brain. Degree centrality was computed with in-house code based on the 3dTcorrMap
utility implemented in AFNI (https://afni.nimh.nih.gov/).

Diffusion-weighted data processing

Diffusion-weighted imaging data were available for 29 out of 30 children. Prior to preprocess-
ing, these data were semiautomatically and visually inspected for motion artifacts by identify-
ing signal dropouts [31]. This inspection revealed that 2 children had to be excluded due to
insufficient data quality (i.e., signal dropout in superior and temporal regions). Accordingly,
the final sample for this analysis comprised 13 children with dyscalculia and 14 controls. Fur-
ther preprocessing was performed using FSL. Data were corrected for motion by affinely align-
ing volumes with different b-values to respective averages previously rigidly aligned with the
individual participant’s MNI T1 image. Subsequently, the diffusion tensor (FSL DTIFIT) and
the fiber orientation distribution for each voxel were determined (FSL BEDPOSTX).
Tractograms were computed by applying probabilistic tractography (FSL PROB-
TRACKX2). Region of interest (RAU OI) masks
: PleasenotethatROIhasbeendefinedasregionofinterestinthesentenc
of target tracts were generated by using each cor-
tical ROI involved, once as seed region and once as target region. We seeded 5,000 streamlines
(curvature threshold = 0.2, step length = 0.5 mm) in each voxel within the GM–WM interface
of the seed region at hand. Tracking was restricted using a rectangular ventral exclusion mask
to quantify structural connectivity of the right PPC and the right DLPFC via the SLF. The cor-
responding mask was defined within the common MNI group template covering the entire x-
y-plane at z = 10 and then aligned with the individual T1 map in MNI space.
Resulting streamline density maps were first log-transformed and then voxel-wise divided
by the log-transformed maximal number of possible streamlines. Summed, log-transformed
and normalized maps were averaged and thresholded at the 80th percentile to extract only the
core part of the respective tract.

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PLOS BIOLOGY Early childhood sources of math deficits in the developing brain

Classification analysis
A searchlight-based multivariate pattern analysis approach was used to identify voxels that sep-
arated individuals with dyscalculia from controls significantly above chance. In contrast to
conventional univariate analyses, multivariate pattern analysis is known to yield a more sensi-
tive and specific classification since signals from individual voxels are jointly analyzed so that a
richer information structure can be decoded. If, for example, differences between groups are
encoded in distributed patterns of activity rather than isolated voxel-level activity, multivariate
pattern analysis is able to distinguish between these groups, while univariate approaches will
not be able to uncover this spatially more complex information. This analysis was imple-
mented such that for each voxel within the entire GM or a certain WM fiber tract we defined a
spherical surrounding region (the searchlight) with a radius of 4 mm (including 7 voxels, 189
mm3) and performed support vector classification analyses for each possible searchlight posi-
tion within a 10-fold cross validation design. The cross-validation was stratified to avoid an
imbalance between the numbers of subjects of each group across folds. Per fold, 3 participants
were selected to be used for testing, while the remaining 27 data sets served for training. Sensi-
tivity, specificity and accuracy were assigned to each voxel at its center and nonparametrically
assessed for significance by running 10,000 permutations of the training and test data (group
labels) to yield a voxel-wise null distribution. During the permutation test correction for false
positives, the observed results were randomly resampled 10,000 times to build an empirical
estimate of the null distribution to draw the classification accuracy from. Voxels were identi-
fied as significant by counting the number of times the accuracy was smaller or greater than
the accuracy value obtained from the permuted data sets, and multiplying this value by the
minimal P value of the permutation test (1/(n+1), n = 10,000). These analyses were carried out
using The Decoding Toolbox Version 3.999 (https://sites.google.com/site/tdtdecodingtoolbox)
and MATLAB 2017b.

Regression analysis
Using the same software tools and parameters for the searchlight, the cross-validation, and the
permutation as in the classification analyses described above, we also conducted searchlight-
based support vector regression analyses. The goal of these analyses was to compute voxel-wise
(not subject-wise) coefficients of determination (R2) to identify significant associations
between the fMRI data and subscale test scores driving the classification results in a certain
cluster. Regression models were run individually for each voxel within the region of interest
before comparing the distributions. Distributions of the coefficients of determination were
compared between groups by running either Student t tests (normally distributed data) or Wil-
coxon signed-rank tests (not normally distributed data) using R–3.6.3.

Effective connectivity analysis

To examine the effective connectivity between pairs of regions of interest, we determined the
linear directional influence of one hemodynamic time series onto the other (Granger causal-
ity). Specifically, we used a signed path coefficient of linear regression framework imple-
mented in the REST-GCA toolbox (http://www.restfmri.net). In this framework, positive and
negative path coefficients reveal whether the preceding activity of a region predicts the
increased or decreased present activity of another region. Granger causality indices were com-
pared between groups by running either Student t tests (normally distributed data) or Wil-
coxon signed-rank tests (not normally distributed data) using R–3.6.3.

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PLOS BIOLOGY Early childhood sources of math deficits in the developing brain

Supporting information
S1 Data. Numerical values (peak classification accuracy) related to the brain image in
Fig 1.
(XLSX)
S2 Data. Numerical values (peak classification accuracy) related to the brain image in
Fig 2.
(XLSX)
S3 Data. Numerical values (Granger causality indices) related to the box plots in Fig 3.
(XLSX)
S4 Data. Numerical values (peak classification accuracy) related to the brain image in
Fig 4.
(XLSX)

Acknowledgments
Members of the Legascreen Consortium are the following: Michael A. Skeide (Max Planck
Institute for Human Cognitive and Brain Sciences, Leipzig, Germany), Indra Kraft (Max
Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany), Gesa Schaadt
(Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany), Nicole
Neef (Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany), Jens
Brauer (Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany),
Liane Dörr (Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Ger-
many), Ivonne Czepezauer (Cognitive Genetics Unit, Fraunhofer Institute for Cell Therapy
and Immunology, Leipzig, Germany), Bent Müller (Cognitive Genetics Unit, Fraunhofer Insti-
tute for Cell Therapy and Immunology, Leipzig, Germany), Arndt Wilcke (Cognitive Genetics
Unit, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany), Holger
Kirsten (Cognitive Genetics Unit, Fraunhofer Institute for Cell Therapy and Immunology,
Leipzig, Germany; Institute for Medical Informatics, Statistics and Epidemiology, University
of Leipzig, Leipzig, Germany; and Leipzig Research Center for Civilization Diseases, Univer-
sity of Leipzig, Leipzig, Germany), Johannes Boltze (School of Life Sciences, University of
Warwick, Coventry, United Kingdom), Frank Emmrich (Cognitive Genetics Unit, Fraunhofer
Institute for Cell Therapy and Immunology, Leipzig, Germany), and Angela D. Friederici
(Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany).

Author Contributions
Conceptualization: Michael A. Skeide.
Data curation: Michael A. Skeide.
Formal analysis: Ulrike Kuhl, Sarah Sobotta, Michael A. Skeide.
Methodology: Ulrike Kuhl, Michael A. Skeide.
Project administration: Michael A. Skeide.
Resources: Michael A. Skeide.
Software: Ulrike Kuhl.
Supervision: Michael A. Skeide.
Visualization: Ulrike Kuhl, Michael A. Skeide.

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PLOS BIOLOGY Early childhood sources of math deficits in the developing brain

Writing – original draft: Michael A. Skeide.

Writing – review & editing: Ulrike Kuhl, Michael A. Skeide.

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