Activation and functional connectivity of cerebellum during reading and during arithmetic in children with combined reading and math disabilities.

Background: Reading and math constitute important academic skills, and as such, reading disability (RD or developmental dyslexia) and math disability (MD or developmental dyscalculia) can have negative consequences for children's educational progress. Although RD and MD are different learning disabilities, they frequently co-occur. Separate theories have implicated the cerebellum and its cortical connections in RD and in MD, suggesting that children with combined reading and math disability (RD + MD) may have altered cerebellar function and disrupted functional connectivity between the cerebellum and cortex during reading and during arithmetic processing. Methods: Here we compared Control and RD + MD groups during a reading task as well as during an arithmetic task on (i) activation of the cerebellum, (ii) background functional connectivity, and (iii) task-dependent functional connectivity between the cerebellum and the cortex. Results: The two groups (Control, RD + MD) did not differ for either task (reading, arithmetic) on any of the three measures (activation, background functional connectivity, task-dependent functional connectivity). Conclusion: These results do not support theories that children's deficits in reading and math originate in the cerebellum.

Neurocognitive mechanisms of co-occurring math difficulties in dyslexia: Differences in executive function and visuospatial processing.

Children with dyslexia frequently also struggle with math. However, studies of reading disability (RD) rarely assess math skill, and the neurocognitive mechanisms underlying co-occurring reading and math disability (RD+MD) are not clear. The current study aimed to identify behavioral and neurocognitive factors associated with co-occurring MD among 86 children with RD. Within this sample, 43% had co-occurring RD+MD and 22% demonstrated a possible vulnerability in math, while 35% had no math difficulties (RD-Only). We investigated whether RD-Only and RD+MD students differed behaviorally in their phonological awareness, reading skills, or executive functions, as well as in the brain mechanisms underlying word reading and visuospatial working memory using functional magnetic resonance imaging (fMRI). The RD+MD group did not differ from RD-Only on behavioral or brain measures of phonological awareness related to speech or print. However, the RD+MD group demonstrated significantly worse working memory and processing speed performance than the RD-Only group. The RD+MD group also exhibited reduced brain activations for visuospatial working memory relative to RD-Only. Exploratory brain-behavior correlations along a broad spectrum of math ability revealed that stronger math skills were associated with greater activation in bilateral visual cortex. These converging neuro-behavioral findings suggest that poor executive functions in general, including differences in visuospatial working memory, are specifically associated with co-occurring MD in the context of RD. RESEARCH HIGHLIGHTS: Children with reading disabilities (RD) frequently have a co-occurring math disability (MD), but the mechanisms behind this high comorbidity are not well understood. We examined differences in phonological awareness, reading skills, and executive function between children with RD only versus co-occurring RD+MD using behavioral and fMRI measures. Children with RD only versus RD+MD did not differ in their phonological processing, either behaviorally or in the brain. RD+MD was associated with additional behavioral difficulties in working memory, and reduced visual cortex activation during a visuospatial working memory task.

The relationship between phonological processing and arithmetic in children with learning disabilities.

Phonological processing skills have not only been shown to be important for reading skills, but also for arithmetic skills. Specifically, previous research in typically developing children has suggested that phonological processing skills may be more closely related to arithmetic problems that are solved through fact retrieval (e.g., remembering the solution from memory) than procedural computation (e.g., counting). However, the relationship between phonological processing and arithmetic in children with learning disabilities (LDs) has not been investigated. Yet, understanding these relationships in children with LDs is especially important because it can help elucidate the cognitive underpinnings of math difficulties, explain why reading and math disabilities frequently co-occur, and provide information on which cognitive skills to target for interventions. In 63 children with LDs, we examined the relationship between different phonological processing skills (phonemic awareness, phonological memory, and rapid serial naming) and arithmetic. We distinguished between arithmetic problems that tend to be solved with fact retrieval versus procedural computation to determine whether phonological processing skills are differentially related to these two arithmetic processes. We found that phonemic awareness, but not phonological memory or rapid serial naming, was related to arithmetic fact retrieval. We also found no association between any phonological processing skills and procedural computation. These results converge with prior research in typically developing children and suggest that phonemic awareness is also related to arithmetic fact retrieval in children with LD. These results raise the possibility that phonemic awareness training might improve both reading and arithmetic fact retrieval skills. RESEARCH HIGHLIGHTS: Relationships between phonological processing and various arithmetic skills were investigated in children with learning disabilities (LDs) for the first time. We found phonemic awareness was related to arithmetic involving fact retrieval, but not to arithmetic involving procedural computation in LDs. The results suggest that phonemic awareness is not only important to skilled reading, but also to some aspects of arithmetic. These results raise the question of whether intervention in phonemic awareness might improve arithmetic fact retrieval skills.

The role of the angular gyrus in arithmetic processing: a literature review.

Since the pioneering work of the early 20th century neuropsychologists, the angular gyrus (AG), particularly in the left hemisphere, has been associated with numerical and mathematical processing. The association between the AG and numerical and mathematical processing has been substantiated by neuroimaging research. In the present review article, we will examine what is currently known about the role of the AG in numerical and mathematical processing with a particular focus on arithmetic. Specifically, we will examine the role of the AG in the retrieval of arithmetic facts in both typically developing children and adults. The review article will consider alternative accounts that posit that the involvement of the AG is not specific to arithmetic processing and will consider how numerical and mathematical processing and their association with the AG overlap with other neurocognitive processes. The review closes with a discussion of future directions to further characterize the relationship between the angular gyrus and arithmetic processing.

Dorsal visual stream activity during coherent motion processing is not related to math ability or dyscalculia.

Math disability (MD) or developmental dyscalculia is a highly prevalent learning disability involving deficits in computation and arithmetic fact retrieval and is associated with dysfunction of parietal and prefrontal cortices. It has been suggested that dyscalculia (and other learning disabilities and developmental disorders) can be viewed in terms of a broader 'dorsal stream vulnerability,' which could explain a range of dorsal visual stream function deficits, including poor coherent visual motion perception. Behavioral evidence from two studies in typical children has linked performance on visual motion perception to math ability, and a third behavioral study reported poorer visual motion perception in a small group of children with MD compared to controls. Visual motion perception relies on the magnocellular-dominated dorsal stream, particularly its constituent area V5/MT. Here we used functional MRI to measure brain activity in area V5/MT during coherent visual motion processing to test its relationship with math ability. While we found bilateral activation in V5/MT in 66 children/adolescents with varied math abilities, we found no relationships between V5/MT activity and standardized math measures. Next, we selected a group of children/adolescents with MD (n = 23) and compared them to typically developing controls (n = 18), but found no differences in activity in V5/MT or elsewhere in the brain. We followed these frequentist statistics with Bayesian analyses, which favored null models in both studies. We conclude that dorsal stream function subserving visual motion processing in area V5/MT is not related to math ability, nor is it altered in those with the math disability dyscalculia.

Shared Neural Circuits for Visuospatial Working Memory and Arithmetic in Children and Adults.

Visuospatial working memory (VSWM) plays an important role in arithmetic problem solving, and the relationship between these two skills is thought to change over development. Even though neuroimaging studies have demonstrated that VSWM and arithmetic both recruit frontoparietal networks, inferences about common neural substrates have largely been made by comparisons across studies. Little work has examined how brain activation for VSWM and arithmetic converge within the same participants and whether there are age-related changes in the overlap of these neural networks. In this study, we examined how brain activity for VSWM and arithmetic overlap in 38 children and 26 adults. Although both children and adults recruited the intraparietal sulcus (IPS) for VSWM and arithmetic, children showed more focal activation within the right IPS, whereas adults recruited the bilateral IPS, superior frontal sulcus/middle frontal gyrus, and right insula. A comparison of the two groups revealed that adults recruited a more left-lateralized network of frontoparietal regions for VSWM and arithmetic compared with children. Together, these findings suggest possible neurocognitive mechanisms underlying the strong relationship between VSWM and arithmetic and provide evidence that the association between VSWM and arithmetic networks changes with age.

Functional neuroanatomy of arithmetic in monolingual and bilingual adults and children.

Prior studies on the brain bases of arithmetic have not focused on (or even described) their participants' language backgrounds. Yet, unlike monolinguals, early bilinguals have the capacity to solve arithmetic problems in both of their two languages. This raises the question whether this ability, or any other experience that comes with being bilingual, affects brain activity for arithmetic in bilinguals relative to monolinguals. Here, we used functional magnetic resonance imaging to compare brain activity in 44 English monolinguals and 44 Spanish-English early bilinguals, during the solving of arithmetic problems in English. We used a factorial design to test for a main effect of bilingual Language Experience. Based on the known modulating roles of arithmetic operation and age, we used two arithmetic tasks (addition and subtraction) and studied two age groups (adults and children). When collapsing across operations and age, we found broad bilateral activation for arithmetic in both the monolingual group and the bilingual group. However, an analysis of variance revealed that there was no effect of Language Experience, nor an interaction of Language Experience with Operation or Age Group. Bayesian analyses within regions of interest chosen for their role in arithmetic further supported the finding of no effect of Language Experience on brain activity underlying arithmetic. We conclude that early bilingualism does not influence the functional neuroanatomy of simple arithmetic.

The neural association between arithmetic and basic numerical processing depends on arithmetic problem size and not chronological age.

The intraparietal sulcus (IPS) is thought to be an important region for basic number processing (e.g. symbol-quantity associations) and arithmetic (e.g. addition). Evidence for shared circuitry within the IPS is largely based on comparisons across studies, and little research has investigated number processing and arithmetic in the same individuals. It is also unclear how the neural overlap between number processing and arithmetic is influenced by age and arithmetic problem difficulty. This study investigated these unresolved questions by examining basic number processing (symbol-quantity matching) and arithmetic (addition) networks in 26 adults and 42 children. Number processing and arithmetic elicited overlapping activity in the IPS in children and adults, however, the overlap was influenced by arithmetic problem size (i.e. which modulated the need to use procedural strategies). The IPS was recruited for number processing, and for arithmetic problems more likely to be solved using procedural strategies. We also found that the overlap between number processing and small-problem addition in children was comparable to the overlap between number processing and large-problem addition in adults. This finding suggests that the association between number processing and arithmetic in the IPS is related to the cognitive operation being performed rather than age.

Developmental specialization of the left intraparietal sulcus for symbolic ordinal processing.

Symbolic numbers have both cardinal (symbol-quantity) and ordinal (symbol-symbol) referents. Despite behavioural evidence suggesting distinct processing of cardinal and ordinal referents, little consensus has emerged from the neuroimaging literature on whether these processes have shared or distinct neural underpinnings. Moreover, it remains unclear how the neural correlates of cardinal and ordinal processing change with age. To address these unresolved questions, we investigated the neural correlates of cardinal (neural distance effect) and ordinal processing (neural reverse distance effect) in 50 children (ages 7-10) and 26 adults (ages 19-26). We found that adults recruited a largely left lateralized set of fronto-parietal regions for ordinal processing, whereas children showed activation in the right lateral orbital and inferior frontal gyri for both ordinal and cardinal processing. Additional analyses suggested that adults recruited the left intraparietal sulcus (IPS) more than children for ordinal processing, suggesting that the IPS may become increasingly tuned to ordinal symbolic properties over development. Together with previous literature documenting the importance of the left IPS for cardinal processing, our results suggest that cardinal and ordinal processing may share neural substrates in the left IPS and that this region may become specialized for both skills over development.

How do individual differences in children's domain specific and domain general abilities relate to brain activity within the intraparietal sulcus during arithmetic? An fMRI study.

Previous research has demonstrated that children recruit the intraparietal sulcus (IPS) during arithmetic, which has largely been attributed to domain-specific processes such as quantity manipulations. However, the IPS has also been found to be important for domain-general abilities, such as visuo-spatial working memory (VSWM). Based on the current literature it is unclear whether individual differences in domain-specific skills, domain-general skills, or a combination of the two, are related to the recruitment of the IPS during arithmetic. This study examines how individual differences in both domain general and domain specific competencies relate to brain activity in the IPS during arithmetic, and whether the relationships are related to how brain activity is measured. In a sample of 44 school-aged children, we found that VSWM was only weakly related to a neural index of arithmetic complexity (neural problem size effect), whereas symbolic number processing skills (symbolic comparison and ordering) were related to overall arithmetic activity (both small and large problems). By simultaneously examining multiple domain-general and domain specific measures, we were also able to determine that symbolic skills were a stronger predictor of brain activity within the IPS than domain general skills such as VSWM and domain specific skills such as non-symbolic number processing. Together, these findings highlight that neural problem size effect may reflect different cognitive processes than brain activity across both small and large arithmetic problems, and that symbolic number processing skills are a critical predictor of variability in IPS activity during arithmetic. Hum Brain Mapp 38:3941-3956, 2017. © 2017 Wiley Periodicals, Inc.

Strong causal claims require strong evidence: A commentary on Wang and colleagues.

In this commentary, we provide a discussion of the findings by Wang, Odic, Halberda, and Feigenson recently published in the Journal of Experimental Child Psychology (2016, Vol. 147, pp. 82-99). The article by Wang and colleagues claims to have revealed a causal link between the so-called "approximate number system" (ANS) and young children's symbolic math abilities. We question this assertion of a causal link through a discussion of methodological limitations inherent in their article. More specifically, we assert that (a) Wang and colleagues did not measure the relationship between change in the ANS and change in symbolic number comparison; (b) the ANS manipulation used (hysteresis) may induce a domain-general effect on motivation rather than domain-specific effects on ANS precision; and (c) the outcome measures of symbolic math are problematic both because a between-participants design was employed and because only a select number of items from standardized measures were used. We discuss several possibilities for future research to more directly assess whether a causal relationship exists between the ANS and symbolic math performance in young children.

Trajectories of Symbolic and Nonsymbolic Magnitude Processing in the First Year of Formal Schooling.

Sensitivity to numerical magnitudes is thought to provide a foundation for higher-level mathematical skills such as calculation. It is still unclear how symbolic (e.g. Arabic digits) and nonsymbolic (e.g. Dots) magnitude systems develop and how the two formats relate to one another. Some theories propose that children learn the meaning of symbolic numbers by scaffolding them onto a pre-existing nonsymbolic system (Approximate Number System). Others suggest that symbolic and nonsymbolic magnitudes have distinct and non-overlapping representations. In the present study, we examine the developmental trajectories of symbolic and nonsymbolic magnitude processing skills and how they relate to each other in the first year of formal schooling when children are becoming more fluent with symbolic numbers. Thirty Grade 1 children completed symbolic and nonsymbolic magnitude processing tasks at three time points in Grade 1. We found that symbolic and nonsymbolic magnitude processing skills had distinct developmental trajectories, where symbolic magnitude processing was characterized by greater gains than nonsymbolic skills over the one-year period in Grade 1. We further found that the development of the two formats only related to one another in the first half of the school year where symbolic magnitude processing skills influenced later nonsymbolic skills. These findings indicate that symbolic and nonsymbolic abilities have different developmental trajectories and that the development of symbolic abilities is not strongly linked to nonsymbolic representations by Grade 1. These findings also suggest that the relationship between symbolic and nonsymbolic processing is not as unidirectional as previously thought.

Drawing connections between white matter and numerical and mathematical cognition: a literature review.

In this review we examine white matter tracts that may support numerical and mathematical abilities and whether abnormalities in these pathways are associated with deficits in numerical and mathematical abilities. Diffusion tensor imaging (DTI) yields indices of white matter integrity and can provide information about the axonal organization of the brain. A growing body of research is using DTI to investigate how individual differences in brain microstructures relate to different numerical and mathematical abilities. Several tracts have been associated with numerical and mathematical abilities such as the superior longitudinal fasciculus, the posterior segment of the corpus callosum, inferior longitudinal fasciculus, corona radiata, and the corticospinal tract. Impairments in mathematics tend to be associated with atypical white matter structures within similar regions, especially in inferior parietal and temporal tracts. This systematic review summarizes and critically examines the current literature on white matter correlates of numerical and mathematical abilities, and provides directions for future research.

Individual differences in left parietal white matter predict math scores on the Preliminary Scholastic Aptitude Test.

Mathematical skills are of critical importance, both academically and in everyday life. Neuroimaging research has primarily focused on the relationship between mathematical skills and functional brain activity. Comparatively few studies have examined which white matter regions support mathematical abilities. The current study uses diffusion tensor imaging (DTI) to test whether individual differences in white matter predict performance on the math subtest of the Preliminary Scholastic Aptitude Test (PSAT). Grades 10 and 11 PSAT scores were obtained from 30 young adults (ages 17-18) with wide-ranging math achievement levels. Tract based spatial statistics was used to examine the correlation between PSAT math scores, fractional anisotropy (FA), radial diffusivity (RD) and axial diffusivity (AD). FA in left parietal white matter was positively correlated with math PSAT scores (specifically in the left superior longitudinal fasciculus, left superior corona radiata, and left corticospinal tract) after controlling for chronological age and same grade PSAT critical reading scores. Furthermore, RD, but not AD, was correlated with PSAT math scores in these white matter microstructures. The negative correlation with RD further suggests that participants with higher PSAT math scores have greater white matter integrity in this region. Individual differences in FA and RD may reflect variability in experience dependent plasticity over the course of learning and development. These results are the first to demonstrate that individual differences in white matter are associated with mathematical abilities on a nationally administered scholastic aptitude measure.

microParaflo biochip for nucleic acid and protein analysis.

We describe in this chapter the use of oligonucleotide or peptide microarrays (arrays) based on microfluidic chips. Specifically, three major applications are presented: (1) microRNA/small RNA detection using a microRNA detection chip, (2) protein binding and function analysis using epitope, kinase substrate, or phosphopeptide chips, and (3) protein-binding analysis using oligonucleotide chips. These diverse categories of customizable arrays are based on the same biochip platform featuring a significant amount of flexibility in the sequence design to suit a wide range of research needs. The protocols of the array applications play a critical role in obtaining high quality and reliable results. Given the comprehensive and complex nature of the array experiments, the details presented in this chapter is intended merely as a useful information source of reference or a starting point for many researchers who are interested in genome- or proteome-scale studies of proteins and nucleic acids and their interactions.

Microfluidic PicoArray synthesis of oligodeoxynucleotides and simultaneous assembling of multiple DNA sequences.

Large DNA constructs of arbitrary sequences can currently be assembled with relative ease by joining short synthetic oligodeoxynucleotides (oligonucleotides). The ability to mass produce these synthetic genes readily will have a significant impact on research in biology and medicine. Presently, high-throughput gene synthesis is unlikely, due to the limits of oligonucleotide synthesis. We describe a microfluidic PicoArray method for the simultaneous synthesis and purification of oligonucleotides that are designed for multiplex gene synthesis. Given the demand for highly pure oligonucleotides in gene synthesis processes, we used a model to improve key reaction steps in DNA synthesis. The oligonucleotides obtained were successfully used in ligation under thermal cycling conditions to generate DNA constructs of several hundreds of base pairs. Protein expression using the gene thus synthesized was demonstrated. We used a DNA assembly strategy, i.e. ligation followed by fusion PCR, and achieved effective assembling of up to 10 kb DNA constructs. These results illustrate the potential of microfluidics-based ultra-fast oligonucleotide parallel synthesis as an enabling tool for modern synthetic biology applications, such as the construction of genome-scale molecular clones and cell-free large scale protein expression.