Altered engagement of the speech motor network is associated with reduced phonological working memory in autism.

Nonword repetition, a common clinical measure of phonological working memory, involves component processes of speech perception, working memory, and speech production. Autistic children often show behavioral challenges in nonword repetition, as do many individuals with communication disorders. It is unknown which subprocesses of phonological working memory are vulnerable in autistic individuals, and whether the same brain processes underlie the transdiagnostic difficulty with nonword repetition. We used functional magnetic resonance imaging (fMRI) to investigate the brain bases for nonword repetition challenges in autism. We compared activation during nonword repetition in functional brain networks subserving speech perception, working memory, and speech production between neurotypical and autistic children. Autistic children performed worse than neurotypical children on nonword repetition and had reduced activation in response to increasing phonological working memory load in the supplementary motor area. Multivoxel pattern analysis within the speech production network classified shorter vs longer nonword-repetition trials less accurately for autistic than neurotypical children. These speech production motor-specific differences were not observed in a group of children with reading disability who had similarly reduced nonword repetition behavior. These findings suggest that atypical function in speech production brain regions may contribute to nonword repetition difficulties in autism.

Socioeconomic dissociations in the neural and cognitive bases of reading disorders.

Childhood socioeconomic status (SES) strongly predicts disparities in reading development, yet it is unknown whether early environments also moderate the cognitive and neurobiological bases of reading disorders (RD) such as dyslexia, the most prevalent learning disability. SES-diverse 6-9-year-old children (n = 155, half with RD) completed behavioral and functional magnetic resonance imaging (fMRI) tasks engaging phonological and orthographic processing, which revealed corresponding double-dissociations in neurocognitive deficits. At the higher end of the SES spectrum, RD was most strongly explained by differences in phonological skill and corresponding activation in left inferior frontal and temporoparietal regions during phonological processing-widely considered the "core deficit" of RD. However, at the lower end of the SES spectrum, RD was most strongly explained by differences in rapid naming skills and corresponding activation in left temporoparietal and fusiform regions during orthographic processing. Findings indicate that children's early environments systematically moderate the neurocognitive systems underlying RD, which has implications for assessment and treatment approaches to reduce SES disparities in RD outcomes. Further, results suggest that reliance on high-SES convenience samples may mask critical heterogeneity in the foundations of both typical and disordered reading development.

Dissociating executive function and ADHD influences on reading ability in children with dyslexia.

Developmental dyslexia (DD) and attention-deficit/hyperactivity disorder (ADHD) are two of the most common neurodevelopmental disorders among school-age children. These disorders frequently co-occur, with up to 40-50% of children with one diagnosis meeting criteria for the other, and similar percentages of children with either DD or ADHD exhibiting impaired executive functions (EF). Although both ADHD and EF deficits are common in dyslexia, there is little evidence about how ADHD and EF deficits specifically influence the brain basis of reading difficulty in dyslexia, and whether the influences of ADHD and EF on dyslexia can be disentangled. The goal of the current study was to investigate, at both behavioral and brain levels, whether reading performance in individuals with dyslexia is more strongly associated with EF or with diagnostic status of comorbid ADHD. We examined reading abilities and EF in children (8-13 years old) with typical reading ability, DD only, or both DD + ADHD. Across both groups with dyslexia, impaired EF was associated with greater impairment on measures loading onto a reading fluency, but not a reading accuracy, factor. There were no significant differences between the DD and DD + ADHD groups on measures of reading fluency or reading accuracy. During functional magnetic resonance imaging (fMRI) while performing a rhyme-matching reading task requiring phonological awareness, typically developing readers showed greater left-hemisphere reading network activation than children with DD or DD + ADHD. Children with DD and DD + ADHD did not show differential activation, but DD children with unimpaired EF showed greater activation than those with impaired EF in reading-related areas. Thus, ADHD status alone had no measurable influence on reading performance or brain activation. Impaired EF in dyslexia, independent of ADHD status, was associated with greater deficits in reading fluency and greater reductions of activation in response to print in the typical left-hemisphere reading network.

Anxiety, Motivation, and Competence in Mathematics and Reading for Children With and Without Learning Difficulties.

Knowledge of the relations among learners' socio-emotional characteristics and competencies as they engage in mathematics and reading is limited, especially for children with academic difficulties. This study examined the relations between anxiety, motivation, and competence in mathematics and reading, within and across domains, in an academically-diverse set of 8-13-year-old learners (n = 146). To measure anxiety and motivation across domains, we paired existing measures of math anxiety and reading motivation with researcher-developed analogs for reading anxiety and math motivation. Participants completed standardized assessments of mathematics and reading, anxiety and motivation surveys for math and reading, and a measure of nonverbal cognitive ability. Results showed high internal consistency for all anxiety and motivation scales (Cronbach's alpha = 0.76-0.91). Pearson correlations showed that within and across domains, participants with higher competence had lower anxiety and higher motivation. Higher anxiety was also associated with lower motivation. Regression analyses showed that for both math and reading, within-domain motivation was a stronger predictor of competence than anxiety. There was a unidirectional across-domain relation: socio-emotional characteristics for reading predicted math competence, after accounting for nonverbal cognitive ability, age, gender, and within-domain anxiety and motivation. Results contribute to knowledge of the socio-emotional characteristics of children with and without learning difficulties in association with reading and math activities. Implications of a unidirectional socio-emotional link between the two domains can advance research and theory of the relations among socio-emotional characteristics and competence for academically-diverse learners.

Sustained attention and behavioral ratings of attention in struggling readers.

Attention is correlated with reading, but the extent to which behavioral ratings and sustained attention relate to reading skills is unclear. We assessed 245 4th and 5th grade struggling readers (mean age = 10.3 years) on behavioral ratings of attention, sustained attention, and reading over a school year. Contributions of behavioral ratings and sustained attention were considered cross-sectionally and longitudinally in the context of other important predictors of reading. Results suggest that sustained measures and behavioral ratings assess distinct, yet overlapping, aspects of attention. Both types of attention accounted for unique variance in comprehension, but not word reading accuracy or fluency, when evaluated cross-sectionally. Results also support the role of behavioral ratings of attention in fluency and in comprehension growth. Findings suggest that multidimensional assessment of attention is useful when considering its relation to reading, and highlights the need to integrate conceptualizations of attention that arise from different theoretical approaches.

Literacy-related skills among children after left or right hemispherectomy.

OBJECTIVE: Following hemispherectomy surgery, children's educational outcomes are of great importance but are understudied. The study goal was to investigate reading, language, and nonverbal cognitive skills in children obligatorily relying on a left versus right hemisphere using a cross-sectional design. METHODS: Participants (ages 6-18) who had undergone left hemispherectomy (LH; n = 10) or right hemispherectomy (RH; n = 14) completed standardized measures of reading, language, and nonverbal cognition. RESULTS: LH and RH groups were balanced for socioeconomic status, sex, and age. Both groups scored below the population mean across standardized measures (RH: -0.79 to -1.95 SDs; LH: -0.97 to -2.32 SDs). Compared to the LH group, the group retaining a functional left hemisphere (RH group) learned to read sooner (p = .011) despite no significant differences for surgery age, and scored higher on untimed real word and pseudoword reading measures (p < .05). Effect sizes were medium (r = 0.34-0.46) for the LH and RH comparison on measures of phonological awareness and both untimed and timed word and pseudoword reading. In examining the association between clinical variables and reading-related outcomes, younger age of post-hemispherectomy reading acquisition and shorter duration between seizure onset and hemispherectomy surgery were associated with higher standardized reading and language test scores (p < .05). SIGNIFICANCE: Investigations of psychoeducational skills in reading, language, and nonverbal cognition among children who have undergone hemispherectomy can offer important insights into compensatory potential for left and right hemispheres as well as inform educational programming for children following medical stabilization.

Executive Functioning with the NIH EXAMINER and Inference Making in Struggling Readers.

Executive functioning (EF) is a domain-general process implicated in reading, but there remains lack of clarity within the domain due to varied assessment methods. We investigated the relation of EF (indexed with the NIH EXAMINER) to word reading, reading fluency, and reading comprehension in struggling readers and evaluated the mediational role of inference making for the EF-comprehension link. Analyses revealed an overall effect of EF on reading, with significant differences between fluency and comprehension, and between single word reading and comprehension, but not between fluency and single-word reading. The EF-reading comprehension relation was fully mediated by inference making.

Disrupted left fusiform response to print in beginning kindergartners is associated with subsequent reading.

Dyslexia is a common neurobiological disorder in which a child fails to acquire typical word reading skills despite adequate opportunity and intelligence. The visual word form area (VWFA) is a region within the left fusiform gyrus that specializes for print over the course of reading acquisition and is often hypoactivated in individuals with dyslexia. It is currently unknown whether atypicalities in this brain region are already present in kindergarten children who will subsequently develop dyslexia. Here, we measured fMRI activation in response to letters and false fonts in bilateral fusiform gyrus in children with and without risk for dyslexia (defined by family history or low scores on assessments of pre-reading skills, such as phonological awareness). We then followed these children longitudinally through the end of second grade to evaluate whether brain activation patterns in kindergarten were related to second-grade reading outcomes. Compared to typical readers who exhibited no risk factors for reading impairment in kindergarten, there was significant hypoactivation to both letters and false-fonts in the left fusiform gyrus in at-risk children who subsequently developed reading impairment, but not in at-risk children who developed typical reading skills. There were no significant differences in letter- or false-font responses in the right fusiform gyrus among the groups. The finding that hypoactivation to print in the VWFA is present in children who subsequently develop reading impairment even prior to the onset of formal reading instruction suggests that atypical responses to print play an early role in the development of reading impairments such as dyslexia.

Early development of letter specialization in left fusiform is associated with better word reading and smaller fusiform face area.

A functional region of left fusiform gyrus termed "the visual word form area" (VWFA) develops during reading acquisition to respond more strongly to printed words than to other visual stimuli. Here, we examined responses to letters among 5- and 6-year-old early kindergarten children (N = 48) with little or no school-based reading instruction who varied in their reading ability. We used functional magnetic resonance imaging (fMRI) to measure responses to individual letters, false fonts, and faces in left and right fusiform gyri. We then evaluated whether signal change and size (spatial extent) of letter-sensitive cortex (greater activation for letters versus faces) and letter-specific cortex (greater activation for letters versus false fonts) in these regions related to (a) standardized measures of word-reading ability and (b) signal change and size of face-sensitive cortex (fusiform face area or FFA; greater activation for faces versus letters). Greater letter specificity, but not letter sensitivity, in left fusiform gyrus correlated positively with word reading scores. Across children, in the left fusiform gyrus, greater size of letter-sensitive cortex correlated with lesser size of FFA. These findings are the first to suggest that in beginning readers, development of letter responsivity in left fusiform cortex is associated with both better reading ability and also a reduction of the size of left FFA that may result in right-hemisphere dominance for face perception.

Socioeconomic Status and Reading Disability: Neuroanatomy and Plasticity in Response to Intervention.

Although reading disability (RD) and socioeconomic status (SES) are independently associated with variation in reading ability and brain structure/function, the joint influence of SES and RD on neuroanatomy and/or response to intervention is unknown. In total, 65 children with RD (ages 6-9) with diverse SES were assigned to an intensive, 6-week summer reading intervention (n = 40) or to a waiting-list control group (n = 25). Before and after, all children completed standardized reading assessments and magnetic resonance imaging to measure cortical thickness. At baseline, higher SES correlated with greater vocabulary and greater cortical thickness in bilateral perisylvian and supramarginal regions-especially in left pars opercularis. Within the intervention group, lower SES was associated with both greater reading improvement and greater cortical thickening across broad, bilateral occipitotemporal and temporoparietal regions following the intervention. Additionally, treatment responders (n = 20), compared with treatment nonresponders (n = 19), exhibited significantly greater cortical thickening within similar regions. The waiting control and nonresponder groups exhibited developmentally typical, nonsignificant cortical thinning during this time period. These findings indicate that effective summer reading intervention is coupled with cortical growth, and is especially beneficial for children with RD who come from lower-SES home environments.

Relation of white-matter microstructure to reading ability and disability in beginning readers.

[Correction Notice: An Erratum for this article was reported in Vol 31(5) of Neuropsychology (see record 2017-22816-001). Errors in the dataset owing to two incorrect scores have skewed results. In the 2nd paragraph of the Results section, the 2nd sentence should read: "Within the typical reader group, FA in the left AF correlated negatively with pseudoword reading (WRMT-III Word Attack: rs = .37, p = .064), but not real-word reading (WRMT-III Word Identification: rs = .07, p = .75)." The 4th sentence of the 3rd paragraph should read: "The negative correlation between FA and Word Attack in the typical reader group was driven by Daxial (Dradial: rs = .19, p = .373, Daxial: rs = .38, p = .060)." The 2nd sentence of the 4th paragraph should read: "Results of this analysis replicated those of the larger reading disability group, with a statistically greater reduction of FA in this more severely affected group (p = .008) that was associated with a significant increase in Dradial (p = .008) and no difference in Daxial (p = .47)." In Table 1, for the typical reader group, the resulting values should read: age, 94.00 ± 7.66; KBIT-2-Matrices, 118.31 ± 15.24; WRMT-III-Word Identification, 119.00 ± 9.33; WRMT-III-Word Attack, 114.04 ± 9.31; and TOWRE-2-Sight Word Efficiency, 114.48 ± 8.07. For the reading disability group, the resulting values for age and TOWRE-2- Phonemic Decoding Efficiency should be 93.65 ± 7.81 and 81.76 ± 9.33, respectively. The p values for age and KBIT-2-Matrices should be .87 and .172, respectively. In Figure 3, the image for the typical reader group has been replaced. All versions of this article have been corrected.] Objective: We examined the white-matter microstructure of the left arcuate fasciculus, which has been associated with reading ability, in beginning readers with or without reading disability. METHOD: Groups were typically reading children (n = 26) or children with reading disability (n = 26), Ages 6-9, and equated on nonverbal cognitive abilities. Diffusion-weighted images were collected and TRACULA was used to extract fractional anisotropy measures from the left arcuate fasciculus. RESULTS: White-matter microstructure was altered in children with reading disability, who exhibited significantly reduced fractional anisotropy in the left arcuate fasciculus. Among typically reading children, lower fractional anisotropy of the left arcuate fasciculus was associated with superior pseudoword reading performance. Both the group differences and variation in reading scores among the children with reading disability were associated with radial diffusivity (but not axial diffusivity), whereas variation in reading scores among typically reading children was associated with axial diffusivity (but not radial diffusivity). CONCLUSIONS: The paradoxical findings that lower fractional anisotropy was associated both with reading disability and also with better phonological awareness in typical reading development suggest that there are different maturational trajectories of white-matter microstructure in typical readers and children with reading disability, and that this difference is unique to the beginning stages of reading acquisition. The finding that reading disability was associated with radial diffusivity, but that variation in ability among typically developing readers was associated with axial diffusivity, suggests that different neural mechanisms may be associated with reading development in children with or without reading disability. (PsycINFO Database Record

Dysfunction of Rapid Neural Adaptation in Dyslexia.

Identification of specific neurophysiological dysfunctions resulting in selective reading difficulty (dyslexia) has remained elusive. In addition to impaired reading development, individuals with dyslexia frequently exhibit behavioral deficits in perceptual adaptation. Here, we assessed neurophysiological adaptation to stimulus repetition in adults and children with dyslexia for a wide variety of stimuli, spoken words, written words, visual objects, and faces. For every stimulus type, individuals with dyslexia exhibited significantly diminished neural adaptation compared to controls in stimulus-specific cortical areas. Better reading skills in adults and children with dyslexia were associated with greater repetition-induced neural adaptation. These results highlight a dysfunction of rapid neural adaptation as a core neurophysiological difference in dyslexia that may underlie impaired reading development. Reduced neurophysiological adaptation may relate to prior reports of reduced behavioral adaptation in dyslexia and may reveal a difference in brain functions that ultimately results in a specific reading impairment.

Shared neuroanatomical substrates of impaired phonological working memory across reading disability and autism.

BACKGROUND: Individuals with reading disability or individuals with autism spectrum disorder (ASD) are characterized, respectively, by their difficulties in reading or social communication, but both groups often have impaired phonological working memory (PWM). It is not known whether the impaired PWM reflects distinct or shared neuroanatomical abnormalities in these two diagnostic groups. METHODS: White-matter structural connectivity via diffusion weighted imaging was examined in sixty-four children, ages 5-17 years, with reading disability, ASD, or typical development (TD), who were matched in age, gender, intelligence, and diffusion data quality. RESULTS: Children with reading disability and children with ASD exhibited reduced PWM compared to children with TD. The two diagnostic groups showed altered white-matter microstructure in the temporo-parietal portion of the left arcuate fasciculus (AF) and in the temporo-occipital portion of the right inferior longitudinal fasciculus (ILF), as indexed by reduced fractional anisotropy and increased radial diffusivity. Moreover, the structural integrity of the right ILF was positively correlated with PWM ability in the two diagnostic groups, but not in the TD group. CONCLUSIONS: These findings suggest that impaired PWM is transdiagnostically associated with shared neuroanatomical abnormalities in ASD and reading disability. Microstructural characteristics in left AF and right ILF may play important roles in the development of PWM. The right ILF may support a compensatory mechanism for children with impaired PWM.

Anthrax toxin-induced rupture of artificial lipid bilayer membranes.

We demonstrate experimentally that anthrax toxin complexes rupture artificial lipid bilayer membranes when isolated from the blood of infected animals. When the solution pH is temporally acidified to mimic that process in endosomes, recombinant anthrax toxin forms an irreversibly bound complex, which also destabilizes membranes. The results suggest an alternative mechanism for the translocation of anthrax toxin into the cytoplasm.

Sizing the Bacillus anthracis PA63 channel with nonelectrolyte poly(ethylene glycols).

Nonelectrolyte polymers of poly(ethylene glycol) (PEG) were used to estimate the diameter of the ion channel formed by the Bacillus anthracis protective antigen 63 (PA(63)). Based on the ability of different molecular weight PEGs to partition into the pore and reduce channel conductance, the pore appears to be narrower than the one formed by Staphylococcus aureus alpha-hemolysin. Numerical integration of the PEG sample mass spectra and the channel conductance data were used to refine the estimate of the pore's PEG molecular mass cutoff (approximately 1400 g/mol). The results suggest that the limiting diameter of the PA(63) pore is <2 nm, which is consistent with an all-atom model of the PA(63) channel and previous experiments using large ions.

Anthrax biosensor, protective antigen ion channel asymmetric blockade.

The significant threat posed by biological agents (e.g. anthrax, tetanus, botulinum, and diphtheria toxins) (Inglesby, T. V., O'Toole, T., Henderson, D. A., Bartlett, J. G., Ascher, M. S., Eitzen, E., Friedlander, A. M., Gerberding, J., Hauer, J., Hughes, J., McDade, J., Osterholm, M. T., Parker, G., Perl, T. M., Russell, P. K., and Tonat, K. (2002) J. Am. Med. Assoc. 287, 2236-2252) requires innovative technologies and approaches to understand the mechanisms of toxin action and to develop better therapies. Anthrax toxins are formed from three proteins secreted by fully virulent Bacillus anthracis, protective antigen (PA, 83 kDa), lethal factor (LF, 90 kDa), and edema factor (EF, 89 kDa). Here we present electrophysiological measurements demonstrating that full-length LF and EF convert the current-voltage relationship of the heptameric PA63 ion channel from slightly nonlinear to highly rectifying and diode-like at pH 6.6. This effect provides a novel method for characterizing functional toxin interactions. The method confirms that a previously well characterized PA63 monoclonal antibody, which neutralizes anthrax lethal toxin in animals in vivo and in vitro, prevents the binding of LF to the PA63 pore. The technique can also detect the presence of anthrax lethal toxin complex from plasma of infected animals. The latter two results suggest the potential application of PA63 nanopore-based biosensors in anthrax therapeutics and diagnostics.

Purified Bacillus anthracis lethal toxin complex formed in vitro and during infection exhibits functional and biological activity.

Anthrax protective antigen (PA, 83 kDa), a pore-forming protein, upon protease activation to 63 kDa (PA(63)), translocates lethal factor (LF) and edema factor (EF) from endosomes into the cytosol of the cell. The relatively small size of the heptameric PA(63) pore (approximately 12 angstroms) raises questions as to how large molecules such as LF and EF can move through the pore. In addition, the reported high binding affinity between PA and EF/LF suggests that EF/LF may not dissociate but remain complexed with activated PA(63). In this study, we found that purified (PA(63))(7)-LF complex exhibited biological and functional activities similar to the free LF. Purified LF complexed with PA(63) heptamer was able to cleave both a synthetic peptide substrate and endogenous mitogen-activated protein kinase kinase substrates and kill susceptible macrophage cells. Electrophysiological studies of the complex showed strong rectification of the ionic current at positive voltages, an effect similar to that observed if LF is added to the channels formed by heptameric PA(63) pore. Complexes of (PA(63))(7)-LF found in the plasma of infected animals showed functional activity. Identifying active complex in the blood of infected animals has important implications for therapeutic design, especially those directed against PA and LF. Our studies suggest that the individual toxin components and the complex must be considered as critical targets for anthrax therapeutics.

Evidence for spontaneous structural changes in a dark-adapted state of photosystem II.

Photosystem II catalyzes photosynthetic water oxidation in plants, green algae, and cyanobacteria. The manganese-containing active site cycles through a series of five oxidation states, S(n), where n refers to the number of oxidizing equivalents stored. In this report, reaction-induced Fourier transform infrared and electron paramagnetic resonance spectra of the S(1)-to-S(2) transition are presented. These data suggest that changes in carboxylate ligation to manganese, changes in secondary structure, and/or changes in polarity occur during dark adaptation in the S(1) state. These spontaneous structural changes are attributed to a S(1)' intermediate, at the same oxidation level as S(1), in the process of photosynthetic water oxidation.

Specific isotopic labeling and photooxidation-linked structural changes in the manganese-stabilizing subunit of photosystem II.

Photosystem II (PSII) oxidizes water to molecular oxygen; the catalytic site is a cluster of four manganese ions. The catalytic site undergoes four sequential light-driven oxidation steps to form oxygen; these sequentially oxidized states are referred to as the Sn states, where n refers to the number of oxidizing equivalents stored. The extrinsic manganese stabilizing protein (MSP) of PSII influences the efficiency and stability of the manganese cluster, as well as the rates of the S state transitions. To understand how MSP influences photosynthetic water oxidation, we have employed isotope editing and difference Fourier transform infrared spectroscopy. MSP was expressed in Escherichia coli under conditions in which MSP aspartic and glutamic acid residues label at yields of 65 and 41%, respectively. Asparagine and glutamine were also labeled by this approach. GC/MS analysis was consistent with minimal scrambling of label into other amino acid residues and with no significant scrambling into the peptide bond. Selectively labeled MSP was then reconstituted to PSII, which had been stripped of native MSP. Difference Fourier transform infrared spectroscopy was used to probe the S1QA to S2QA- transition at 200 K, as well as the S1QB to S2QB- transition at 277 K. These experiments show that aspargine, glutamine, and glutamate residues in MSP are perturbed by photooxidation of manganese during the S1 to S2 transition.

Sucrose and glycerol effects on photosystem II.

Photosystem II catalyzes the oxidation of water and the reduction of plastoquinone. The active site cycles among five oxidation states, which are called the S(n) states. PSII purification procedures include the use of the cosolvents, sucrose and/or glycerol, to stabilize water splitting activity and for cryoprotection. In this study, the effects of sucrose and glycerol on PSII were investigated. Sucrose addition was observed to stimulate the steady-state rate of oxygen evolution in the range from 0 to 1.35 M. Glycerol addition was observed to stimulate oxygen evolution in the range from 0 to 30%. Both cosolvents were observed to be inhibitory at higher concentrations. Sucrose addition was shown to have no effect on the rate of Q(A)(-) oxidation or on the K(M) for exogenous acceptor. PSII was then treated to remove extrinsic proteins. In these samples, sucrose addition stimulated activity, but glycerol addition was inhibitory at concentrations higher than approximately 0.5 M. This inhibitory effect of glycerol at relatively low concentrations is attributed to glycerol binding to the active site, when extrinsic subunits are not present. Reaction induced FTIR spectra, associated with the S(1) to S(2) transition of the water-oxidizing complex, exhibited significant differences throughout the 1,800-1,200 cm(-1) region, when glycerol- and sucrose-containing samples were compared. These measurements suggest a cosolvent-induced shift in the pK(A) of an aspartic or glutamic acid side chain, as well as structural changes at the active site. These structural alterations are attributed to a change in preferential hydration of the oxygen-evolving complex.