Developmental dyslexia (DD) is a neurodevelopmental disorder that results in poor reading proficiency due to atypical neurobiological attributes. Despite many opportunities to learn, the most treatment resistant cases of DD can still have severe reading problems that persist into adulthood. The current manuscript presents methodology and preliminary results for a study which aims to assess the impact of a combined accelerated theta burst stimulation (aTBS) and individualized reading instruction paradigm to improve reading outcomes in young adults with persistent DD. This multiple baseline, single-subject design assesses the effectiveness of combining aTBS and reading instruction for the treatment of DD. The current study took place over 5 cohorts with 2-4 participants per cohort. Each cohort participated in 10 nonconsecutive treatment days over five weeks, with two to three treatment days per week, each with two treatment sessions per day (20 sessions). Treatment days consisted of two sessions that included an aTBS session immediately followed by a one-on-one 30-min reading intervention administered by a trained reading specialist. Preliminary results indicate that combined aTBS and reading instruction improves oral reading fluency and accuracy above reading intervention alone. Additionally, functional neuroimaging results suggest that combined treatment has differing impact on brain regions supporting reading compared to instruction alone. The current study design provides promising preliminary support for the use of combined brain stimulation and behavioral instruction to improve reading outcomes for young adults with persistent DD.

Successful coordination of the functional networks underlying reading is highly dependent on the underlying white matter tracts that connect these regions. Continuous theta burst stimulation (cTBS) can temporarily inhibit brain activity in targeted brain networks and has been shown to modulate reading ability. It was hypothesized that measures of diffusivity would predict change in reading efficiency following stimulation to the left temporal-parietal junction (TPJ), a targeted node of the dorsal stream of the reading network. Fifty-three adults between the ages of 18 and 50 years (M = 22.79, SD = 5.40; 34 female) with a range in reading ability completed sight word and pseudoword fluency measures prior to and immediately following cTBS to either the left or right TPJ or a control site. Participants also completed an MRI session including anatomical and diffusion weighted imaging sequences. Regression analyses were conducted to predict change in reading fluency following cTBS. Tracts associated with the reading network including the arcuate fasciculus, inferior longitudinal fasciculus, and portions of the superior longitudinal fasciculus, as well as the corpus callosum significantly predicted reliable change in a test of word reading efficiency-sight word efficiency subtest following stimulation of the left TPJ. These findings suggest that increased diffusivity of white matter tracts associated with the left hemisphere reading network and their right hemisphere homologues may support the impact of cTBS following stimulation to a targeted node of the reading network. Individual differences in white matter diffusivity may underlie differences in behavioral outcomes following neuromodulation.

Background: Transcranial magnetic stimulation (TMS) is considered a promising technique to noninvasively modulate cortical excitability and enhance cognitive functions. Despite the growing interest in using TMS to facilitate reading performance in learning disabilities, the immediate TMS-induced effects on brain activity during reading and language tasks in adults with typically developed reading skills remain to be further investigated. In the current study, we explored how a single offline session of intermittent theta burst stimulation (iTBS) delivered to core left-hemisphere nodes of the dorsal and ventral reading network changes brain activity during a spoken and written reading task. Methods: A total of 25 adults with typically developed reading skills participated in a sandwich design TMS-functional magnetic resonance imaging (fMRI) study, which was comprised of a baseline fMRI picture-word identification task that involved matching written or spoken words to picture cues, a single transcranial magnetic stimulation (TMS) session to either the left supramarginal gyrus (SMG) or the left middle temporal gyrus (MTG), followed by a post-stimulation fMRI session. A whole-brain analysis based on the general lineal model (GLM) was used to identify overall activated regions during the processing of spoken and written words. To identify differences between pre-and post-stimulation fMRI sessions, a paired sample t-test was conducted for each group separately (SMG and MTG groups). Results: Significant differences were found between pre-and post-stimulation fMRI sessions, with higher functional activation (post > pre) for spoken words only following SMG stimulation, and for both spoken and written words following MTG stimulation, in regions associated with the reading network and additional cognitive and executive control regions. Conclusions: Our results showed how a single-offline TMS session can modulate brain activity at ~20 minutes post-stimulation during spoken and written word processing. The selective contribution of the SMG stimulation for auditory (spoken) word processing provides further evidence of the distinct role of the dorsal and ventral streams within the reading network. These findings could contribute to the development of neuromodulatory interventions for individuals with reading and language impairments. Clinical Trial Registration: No: NCT04041960. Registered 29 July, 2019, https://clinicaltrials.gov/study/NCT04041960?cond=NCT04041960&rank=1 .

Objective: Both structural and functional brain changes have been individually associated with developing cognitive processes such as reading. However, there is limited research about the combined influence of resting-state functional and structural magnetic resonance imaging (rs-fMRI and sMRI) features in reading development, which could provide insights into the interplay between brain structure and function in shaping cognitive growth. We propose a method called inter- modality source coupling (IMSC) to study the coupling between the rs-fMRI and sMRI and its relationship to reading ability in school-age children. Methods: This approach is applied to baseline data from four thousand participants (9-11 years) and replicated in a second group. Our analysis focused on the relationship of IMSC to overall reading score. Results: Our findings indicate that higher reading ability was linked with increased function-structure coupling among higher-level cortical regions, particularly those links between the inferior parietal lobule and inferior frontal areas, and conversely, lower reading ability was associated with enhanced function-structure coupling among the fusiform and lingual gyrus. Our study found evidence of spatial correspondence between the data indicating an interplay between brain structure and function in our participants. Conclusion: Our approach revealed a linked pattern of whole brain structure to the corresponding functional connectivity pattern that correlated with reading ability. This novel IMSC analysis method provides a new approach to study the multimodal relationship between brain function and structure. Significance: These findings have interesting implications for understanding the multimodal complexity underlying the development of the neural basis for reading ability in school-aged children.

The measurement of autism characteristics can be challenging due to variability of social impairments and restricted and repetitive behaviors or interests (RRBs). Psychometrically strong measures such as the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2) can improve our capacity for thorough autism assessment. The conceptualization of the ADOS-2 has been shaped by research exploring the structure of its items, which evaluate autism traits associated with social affect and RRBs. Continuously refining our understanding of these items and their relations to other characteristics, such as cognition, is crucial for more accurate autism assessment and diagnosis. This study used data from a sample of 188 school-age children with mostly average cognitive functioning referred for clinical autism evaluations to (1) test the dimensionality of the ADOS-2, Module 3 (appropriate for children with relatively higher verbal ability), across two sets of items (i.e., algorithm only, algorithm with three non-algorithm RRB items) using confirmatory factor analysis (CFA) and (2) examine the relations of cognition to the dimensions tested in the ADOS-2. A bifactor model, featuring a general autism trait and two subfactors (RRB and Social Affect), provided superior fit for algorithm-only and algorithm with three non-algorithm items. Cognitive functioning was not significantly related to the general or specific factors in the model with only algorithm items. While the findings support the validity of the ADOS-2, it may not fully capture RRBs among children referred for autism. This study enhances our understanding of the ADOS-2, highlighting the utility of a bifactor model for characterizing its dimensionality, measuring autism traits with minimal cognitive influence, and identifying its limitations in assessing RRBs.

This study utilized a neuroimaging task to assess working memory (WM) network recruitment during single word reading. Associations between WM and reading comprehension skills are well documented. Several converging models suggest WM may also contribute to foundational reading skills, but few studies have assessed this contribution directly. Two groups of children (77 developmental dyslexia (DD), 22 controls) completed a functional magnetic resonance imaging (fMRI) task to identify activation of a priori defined regions of the WM network. fMRI trials consisted of familiar word, pseudoword, and false font stimuli within a 1-back oddball task to assess how activation in the WM network differs in response to stimuli that can respectively be processed using word recognition, phonological decoding, or non-word strategies. Results showed children with DD recruited WM regions bilaterally in response to all stimulus types, whereas control children recruited left-lateralized WM regions during the pseudoword condition only. Group-level comparisons revealed activation differences in the defined WM network regions for false font and familiar word, but not pseudoword conditions. This effect was driven by increased activity in participants with DD in right hemisphere frontal, parietal, and motor regions despite poorer task performance. Findings suggest the WM network may contribute to inefficient decoding and word recognition strategies in children with DD.

Objective:Children who suffer from brain insults (i.e., traumatic brain injury (TBI), chemotherapy and radiation treatment for brain tumors) are susceptible to late-emerging cognitive sequelae. Even with similar neurological risk variables, variability in long-term cognitive outcomes remains an area of investigation for researchers of acquired brain injury. Given the potential for genetic factors to influence response to chemoradiation, researchers have examined associations between germline, inherited, single nucleotide polymorphisms (SNPs), and neurocognitive outcomes for cancer survivors. Children who sustain an uncomplicated mild TBI generally recover without long-term neuropsychological consequences. However, TBI survivors have overlapping mechanism categories with cancer survivors through secondary injury variables that can be influenced by genomic variation (e.g., oxidative stress and neuroinflammation). Furthermore, the study of genomic vulnerability is limited in heterogenous groups of pediatric TBI survivors. This study aims to identify associations between genotype and long-term neurocognitive outcomes for acquired brain injury survivors by utilizing machine learning to uncover pathophysiological similarities and differences between groups.Participants and Methods:Fourteen brain tumor survivors, 139 traumatic brain injury survivors, and 63 healthy, age-matched controls completed the Letter N-back task to obtain performances on core neurocognitive skills (attention, working memory, and processing speed). Ten targeted genotypes were examined across five pathophysiological pathways (neurotransmission, oxidative stress, neuroinflammation, plasticity, growth and repair, and folate metabolism). Data were trained and tested utilizing three regression machine learning models. Mean estimated error and R2 were generated for each neurocognitive outcome. A feature importance score for models with positive variance was generated to determine how predictive a given SNP is for neurocognitive outcomes.Results:Genotype only accounted for a small amount of variance in cognitive outcomes when all clinical groups were combined. The mean absolute error for the best-fitting models from analyses where all groups were combined decreased when groups were examined separately; however, the differences in model R2 values were not significant. The relationship between brain tumor survivors and processing speed performance depended on genotype. Two SNPs had positive feature importance at the interaction level (rs58225473 and rs1801394). These SNPs are located on the CACNB2 and MTR genes and have functional consequences for neurotransmission and folate metabolism. Models of traumatic brain injury survivors did not explain positive variance and could not be examined for feature importance. Additionally, even when removing the only mechanism of action that should not be relevant for TBI survivors (folate metabolism polymorphisms), the TBI models still did not explain positive variance.Conclusions:Findings of the importance of two key SNPs on MTR and CACNB2 genes align with recent systematic reviews, which found associations between these polymorphisms and neuropsychological outcomes in more than one group or cohort of pediatric cancer survivors. Models for TBI survivors were limited by the heterogeneity of the group and ceiling effects on performance. An understanding of genetic vulnerabilities influenced by treatment and injury-related factors in acquired brain injury will inform our understanding of the developing and recovering childhood brain. The current study is an initial contribution to this goal and highlights the utility of machine learning methodology for future studies that examine the influence of genetic heterogeneity in pediatric acquired brain injury.

Impairment in both cognition and instrumental activities of daily living (iADL) are key diagnostic features of dementia. Few studies have compared trajectories of cognition and iADL. By comparing trajectories of cognitive decline with both self-rated and informant rated iADL, the study determines whether these aspects are related or decline in parallel and where there is a difference between perceptions of change. Data from the Improving the experience of Dementia and Enhancing Active Life (IDEAL) study were used. The study comprises 1537, 1183, and 851 people with dementia, and 1277, 977, and 749 carers at baseline (T1), 12 months later (Time 2, T2), and 24 months later (Time 3, T3), respectively. Cognition was assessed with the Addenbrooke’s Cognitive Examination-III (ACE-III), higher scores indicate fewer cognitive difficulties. iADL was assessed using the Functional Activities Questionnaire (FAQ), higher scores indicate more iADL difficulties. Both self-ratings (FAQ-S) and informant ratings (FAQ-I) were collected. Because of the differences in the scale and distribution of FAQ and ACE-III, scores were converted to ranks to enable comparison of trajectories between the two measures; deciles were calculated at T1 and imposed on T2 and T3 scores. As ACE-III decreased both FAQ-S and FAQ-I increased suggesting that people with dementia with more cognitive difficulties were rated as having greater iADL difficulties by both people with dementia themselves and their carers. FAQ-S declined on average by -0.10 (-0.26, 0.06) decile points per timepoint more than ACE-III. As confidence intervals overlapped zero this suggests that FAQ-S and ACE-III ratings declined at a similar rate. FAQ-I declined on average by -0.31 (-0.43, -0.19) decile points per timepoint more than ACE-III. The trajectory over the two years suggests that FAQ-I ratings declined at a significantly greater rate than ACE-III scores. Both cognition and iADL, whether self- or informant-rated declined over two years. Trajectory analysis suggests that self-rated iADL was generally concordant with cognitive decline, whereas informant-rated iADL reflected more perceived decline than cognition. Therefore, either cognition and perceived iADL decline at different rates or informants overestimate increasing iADL difficulties compared to both cognition and self-ratings.

The current systematic review examines the behavioral effects of TMS on reading. Transcranial magnetic stimulation (TMS) to targeted nodes of the brain's reading network has been shown to impact reading. Extracted data included (a) study characteristics, (b) methodology, (c) targeted nodes, (d) control paradigm, (e) type of reading task, (f) adverse effects, and (g) main findings. Data was classified by type of reading task: 1) phonological processing, 2) semantic judgment, 3) lexical decision, 4) whole word reading, and 5) visual or text characteristics. Seventy records from 46 studies (n = 844) were identified. Results indicate that TMS modulates semantic judgments when focused in the anterior aspects of the reading circuit, phonological processes after stimulation within the dorsal circuit, and impacts single word recognition and contextual reading when administered to the ventral circuit. Findings suggest that changes in specific behavioral aspects of reading following TMS may contribute to identification of foci for use as part of reading interventions.

Lexical decision making (LD) is a complex skill that is primarily facilitated by a left-lateralized reading network associated with proficient reading (1). There are two major pathways associated with the reading network: the dorsal pathway and the ventral pathway. The dorsal pathway consists of the supramarginal temporal gyrus (SMG), superior temporal gyrus and the inferior frontal gyrus (IFG) and is associated with pseudoword reading. The ventral pathway consists of the middle temporal gyrus (MTG) and the IFG and is associated with word recognition (2,3,4). Research suggests that fractional anisotropy (FA), a measure of white matter (WM) integrity, in the reading network has an impact on an array of language-related tasks such as LD (5). The aim of the current study was to examine relations between WM integrity in tracts associated with the reading network, and change in reaction time on the LD task, following theta-burst stimulation (TBS), to the MTG or SMG.

Statistical views of reading highlight the link between proficient literacy and the assimilation of various regularities embedded in writing systems, including those in the mapping between print and meaning. Still, orthographic-semantic (O-S) regularities remain relatively understudied, with open questions regarding 3 issues: (a) how O-S regularities should be quantified, (b) how they impact the behavior of proficient readers, and (c) whether individual differences in sensitivity to these regularities predict reading skills. The goal of the current article is to address these questions. We start by reviewing previous studies estimating print-meaning regularities, where orthography-to-semantics consistency (OSC) is defined as the mean semantic similarity between a word and its orthographic neighbors. While we adopt this general strategy, we identify a potential confound in previous operational definitions. We therefore offer a modified measure, which we use to examine group-level OSC effects in available data sets of single word recognition and reading for comprehension. Our findings validate the existence of OSC effects but reveal variation across tasks, with OSC effects emerging more strongly in tasks involving a direct mapping of print to meaning. Next, we present a reanalysis of word naming data from 399 second through fifth graders, where we examine individual differences in reliance on O-S regularities and their relation to participants' reading skills. We show that early readers whose naming accuracy is more influenced by OSC (i.e., those who rely more on O-S) have better passage comprehension abilities. We conclude by discussing the role of O-S regularities in proficient reading and literacy acquisition. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Adults with reading disabilities (RD) often struggle with slow and dysfluent reading throughout their life, even following behavioral intervention. Research suggests that improvement in reading speed and fluency is accompanied by critical changes in the brain's left-lateralized reading network. This network consists of two major pathways: a dorsal pathway with a major node at the supramarginal gyrus (SMG), and a ventral pathway with a major node at the middle temporal gyrus (MTG). Theta-burst stimulation (TBS) to key nodes of the reading network (MTG and SMG) has been shown to produce behavioral changes in word reading (1,3,4).

Many children and adolescents with reading comprehension difficulties demonstrate impairment in lexical and sublexical foundational skills, and require intervention for multiple levels of the reading system. This paper provides a merged analysis of results from four controlled intervention studies conducted by our research group: Children and adolescents with reading disabilities (RD) received multiple-component remediation at different ages (early elementary, middle school, high school). All participants demonstrated multi-faceted reading impairment, and all received intervention targeting decoding, word reading, text reading, and comprehension skills. Studies with younger children (Grades 1–3) demonstrated more robust comprehension effects on multiple comprehension measures, while studies with older readers demonstrated more equivocal comprehension effects despite gain on more foundational skills. A parallel moderated-mediation model, using data merged across studies, revealed that intervention-related decoding and word reading change mediated the relationship between intervention and reading comprehension gains. This mediation effect was strongly moderated by age, with younger children demonstrating the greatest mediation. The younger the child, the greater the effects of intervention and the more comprehension gains depended on decoding gains.

Posterior cerebellar lobules are active during executive function (EF) tasks and are functionally connected to EF-associated cortical networks such as the fronto-parietal network (FPN) and cingulo-opercular network (CON). Despite evidence that EF and cerebello-cortical connectivity develop on a similar time scale, developmental relationships between EFs and cerebello-cortical connectivity have not been directly investigated. We therefore examined relationships between cerebello-cortical connectivity and EF performance in a typically developing sample ages 8 - 21. Resting-state functional connectivity between posterior cerebellum and FPN (middle frontal gyrus, posterior parietal lobules)/CON (anterior cingulate, insula) was computed using independent components analysis. Using conditional process models, we tested the hypothesis that cerebellum - PFC connectivity would mediate the relationship between FPN/CON and EF, and that cerebello-cortical connectivity, and connectivity - EF relationships, would become stronger with increasing age. Cerebellum - CON connectivity strengthened with age, but a relationship between cerebellum - anterior cingulate cortex (ACC) connectivity and attention efficiency was significant only in younger children. Results suggest that during childhood, the posterior cerebellum and ACC may support sustained and executive attention, though age has a stronger effect on EF. These findings may help to guide further studies of executive dysfunction in neurodevelopmental disorders.

Young children with developmental disabilities (DD) exhibit a range of strengths and weaknesses in cognitive, language, and adaptive skills. Identifying individual patterns of abilities across these domains is important for informing interventions. This study examines how 129 toddlers with significant developmental delays and less than 10 spoken words perform across different developmental domains and assessment methods (i.e., caregiver report and clinician-administered tests). Children exhibited statistically and clinically meaningful strengths and weaknesses across developmental domains, which may have important implications for differential interventions. Caregiver-reported and clinician-rated measures of cognition, language and adaptive functioning were highly related. However, the relation between caregiver report and clinician ratings was weaker for a subgroup of children with relatively more limited expressive language compared to other children in the sample.

Background: Assessments of functional connectivity of default mode network (DMN) and positive task-related networks (TRNs) using independent component analysis (ICA) may help describe long-term effects of childhood brain tumors and adjuvant treatments. Methods: Aiming to identify potential neuronal markers that may aid in prognosis and inform interventions to optimize outcomes, this study used ICA to evaluate the presence of functional connectivity networks and their recruitment during a letter n-back task in 23 adult survivors of childhood posterior fossa tumors (9 low grade, 14 high grade) at least 5 years past diagnosis compared with 40 age- and sex-matched healthy peers. Results: DMN components generally demonstrated increasing disengagement as task difficulty increased, and relationships between effective DMN disengagement and improved performance were observed in healthy controls (HCs). Low-grade brain tumor survivors (LGS) demonstrated unique patterns in DMN recruitment that suggested increased involvement of the medial prefrontal cortex in LGS during tasks. TRN components generally demonstrated increasing engagement, which was related to improved task performance in HCs for one executive control network (ECN) component. High-grade brain tumor survivors (HGS) demonstrated distinct challenges recruiting an ECN component at more difficult task levels and showed a relationship between recruitment of another ECN component and task performance, indicating a potential compensatory mechanism for some HGS. Conclusions: Findings suggest the importance of cognitive intervention in both survivor groups and the necessity to track LGS despite their cognitive abilities often resembling those of their healthy peers.

Adolescents with reading disability (RD) participated in a randomized controlled trial evaluating the efficacy of a multiple-component reading intervention with motivational components (PHAST). A total of 514 youth in 6th, 7th, and 8th grade formed instructional groups (4-8) that were randomly assigned to one of three conditions-one of two PHAST interventions (additional comprehension or fluency training) or a remedial reading control condition. Intervention occurred in participants' schools, 40-60 min daily, 3-5x/week, for 100-125 hr total. Over four outcome assessments. multilevel growth models evaluated intervention/control differences in growth over time, and post-intervention effect sizes. The two PHAST interventions were associated with equivalent positive outcomes, and their data combined. PHAST participants out-performed Control participants on 8 of 16 outcomes, demonstrating greater growth on standardized and experimental reading and spelling outcomes. PHAST-instructed students demonstrated higher sense of reading competence, and increased attributions of reading success to their own abilities. Intervention effect sizes (Hedge's g) comparing PHAST versus Control growth were larger for foundational reading skills (.78 for nonword decoding, .56 for word identification) than for reading comprehension (.36 for passage comprehension), for which effects were more equivocal. An effect size of .61 was obtained for sense of reading competence. A year later, the PHAST participants demonstrated continued improvement on later-developing reading skills like word reading efficiency, reading fluency, and reading comprehension. Intensive reading intervention in middle school can produce gains on multiple dimensions of reading skill and motivation and foster continuing growth of higher-order reading skills.

s Brain Stimulation 14 (2021) 1589e1707 (diff1⁄48.0mm, ICC1⁄40.26, p1⁄40.10), which had the greatest surface area (F2,221⁄47.5, p<0.01) and volume (F2,201⁄47.9, p<0.01). The M1HAND representation was most lateral (MNI X:-30,Y:-24, p<0.01) followed by overlapping, but statistically different M1TRUNK (MNI X:-10,Y:-21) and M1LEG (MNI X:-6,Y:-24,p1⁄40.04) representations, without differences in anteroposterior location (p>0.05). Conclusion: fMRI and TMS can produce distinct COG in diffuse motor maps, but generally agree well. M1TRUNK was distinct but overlapped with M1LEG, underlining the importance of maximizing stimulation focality.

There is now considerable evidence regarding the types of interventions that are effective at remediating reading disabilities on average. It is generally unclear, however, what predicts the magnitude of individual-level change following a given intervention. We examine new predictors of intervention gains that are theoretically grounded in computational models of reading and focus on individual differences in the functional organization of the reading system. Specifically, we estimate the extent to which children with reading disabilities (n=118 3rd-4th graders) rely on two sources of information during an oral word reading task - print-speech correspondences and semantic imageability - before and after a phonologically-weighted intervention. We show that children who relied more on print-speech regularities and less on imageability pre-intervention had better intervention gains. In parallel, children who over the course of the intervention exhibited greater increases in their reliance on print-speech correspondences and greater decreases in their reliance on imageability had better intervention outcomes. Importantly, these two factors were differentially related to specific reading task outcomes, with greater reliance on print-speech correspondences associated with pseudoword naming, while (lesser) reliance on imageability related to word reading and comprehension. We discuss the implications of these findings for theoretical models of reading acquisition and educational practice.