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Early childhood is a critical period for structural brain development as well as an important window for the identification and remediation of reading difficulties. Recent research supports the implementation of interventions in at-risk populations as early as kindergarten or first grade, yet the neurocognitive mechanisms following such interventions remain understudied. To address this, we investigated cortical structure by means of anatomical MRI before and after a 12-week tablet-based intervention in: (1) at-risk children receiving phonics-based training ( n = 29; n = 16 complete pre-post datasets), (2) at-risk children engaging with AC training ( n = 24; n = 15 complete pre-post datasets) and (3) typically developing children ( n = 25; n = 14 complete pre-post datasets) receiving no intervention. At baseline, we found higher surface area of the right supramarginal gyrus in at-risk children compared to typically developing peers, extending previous evidence that early anatomical differences exist in children who may later develop dyslexia. Our longitudinal analysis revealed significant post-intervention thickening of the left supramarginal gyrus, present exclusively in the intervention group but not the active control or typical control groups. Altogether, this study contributes new knowledge to our understanding of the brain morphology associated with cognitive risk for dyslexia and response to early intervention, which in turn raises new questions on how early anatomy and plasticity may shape the trajectories of long-term literacy development., Competing Interests: Competing Interests: The authors have declared that no competing interests exist., (© 2023 Massachusetts Institute of Technology.)

A growing body of neuroimaging evidence shows that white matter can change as a result of experience and structured learning. Although the majority of previous work has used diffusion MRI to characterize such changes in white matter, diffusion metrics offer limited biological specificity about which microstructural features may be driving white matter plasticity. Recent advances in myelin-specific MRI techniques offer a promising opportunity to assess the specific contribution of myelin in learning-related plasticity. Here we describe the application of such an approach to examine structural plasticity during an early intervention in preliterate children at risk for dyslexia. To this end, myelin water imaging data were collected before and after a 12-week period in (1) at-risk children following early literacy training (n = 13-24), (2) at-risk children engaging with other non-literacy games (n = 10-17) and (3) children without a risk receiving no training (n = 11-22). Before the training, regional risk-related differences were identified, showing higher myelin water fraction (MWF) in right dorsal white matter in at-risk children compared to the typical control group. Concerning intervention-specific effects, our results revealed an increase across left-hemispheric and right ventral MWF over the course of training in the at-risk children receiving early literacy training, but not in the at-risk active control group or the no-risk typical control group. Overall, our results provide support for the use of myelin water imaging as a sensitive tool to investigate white matter and offer a first indication of myelin plasticity in young children at the onset of literacy acquisition., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Musical training has long been viewed as a model for experience-dependent brain plasticity. Reports of musical training-induced brain plasticity are largely based on cross-sectional studies comparing musicians to non-musicians, which cannot address whether musical training itself is sufficient to induce these neurobiological changes or whether pre-existing neuroarchitecture before training predisposes children to succeed in music. Here, in a longitudinal investigation of children from infancy to school age (n = 25), we find brain structure in infancy that predicts subsequent music aptitude skills at school-age. Building on prior evidence implicating white matter organization of the corticospinal tract as a neural predisposition for musical training in adults, here we find that structural organization of the right corticospinal tract in infancy is associated with school-age tonal and rhythmic musical aptitude skills. Moreover, within the corpus callosum, an inter-hemispheric white matter pathway traditionally linked with musical training, we find that structural organization of this pathway in infancy is associated with subsequent tonal music aptitude. Our findings suggest predispositions prior to the onset of musical training from as early as infancy may serve as a scaffold upon which ongoing musical experience can build. RESEARCH HIGHLIGHTS: Structural organization of the right corticospinal tract in infancy is associated with school-age musical aptitude skills. Longitudinal associations between the right corticospinal tract in infancy and school-age rhythmic music aptitude skills remain significant even when controlling for language ability. Findings support the notion of predispositions for success in music, and suggest that musical predispositions likely build upon a neural structural scaffold established in infancy. Findings support the working hypothesis that a dynamic interaction between predisposition and experience established in infancy shape the trajectory of long-term musical development., (© 2022 John Wiley & Sons Ltd.)

The home language and literacy environment (HLLE) in infancy has been associated with subsequent pre-literacy skill development and HLLE at preschool-age has been shown to correlate with white matter organization in tracts that subserve pre-reading and reading skills. Furthermore, childhood socioeconomic status (SES) has been linked with both HLLE and white matter organization. It is important to understand whether the relationships between environmental factors such as HLLE and SES and white matter organization can be detected as early as infancy, as this period is characterized by rapid brain development that may make white matter pathways particularly susceptible to these early experiences. Here, we hypothesized that HLLE (1) relates to white matter organization in pre-reading and reading-related tracts in infants, and (2) mediates a link between SES and white matter organization. To test these hypotheses, infants (mean age: 8.6 ± 2.3 months, N = 38) underwent diffusion-weighted imaging MRI during natural sleep. Image processing was performed with an infant-specific pipeline and fractional anisotropy (FA) was estimated from the arcuate fasciculus (AF) and superior longitudinal fasciculus (SLF) bilaterally using the baby automated fiber quantification method. HLLE was measured with the Reading subscale of the StimQ (StimQ-Reading) and SES was measured with years of maternal education. Self-reported maternal reading ability was also quantified and applied to our statistical models as a proxy for confounding genetic effects. StimQ-Reading positively correlated with FA in left AF and to maternal education, but did not mediate the relationship between them. Taken together, these findings underscore the importance of considering HLLE from the start of life and may inform novel prevention and intervention strategies to support developing infants during a period of heightened brain plasticity., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Developmental dyslexia is considered to be most effectively addressed with preventive phonics-based interventions, including grapheme-phoneme coupling and blending exercises. These intervention types require intact speech perception abilities, given their large focus on exercises with auditorily presented phonemes. Yet some children with (a risk for) dyslexia experience problems in this domain due to a poorer sensitivity to rise times, i.e., rhythmic acoustic cues present in the speech envelope. As a result, the often subtle speech perception problems could potentially constrain an optimal response to phonics-based interventions in at-risk children. The current study therefore aimed (1) to extend existing research by examining the presence of potential speech perception deficits in pre-readers at cognitive risk for dyslexia when compared to typically developing peers and (2) to explore the added value of a preventive auditory intervention for at-risk pre-readers, targeting rise time sensitivity, on speech perception and other reading-related skills. To obtain the first research objective, we longitudinally compared speech-in-noise perception between 28 5-year-old pre-readers with and 30 peers without a cognitive risk for dyslexia during the second half of the third year of kindergarten. The second research objective was addressed by exploring growth in speech perception and other reading-related skills in an independent sample of 62 at-risk 5-year-old pre-readers who all combined a 12-week preventive phonics-based intervention (GraphoGame-Flemish) with an auditory story listening intervention. In half of the sample, story recordings contained artificially enhanced rise times (GG-FL_EE group, n  = 31), while in the other half, stories remained unprocessed (GG-FL_NE group, n  = 31; Clinical Trial Number S60962-https://www.uzleuven.be/nl/clinical-trial-center). Results revealed a slower speech-in-noise perception growth in the at-risk compared to the non-at-risk group, due to an emerged deficit at the end of kindergarten. Concerning the auditory intervention effects, both intervention groups showed equal growth in speech-in-noise perception and other reading-related skills, suggesting no boost of envelope-enhanced story listening on top of the effect of combining GraphoGame-Flemish with listening to unprocessed stories. These findings thus provide evidence for a link between speech perception problems and dyslexia, yet do not support the potential of the auditory intervention in its current form., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Vanden Bempt, Van Herck, Economou, Vanderauwera, Vandermosten, Wouters and Ghesquière.)

Recent prereading evidence demonstrates that white matter alterations are associated with dyslexia even before the onset of reading instruction. At the same time, remediation of reading difficulties is suggested to be most effective when provided as early as kindergarten, yet evidence is currently lacking on the early neuroanatomical changes associated with such preventive interventions. To address this open question, we investigated white matter changes following early literacy intervention in Dutch-speaking prereaders (aged 5-6 years) with an increased cognitive risk for developing dyslexia. Diffusion-weighted images were acquired before and after a 12-week digital intervention in three groups: (i) at-risk children receiving phonics-based training (n = 31); (ii) at-risk children engaging with active control training (n = 25); and (iii) typically developing children (n = 27) receiving no intervention. Following automated quantification of white matter tracts relevant for reading, we first examined baseline differences between at-risk and typically developing children, revealing bilateral dorsal and ventral differences. Longitudinal analyses showed that white matter properties changed within the course of the training; however, the absence of intervention-specific results suggests that these changes rather reflect developmental effects. This study contributes important first insights on the neurocognitive mechanisms of intervention that precedes formal reading onset., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Diffusion-weighted imaging studies have repeatedly shown that white matter correlates with reading throughout development. However, the neurobiological interpretation of this relationship is constrained by the limited microstructural specificity of diffusion imaging. A critical component of white matter microstructure is myelin, which can be investigated noninvasively using MRI. Here, we examined the link between myelin water fraction (MWF) and reading ability in 10-year-old children (n = 69). To better understand this relationship, we additionally investigated how these two variables relate to fractional anisotropy (FA; a common index of diffusion-weighted imaging). Our analysis revealed that lower MWF coheres with better reading scores in left-hemispheric tracts relevant for reading. While we replicated previous reports on a positive relationship between FA and MWF, we did not find any evidence for an association between reading and FA. Together, these findings contrast previous research suggesting that poor reading abilities might be rooted in lower myelination and emphasize the need for further longitudinal research to understand how this relationship evolves throughout reading development. Altogether, this study contributes important insights into the role of myelin-related processes in the relationship between reading and white matter structure., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Dyslexia has frequently been related to atypical auditory temporal processing and speech perception. Results of studies emphasizing speech onset cues and reinforcing the temporal structure of the speech envelope, that is, envelope enhancement (EE), demonstrated reduced speech perception deficits in individuals with dyslexia. The use of this strategy as auditory intervention might thus reduce some of the deficits related to dyslexia. Importantly, reading-skill interventions are most effective when they are provided during kindergarten and first grade. Hence, we provided a tablet-based 12-week auditory and phonics-based intervention to pre-readers at cognitive risk for dyslexia and investigated the effect on auditory temporal processing with a rise time discrimination (RTD) task. Ninety-one pre-readers at cognitive risk for dyslexia (aged 5-6) were assigned to two groups receiving a phonics-based intervention and playing a story listening game either with (n = 31) or without (n = 31) EE or a third group playing control games and listening to non-enhanced stories (n = 29). RTD was measured directly before, directly after and 1 year after the intervention. While the groups listening to non-enhanced stories mainly improved after the intervention during first grade, the group listening to enhanced stories improved during the intervention in kindergarten and subsequently remained stable during first grade. Hence, an EE intervention improves auditory processing skills important for the development of phonological skills. This occurred before the onset of reading instruction, preceding the maturational improvement of these skills, hence potentially giving at risk children a head start when learning to read. A video abstract of this article can be viewed at https://www.youtube.com/watch?v=e0BfT4dGXNA., (© 2021 John Wiley & Sons Ltd.)

Background: Enjoyment plays a key role in the success and feasibility of serious gaming interventions. Unenjoyable games will not be played, and in the case of serious gaming, learning will not occur. Therefore, a so-called GameFlow model has been developed, which intends to guide (serious) game developers in the process of creating and evaluating enjoyment in digital (serious) games. Regarding language learning, a variety of serious games targeting specific language components exist in the market, albeit often without available assessments of enjoyment or feasibility., Objective: This study evaluates the enjoyment and feasibility of a tablet-based, serious story-listening game for kindergarteners, developed based on the principles of the GameFlow model. This study also preliminarily explores the possibility of using the game to foster language comprehension., Methods: Within the framework of a broader preventive reading intervention, 91 kindergarteners aged 5 years with a cognitive risk for dyslexia were asked to play the story game for 12 weeks, 6 days per week, either combined with a tablet-based phonics intervention or control games. The story game involved listening to and rating stories and responding to content-related questions. Game enjoyment was assessed through postintervention questionnaires, a GameFlow-based evaluation, and in-game story rating data. Feasibility was determined based on in-game general question response accuracy (QRA), reflecting the difficulty level, attrition rate, and final game exposure and training duration. Moreover, to investigate whether game enjoyment and difficulty influenced feasibility, final game exposure and training duration were predicted based on the in-game initial story ratings and initial QRA. Possible growth in language comprehension was explored by analyzing in-game QRA as a function of the game phase and baseline language skills., Results: Eventually, data from 82 participants were analyzed. The questionnaire and in-game data suggested an overall enjoyable game experience. However, the GameFlow-based evaluation implied room for game design improvement. The general QRA confirmed a well-adapted level of difficulty for the target sample. Moreover, despite the overall attrition rate of 39% (32/82), 90% (74/82) of the participants still completed 80% of the game, albeit with a large variation in training days. Higher initial QRA significantly increased game exposure (β=.35; P<.001), and lower initial story ratings significantly slackened the training duration (β=-0.16; P=.003). In-game QRA was positively predicted by game phase (β=1.44; P=.004), baseline listening comprehension (β=1.56; P=.002), and vocabulary (β=.16; P=.01), with larger QRA growth over game phases in children with lower baseline listening comprehension skills (β=-0.08; P=.04)., Conclusions: Generally, the story game seemed enjoyable and feasible. However, the GameFlow model evaluation and predictive relationships imply room for further game design improvements. Furthermore, our results cautiously suggest the potential of the game to foster language comprehension; however, future randomized controlled trials should further elucidate the impact on language comprehension., (©Femke Vanden Bempt, Maria Economou, Ward Dehairs, Maaike Vandermosten, Jan Wouters, Pol Ghesquière, Jolijn Vanderauwera. Originally published in JMIR Serious Games (https://games.jmir.org), 23.03.2022.)

Background/aim: Immunotherapy with PD-1/PDL1 blocking monoclonal antibodies has improved survival compared to the standard-of-care chemotherapy for several malignancies at different stages of these malignancies. Due to several reasons, many cancer patients in medical need have no access to these drugs. In this study, we aimed to investigate whether a low dose of nivolumab could also lead to a therapeutic response., Patients and Methods: Patients with advanced cancer were treated with a flat low dose of 10 mg of nivolumab IV every two weeks at no drug cost., Results: Disease control was noted in nine of the 18 patients. Two patients achieved complete remission, two had prolonged partial remission, and five had stable disease, of these only two experienced adverse events., Conclusion: A flat low dose of nivolumab may have clinical activity and is a cheap therapeutic option in patients in medical need for whom standard-dose immune checkpoint inhibitors are not accessible for any reason., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Dyslexia is targeted most effectively when (1) interventions are provided preventively, before the onset of reading instruction, and (2) remediation programs combine letter-sound training with phoneme blending. Given the growing potential of technology in educational contexts, there has been a considerable increase of letter-sound trainings embedded in digital serious games. One such intervention is GraphoGame. Yet, current evidence on the preventive impact of GraphoGame is limited by the lack of adaptation of the original learning content to the skills of pre-readers, short training duration, and a restricted focus on explicitly trained skills. Therefore, the current study aims at investigating the impact of a preventive, and pre-reading adapted GraphoGame training (i.e., GraphoGame-Flemish, GG-FL) on explicitly trained skills and non-specifically trained phonological and language abilities. Following a large-scale screening ( N = 1225), the current study included 88 pre-reading kindergarteners at cognitive risk for dyslexia who were assigned to three groups training either with GG-FL ( n = 31), an active control game ( n = 29), or no game ( n = 28). Before and after the 12-week intervention, a variety of reading-related skills were assessed. Moreover, receptive letter knowledge and phonological awareness were measured every three weeks during the intervention period. Results revealed significantly larger improvements in the GG-FL group on explicitly trained skills, i.e., letter knowledge and word decoding, without finding transfer-effects to untrained phonological and language abilities. Our findings imply a GG-FL-driven head start on early literacy skills in at-risk children. A follow-up study should uncover the long-term impact and the ability of GG-FL to prevent actual reading failure., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Vanden Bempt, Economou, Van Herck, Vanderauwera, Glatz, Vandermosten, Wouters and Ghesquière.)

Although the neural basis of dyslexia has intensively been investigated, results are still unclear about the existence of a white matter deficit in the arcuate fasciculus (AF) throughout development. To unravel this ambiguity, we examined the difference in fractional anisotropy (FA) of the AF between children developing dyslexia and children developing typical reading skills in a longitudinal sample with three MRI time points throughout reading development: the pre-reading stage (5-6 years old), the early reading stage (7-8 years old) and the advanced reading stage (9-10 years old). Applying along-the-tract analyses of white matter organization, our results confirmed that a white matter deficit existed in the left AF prior to the onset of formal reading instruction in children who developed dyslexia later on. This deficit was consistently present throughout the course of reading development. Additionally, we evaluated the use of applying a continuous approach on the participants' reading skills rather than the arbitrary categorization in individuals with or without dyslexia. Our results confirmed the predictive relation between FA and word reading measurements later in development. This study supports the use of longitudinal approaches to investigate the neural basis of the developmental process of learning to read and the application of triangulation, i.e. using multiple research approaches to help gain more insight and aiding the interpretation of obtained results., Competing Interests: Declarations of Competing Interest None., (Copyright © 2021. Published by Elsevier Inc.)

Rapid and widespread changes in brain anatomy and physiology in the first five years of life present substantial challenges for developmental structural, functional, and diffusion MRI studies. One persistent challenge is that methods best suited to earlier developmental stages are suboptimal for later stages, which engenders a trade-off between using different, but age-appropriate, methods for different developmental stages or identical methods across stages. Both options have potential benefits, but also biases, as pipelines for each developmental stage can be matched on methods or the age-appropriateness of methods, but not both. This review describes the data acquisition, processing, and analysis challenges that introduce these potential biases and attempts to elucidate decisions and make recommendations that would optimize developmental comparisons., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Phonological processing skills are known as the most robust cognitive predictor of reading ability. Therefore, the neural determinants of phonological processing have been extensively investigated by means of either neurofunctional or neurostructural techniques. However, to fully understand how the brain represents and processes phonological information, there is need for studies that combine both methods. The present study applies such a multimodal approach with the aim of investigating the pre-reading relation between neural measures of auditory temporal processing, white matter properties of the reading network and phonological processing skills. We administered auditory steady-state responses, diffusion-weighted MRI scans and phonological awareness tasks in 59 pre-readers. Our results demonstrate that a stronger rightward lateralization of syllable-rate (4 Hz) processing coheres with higher fractional anisotropy in the left fronto-temporoparietal arcuate fasciculus. Both neural features each in turn relate to better phonological processing skills. As such, the current study provides novel evidence for the existence of a pre-reading relation between functional measures of syllable-rate processing, structural organization of the arcuate fasciculus and cognitive precursors of reading development. Moreover, our findings demonstrate the value of combining different neural techniques to gain insight in the underlying neural systems for reading (dis)ability., (Copyright © 2020. Published by Elsevier Ltd.)

Research demonstrated that a dyslexia diagnosis is mainly given after the most effective time for intervention has passed, referred to as the dyslexia paradox. Although some pre-reading cognitive measures have been found to be strong predictors of early literacy acquisition, i.e., phonological awareness (PA), letter knowledge (LK), and rapid automatized naming (RAN), more insight in the variability of pre-reading profiles might be of great importance for early identification of children who have an elevated risk for developing dyslexia and to provide tailor-made interventions. To address this issue, this study used a latent profile analysis (LPA) to disentangle different pre-reading profiles in a sample of 1091 Dutch-speaking kindergartners. Four profiles emerged: high performers (16.50%), average performers (40.24%), below-average performers with average IQ (25.57%), and below-average performers with below-average IQ (17.69%). These results suggested two at-risk profiles diverging in IQ, which are presumably more likely to develop dyslexia later on. Although below-average profiles differed significantly in rapid naming and IQ, no clear evidence for the double-deficit theory was found in Dutch-speaking kindergartners. Educational level and reading history of the parents appeared to be predictive for children's classification membership. Our results point towards the heterogeneity that is already present in kindergartners and the possibility to identify at-risk profiles prior to reading instruction, which may be the foundation for earlier targeted interventions. However, more extended research is needed to determine the stability of these profiles across time and across different languages.

Neuroplasticity following bilateral deafness and auditory restoration has been repeatedly investigated. In clinical practice, however, a significant number of patients present a severe-to-profound unilateral hearing loss (UHL). To date, less is known about the neuroplasticity following monaural hearing deprivation and auditory input restoration. This article provides an overview of the current research insights on the impact of UHL on the brain and the effect of auditory input restoration with a cochlear implant (CI). An exhaustive systematic review of the literature was performed selecting 38 studies that apply different neural analyses techniques. The main results show that the hearing ear becomes functionally dominant after monaural deprivation, reshaping the lateralization of the neural network for auditory processing, a process that can be considered to influence auditory restoration. Furthermore, animal models predict that the onset time of UHL impacts auditory restoration. Hence, the results seem to advocate for early restoration of UHL, although further research is required to disambiguate the effects of duration and onset of UHL on auditory restoration and on structural neuroplasticity following UHL deprivation and restoration. Ongoing developments on CI devices compatible with Magnetic Resonance Imaging (MRI) examinations will provide a unique opportunity to investigate structural and functional neuroplasticity following CI restoration more directly.

There is an ongoing debate whether phonological deficits in dyslexics should be attributed to (a) less specified representations of speech sounds, like suggested by studies in young children with a familial risk for dyslexia, or (b) to an impaired access to these phonemic representations, as suggested by studies in adults with dyslexia. These conflicting findings are rooted in between study differences in sample characteristics and/or testing techniques. The current study uses the same multivariate functional MRI (fMRI) approach as previously used in adults with dyslexia to investigate phonemic representations in 30 beginning readers with a familial risk and 24 beginning readers without a familial risk of dyslexia, of whom 20 were later retrospectively classified as dyslexic. Based on fMRI response patterns evoked by listening to different utterances of /bA/ and /dA/ sounds, multivoxel analyses indicate that the underlying activation patterns of the two phonemes were distinct in children with a low family risk but not in children with high family risk. However, no group differences were observed between children that were later classified as typical versus dyslexic readers, regardless of their family risk status, indicating that poor phonemic representations constitute a risk for dyslexia but are not sufficient to result in reading problems. We hypothesize that poor phonemic representations are trait (family risk) and not state (dyslexia) dependent, and that representational deficits only lead to reading difficulties when they are present in conjunction with other neuroanatomical or-functional deficits., (© 2019 John Wiley & Sons Ltd.)

Many studies have focused on neuroanatomical anomalies in dyslexia, yet primarily in school-aged children and adults. In the present study, we investigated gray matter surface area and cortical thickness at the pre-reading stage in a cohort of 54 children, 31 with a family risk for dyslexia and 23 without a family risk for dyslexia, of whom 16 children developed dyslexia. Surface-based analyses in the core regions of the reading network in the left hemisphere and in the corresponding right hemispheric regions were performed in FreeSurfer. Results revealed that pre-readers who develop dyslexia show reduced surface area in bilateral fusiform gyri. In addition, anomalies related to a family risk for dyslexia, irrespectively of later reading ability, were observed in the area of the bilateral inferior and middle temporal gyri. Differences were apparent in surface area, as opposed to cortical thickness. Results indicate that the neuroanatomical anomalies, since they are observed in the pre-reading phase, are not the consequence of impoverished reading experience., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

A child's school achievement is influenced by environmental factors. The environmental factors, when represented by socio-economic status (SES) of the family, have been demonstrated to be related to the reading skills of a child. The neural correlates of the relation between SES and reading have been less thoroughly investigated. The present study expands current research by exploring the relation between SES, quantified by paternal educational level, reading of the offspring and the structure of white matter pathways in the left hemisphere as derived from DTI-based tractography analyses. Therefore, three dorsal white matter pathways, i.e. the long, anterior and posterior segments of the arcuate fasciculus (AF), and three ventral white matter pathways, i.e. the inferior fronto-occipital fasciculus (IFOF), the inferior longitudinal fasciculus (ILF) and the uncinate fasciculus (UF), were manually dissected in the left hemisphere of 34 adolescents with a wide range of reading skills. The results demonstrated a relation between word reading, SES quantified by paternal educational level, and fractional anisotropy (FA) within the left dorsal AF segment and the left ventral UF. Thus, the present study proposes a relationship between paternal educational level and a specific white matter pathway that is important for reading, aiming to guide future research that can determine processes underlying this relationship., Competing Interests: The authors have declared that no competing interests exist.

Two hypotheses have been proposed about the etiology of neurodevelopmental learning disorders, such as dyslexia and dyscalculia: representation impairments and disrupted access to representations. We implemented a multi-method brain imaging approach to directly investigate these representation and access hypotheses in dyscalculia, a highly prevalent but understudied neurodevelopmental disorder in learning to calculate. We combined several magnetic resonance imaging methods and analyses, including univariate and multivariate analyses, functional and structural connectivity. Our sample comprised 24 adults with dyscalculia and 24 carefully matched controls. Results showed a clear deficit in the non-symbolic magnitude representations in parietal, temporal and frontal regions, as well as hyper-connectivity in visual brain regions in adults with dyscalculia. Dyscalculia in adults was thereby related to both impaired number representations and altered connectivity in the brain. We conclude that dyscalculia is related to impaired number representations as well as altered access to these representations., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

In this study, we examined the learning of new grapheme-phoneme correspondences in individuals with and without dyslexia. Additionally, we investigated the relation between grapheme-phoneme learning and measures of phonological awareness, orthographic knowledge and rapid automatized naming, with a focus on the unique joint variance of grapheme-phoneme learning to word and non-word reading achievement. Training of grapheme-phoneme associations consisted of a 20-min training program in which eight novel letters (Hebrew) needed to be paired with speech sounds taken from the participant's native language (Dutch). Eighty-four third grade students, of whom 20 were diagnosed with dyslexia, participated in the training and testing. Our results indicate a reduced ability of dyslexic readers in applying newly learned grapheme-phoneme correspondences while reading words which consist of these novel letters. However, we did not observe a significant independent contribution of grapheme-phoneme learning to reading outcomes. Alternatively, results from the regression analysis indicate that failure to read may be due to differences in phonological and/or orthographic knowledge but not to differences in the grapheme-phoneme-conversion process itself.

Insight in the developmental trajectory of the neuroanatomical reading correlates is important to understand related cognitive processes and disorders. In adults, a dual pathway model has been suggested encompassing a dorsal phonological and a ventral orthographic white matter system. This dichotomy seems not present in pre-readers, and the specific role of ventral white matter in reading remains unclear. Therefore, the present longitudinal study investigated the relation between ventral white matter and cognitive processes underlying reading in children with a broad range of reading skills (n = 61). Ventral pathways of the reading network were manually traced using diffusion tractography: the inferior fronto-occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF) and uncinate fasciculus (UF). Pathways were examined pre-reading (5-6 years) and after two years of reading acquisition (7-8 years). Dimension reduction for the cognitive measures resulted in one component for pre-reading cognitive measures and a separate phonological and orthographic component for the early reading measures. Regression analyses revealed a relation between the pre-reading cognitive component and bilateral IFOF and left ILF. Interestingly, exclusively the left IFOF was related to the orthographic component, whereas none of the pathways was related to the phonological component. Hence, the left IFOF seems to serve as the lexical reading route, already in the earliest reading stages., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Pediatric brain volumetric analysis based on Magnetic Resonance Imaging (MRI) is of particular interest in order to understand the typical brain development and to characterize neurodevelopmental disorders at an early age. However, it has been shown that the results can be biased due to head motion, inherent to pediatric data, and due to the use of methods based on adult brain data that are not able to accurately model the anatomical disparity of pediatric brains. To overcome these issues, we proposed child metrix , a tool developed for the analysis of pediatric neuroimaging data that uses an age-specific atlas and a probabilistic model-based approach in order to segment the gray matter (GM) and white matter (WM). The tool was extensively validated on 55 scans of children between 5 and 6 years old (including 13 children with developmental dyslexia) and 10 pairs of test-retest scans of children between 6 and 8 years old and compared with two state-of-the-art methods using an adult atlas, namely ico brain (applying a probabilistic model-based segmentation) and Freesurfer (applying a surface model-based segmentation). The results obtained with child metrix showed a better reproducibility of GM and WM segmentations and a better robustness to head motion in the estimation of GM volume compared to Freesurfer. Evaluated on two subjects, child metrix showed good accuracy with 82-84% overlap with manual segmentation for both GM and WM, thereby outperforming the adult-based methods (icobrain and Freesurfer), especially for the subject with poor quality data. We also demonstrated that the adult-based methods needed double the number of subjects to detect significant morphological differences between dyslexics and typical readers. Once further developed and validated, we believe that child metrix would provide appropriate and reliable measures for the examination of children's brain.

Research on the neural correlates of developmental dyslexia indicates atypical anatomical lateralization of the planum temporale, a higher-order cortical auditory region. Yet whether this atypical lateralization precedes reading acquisition and is related to a familial risk for dyslexia is not currently known. In this study, we address these questions in 2 separate cohorts of young children and adolescents with and without a familial risk for dyslexia. Planum temporale surface area was manually labeled bilaterally, on the T1-weighted MR brain images of 54 pre-readers (mean age: 6.2 years, SD: 3.2 months; 33 males) and 28 adolescents (mean age: 14.7 years, SD: 3.3 months; 11 males). Half of the pre-readers and adolescents had a familial risk for dyslexia. In both pre-readers and adolescents, group comparisons of left and right planum temporale surface area showed a significant interaction between hemisphere and family history of dyslexia, with participants who had no family risk for dyslexia showing greater leftward asymmetry of the planum temporale. This effect was confirmed when analyses were restricted to normal reading participants. Altered planum temporale asymmetry thus seems to be related to family history of dyslexia., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Neural anomalies have been demonstrated in dyslexia. Recent studies in pre-readers at risk for dyslexia and in pre-readers developing poor reading suggest that these anomalies might be a cause of their reading impairment. Our study goes one step further by exploring the neurodevelopmental trajectory of white matter anomalies in pre-readers with and without a familial risk for dyslexia (n=61) of whom a strictly selected sample develops dyslexia later on (n=15). We collected longitudinal diffusion MRI and behavioural data until grade 3. The results provide evidence that children with dyslexia exhibit pre-reading white matter anomalies in left and right long segment of the arcuate fasciculus (AF), with predictive power of the left segment above traditional cognitive measures and familial risk. Whereas white matter differences in the left AF seem most strongly related to the development of dyslexia, differences in the left IFOF and in the right AF seem driven by both familial risk and later reading ability. Moreover, differences in the left AF appeared to be dynamic. This study supports and expands recent insights into the neural basis of dyslexia, pointing towards pre-reading anomalies related to dyslexia, as well as underpinning the dynamic character of white matter., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Previous studies have shown that the link between parental and offspring's reading is mediated by the cognitive system of the offspring, yet information about the mediating role of the neurobiological system is missing. This family study includes cognitive and diffusion MRI (dMRI) data collected in 71 pre-readers as well as parental reading and environmental data. Using sequential path analyses, which take into account the interrelationships between the different components, we observed mediating effects of the neurobiological system. More specifically, fathers' reading skills predicted reading of the child by operating through a child's left ventral white matter pathway. For mothers no clear mediating role of the neural system was observed. Given that our study involves children who have not yet learned to read and that environmental measures were taken into account, the paternal effect on a child's white matter pathway is unlikely to be only driven by environmental factors. Future intergenerational studies focusing on the genetic, neurobiological and cognitive level of parents and offspring will provide more insight in the relative contribution of parental environment and genes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Recent evidence suggests that a fundamental deficit in the synchronization of neural oscillations to temporal information in speech may underlie phonological processing problems in dyslexia. Since previous studies were performed cross-sectionally in school-aged children or adults, developmental aspects of neural auditory processing in relation to reading acquisition and dyslexia remain to be investigated. The present longitudinal study followed 68 children during development from pre-reader (5 years old) to beginning reader (7 years old) and more advanced reader (9 years old). Thirty-six children had a family risk for dyslexia and 14 children eventually developed dyslexia. EEG recordings of auditory steady-state responses to 4 and 20 Hz modulations, corresponding to syllable and phoneme rates, were collected at each point in time. Our results demonstrate an increase in neural synchronization to phoneme-rate modulations around the onset of reading acquisition. This effect was negatively correlated with later reading and phonological skills, indicating that children who exhibit the largest increase in neural synchronization to phoneme rates, develop the poorest reading and phonological skills. Accordingly, neural synchronization to phoneme-rate modulations was found to be significantly higher in beginning and more advanced readers with dyslexia. We found no developmental effects regarding neural synchronization to syllable rates, nor any effects of a family risk for dyslexia. Altogether, our findings suggest that the onset of reading instruction coincides with an increase in neural responsiveness to phoneme-rate modulations, and that the extent of this increase is related to (the outcome of) reading development. Hereby, dyslexic children persistently demonstrate atypically high neural synchronization to phoneme rates from the beginning of reading acquisition onwards., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

A fundamental deficit in the synchronization of neural oscillations to temporal information in speech could underlie phonological processing problems in dyslexia. In this study, the hypothesis of a neural synchronization impairment is investigated more specifically as a function of different neural oscillatory bands and temporal information rates in speech. Auditory steady-state responses to 4, 10, 20 and 40Hz modulations were recorded in normal reading and dyslexic adolescents to measure neural synchronization of theta, alpha, beta and low-gamma oscillations to syllabic and phonemic rate information. In comparison to normal readers, dyslexic readers showed reduced non-synchronized theta activity, reduced synchronized alpha activity and enhanced synchronized beta activity. Positive correlations between alpha synchronization and phonological skills were found in normal readers, but were absent in dyslexic readers. In contrast, dyslexic readers exhibited positive correlations between beta synchronization and phonological skills. Together, these results suggest that auditory neural synchronization of alpha and beta oscillations is atypical in dyslexia, indicating deviant neural processing of both syllabic and phonemic rate information. Impaired synchronization of alpha oscillations in particular demonstrated to be the most prominent neural anomaly possibly hampering speech and phonological processing in dyslexic readers., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Diffusion tensor imaging (DTI) studies have shown that left temporoparietal white matter is related to phonological aspects of reading. However, DTI lacks the sensitivity to disentangle whether phonological processing is sustained by intrahemispheric connections, interhemispheric connections, or projection tracts. Spherical deconvolution (SD) is a nontensor model which enables a more accurate estimation of multiple fiber directions in crossing fiber regions. Hence, this study is the first to investigate whether the observed relation with reading aspects in left temporoparietal white matter is sustained by a particular pathway by applying a nontensor model. Second, measures of degree of diffusion anisotropy, which indirectly informs about white matter organization, were compared between DTI and SD tractography. In this study, 71 children (5-6 years old) participated. Intrahemispheric, interhemispheric, and projection pathways were delineated using DTI and SD tractography. Anisotropy indices were extracted, that is, fractional anisotropy (FA) in DTI and quantitative hindrance modulated orientational anisotropy (HMOA) in SD. DTI results show that diffusion anisotropy in both the intrahemispheric and projection tracts was positively correlated to phonological awareness; however, the effect was confounded by subjects' motion. In SD, the relation was restricted to the left intrahemispheric connections. A model comparison suggested that FA was, relatively to HMOA, more confounded by fiber crossings; however, anisotropy indices were highly related. In sum, this study shows the potential of SD to quantify white matter microstructure in regions containing crossing fibers. More specifically, SD analyses show that phonological awareness is sustained by left intrahemispheric connections and not interhemispheric or projection tracts., (© 2015 Wiley Periodicals, Inc.)

In adults and school-aged children, phonological aspects of reading seem to be sustained by left dorsal regions, while ventral regions seem to be involved in orthographic word recognition. Yet, given that the brain reorganises during reading acquisition, it is unknown when and how these reading routes emerge and whether neural deficits in dyslexia predate reading onset. Using diffusion MRI in 36 pre-readers with a family risk for dyslexia (FRD(+)) and 35 well matched pre-readers without a family risk (FRD(-)), our results show that phonological predictors of reading are sustained bilaterally by both ventral and dorsal tracts. This suggests that a dorsal and left-hemispheric specialisation for phonological aspects of reading, as observed in adults, is presumably gradually formed throughout reading development. Second, our results indicate that FRD(+) pre-readers display mainly white matter differences in left ventral tracts. This suggests that atypical white matter organisation previously found in dyslexic adults may be causal rather than resulting from a lifetime of reading difficulties, and that the location of such a deficit may vary throughout development. While this study forms an important starting point, longitudinal follow-up of these children will allow further investigation of the dynamics between emerging literacy development and white matter connections., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Primary Objective: Paediatric traumatic brain injury (TBI) has been associated with acute and long-term mathematical difficulties. Little is known about the recovery of these impairments in children with mild TBI (mTBI) and their underlying pathophysiology, such as white matter abnormalities., Research Design: A prospective longitudinal study followed the recovery of mathematical abilities and white matter in children with mTBI from the sub-acute (1 month post-injury) to chronic stage (6-8 months post-injury) of recovery., Methods and Procedures: Twenty children with mTBI and 20 matched controls completed mathematics tests. Diffusion Tensor Imaging (DTI) metrics of white matter pathways corpus callosum (CC), superior and longitudinal fasciculi were examined with DTI-tractography., Main Outcomes and Results: Mathematical difficulties and white matter abnormalities in the CC observed shortly after the injury resolved after 6-8 months of recovery. Children with mTBI continued to show working memory deficits. Longitudinal DTI data suggest continued maturation of the CC in controls, but little maturation of the damaged CC in children with mTBI., Conclusions: Children with mTBI recovered in terms of mathematical abilities and white matter. These children continued to show working memory deficits, which might interfere with learning at school.

Background: Both hepatic arterial infusion (HAI) of chemotherapy and cetuximab (CET) have interesting activity for the treatment of colorectal cancer liver metastases (CRC-LM)., Patients and Methods: Intravenous CET with HAI oxaliplatin (OXA) or i.v. Irinotecan (IRI) followed by HAI of infusion of folic acid modulated 5-fluorouracil 5-FU/l-FA was administered to patients (pts) with CRC-LM who had failed at least one line of prior chemotherapy., Results: Eight pts received i.v. CET with HAI-OXA (5 pts) and i.v.-IRI (3 pts) and HAI-5-FU/l-FA. Adverse events: repeated grade 3 skin toxicity (1 pt), abdominal pain with elevated liver enzymes and asthenia (2 pts), duodenal ulcer (2 pts) with catheter migration and intestinal bleeding (1 pt), reversible interstitial pneumonitis (1 pt), and cystic bile duct dilatation (2 pts) with arteriobiliary fistulisation (1 pt). A partial response was documented in 5 pts (62%). The median time to progression was 8.7 months (95% confidence interval 8-14 months)., Conclusion: Intravenous administration of CET with HAI of chemotherapy is feasible and has promising activity but is associated with specific toxicity.