Neurological and psychiatric adverse effects of long-term methylphenidate treatment in ADHD: A map of the current evidence.

Methylphenidate (MPH), the most common medication for children with Attention Deficit/Hyperactivity Disorder (ADHD) in many countries, is often prescribed for long periods of time. Any long-term psychotropic treatment in childhood raises concerns about possible adverse neurological and psychiatric outcomes. We aimed to map current evidence regarding neurological and psychiatric outcomes, adverse or beneficial, of long-term MPH (> 1 year) treatment in ADHD. We coded studies using a "traffic light" system: Green: safe/favours MPH; Amber: warrants caution; Red: not safe/not well-tolerated. Un-categorisable study findings were coded as "Unclear". Although some evidence suggests an elevated risk of psychosis and tics, case reports describe remission on discontinuation. Several studies suggest that long-term MPH may reduce depression and suicide in ADHD. Evidence suggests caution in specific groups including pre-school children, those with tics, and adolescents at risk for substance misuse. We identified a need for more studies that make use of large longitudinal databases, focus on specific neuropsychiatric outcomes, and compare outcomes from long-term MPH treatment with outcomes following shorter or no pharmacological intervention.

Accuracy and bias of automatic hippocampal segmentation in children and adolescents.

The hippocampus (Hc) is of great importance in various psychiatric diseases in adults, children and adolescents. Automated Hc segmentation has been widely used in adults, implying sufficient overlap with manual segmentation. However, estimation biases related to the Hc volume have been pointed out. This may particularly apply to children who show age-related Hc volume changes, thus, questioning the accuracy of automated Hc segmentation in this age group. The aim of this study was to compare manual segmentation with automated segmentation using the widely adopted FreeSurfer (FS) and MAGeT-Brain software. In 70 children and adolescents (5-16 years, mean age 10.6 years), T1-weighted images were acquired on one of two identical 3T scanners. Automated segmentation was performed using the FS subcortical segmentation, the FS hippocampal subfields segmentation and the MAGeT-Brain software. In comparison with manual segmentation, volume differences, Dice similarity coefficient (DSC), Bland-Altman plot, intraclass correlation coefficient (ICC) and left-right consistency of automated segmentation were calculated. The average percentage of volume differences (PVD) with manual segmentation was 56.8% for FS standard segmentation, 32.2% for FS subfield segmentation and - 15.6% for MAGeT-Brain. The FS Hc subfields segmentation (left/right DSC = 0.86/0.87) and MAGeT-Brain (both hemispheres DSC = 0.91) resulted in a higher volume overlap with manual segmentation compared with the FS subcortical segmentation (DSC = 0.79/0.78). In children aged 5-10.5 years, MAGeT-Brain yielded the highest overlap (DSC = 0.92/0.93). Contrary volume estimation biases were detected in FS and MAGeT-Brain: FS showed larger volume overestimation in smaller Hc volumes, while MAGeT-Brain showed more pronounced volume underestimation in larger Hc volumes. While automated Hc segmentation using FS hippocampal subfields or MAGeT-Brain resulted in adequate volume overlap with manual segmentation, estimation biases compromised the reliability of automated procedures in children and adolescents.

[Differential diagnosis of primary and secondary mathematical learning disability ­ indications from the dyscalculia test Basis-Math 4­8]. / Differenzialdiagnose zwischen primärer Rechenstörung und sekundärer Rechenschwäche: Hinweise aus dem Basis-Math 4-8.

Studies in children with AD(H)D without mathematical learning disability (MLD) as well as studies on the effects of methylphenidate on arithmetic have shown that most deficits in mathematics and most error types commonly described as specific to developmental dyscalculia (e. g., finger-counting, fact-retrieval deficit, complex counting, difficulties with carry/borrow procedures, self-corrections) cannot be classified as such and should thus not be used for the differential diagnosis of primary dyscalculia and secondary MLD. This article proposes using the overall score in the dyscalculia test Basis-Math 4-8 (Moser Opitz et al., 2010) as well as implausible subtraction errors as a marker for dyscalculia and the number of self-corrections made during the test as a cognitive marker for attention deficits. Hierarchical cluster analyses were calculated in a sample of 51 clinically referred children with normal IQ and suspicion of MLD, using IQ, years of schooling, overall score of the Basis-Math 4­8 and number of self-corrections in this test as variables. The results revealed a subgroup with primary dyscalculia as well as three subgroups with secondary MLD (two with attention deficit hyperactivity disorder, one with depression and one small subgroup with high IQ). In conclusion, the Basis-Math 4­8 (Moser Opitz et al., 2010) can offer substantial information for the differential diagnosis of dyscalculia and secondary deficits in mathematics due to attention problems and enable optimization of treatment decisions for the different groups.

Patterns of linguistic and numerical performance in aphasia.

BACKGROUND: Empirical research on the relationship between linguistic and numerical processing revealed inconsistent results for different levels of cognitive processing (e.g., lexical, semantic) as well as different stimulus materials (e.g., Arabic digits, number words, letters, non-number words). Information of dissociation patterns in aphasic patients was used in order to investigate the dissociability of linguistic and numerical processes. The aim of the present prospective study was a comprehensive, specific, and systematic investigation of relationships between linguistic and numerical processing, considering the impact of asemantic vs. semantic processing and the type of material employed (numbers compared to letters vs. words). METHODS: A sample of aphasic patients (n = 60) was assessed with a battery of linguistic and numerical tasks directly comparable for their cognitive processing levels (e.g., perceptual, morpho-lexical, semantic). RESULTS AND CONCLUSIONS: Mean performance differences and frequencies of (complementary) dissociations in individual patients revealed the most prominent numerical advantage for asemantic tasks when comparing the processing of numbers vs. letters, whereas the least numerical advantage was found for semantic tasks when comparing the processing of numbers vs. words. Different patient subgroups showing differential dissociation patterns were further analysed and discussed. A comprehensive model of linguistic and numerical processing should take these findings into account.

In how many ways is the approximate number system associated with exact calculation?

The approximate number system (ANS) has been consistently found to be associated with math achievement. However, little is known about the interactions between the different instantiations of the ANS and in how many ways they are related to exact calculation. In a cross-sectional design, we investigated the relationship between three measures of ANS acuity (non-symbolic comparison, non-symbolic estimation and non-symbolic addition), their cross-sectional trajectories and specific contributions to exact calculation. Children with mathematical difficulties (MD) and typically achieving (TA) controls attending the first six years of formal schooling participated in the study. The MD group exhibited impairments in multiple instantiations of the ANS compared to their TA peers. The ANS acuity measured by all three tasks positively correlated with age in TA children, while no correlation was found between non-symbolic comparison and age in the MD group. The measures of ANS acuity significantly correlated with each other, reflecting at least in part a common numerosity code. Crucially, we found that non-symbolic estimation partially and non-symbolic addition fully mediated the effects of non-symbolic comparison in exact calculation.

[From brain imaging to good teaching? implicating from neuroscience for research on learning and instruction]. / Vom Hirnbild zum guten Unterricht. Implikationen von neuropsychologischen und Bildgebungsbefuden für die Lehr-Lern-Forschung.

Psychiatric disorders in childhood and adolescence, in particular attention deficit disorder or specific learning disorders like developmental dyslexia and developmental dyscalculia, affect academic performance and learning at school. Recent advances in neuroscientific research have incited an intensive debate both in the general public and in the field of educational and instructional science as well as to whether and to what extent these new findings in the field of neuroscience might be of importance for school-related learning and instruction. In this review, we first summarize neuroscientific findings related to the development of attention, working memory and executive functions in typically developing children and then evaluate their relevance for school-related learning. We present an overview of neuroimaging studies of specific learning disabilities such as developmental dyslexia and developmental dyscalculia, and critically discuss their practical implications for educational and teaching practice, teacher training, early diagnosis as well as prevention and disorder-specific therapy. We conclude that the new interdisciplinary field of neuroeducation cannot be expected to provide direct innovative educational applications (e.g., teaching methods). Rather, the future potential of neuroscience lies in creating a deeper understanding of the underlying cognitive mechanisms and pathomechanisms of learning processes and learning disorders.

Number representation: a question of look? The distance effect in comparison of English and Turkish number words.

Cohen Kadosh found that Hebrew number words and Arabic digits elicited different distance effects. The numerical distance effect (i.e., faster reaction times and smaller error rates for numbers with larger distance to a standard number, e.g., 5) was smaller for number words than for digits. The author suggested that the result indicated a notation-dependent (i.e., nonabstract) numerical representation. Alternatively, however, it is possible that the distance effect was decreased by perceptual features of the Hebrew number words used as stimuli. To test this hypothesis, we replicated the study of Cohen Kadosh, but with English and Turkish number words compared to Arabic digits. The perceptual features of Turkish number words lead to the hypothesis that the opposite effect should be present: an increased distance effect for number words compared to Arabic digits. On the other hand, English number words show features similar to those of Hebrew number words, thus leading to the expectation of a decreased distance effect for them. Our results confirmed our hypotheses. We conclude that the distance effect can be influenced also by perceptual features in addition to the impact of numerical representations.

Diagnosing developmental dyscalculia on the basis of reliable single case FMRI methods: promises and limitations.

FMRI-studies are mostly based on a group study approach, either analyzing one group or comparing multiple groups, or on approaches that correlate brain activation with clinically relevant criteria or behavioral measures. In this study we investigate the potential of fMRI-techniques focusing on individual differences in brain activation within a test-retest reliability context. We employ a single-case analysis approach, which contrasts dyscalculic children with a control group of typically developing children. In a second step, a support-vector machine analysis and cluster analysis techniques served to investigate similarities in multivariate brain activation patterns. Children were confronted with a non-symbolic number comparison and a non-symbolic exact calculation task during fMRI acquisition. Conventional second level group comparison analysis only showed small differences around the angular gyrus bilaterally and the left parieto-occipital sulcus. Analyses based on single-case statistical procedures revealed that developmental dyscalculia is characterized by individual differences predominantly in visual processing areas. Dyscalculic children seemed to compensate for relative under-activation in the primary visual cortex through an upregulation in higher visual areas. However, overlap in deviant activation was low for the dyscalculic children, indicating that developmental dyscalculia is a disorder characterized by heterogeneous brain activation differences. Using support vector machine analysis and cluster analysis, we tried to group dyscalculic and typically developing children according to brain activation. Fronto-parietal systems seem to qualify for a distinction between the two groups. However, this was only effective when reliable brain activations of both tasks were employed simultaneously. Results suggest that deficits in number representation in the visual-parietal cortex get compensated for through finger related aspects of number representation in fronto-parietal cortex. We conclude that dyscalculic children show large individual differences in brain activation patterns. Nonetheless, the majority of dyscalculic children can be differentiated from controls employing brain activation patterns when appropriate methods are used.

Transcoding abilities in typical and atypical mathematics achievers: the role of working memory and procedural and lexical competencies.

Transcoding between numerical systems is one of the most basic abilities acquired by children during their early school years. One important topic that requires further exploration is how mathematics proficiency can affect number transcoding. The aim of the current study was to investigate transcoding abilities (i.e., reading Arabic numerals and writing dictation) in Brazilian children with and without mathematics difficulties, focusing on different school grades. We observed that children with learning difficulties in mathematics demonstrated lower achievement in number transcoding in both early and middle elementary school. In early elementary school, difficulties were observed in both the basic numerical lexicon and the management of numerical syntax. In middle elementary school, difficulties appeared mainly in the transcoding of more complex numbers. An error analysis revealed that the children with mathematics difficulties struggled mainly with the acquisition of transcoding rules. Although we confirmed the previous evidence on the impact of working memory capacity on number transcoding, we found that it did not fully account for the observed group differences. The results are discussed in the context of a maturational lag in number transcoding ability in children with mathematics difficulties.

Explaining school mathematics performance from symbolic and nonsymbolic magnitude processing: similarities and differences between typical and low-achieving children

Magnitude processing is one of the most central cognitive mechanisms that underlie persistent mathematics difficulties. No consensus has yet been reached about whether these difficulties can be predominantly attributed to deficits in symbolic or nonsymbolic magnitude processing. To investigate this issue, we assessed symbolic and nonsymbolic magnitude representations in children with low or typical achievement in school mathematics. Response latencies and the distance effect were comparable between groups in both symbolic and nonsymbolic tasks. The results indicated that both typical and low achievers were able to access magnitude representation via symbolic and nonsymbolic processing. However, low achievers presented higher error rates than typical achievers, especially in the nonsymbolic task. Furthermore, measures of nonsymbolic magnitude explained individual differences in school mathematics better than measures of symbolic magnitude when considering all of the children together. When examining the groups separately, symbolic magnitude representation explained differences in school mathematics in low achievers but not in typical achievers. These results suggest that symbolic magnitude is more relevant to solving arithmetic problems when mathematics achievement is particularly low. In contrast, individual differences in nonsymbolic processing appear to be related to mathematics achievement in a more general manner.

Explaining school mathematics performance from symbolic and nonsymbolic magnitude processing: similarities and differences between typical and low-achieving children

Magnitude processing is one of the most central cognitive mechanisms that underlie persistent mathematics difficulties. No consensus has yet been reached about whether these difficulties can be predominantly attributed to deficits in symbolic or nonsymbolic magnitude processing. To investigate this issue, we assessed symbolic and nonsymbolic magnitude representations in children with low or typical achievement in school mathematics. Response latencies and the distance effect were comparable between groups in both symbolic and nonsymbolic tasks. The results indicated that both typical and low achievers were able to access magnitude representation via symbolic and nonsymbolic processing. However, low achievers presented higher error rates than typical achievers, especially in the nonsymbolic task. Furthermore, measures of nonsymbolic magnitude explained individual differences in school mathematics better than measures of symbolic magnitude when considering all of the children together. When examining the groups separately, symbolic magnitude representation explained differences in school mathematics in low achievers but not in typical achievers. These results suggest that symbolic magnitude is more relevant to solving arithmetic problems when mathematics achievement is particularly low. In contrast, individual differences in nonsymbolic processing appear to be related to mathematics achievement in a more general manner.(AU)

The role of finger representations and saccades for number processing: an FMRI study in children.

A possible functional role of finger representations for the development of early numerical cognition has been the subject of recent debate; however, until now, only behavioral studies have directly supported this view. Working from recent models of number processing, we focused on the neural networks involved in numerical tasks and their relationship to the areas underlying finger representations and saccades in children aged 6-12 years. We were able to differentiate three parietal circuits that were related to distinct aspects of number processing. Abstract magnitude processing was subserved by an association area also activated by saccades and visually guided finger movements. Addition processes led to activation in an area only engaged during saccade encoding, whereas counting processes resulted in the activation of an area only activated during visually guided finger movements, namely in the anterior intraparietal sulcus. Apart from this area, a large network of specifically finger-related brain areas including the ventral precentral sulcus, supplementary motor area, dorso-lateral prefrontal cortex, insula, thalamus, midbrain, and cerebellum was activated during (particularly non-symbolic) exact addition but not during magnitude comparison. Moreover, a finger-related activation cluster in the right ventral precentral sulcus was only present during non-symbolic addition and magnitude comparison, but not during symbolic number processing tasks. We conclude that finger counting may critically mediate the step from non-symbolic to symbolic and exact number processing via somatosensory integration processes and therefore represents an important example of embodied cognition.

A hand full of numbers: a role for offloading in arithmetics learning?

Finger counting has been associated to arithmetic learning in children. We examined children with (n = 14) and without (n = 84) mathematics learning difficulties with ages between 8 and 11 years. Deficits in finger gnosia were found in association to mathematical difficulties. Finger gnosia was particularly relevant for the performance in word problems requiring active manipulation of small magnitudes in the range between 1 and 10. Moreover, the deficits in finger gnosia could not be attributed to a shortage in working memory capacity but rather to a specific inability to use fingers to transiently represent magnitudes, tagging to be counted objects, and reducing the cognitive load necessary to solve arithmetic problems. Since finger gnosia was more related to symbolic than to non-symbolic magnitude processing, finger-related representation of magnitude seems to be an important link for learning the mapping of analog onto discrete symbolic magnitudes.

Sensitivity, reproducibility, and reliability of self-paced versus fixed stimulus presentation in an fMRI study on exact, non-symbolic arithmetic in typically developing children aged between 6 and 12 years.

Fixed stimulus presentation times pose several methodological problems for developmental functional magnetic resonance imaging (fMRI) studies that can be avoided by self-paced study designs. Yet, methodological issues of self-paced stimulus presentation for fMRI studies are largely understudied. Therefore, we compared sensitivity, reproducibility, and reliability of neural activation of a fixed and a self-paced design for an exact, non-symbolic addition paradigm in a sample of children aged 6-12 years. Both design types were comparable in sensitivity, and the self-paced design was superior in reproducibility and reliability. Therefore, self-paced study designs seem to be a valid option for developmental fMRI studies on higher cognition.

Math Anxiety and Math Ability in Early Primary School Years.

Mathematical learning disabilities (MLDs) are often associated with math anxiety, yet until now, very little is known about the causal relations between calculation ability and math anxiety during early primary school years. The main aim of this study was to longitudinally investigate the relationship between calculation ability, self-reported evaluation of mathematics, and math anxiety in 140 primary school children between the end of first grade and the middle of third grade. Structural equation modeling revealed a strong influence of calculation ability and math anxiety on the evaluation of mathematics but no effect of math anxiety on calculation ability or vice versa-contrasting with the frequent clinical reports of math anxiety even in very young MLD children. To summarize, our study is a first step toward a better understanding of the link between math anxiety and math performance in early primary school years performance during typical and atypical courses of development.

Mind the gap between both hands: evidence for internal finger-based number representations in children's mental calculation.

At a certain stage of development, virtually all children use some kind of external finger-based number representation. However, only little is known about how internal traces of this early external representation may still influence calculation even when finger calculation ceases to be an efficient tool in mental calculation. In the present study, we provide evidence for a disproportionate number of split-five errors (i.e., errors with a difference of +/-5 from the correct result) in mental addition and subtraction (e.g., 18 - 7 = 6). We will argue that such errors may have different origins. For complex problems and initially also for simple problems they are due to failure to keep track of 'full hands' in counting or calculation procedures. However, for simple addition problems split-five errors may later also be caused by mistakes in directly retrieving the result from declarative memory. In general, the present results are interpreted in terms of a transient use of mental finger patterns - in particular the whole hand pattern - in children's mental calculation.

Spatial representations of numbers in children and their connection with calculation abilities.

Evidence for a connection between number and space processing comes from behavioural, patient, and brain imaging data, but only a few studies have addressed this issue in children. We asked children (n=118) at the age of 8-9 years to decide which one of the two numerical distances in a visually presented number triplet was numerically larger. Numerical and spatial distances were manipulated independently, resulting in congruent, neutral, and incongruent conditions. The spatial distances between the numbers clearly affected the comparison of numerical distances: reactions times were faster and error rates smaller for congruent than for incongruent trials. These findings are in line with the assumption of a spatial layout of mental number representations in third graders. Correlations between the size of the congruity effect and calculation abilities were found to be differently marked for girls and boys: a positive correlation was found for boys, while a marginally negative correlation was obtained for girls.

[German version of the math anxiety questionnaire (FRA) for 6- to 9-year-old children]. / Deutschsprachige Version des Fragebogens für Rechenangst (FRA) für 6- bis 9-jährige Kinder.

OBJECTIVES: Is the FRA a reliable and valid instrument? Are there any gender differences concerning math anxiety? Are there any developmental changes in this regard in the course of the early grades? METHODS: Together with the dyscalculia test TEDI-MATH, the FRA was presented to a total of 450 children from the first to the third grade of primary school (at least 40 girls and 40 boys per semester). RESULTS: The total scale has an internal consistency (Cronbach's alpha) between 0.83 and 0.91. Correlations between arithmetic skills and the FRA scales were mostly significant. The significantly higher negative scores for girls were taken into account by providing standard scores corrected for gender. No systematic developmental changes could be observed. CONCLUSIONS: The FRA is the first German math anxiety questionnaire for primary school children. High reliability, standard scores corrected for gender, and economic handling make it an instrument well suited for use in clinical settings (e.g., dyscalculia diagnostics and intervention).