Effects of Discipline-Specific Strategy Instruction on Historical Writing Growth of Students With Writing Difficulties.

This article reports the results from a study investigating the effects of a discipline-specific reading and writing intervention (I3C/PROVE IT!) with fourth and fifth graders. Participants included 237 students with writing difficulties (WD) from an initial pool of 608 upper elementary school students in a larger study. Teachers and students were randomly assigned to I3C/PROVE IT! or business-as-usual conditions and then provided instruction on reading historical documents and writing evidence-based arguments. Findings indicated that over a period of almost 3 months, the historical writing growth trajectories of students with WD in I3C/PROVE IT! classrooms were significantly greater than their peers in business-as-usual classrooms. Significant findings favoring I3C/PROVE IT! students also generalized to domain-general measures. This study provides evidence for the benefits of discipline-specific interventions in social studies for students with WD. Limitations and directions for future research are discussed.

Executive, language and fluency dysfunction are markers of localised TDP-43 cerebral pathology in non-demented ALS.

OBJECTIVE: Approximately 35% of patients with amyotrophic lateral sclerosis (ALS) exhibit mild cognitive deficits in executive functions, language and fluency, without dementia. The precise pathology of these extramotor symptoms has remained unknown. This study aimed to determine the pathological correlate of cognitive impairment in patients with non-demented ALS. METHODS: In-depth neuropathological analysis of 27 patients with non-demented ALS who had undergone cognitive testing (Edinburgh Cognitive and Behaviour ALS Screen (ECAS)) during life. Analysis involved assessing 43 kDa Tar-DNA binding protein (TDP-43) accumulation in brain regions specifically involved in executive functions, language functions and verbal fluency to ascertain whether functional deficits would relate to a specific regional distribution of pathology. RESULTS: All patients with cognitive impairment had TDP-43 pathology in extramotor brain regions (positive predictive value of 100%). The ECAS also predicted TDP-43 pathology with 100% specificity in brain regions associated with executive, language and fluency domains. We also detected a subgroup with no cognitive dysfunction, despite having substantial TDP-43 pathology, so called mismatch cases. CONCLUSIONS: Cognitive impairment as detected by the ECAS is a valid predictor of TDP-43 pathology in non-demented ALS. The profile of mild cognitive deficits specifically predicts regional cerebral involvement. These findings highlight the utility of the ECAS in accurately assessing the pathological burden of disease.

Cerebellar GABAergic correlates of cognition-mediated verbal fluency in physiology and schizophrenia.

OBJECTIVE: Defective cerebellar GABAergic inhibitory control may participate to the cognitive impairments seen in SZ. We tested the prediction of a model for the relationship between cerebellar GABA concentration and the associative/executive processes required by verbal fluency in patients with schizophrenia (SZ) and matched healthy controls (HC). METHOD: Magnetic resonance spectroscopy of GABA was performed using a 3 Tesla scanner and verbal fluency assessed by the Controlled Word (WFT) and Semantic (SFT) Fluency tests. Cerebellar GABA measurements were obtained using the MEGA-PRESS acquisition sequence. Linear correlations between cerebellar GABA levels and the WFT, SFT score were performed to test differences between correlation coefficients of SZ and HC. Quantile regressions between GABA levels and the WFT score were performed. RESULTS: Higher cerebellar GABA concentration was associated in SZ with lower phonemic fluency and reduced number of switches among subcategories as opposed to what observed in HC (with higher cerebellar GABA associated with higher number of words and phonemic switches). GABA levels explained phonemic fluency in SZ performing above the group mean. CONCLUSION: Studying cerebellar GABA provides a valid heuristic to explore the molecular mechanisms of SZ. This is crucial for developing pharmacological treatments to improve cognition and functional recovery in SZ.

Axon guidance pathways served as common targets for human speech/language evolution and related disorders.

Human and several nonhuman species share the rare ability of modifying acoustic and/or syntactic features of sounds produced, i.e. vocal learning, which is the important neurobiological and behavioral substrate of human speech/language. This convergent trait was suggested to be associated with significant genomic convergence and best manifested at the ROBO-SLIT axon guidance pathway. Here we verified the significance of such genomic convergence and assessed its functional relevance to human speech/language using human genetic variation data. In normal human populations, we found the affected amino acid sites were well fixed and accompanied with significantly more associated protein-coding SNPs in the same genes than the rest genes. Diseased individuals with speech/language disorders have significant more low frequency protein coding SNPs but they preferentially occurred outside the affected genes. Such patients' SNPs were enriched in several functional categories including two axon guidance pathways (mediated by netrin and semaphorin) that interact with ROBO-SLITs. Four of the six patients have homozygous missense SNPs on PRAME gene family, one youngest gene family in human lineage, which possibly acts upon retinoic acid receptor signaling, similarly as FOXP2, to modulate axon guidance. Taken together, we suggest the axon guidance pathways (e.g. ROBO-SLIT, PRAME gene family) served as common targets for human speech/language evolution and related disorders.

Early neuroimaging markers of FOXP2 intragenic deletion.

FOXP2 is the major gene associated with severe, persistent, developmental speech and language disorders. While studies in the original family in which a FOXP2 mutation was found showed volume reduction and reduced activation in core language and speech networks, there have been no imaging studies of different FOXP2 mutations. We conducted a multimodal MRI study in an eight-year-old boy (A-II) with a de novo FOXP2 intragenic deletion. A-II showed marked bilateral volume reductions in the hippocampus, thalamus, globus pallidus, and caudate nucleus compared with 26 control males (effect sizes from -1 to -3). He showed no detectable functional MRI activity when repeating nonsense words. The hippocampus is implicated for the first time in FOXP2 diseases. We conclude that FOXP2 anomaly is either directly or indirectly associated with atypical development of widespread subcortical networks early in life.

Moderna investigación educativa en el síndrome de Down (II Parte) / No disponible

Down Syndrome Education International ha publicado 21 breves artículos que describen los modernos avances realizados en la investigación educativa sobre el síndrome de Down, y las cuestiones que aún están por resolver. Ofrecemos en esta continuación los artículos 6 a 13 que versan sobre la educación integrada, las habilidades sociales, el desarrollo del lenguaje, el aprendizaje de números, el autismo en el síndrome de Down, la motivación, la atención temprana y el manejo de conductas difíciles

Down Syndrome Education International has edited short articles which describe modern advances in the field of educational research in Down syndrome, and face to the questions that remain unresolved. We offer a second series (articles 6-13), dealing on inclusive education, social abilities, speech development, numerical learning, autism in Down syndrome, motivation, early intervention, challenging behavior

Relaciones entre trastornos del lenguaje y competencia socioemocional / Relationships between language disorders and socio-emotional competence

Introducción. Existe una comorbilidad elevada entre los trastornos del lenguaje y los problemas conductuales, emocionales y sociales. Objetivo. Revisar la bibliografía existente sobre las dificultades sociales y emocionales de los niños con trastorno específico del lenguaje desde una perspectiva evolutiva. Desarrollo. En la infancia temprana, los resultados acerca de este tipo de dificultades en niños con un retraso del lenguaje no son concluyentes. Sin embargo, desde el período de educación infantil, la investigación advierte de una mayor ocurrencia e alteraciones en el área social y emocional. Los estudios longitudinales que han permitido determinar el ajuste psicosocial en la adolescencia indican un mayor riesgo de presentar experiencias de victimización y bullying o de desarrollar ansiedad y depresión a largo plazo, aunque algunos trabajos ofrecen una panorámica más alentadora. Conclusiones. La afectación de la comprensión y del componente pragmático del lenguaje es un predictor importante en la manifestación de alteraciones socioemocionales. En los trastornos mixtos comprensivos-expresivos, una dificultad de procesamiento general podría justificar, al menos parcialmente, esta asociación. A su vez, es probable que limitaciones en el desarrollo de la cognición social contribuyan a explicar, en cierta medida, las dificultades de las personas con trastornos pragmáticos, si bien no existe una consistencia en la investigación en este sentido (AU)

Introduction. The rate of comorbidity between language disorders and behavioural, emotional and social problems is high. Aim. To review the literature on the social and emotional difficulties of children with specific language impairment from a developmental perspective. Development. In early childhood, findings concerning this kind of difficulties in children with delayed language development are not conclusive. Yet, as of the period of preschool education, research points to a greater occurrence of difficulties in the social and emotional area. The longitudinal studies that have made it possible to determine the psychosocial adjustment of teenagers suggest a greater risk of presenting experiences involving victimisation and bullying or of developing anxiety and depression in the long term, although some studies offer a more promising scenario. Conclusions. Disorders involving comprehension and the pragmatic component of language are an important predictor in the manifestation of socio-emotional alterations. In mixed comprehension-expression disorders, general difficulty in processing could at least partially account for this association. In turn, these limitations in the development of social cognition are likely to help explain, at least up to a point, the difficulties experienced by persons with pragmatic disorders, although the research conducted to date is not consistent in this sense (AU)

Absent CNKSR2 causes seizures and intellectual, attention, and language deficits.

Synaptic function is central to brain function. Understanding the synapse is aided by studies of patients lacking individual synaptic proteins. Common neurological diseases are genetically complex. Their understanding is likewise simplified by studies of less common monogenic forms. We detail the disease caused by absence of the synaptic protein CNKSR2 in 8 patients ranging from 6 to 62 years old. The disease is characterized by intellectual disability, attention problems, and abrupt lifelong language loss following a brief early childhood epilepsy with continuous spike-waves in sleep. This study describes the phenotype of CNKSR2 deficiency and its involvement in systems underlying common neurological disorders.

5-HT2 receptor distribution shown by [18F] setoperone PET in high-functioning autistic adults.

The serotonergic system is implicated in disordered emotional behavior. Autism is characterized by impaired processing of emotional information. The serotonergic (5-HT) system is also critically involved in brain development, and abnormal brain synthesis of serotonin is observed in autism. Furthermore, whole blood and platelet serotonin have been reported to be elevated in autism. The authors examined the CNS serotonin system in autism in vivo. 5-HT2 receptors were visualized by PET imaging of [18F]setoperone-binding in this pilot study of 6 high-functioning autistic adults and 10 matched-control participants. Autism subjects had less thalamic [18F]setoperone binding than controls, when covaried for age, but no difference reached significance in other areas. A negative relationship between thalamic binding and history of language impairment was also observed. Further studies will be needed to gain a clearer picture of the role of the 5-HT system in autism.

The aromatase gene CYP19A1: several genetic and functional lines of evidence supporting a role in reading, speech and language.

Inspired by the localization, on 15q21.2 of the CYP19A1 gene in the linkage region of speech and language disorders, and a rare translocation in a dyslexic individual that was brought to our attention, we conducted a series of studies on the properties of CYP19A1 as a candidate gene for dyslexia and related conditions. The aromatase enzyme is a member of the cytochrome P450 super family, and it serves several key functions: it catalyzes the conversion of androgens into estrogens; during early mammalian development it controls the differentiation of specific brain areas (e.g. local estrogen synthesis in the hippocampus regulates synaptic plasticity and axonal growth); it is involved in sexual differentiation of the brain; and in songbirds and teleost fishes, it regulates vocalization. Our results suggest that variations in CYP19A1 are associated with dyslexia as a categorical trait and with quantitative measures of language and speech, such as reading, vocabulary, phonological processing and oral motor skills. Variations near the vicinity of its brain promoter region altered transcription factor binding, suggesting a regulatory role in CYP19A1 expression. CYP19A1 expression in human brain correlated with the expression of dyslexia susceptibility genes such as DYX1C1 and ROBO1. Aromatase-deficient mice displayed increased cortical neuronal density and occasional cortical heterotopias, also observed in Robo1-/- mice and human dyslexic brains, respectively. An aromatase inhibitor reduced dendritic growth in cultured rat neurons. From this broad set of evidence, we propose CYP19A1 as a candidate gene for human cognitive functions implicated in reading, speech and language.

Cntnap2 expression in the cerebellum of Foxp2(R552H) mice, with a mutation related to speech-language disorder.

Foxp2(R552H) knock-in (KI) mice carrying a mutation related to human speech-language disorder exhibit impaired ultrasonic vocalization and poor Purkinje cell development. Foxp2 is a forkhead domain-containing transcriptional repressor that associates with its co-repressor CtBP; Foxp2(R552H) displays reduced DNA binding activity. A genetic connection between FOXP2 and CNTNAP2 has been demonstrated in vitro, but not in vivo. Here we show that Cntnap2 mRNA levels significantly increased in the cerebellum of Foxp2(R552H) KI pups, although the cerebellar population of Foxp2-positive Purkinje cells was very small. Furthermore, Cntnap2 immunofluorescence did not decrease in the poorly developed Purkinje cells of Foxp2(R552H) KI pups, although synaptophysin immunofluorescence decreased. Cntnap2 and CtBP were ubiquitously expressed, while Foxp2 co-localized with CtBP only in Purkinje cells. Taken together, these observations suggest that Foxp2 may regulate ultrasonic vocalization by associating with CtBP in Purkinje cells; Cntnap2 may be a target of this co-repressor.

The role of the urokinase receptor in epilepsy, in disorders of language, cognition, communication and behavior, and in the central nervous system.

As a key component of the plasminogen activation system, uPAR, the receptor for the plasminogen activator of the urokinase type, is involved in many physiological and pathological processes. Besides its classical roles, there has been increased evidence that uPAR or uPAR-associated pathways, participate in the development, in the functioning and in the pathology of the central nervous system. Qualitative and quantitative changes in the expressions of uPAR and of its canonical ligand uPA have been observed in a large variety of epileptic disorders, either in human or in animal models, as well as in other brain diseases (stroke and brain trauma, multiple sclerosis, Alzheimer's disease, cerebral malaria, HIV-associated leukoencephalopathy and encephalitis). The variety of such pathological conditions and the different brain areas and cell types involved, likely reflects the wide range and the complexity of the multiple and somehow intertwined pathophysiological mechanisms related with uPAR. In the mouse, the knock-out of the Upar-encoding gene (Plaur) leads to significant and nearly complete loss in parvalbumin-containing interneurons during brain development. This is associated with increased susceptibility to spontaneous and chemically-induced seizures and with increased anxiety and impaired social interactions. The recent identification of the novel uPAR ligand SRPX2 (Sushi repeat protein, X-linked 2) and the regulation of both the SRPX2 and PLAUR genes by transcription factor FOXP2 has shed novel and exciting insights into the role of uPAR-related molecular networks in rolandic epilepsy, in developmental verbal dyspraxia, in perisylvian polymicrogyria, and generally in disorders of the speech areas and circuits. uPAR, its regulators and partners, as well as other proteins containing Ly-6/uPAR/alpha-neurotoxin domains, represent key entry points for present and future studies not only on speech-related disorders but also on epilepsy and autism spectrum disorders.

Abeta amyloid deposition in the language system and how the brain responds.

Post-mortem measures of Abeta amyloid deposition correlate only weakly with cognitive dysfunction antemortem. We tested the hypothesis that functional reorganization forms a critical intermediary step between Abeta amyloid-associated brain injury and clinical disease expression. Fifteen patients with early-stage probable Alzheimer's disease (AD) and 16 cognitively intact controls participated in this combined functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) study. The fMRI design had two factors: task (associative-semantic versus visuoperceptual judgement) and input-modality (written words versus pictures). We measured Abeta amyloid by means of Pittsburgh Compound B (11C-PIB). In the posterior third of the left superior temporal sulcus (STS), the fMRI response during the associative-semantic compared with the visuoperceptual task was lower in AD than in controls, in particular for words. Response amplitude correlated inversely with PIB uptake in this region. Contralaterally, the functional pattern differed substantially: the fMRI response in the right posterior STS during the associative-semantic versus the visuoperceptual task was higher in AD than in controls. Accuracy on the Boston Naming test correlated positively with the degree to which AD patients were able to recruit the right STS (r = 0.84, P(corrected) = 0.014). PIB uptake did not correlate with naming accuracy. Functional reorganization of the language system in response to Abeta amyloid-related brain injury exists in early-stage AD and determines the degree of anomia more than Abeta amyloid load per se does.

Intracellular distribution of a speech/language disorder associated FOXP2 mutant.

Although a mutation (R553H) in the forkhead box (FOX)P2 gene is associated with speech/language disorder, little is known about the function of FOXP2 or its relevance to this disorder. In the present study, we identify the forkhead nuclear localization domains that contribute to the cellular distribution of FOXP2. Nuclear localization of FOXP2 depended on two distally separated nuclear localization signals in the forkhead domain. A truncated version of FOXP2 lacking the leu-zip, Zn2+ finger, and forkhead domains that was observed in another patient with speech abnormalities demonstrated an aggregated cytoplasmic localization. Furthermore, FOXP2 (R553H) mainly exhibited a cytoplasmic localization despite retaining interactions with nuclear transport proteins (importin alpha and beta). Interestingly, wild type FOXP2 promoted the transport of FOXP2 (R553H) into the nucleus. Mutant and wild type FOXP2 heterodimers in the nucleus or FOXP2 R553H in the cytoplasm may underlie the pathogenesis of the autosomal dominant speech/language disorder.

SRPX2 mutations in disorders of language cortex and cognition.

The rolandic and sylvian fissures divide the human cerebral hemispheres and the adjacent areas participate in speech processing. The relationship of rolandic (sylvian) seizure disorders with speech and cognitive impairments is well known, albeit poorly understood. We have identified the Xq22 gene SRPX2 as being responsible for rolandic seizures (RSs) associated with oral and speech dyspraxia and mental retardation (MR). SRPX2 is a secreted sushi-repeat containing protein expressed in neurons of the human adult brain, including the rolandic area. The disease-causing mutation (N327S) resulted in gain-of-glycosylation of the secreted mutant protein. A second mutation (Y72S) was identified within the first sushi domain of SRPX2 in a male with RSs and bilateral perisylvian polymicrogyria and his female relatives with mild MR or unaffected carrier status. In cultured cells, both mutations were associated with altered patterns of intracellular processing, suggesting protein misfolding. In the murine brain, Srpx2 protein expression appeared in neurons at birth. The involvement of SRPX2 in these disorders suggests an important role for SRPX2 in the perisylvian region critical for language and cognitive development.

Steroid hormones and cognitive functioning in aging men: a mini-review.

The decrease in testosterone (T) production in aging men has been well documented. Because the majority of circulating estradiol (E2) in men arises through aromatization of T, levels of E2 decrease as well with increasing age. It is also clear that some proportion of men develop impairments in aspects of cognition, particularly in explicit memory and language abilities with normal aging. Although there is a paucity of studies that have attempted to determine whether the decline in the endocrine and cognitive changes in older men are related, findings from the extant literature provide some support for the notion that estrogen is important for aspects of memory in aging men, just as it is in women, whereas T helps to maintain visuospatial abilities. More definitive conclusions on the relationship between the sex hormones and specific cognitive functions in men await more careful investigation in this area in the future.

FOXP2 expression during brain development coincides with adult sites of pathology in a severe speech and language disorder.

Disruption of FOXP2, a gene encoding a forkhead-domain transcription factor, causes a severe developmental disorder of verbal communication, involving profound articulation deficits, accompanied by linguistic and grammatical impairments. Investigation of the neural basis of this disorder has been limited previously to neuroimaging of affected children and adults. The discovery of the gene responsible, FOXP2, offers a unique opportunity to explore the relevant neural mechanisms from a molecular perspective. In the present study, we have determined the detailed spatial and temporal expression pattern of FOXP2 mRNA in the developing brain of mouse and human. We find expression in several structures including the cortical plate, basal ganglia, thalamus, inferior olives and cerebellum. These data support a role for FOXP2 in the development of corticostriatal and olivocerebellar circuits involved in motor control. We find intriguing concordance between regions of early expression and later sites of pathology suggested by neuroimaging. Moreover, the homologous pattern of FOXP2/Foxp2 expression in human and mouse argues for a role for this gene in development of motor-related circuits throughout mammalian species. Overall, this study provides support for the hypothesis that impairments in sequencing of movement and procedural learning might be central to the FOXP2-related speech and language disorder.

Evidence of bilateral temporal lobe involvement in primary progressive aphasia: a SPECT study.

UNLABELLED: Primary progressive aphasia (PPA) is rare. Only limited series have been reported with SPECT or PET. Moreover, in the majority of studies, the left-to-right asymmetry ratio was used, leading to difficulties in right hemisphere analyzes. METHODS: Twenty-nine patients with clinical criteria of PPA (Mesulam and Weintraub) were included and compared with 12 control subjects. Complete language examination was performed in all patients. SPECT was performed on a double-head gamma camera after intravenous injection of hexamethylpropyleneamine oxime (22 patients and 12 control subjects) or ethylcysteinate dimer (7 patients). Nineteen regions of interest (ROIs) were drawn on each hemisphere in all patients using the Talairach atlas. The perfusion index (PI = cortex-to-cerebellum ratio) was calculated for each ROI. Atrophy was quantified on MRI by consensus of 3 observers in 16 cortical ROIs. ANOVAs were used to compare the PI between (a). patients and control subjects, (b). patients with (n = 15) or without (n = 14) lexicosemantic abnormalities (LS+ vs. LS-) and patients with (n = 19) or without (n = 10) arthric disorders (A+ vs. A-), and (c). patients with or without atrophy. RESULTS: In the 29 patients, the PI was significantly lower in the left temporopolar, left lateral temporal, left Wernicke, left parietal, and right lateral temporal cortex when compared with control subjects (P < 0.001). In LS+ patients versus control subjects, the PI significantly decreased in the left temporal cortex (lateral temporal; medial temporal; temporopolar; Wernicke), left Broca, left parietal, and right lateral temporal cortex (P < 0.001). In addition, LS+ versus LS- comparison showed a significant decrease in the left lateral, left medial temporal, and left Broca cortex (P < 0.001). In comparison with control subjects, the PI was not significantly different in A+ patients, whereas in A- patients the PI was significantly decreased in the left and right lateral temporal cortex, left Wernicke, and left parietal cortex. Moreover, the PI significantly decreased in the left lateral temporal region in A+ patients compared with A- patients. Finally, in patients without atrophy, the PI significantly decreased in the right and left lateral temporal cortex and the left parietal cortex (P < 0.01). CONCLUSION: Our study demonstrates that right-handed patients with PPA present a decreased perfusion in the bilateral temporal cortex. Moreover, in these regions, morphologic abnormalities are preceded by perfusion abnormalities. Finally, our results show that large left temporal dysfunction occurs in patients with LS disorders.

Effects of cholinergic blockade on language in healthy young women. Implications for the cholinergic hypothesis in dementia of the Alzheimer type.

To investigate the effect of cholinergic blockade on language, 22 healthy young women performed tests of reading, spelling and oral language after a subcutaneous injection of 0.4 or 0.6 mg scopolamine. The results were compared with the performance after 0.6 mg methylscopolamine, which produce no central cholinergic effects. The reading and spelling tests were constructed to evaluate the lexical and phonological strategies for reading and spelling of single words. After scopolamine there were dose-dependent impairments in reading, spelling, verbal fluency and object naming. In 25-60% of the subjects receiving 0.6 mg scopolamine there were clinically significant impairments on tests assessing the lexical and phonological strategies. This pattern is similar to the deficits in reading and spelling observed in patients with dementia of the Alzheimer type. Cholinergic loss may be associated with the language impairments found in dementia of the Alzheimer type.