Cognitive Training for Visuospatial Processing in Children Aged 5½ to 6 Years Born Very Preterm With Working Memory Dysfunction

Importance Compared with term-born peers, children born very preterm generally perform poorly in executive functions, particularly in working memory and inhibition. By taking advantage of neuroplasticity, computerized cognitive training of working memory in those children could improve visuospatial processing by boosting visual inhibition via working memory. Objective To evaluate the long-term effect of cognitive working memory training on visuospatial processing in children aged 5½ to 6 years born very preterm who have working memory impairment. Design, Setting, and Participants This multicenter (18 French university hospitals), open-label randomized clinical trial with 2 parallel groups (EPIREMED) was conducted from November 2016 to April 2018, with the last follow-up during August 2019. Eligible children from the EPIPAGE 2 cohort were aged 5½ to 6 years, were born between 24 and 34 weeks’ gestation, and had a global intelligence quotient greater than 70 and a working memory index less than 85. Data were analyzed from February to December 2020. Intervention Children were randomized 1:1 to standard care management and a working memory cognitive training program (Cogmed software) for 8 weeks (25 sessions) (intervention) or to standard management (control). Main Outcomes and Measures The primary outcome was the visuospatial index score from the Wechsler Preschool and Primary Scale of Intelligence, 4th Edition. Secondary outcomes were working memory, intellectual functioning, executive and attention processes, language skills, behavior, quality of life, and schooling. Neurobehavioral assessments were performed at inclusion and after finishing training at 6 months (intermeditate assessment; secondary outcomes) and at 16 months (final assessment; primary outcome). Results There were 169 children randomized, with a mean (SD) age of 5 years 11 months (2 months); 91 (54%) were female. Of the participants, 84 were in the intervention group (57 of whom [68%] completed at least 15 cognitive training sessions) and 85 were in the control group. The posttraining visuospatial index score was not different between groups at a mean (SD) of 3.0 (1.8) months (difference, −0.6 points; 95% CI, −4.7 to 3.5 points) or 12.9 (2.6) months (difference, 0.1 points; 95% CI, −5.4 to 5.1 points). The working memory index score in the intervention group significantly improved from baseline at the intermediate time point (difference, 4.7 points; 95% CI, 1.2-8.1 points), but this improvement was not maintained at the final assessment. Conclusions and Relevance This randomized clinical trial found no lasting effect of a cognitive training program on visuospatial processing in children aged 5½ to 6 years with working memory disorders who were born very preterm. The findings suggest that this training has limited long-term benefits for improving executive function. Transient benefits seemed to be associated with the developmental state of executive functions. Trial Registration ClinicalTrials.gov Identifier: NCT0275779

Mutations in the HECT domain of NEDD4L lead to AKT-mTOR pathway deregulation and cause periventricular nodular heterotopia.

Neurodevelopmental disorders with periventricular nodular heterotopia (PNH) are etiologically heterogeneous, and their genetic causes remain in many cases unknown. Here we show that missense mutations in NEDD4L mapping to the HECT domain of the encoded E3 ubiquitin ligase lead to PNH associated with toe syndactyly, cleft palate and neurodevelopmental delay. Cellular and expression data showed sensitivity of PNH-associated mutants to proteasome degradation. Moreover, an in utero electroporation approach showed that PNH-related mutants and excess wild-type NEDD4L affect neurogenesis, neuronal positioning and terminal translocation. Further investigations, including rapamycin-based experiments, found differential deregulation of pathways involved. Excess wild-type NEDD4L leads to disruption of Dab1 and mTORC1 pathways, while PNH-related mutations are associated with deregulation of mTORC1 and AKT activities. Altogether, these data provide insights into the critical role of NEDD4L in the regulation of mTOR pathways and their contributions in cortical development