Entrenamiento de la Función Ejecutiva en Niños Muy ...³n_ejecutiva.pdfEl objetivo del presente...

Entrenamiento de la Función Ejecutiva en Niños Muy Prematuros: un ensayo randomizado controlado

Carolien A. van Houdt · Aleid G. van Wassenaer‑Leemhuis · Jaap Oosterlaan · Marsh Königs · Corine Koopman‑Esseboom · A. R. Céleste Laarman · Anton H. van Kaam · Cornelieke S. H. Aarnoudse‑Moens

Resumen

El objetivo del presente estudio fue determinar si el entrenamiento de la función ejecutiva (FE) a través del juego, es efectivo para mejorar la atención, FE y desempeño académico en niños muy prematuros (MPT) y/o extremadamente prematuros (EPT) a la edad de 8-12 años. Se llevó a cabo un estudio randomizado, controlado multicéntrico, doble ciego, placebo- y lista de espera (NTR5365) en dos hospitales académicos en los Países Bajos. Ochenta y cinco niños con problemas de atención determinados puntuados por sus padres en la Checklist de Comportamiento infantil (CBC) fueron randomizados en uno de tres tratamientos: entrenamiento de FE, entrenamiento placebo o lista de espera. Entrenamiento de FE o placebo fue completado en el hogar (6 semanas, 25 sesiones de 30-45 minutos cada una). Los niños tuvieron evaluaciones basales, 2 semanas después de iniciar el entrenamiento o de estar en lista de espera, y cinco meses después de la primera visita de seguimiento para los resultados primarios (escalas parentales y del docente de atención) y resultados secundarios (escalas parentales y de maestros de FE de la vida diaria, tareas computarizadas de FE y desempeño académico). Para todas las medidas de resultados se realizaron análisis lineares de modelo mixto. No hubo diferencias significativas en la mejoría en el tiempo acerca de los puntajes padre-y maestro de atención, puntajes padre-maestro de FE de la vida diaria, tareas FE computarizadas, y desempeño académico (aritmética y lectura) entre entrenamiento FE, entrenamiento placebo y lista de espera. En conclusión el entrenamiento de FE con formato de juego no mejora la atención, FE o desempeño académico en niños MPT con problemas de atención medidos por padres.

Palabras claves: Intervención ▪ Prematurez ▪ Atención ▪ Conducta ▪ Aritmética ▪ Lectura

Introducción

En los países occidentales, 0.7-1.4% de todos los niños nacidos vivos nacen MPT (EG <32 sem) (1). Debido a los avances en el cuidado médico, las tasas de sobrevida han aumentado y aproximadamente 65% de los niños nacidos EPT no presentan discapacidades mayores (2). Sin embargo, problemas más sutiles en varias áreas son frecuentes (3), lo cual puede tener un significativo impacto negativo en las vidas de padres

y niños. Uno de los principales y más persistentes problemas de los niños MPT es el funcionamiento de la atención (4, 5). Los niños MPT tienen riesgo 2 a 4 veces superior de ser diagnosticados con Desorden por Déficit de Atención/ Hiperactividad (TDAH) (6, 7), particularmente en el subtipo inatento (8), y un riesgo aumentado para diagnóstico de Trastorno de Espectro Autista (TEA) (8, 9). También en TEA, son comunes los problemas de atención (10) y varios estudios han mostrado elevadas frecuencias de comorbilidad de TDAH en niños con TEA (11-15). Pese a que los síntomas conductuales y atencionales de los niños MPT pueden replicar aquellos de los niños TDAH o TEA en algunos aspectos, tales como síntomas de inatención, los sustratos biológicos subyacentes parecen diferir. Por ejemplo, un estudio reciente, que comparó adolescentes con TDAH y adolescentes PT en medidas electrofisiológicas asociadas con el procesamiento de atención e inhibitorio, encontró que los adolescentes PT mostraban superposición de ambos déficits con aquellos encontrados en adolescentes con TDAH y déficits únicos de los adolescentes PT (16). Más aún, la presentación clínica también es diferente. Por ejemplo, la asociación entre el Trastorno de Oposición Desafiante (TOD) y Trastorno de Conducta (TC) es mucho más fuerte en la población general que en niños nacidos EPT (8). Entonces, las intervenciones que fueron inefectivas en niños con TDAH pueden ser efectivas en niños MPT con problemas de atención y viceversa.

Los déficits en Fes son considerados importantes en la compleja neuropsicología de TDAH y TEA (17-26). El funcionamiento ejecutivo es un término paraguas para un grupo de funciones cognitivas de alta gama que permiten conducta de máxima y mínima, dirigida al objetivo, con funciones centrales incluyendo memoria de trabajo, inhibición y flexibilidad cognitiva (27). La investigación ha indicado que pobres Fes están fuertemente asociadas también con problemas de atención de los niños MPT (28-30). Ambos, TEA y TDAH son alteraciones del ND que afectan los circuitos fronto-estriado y fronto-parietal que son importantes para las Fes (31), y el nacimiento MPT ha mostrado afectar la integridad de la red de sustancia blanca y de las estructuras del cerebro asociadas con Fes (32-39).

Las intervenciones de entrenamiento computarizado para mejorar Fes pueden por tanto ser un camino para mejorar los problemas atencionales que presentan los niños MPT. Cogmed Working Memory Training (CWMT) es ampliamente empleado con TDAH (40). Ha sido acuñado como un prometedor entrenamiento computarizado para problemas atencionales (41), pese a que estudios más recientes sugieren que podría no ser tan efectivo como se pensó previamente (42). En niños MPT, un reciente ensayo randomizado controlado no mostró efectos de CWMT en ninguna medida de resultado, incluyendo funcionamiento de atención (43). Sin embargo, CWMT solamente entrena la memoria de trabajo, mientras que los niños MPT muestran problemas en la inhibición y la flexibilidad cognitiva también (5, 44, 45). Recientemente, fue desarrollado el entrenamiento BrainGame

Brian (46), dirigido no solo a la memoria de trabajo, sino también a la inhibición y flexibilidad cognitiva. El entrenamiento BrainGame Brian va más allá que CWMT agregando elementos de juego y empleando refuerzos fuertes e inmediatos para optimizar el estado de motivación de los niños. A la fecha, los efectos del entrenamiento BrainGame Brian ha sido evaluado en tres estudios incluyendo niños con diagnóstico clínico de TDAH y TEA. Estos estudios han mostrado consistentemente mejoras en la memoria de trabajo viso-espacial, pero sin efectos consistentes en otras Fes u otras funciones no entrenadas (47-49). Previamente, nuestro grupo mostró en un estudio piloto no-randomizado pequeño que el entrenamiento con BrainGame Brian era una intervención factible para los niños MPT. Se encontraron beneficios clínicos significativos para la memoria de trabajo viso-espacial (50).

El presente estudio examinó, empleando un diseño doble ciego, randomizado controlado incluyendo una condición placebo- y lista de espera, si el entrenamiento FE con formato juego (ej., BrainGame Brian) mejora el funcionamiento atencional en niños MPT (EG <30 sem) y/o EBPN (PN< 1000 g) a la edad de 8 a 12 años. También examinamos los efectos de entrenamiento de FE formato-juego sobre medidas de resultados secundarios. Dado que se cree que el entrenamiento de FE mejora el funcionamiento atencional través de mejorar las Fes, examinamos si el entrenamiento de FE formato-juego en efecto mejoraba las Fes. Por último, como los problemas atencionales y déficits en FE están fuertemente unidos a peor desempeño académico en niños MPT (28, 29, 51-54), también investigamos si el entrenamiento de FE con formato-juego mejora el desempeño académico, más específicamente desempeño en aritmética y lectura.

Métodos

Diseño del ensayo y consideraciones éticas

Este ensayo multi-céntrico randomizado, doble-ciego, controlado placebo y lista de espera fue conducido en dos hospitales en los Países Bajos (Amsterdam University Medical Centers y University Medical Center Utrecht). Los Comités de Ética Médica en ambos centros aprobaron el protocolo de estudio y la ejecución de los procedimientos del estudio estuvo acorde a la declaración de Helsinki. El trabajo fue registrado en el Dutch Trial Registry (NTR5365). Se siguieron las guías CONSORT.

Participantes

Los padres de niños 7-12 años nacidos MPT y/o EBPN (en síntesis: MPT) que ingresaron a la UCIN en uno de los dos centros participantes y que se unieron a un programa de seguimiento neonatal, fueron invitados para completar la versión holandés del CBCL6- 18 (55). Los niños cuyos padres consignaron problemas de atención en el CBCL6-18 (T≥55 en

la escala Problemas de Atención {56}, como sugiere la investigación este T-score es el corte óptimo para screening de TDAH {56}) fueron elegibles para este estudio tan pronto como alcanzaban la edad mínima cronológica de 8 años. Criterios de exclusión fueron el estimativo de CI <80, problemas motores demasiado profundos como para permitir el uso de la computadora y no uso de lengua holandesa en el hogar.

Randomización y blindaje

Los niños que cumplieron los criterios de inclusión fueron asignados randomizadamente a una de tres condiciones de tratamiento: entrenamiento-, placebo-o lista de espera. La asignación a las condiciones de tratamiento fue estratificada por edad (debajo o por encima de 10.5 años de edad) y severidad de los problemas de atención score-T de problemas de atención debajo o por encima de 65), con proporciones iguales de niños asignados a cada condición dentro de cada estrato. Para asegurar el blindaje a la condición entrenamiento-o placebo, los padres solo eran informados acerca de si su hijo fue randomizado a alguna de las dos condiciones de tratamiento o la de lista de espera y en caso que más niños de la misma familia fueran incluidos en el estudio, uno de ellos era randomizado y el otro asignado a la misma condición. Un generador de número aleatorio se empleó para las listas de randomización. Un investigador no involucrado en el estudio fue responsable de la randomización y entregó al asistente de la prueba un sobre cerrado con una nota mostrando “lista de espera” o un usuario y contraseña, que era abierto por el niño y sus padres después de la investigación basal. Los asistentes de prueba que jugaron en la primera sesión de entrenamiento con el niño fueron desenmascarados debido a diferencias en las tareas de entrenamiento (ver más abajo) entre la condición entrenamiento- y placebo y no fueron involucrados en las evaluaciones de seguimiento de estos niños. Los padres, niños y administradores de test estuvieron al tanto de la asignación del niño a la condición lista de espera. Los datos fueron analizados cegados a las asignaciones de tratamiento.

Intervención

Intervención BrainGame Brian

BrainGame Brian es un entrenamiento de FE computarizado con formato de juego, realizado por el niño en el hogar. Una elaborada descripción del entrenamiento BainGame Brian puede encontrarse en Prins et al. (46). BrainGame Brian es un ambiente de juego, en el cual tres tareas de entrenamiento de FE, una por cada Fe central, están incrustadas. En cada una de las 25 sesiones de entrenamiento, los niños tienen que ayudar al personaje principal, Brian, a resolver problemas para otros personajes del mundo del juego. Para lograrlo, ellos juegan las tres tareas de entrenamiento de FE, lo cual lleva a la creación de

una invención que resuelve el problema. Por ejemplo, Brian encuentra un personaje que tiene un problema esquilando sus ovejas. Jugando los tres trabajos de entrenamiento de FE, una máquina de esquilar es inventada, lo cual resuelve el problema y permanece visible en el mundo del juego a lo largo del resto de las sesiones para optimizar el estado motivacional y el auto-control de los niños. En cada sesión, los niños juegan en las tres tareas de entrenamiento dos veces. En total, 25 sesiones son jugadas, y el niño y padres fueron instruidos para jugar con el entrenamiento BrainGame Brian 4 veces a la semana (aproximadamente 30-45 minutos por sesión). Después de cada sesión, los datos de la sesión eran guardados en la base de datos, que fue accesible para los investigadores para monitorear la fidelidad al régimen de entrenamiento. No hubo apoyo adicional de los investigadores en cuanto a la motivación y/o devolución fuera de la interfase de la computadora. Para nuestro trabajo randomizado controlado, se emplearon dos versiones del entrenamiento de FE BrainGame Brian: el entrenamiento de FE BrainGame Brian y la versión placebo de BrainGame Brian. En la versión placebo todo es idéntico excepto que los trabajos de entrenamiento de FE fueron reemplazados por versiones placebo de estas tareas. Ver más abajo las descripciones de las tareas de entrenamiento para ambas versiones de entrenamiento.

Tareas de entrenamiento en condición `entrenamiento

En la tarea de memoria del trabajo, se pide a los niños que repitan una secuencia de puntos en una grilla 4x4 de una manera específica (ej., hacia adelante, hacia atrás). Las instrucciones para este trabajo cambian cada cinco sesiones para aumentar las demandas en la memoria de trabajo. En la tarea de inhibición, se pide a los niños que presionen un botón en una ventana de tiempo específica (objetivo), pero abstenerse de presionar el botón cuando una señal de “STOP” aparece. En el trabajo de flexibilidad cognitiva, se solicita a los niños que elijan objetos de acuerdo a una de dos reglas, con la regla de selección cambiando cada tres a cinco pruebas. Después de cada bloque de tres tareas de entrenamiento, el nivel de dificultad de cada tarea es automáticamente ajustado al desempeño del niño.

Tareas de entrenamiento en condición placebo

En las versiones placebo de las tareas de entrenamiento de FE, los elementos de real entrenamiento de Fes fueron retirados, y el nivel de dificultad fue establecido en el nivel de dificultad más bajo para todas las sesiones de desempeño del niño. En la versión placebo de la tarea de memoria de trabajo, se pide a los niños que repitan secuencias en el mismo orden que son presentadas (lo cual requiere memoria corto-plazo, no memoria de trabajo). Esta instrucción permanece igual a lo largo de todas las sesiones de entrenamiento. En la versión placebo de la tarea de inhibición, no aparecen letreros de “STOP” (entonces los

niños no tienen que inhibir respuestas). En la versión placebo de la tarea de flexibilidad cognitiva, la regla de selección nunca cambia (así no es requerida la flexibilidad cognitiva).

Condición lista de espera

Los niños en lista de espera no juegan el BrainGame Brian y fueron instruidos para desempeñar las mismas actividades en el período de espera que hacen normalmente.

Procedimiento

Luego de obtener el consentimiento informado escrito de los padres y, si correspondía, de los niños de 12 años, y consentimiento in formado verbal de los niños menores de 12 años de edad, los participantes completaron un examen neurocognitivo basal incluyendo medidas de CI, FE y funcionamiento académico. Se solicitó a padres y maestros que completaran cuestionarios sobre la atención del niño y conducta en la FE de la vida diaria. Si los niños eran randomizados hacia la condición entrenamiento- o placebo, se hizo una visita al hogar para instruir a niños y padres y jugar la primera sesión.

Mediciones

El resultado primario fue padre-maestro- puntaje de atención medido con el cuestionario Strengths and Weaknesses de síntomas de TDAH y Normal Behavior (SWAN- fortalezas y debilidades y comportamiento normal) (57). Los resultados secundarios fueron (1) FE de la vida diaria informada por padres y maestros medidos con Behavior Rating Inventory of Executive Function (BRIEF- Inventario de puntaje de Función ejecutiva de comportamiento) (58), (2) memoria de trabajo verbal medida empleando el sub-test Digit Span Backward del WISC-III-NL (59), (3) memoria de trabajo visoespacial medida con el Grid Task, condición reversa (60), (4) inhibición medida con el Stop Signal Task (61), (5) flexibilidad cognitiva medida con el test Multisensory Integration (MSIT) (62), (6) aritmética medida con TempoTest Automatiseren (TTA) (63) y (7) lectura Técnica medida con el test Brus Een Minuut (B-EMT) (64). Descripciones detalladas de las tareas y de las medidas de resultados pueden encontrarse en el Material Suplementario 1. Otros resultados secundarios relacionados con funciones no entrenadas fueron también examinados, pero no fueron incluidos en el presente trabajo sobre los principales resultados (65).

CI, características demográficas y características médicas en el período neonatal

CI fue estimado con una forma abreviada de la versión holandesa del WISC-III-NL tercera edición (59), comprendiendo los subtests Vocabulario y Diseño de Bloque. Los padres proveyeron información demográfica. Digit Span (59) y Grid Task (60) en condiciones anterógradas (repetir una secuencia de digitos hablando o puntos en una grilla en orden

prospectivo respectivamente), fueron administrados para proveer máxima amplitud prospectiva. Los datos médicos neonatales se obtuvieron de los registros médicos.

Análisis estadístico

Los cálculos de tamaño muestral determinaron que, para detectar un efecto de intervención medio (d de Cohen= 0.5) en nuestra medida de resultado primario con una correlación intra-sujeto de 0.295 (50) con un poder de 80% y un nivel de significancia de 0.05, 39 niños eran necesarios en cada brazo de intervención.

Para el análisis estadístico se empleó IBM SPSS Statistics versión 24 (66). Los valores atípicos fueron establecidos en tres DSs (67). Faltaron datos para menos del 5% de los niños, excepto para: los exámenes basales del docente SWAN (12.9%), BRIEF del maestro (14.1%) y la tarea STOP SIGNAL (9.4%); en las primeras evaluaciones de seguimiento el SWAN docente (30.1%), BRIEF de maestro (30.1%), Grid Task Backwards (6.8%) y MSIT (9.6%); las evaluaciones segundas de seguimiento del SWAN docente (44.9%), BRIEF de los padres (5.8%), BRIEF del maestro (40.6%), Grid Task Backwards (17.4%), tarea STOP SIGNAL (10.1%) y MSIT (7.2%). Los datos faltantes no fueron considerados.

Los datos fueron analizados sobre la base intención-de-tratar. Para examinar si el abandono del estudio fue selectivo, los niños que completaron y los que no todos los exámenes fueron comparados en todas sus características demográficas y médicas neonatales con t test independiente y chi cuadrado.

Para evaluar si el entrenamiento BrainGame Brian mejora la atención, FE y desempeño académico, se hicieron análisis de modelo linear para todas las medidas de resultado primarios y secundario con un intercepto aleatorio para dar cuenta de dependencia de datos debido a lazos familiares, y factores fijos de condición de tratamiento (entrenamiento, placebo o lista de espera), tiempo (basal, primera evaluación y segunda evaluación de seguimiento) y las interacciones entre los dos. Todos los datos disponibles (también de los participantes con datos faltantes) fueron usados en los análisis de modelo linear mixto. Se reportaron estimativos de medias marginales para ayudar a la interpretación de resultados.

Resultados

Participantes

El flujo de participantes a lo largo del proceso del estudio se muestra en la Fig. 1. Brevemente, 434 de los 1019 padres devolvieron el cuestionario completo. Las razones principales para no devolver el cuestionario fueron falta de tiempo o falta de interés. De

234 niños con puntajes de atención elevados que fueron invitados a participar, 97 aceptaron. Razones para no participar fueron: agendas muy ocupadas para el niños y/o la familia, o falta de interés. Dos niños abandonaron el estudio antes de la randomización. Diez niños fueron excluidos debido a una estimación de CI <80. Los restantes 85 niños fueron randomizados a una condición de tratamiento (ver Fig. 1). Todos los niños en el entrenamiento de FE y entrenamiento placebo que tuvieron al menos una evaluación de seguimiento, completaron las 25 sesiones.

La randomización asignó 29 niños a la condición tratamiento, 26 niños a la condición placebo y 30 a la condición lista de espera. Doce niños dejaron el estudio antes de lña primera visita de seguimiento y cuatro antes de la segunda visita de seguimiento. Razones para el abandono fueron: no poder incorporar las sesiones de entrenamiento en una agenda muy ocupada o el niño no quiso completar el entrenamiento (n=9), falta de tiempo o de deseo para programar visita (s) de seguimiento en el momento apropiado (n=5) o aparición de enfermedad severa (n=2). De los niños incluidos 81% completaron todas las evaluaciones. Los análisis de abandono no mostraron diferencias demográficas ni de características neonatales entre los niños que completaron todas las evaluaciones y los que no (todos los valores de p>0.14). Dado que no hubo evaluación de datos de los niños no participantes, no pudimos hacer análisis de abandono en cuanto a la representatividad de nuestra muestra. Sin embargo, cuando se comparó con niños MPT incluidos en estudios de cohortes previas de nuestro grupo de investigación, la EG y PN de los niños incluidos fue similar (EG alrededor 28 semanas y PN alrededor 1000 gramos {3, 68}). El nivel de educación parental de nuestra muestra fue alto en 61% de los niños, comparados con aproximadamente 45% de la población holandesa en general entre 25-45 años de edad que es altamente educada (69). Las evaluaciones tomaron lugar entre Octubre 2015 y Septiembre 2018. Las características demográficas y neonatales médicas se presentan en la Tabla 1.

Medidas de resultado primario y secundario

No hubo diferencias significativas en el tiempo entre las tres condiciones de tratamiento en los cuestionarios de padres y maestros, indicando ningún efecto beneficioso del entrenamiento BrainGame Brian comparado con el placebo o lista de espera.

Tampoco hubo diferencias significativas en el tiempo entre las tres condiciones de tratamiento para ninguna de las medidas de FE, indicando ningún efecto beneficioso del entrenamiento BrainGame Brian comparado con placebo o lista de espera. Por último, no hubo diferencias significativas en el tiempo entre las tres condiciones de tratamiento a lo largo del tiempo para TTA y B-EMT, indicando ningún efecto beneficioso del entrenamiento BrainGame Brian comparado con las condiciones placebo o lista de espera.

Hubo significativos efectos principales de tiempo para el informe docente en BRIEF memoria de trabajo y Score Total, Grid Task Backwards, tarea Stop Signal, TTA y B- EMT, todas indicando mejor desempeño en el tiempo. Hubo significativos efectos principales de grupo para Grid Task Backwards y MSIT, mostrando peor desempeño en el grupo placebo que en el grupo de entrenamiento con BrainGame Brian y el grupo lista de espera, sin diferencia entre estos dos últimos (Tabla 2 y 3).

Discusión

El presente estudio investigó si el entrenamiento de FE con formato-juego mejora el funcionamiento de la atención en niños nacidos MPT y/o EBPN (en síntesis: MPT) con problemas de atención puntuados por sus padres. Resultados adicionales incluyeron tareas de FE computarizadas, reportes de padres-maestros de FE de vida diaria y desempeño académico. Los resultados de nuestro TRC no proveyeron evidencia de efectos benéficos en ninguna de las medidas de resultado examinadas.

En niños con TDAH, se encontraron efectos positivos del entrenamiento BrainGame Brian y CWMT sobre la memoria de trabajo (48, 70-72). Debido a que los síntomas conductuales de inatención en niños nacidos MPT reflejan aquellos de los niños con TDAH, esperábamos efectos positivos en niños MPT. Sin embargo, los resultados de nuestro estudio no indicaron efectos positivos de entrenar con BrainGame Brian en niños nacidos MPT. Los resultados de nuestro estudio están en línea con un trabajo randomizado controlado investigando los efectos de CWMT en niños MPT, sin efectos positivos de CWMT sobre el funcionamiento de la atención, el desempeño de la memoria de trabajo y el desempeño académico (43). También, nosotros analizamos recientemente nuestros otros resultados secundarios incluyendo el funcionamiento conductual y emocional y la auto-percepción de competencia (65). Ninguna de estas funciones no entrenadas fue mejorada por el entrenamiento BrainGame Brian. Nuestros resultados también están en línea con meta-análisis previos que investigaron el efecto de CWMT en medidas de transferencias alejadas en niños con TDAH (41, 42, 73, 74). Pese al paralelismo conductual entre TDAH y los síntomas de inatención en niños nacidos MPT, los puntos subyacentes de estos síntomas pueden ser realmente diferentes. Un estudio reciente, por ejemplo, empleó medidas de electroencefalografía (EEG) asociadas con el procesamiento de la atención e inhibición, demostrando que los adolescentes nacidos prematuros muestran patrones únicos de actividad neural aberrante al comparar con adolescentes con TDAH, sugestivo de déficits más generalizados en adolescentes nacidos prematuros comparados con adolescentes con TDAH (16). Esto implica que las intervenciones que no son efectivas en niños con TDAH pueden ser efectivas en niños MPT con problemas de atención y viceversa, y examinar efectos de la intervención en ambas poblaciones en lugar de una población y luego generalizar los resultados a la otra población, es extremadamente importante.

Un importante pre-requisito para mejora de FE y/o función de atención siguiendo al entrenamiento de FE es la plasticidad de las redes de la sustancia blanca y ganglios basales. En niños MPT, la integridad del tracto de sustancia blanca comprometido y las anormalidades de sustancia blanca están asociadas con problemas de FE y de atención (75-77). Más aún, el daño a los ganglios basales está también asociado con problemas de atención (78) y es frecuentemente observado en niños nacidos MPT (79). La investigación ha mostrado que el entrenamiento de FE puede inducir cambios neuronales en áreas del cerebro asociadas con la atención en niños MPT (80) y que el ejercicio de intervención puede inducir mejoras en la integridad de la sustancia blanca en niños (81). Parece entonces que el cerebro MPT muestra la plasticidad requerida para la mejora de FE y/o funcionamiento de atención. Posiblemente, la intensidad y duración de BrainGame Brian y CWMT en sus formas actuales no son suficientes para inducir cambios en la FE en niños MPT. Esto es apoyado por el hecho de que todos los niños en la condición entrenamiento de FE que tuvieron al menos una evaluación de seguimiento (24 de 29, 83%) completaron

todas las sesiones de entrenamiento, descartando por tanto que la falta de resultados positivos fue debida a no cumplimiento del régimen de entrenamiento. Debido a que no incluimos mediciones del cerebro, no podemos descartar que el entrenamiento BrainGame Brian indujera cambios en el cerebro que no llevaron subsiguientemente a cambios en la atención, comportamiento o desempeño académico. Sin embargo, un reciente trabajo randomizado controlado sobre CWMT en niños nacidos EPT concluyó que los cambios en el cerebro (tanto estructurales como

funcionales) generalmente no difirieron entre CWMT y placebo (82). Entonces, para inducir cambios en las medidas del cerebro y atención, conducta o desempeño académico, es posible que sea necesario un entrenamiento más intenso y prolongado. Más aún, la motivación de los niños podría jugar un rol en los (ausencia de) efectos del entrenamiento. En nuestro estudio, no medimos esto. Sin embargo, en un estudio piloto previo de nuestro grupo, se reportó que “la mayoría de los padres fueron positivos acerca de BrainGame Brian, en cuanto a que es divertido y motivante” (50).

Dada la evidencia creciente de infectividad del entrenamiento de FE, deben ser investigadas intervenciones alternativas. Una alternativa que podría venir a la mente es enfocar habilidades cognitivas de orden menor con entrenamiento cognitivo, en lugar de FE (que son habilidades de alto orden). Sin embargo, la condición de entrenamiento con placebo puede ser considerada como un entrenamiento cognitivo de orden bajo: el niño no entrena Fes, pero tiene que mantenerse alerta y prestar atención a la tarea para desempeñarse correctamente. Si el entrenamiento de bajo orden fuera efectivo, podríamos entonces esperar encontrar mayores mejoras siguiendo al entrenamiento placebo que con el entrenamiento de FE o lista de espera, que no fue el caso. Un meta-análisis reciente sobre entrenamiento de FE en niños MPT en edad pre-escolar específicamente (3-6 años

de edad) concluyó que el entrenamiento de FE tiene resultados positivos en esta población, especialmente cuando es no-computarizado y en grupo (83). Por lo tanto, sugerimos que el foco sea dirigido hacia programas de entrenamiento que se enfoquen en niños más pequeños, combinen ejercicios y pruebas demandantes de Fes y se lleven a cabo en grupos.

Una limitación del presente estudio es no cumplir con los números requeridos de acuerdo a nuestro cálculo de potencia. Sin embargo, las diferencias entre grupos en el tiempo fueron pequeñas y no significativas clínicamente. Otra limitación es que el estudio actual incluyó niños con problemas de atención, y no necesariamente niños con problemas de FE. El racional fue que estudios previos han mostrado que los déficits de FE tienen un rol importante subyacente a los problemas de atención observados en varios niños prematuros (28-30). Por último, pese a esfuerzos sustanciales, un gran número de cuestionarios de docentes estaba faltando, especialmente en la segunda visita de seguimiento. Sin embargo, análisis adicionales revelaron que no había diferencias significativas en nuestra medida de resultado primario de maestro en la segunda visita de seguimiento, ni hubo diferencias significativas en los datos demográficos entre estos niños. Las fortalezas del presente estudio son la incorporación de condiciones placebo- y lista de espera, análisis de intención de tratar, evaluación comprensiva de un amplio rango de resultados utilizando técnicas multi-dimensionales (cuestionarios y pruebas basadas en desempeño) e informantes (cuestionarios de padres y docentes), y examen de efectos directos y efectos cinco meses después de que terminara la intervención.

Conclusión

El entrenamiento de FE formato-juego no es efectivo para mejorar la atención, FE o funcionamiento académico en niños MPT con problemas de atención. La investigación futura podrá investigar si alteraciones del entrenamiento de FE pueden hacer que este entrenamiento sea efectivo en niños MPT. Por ejemplo, la efectividad puede ser favorecida con tareas de entrenamiento más ecológicamente válidas e intrínsecamente recompensante y/o con entrenamiento más prolongado y más intensivo (84). Paralelo a esto, la investigación también debería mirar más allá del entrenamiento formato-juego buscando intervenciones que mejoren FE y áreas asociadas de funcionamiento.

Referencias

1.Delnord M, Hindori-Mohangoo AD, Smith LK, Szamotulska K, Richards JL, Deb-Rinker P, Rouleau J, Velebil P, Zile I, Sakkeus L (2017) Variations in very preterm birth rates in 30 high-income countries: are valid international comparisons possible using routine data? BJOG Int J Obstet Gynaecol 124 (5):785–794 2. Lorenz JM (2011) Survival and long-term neurodevelopmental outcome of the extremely preterm infant. A systematic review. Saudi Med J 32(9):885–894 3. Potharst ES, van Wassenaer AG, Houtzager BA, van Hus JW, Last BF, Kok JH (2011) High incidence of multi-domain disabilities in very preterm children at five years of age. J Pediatr 159(1):79–85. https ://doi.org/10.1016/j.jpeds .2010.12.055 4. Shum D, Neulinger K, O’Callaghan M, Mohay H (2008) Attentional problems in children born very preterm or with extremely low birth weight at 7–9 years. Arch Clin Neuropsychol 23(1):103– 112. https ://doi.org/10.1016/j.acn.2007.08.006 5. Aarnoudse-Moens CSH, Weisglas-Kuperus N, van Goudoever JB, Oosterlaan J (2009) Meta-analysis of neurobehavioral outcomes in very preterm and/or very low birth weight children. Pediatrics 124(2):717–728. https ://doi.org/10.1542/peds.2008-2816 6. Bhutta AT, Cleves MA, Casey PH, Cradock MM, Anand KJ (2002) Cognitive and behavioral outcomes of school-aged children who were born preterm: a meta-analysis. JAMA 288(6):728–737 7. Allotey J, Zamora J, Cheong-See F, Kalidindi M, Arroyo-Manzano D, Asztalos E, van der Post J, Mol BW, Moore D, Birtles D, Khan KS, Thangaratinam S (2017) Cognitive, motor, behavioural and academic performances of children born preterm: a metaanalysis and systematic review involving 64 061 children. BJOG Int J Obstet Gynaecol. https ://doi.org/10.1111/1471-0528.14832 8. Johnson S, Hollis C, Kochhar P, Hennessy E, Wolke D, Marlow N (2010) Psychiatric disorders in extremely preterm children: longitudinal finding at age 11 years in the EPICure study. J Am Acad Child Adolesc Psychiatry 49(5):453–463.e451 9. Johnson S, Hollis C, Kochhar P, Hennessy E, Wolke D, Marlow N (2010) Autism spectrum disorders in extremely preterm children. J Pediatr 156(4):525–531.e522. https ://doi.org/10.1016/j.jpeds .2009.10.041 10. Sturm H, Fernell E, Gillberg C (2004) Autism spectrum disorders in children with normal intellectual levels: associated impairments and subgroups. Dev Med Child Neurol 46(7):444–447 11. Gadow KD, DeVincent CJ, Pomeroy J (2006) ADHD symptom subtypes in children with pervasive developmental disorder. J Autism Dev Disord 36(2):271–283. https ://doi.org/10.1007/s1080 3-005-0060-3 12. Holtmann M, Bolte S, Poustka F (2007) Attention deficit hyperactivity disorder symptoms in pervasive developmental disorders: association with autistic behavior domains and coexisting psychopathology. Psychopathology 40(3):172–177. https ://doi.org/10.1159/00010 0007 13. Lee DO, Ousley OY (2006) Attention-deficit hyperactivity disorder symptoms in a clinic sample of children and adolescents with pervasive developmental disorders. J Child Adolesc Psychopharmacol 16(6):737–746. https ://doi.org/10.1089/cap.2006.16.737 14. Simonoff E, Pickles A, Charman T, Chandler S, Loucas T, Baird G (2008) Psychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a population-derived sample. J Am Acad Child Adolesc Psychiatry 47(8):921–929. https ://doi.org/10.1097/CHI.0b013 e3181 79964 f 15. Yoshida Y, Uchiyama T (2004) The clinical necessity for assessing attention deficit/hyperactivity disorder (AD/HD) symptoms in children with high-functioning pervasive developmental disorder (PDD). Eur Child Adolesc Psychiatry 13(5):307–314. https ://doi.org/10.1007/s0078 7-004-0391-1

16. Rommel AS, James SN, McLoughlin G, Brandeis D, Banaschewski T, Asherson P, Kuntsi J (2017) Association of preterm birth with attention-deficit/hyperactivity disorder-like and wider-ranging neurophysiological impairments of attention and inhibition. J Am Acad Child Adolesc Psychiatry 56(1):40– 50. https ://doi.org/10.1016/j.jaac.2016.10.006 17. Barkley RA (1997) Behavioral inhibition, sustained attention, and executive functions: constructing a unifying theory of ADHD. Psychol Bull 121(1):65–94 18. Pennington BF, Ozonoff S (1996) Executive functions and developmental psychopathology. J Child Psychol Psychiatry 37(1):51–87 19. Castellanos FX, Tannock R (2002) Neuroscience of attentiondeficit/ hyperactivity disorder: the search for endophenotypes. Nat Rev Neurosci 3(8):617–628. https ://doi.org/10.1038/nrn896 20. Schachar R, Mota VL, Logan GD, Tannock R, Klim P (2000) Confirmation of an inhibitory control deficit in attention-deficit/hyperactivity disorder. J Abnorm Child Psychol 28(3):227–235. https ://doi.org/10.1023/a:10051 40103 162 21. Willcutt EG, Doyle AE, Nigg JT, Faraone SV, Pennington BFJBp (2005) Validity of the executive function theory of attention- deficit/hyperactivity disorder: a meta-analytic review 57 (11):1336–1346 22. Corbett BA, Constantine LJ, Hendren R, Rocke D, Ozonoff S (2009) Examining executive functioning in children with autism spectrum disorder, attention deficit hyperactivity disorder and typical development. Psychiatry Res 166(2–3):210–222. https ://doi.org/10.1016/j.psych res.2008.02.005 23. Ozonoff S, Cook I, Coon H, Dawson G, Joseph RM, Klin A, McMahon WM, Minshew N, Munson JA, Pennington BF, Rogers SJ, Spence MA, Tager-Flusberg H, Volkmar FR, Wrathall D (2004) Performance on Cambridge neuropsychological test automated battery subtests sensitive to frontal lobe function in people with autistic disorder: evidence from the collaborative programs of excellence in autism network. J Autism Dev Disord 34(2):139–150 24. Damasio AR, Maurer RG (1978) A neurological model for childhood autism. Arch Neurol 35(12):777–786 25. Geurts HM, de Vries M, van den Bergh SFWM (2014) Executive functioning theory and autism. In: Goldstein S, Naglieri JA (eds) Handbook of executive functioning. Springer, New York, pp 121–141. https ://doi.org/10.1007/978-1-4614-8106-5_8 26. Russell JE (1997) Autism as an executive disorder. Oxford University Press, Oxford 27. Miyake A, Friedman NP, Emerson MJ, Witzki AH, Howerter A, Wager TD (2000) The unity and diversity of executive functions and their contributions to complex "frontal lobe" tasks: a latent variable analysis. Cogn Psychol 41(1):49–100. https ://doi.org/10.1006/cogp.1999.0734 28. Aarnoudse-Moens CSH, Weisglas-Kuperus N, Duivenvoorden HJ, van Goudoever JB, Oosterlaan J (2013) Executive function and IQ predict mathematical and attention problems in very preterm children. PLoS ONE 8(2):e55994. https ://doi.org/10.1371/journal.pone.00559 94 29. Mulder H, Pitchford NJ, Marlow N (2010) Processing speed and working memory underlie academic attainment in very preterm children. Arch Dis Child Fetal Neonatal Ed 95(4):F267–272. https://doi.org/10.1136/adc.2009.16796 5 30. de Kieviet JF, van Elburg RM, Lafeber HN, Oosterlaan J (2012) Attention problems of very preterm children compared with agematched term controls at school-age. J Pediatr 161(5):824–829. https ://doi.org/10.1016/j.jpeds .2012.05.010 31. Craig F, Lamanna AL, Margari F, Matera E, Simone M, Margari L (2015) Overlap between autism spectrum disorders and attention deficit hyperactivity disorder: searching for distinctive/common clinical features. Autism Res 8(3):328–337. https ://doi.org/10.1002/aur.1449

32. Inder TE, Wells SJ, Mogridge NB, Spencer C, Volpe JJ (2003) Defining the nature of the cerebral abnormalities in the premature infant: a qualitative magnetic resonance imaging study. J Pediatr143(2):171–179. https ://doi.org/10.1067/s0022 -3476(03)00357 -3 33. Miller SP, Ferriero DM, Leonard C, Piecuch R, Glidden DV, Partridge JC, Perez M, Mukherjee P, Vigneron DB, Barkovich AJ (2005) Early brain injury in premature newborns detected with magnetic resonance imaging is associated with adverse early neurodevelopmental outcome. J Pediatr 147(5):609–616. https ://doi.org/10.1016/j.jpeds .2005.06.033 34. Cheong JL, Thompson DK, Wang HX, Hunt RW, Anderson PJ, Inder TE, Doyle LW (2009) Abnormal white matter signal on MR imaging is related to abnormal tissue microstructure. AJNR Am J Neuroradiol 30(3):623–628. https ://doi.org/10.3174/ajnr.A1399 35. Volpe JJ (2009) Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances. Lancet Neurol 8(1):110–124. https ://doi.org/10.1016/s1474 -4422(08)70294-1 36. Stuss DT (2011) Functions of the frontal lobes: relation to executive functions. J Int Neuropsychol Soc JINS 17(5):759–765. https://doi.org/10.1017/s1355 61771 10006 95 37. Anderson V, Levin HS, Jacobs R (2002) Executive functions after frontal lobe injury: a developmental perspective. In: Principles of frontal lobe function. Oxford University Press, New York, pp 504–527. https ://doi.org/10.1093/acpro f:oso/97801 95134971.003.0030 38. Hazy TE, Frank MJ, O’Reilly RC (2007) Towards an executive without a homunculus: computational models of the prefrontal cortex/basal ganglia system. Philos Trans R Soc Lond B Biol Sci 362(1485):1601–1613. https ://doi.org/10.1098/rstb.2007.2055 39. Miller EK, Cohen JD (2001) An integrative theory of prefrontal cortex function. Annu Rev Neurosci 24:167–202. https ://doi.org/10.1146/annur ev.neuro .24.1.167 40. Söderqvist S, Nutley S (2016) Cogmed working memory training. Comput Softw 41. Spencer-Smith M, Klingberg T (2016) Correction: Benefits of a working memory training program for inattention in daily life: a systematic review and meta-analysis. PLoS ONE 11(11):e0167373. https ://doi.org/10.1371/journ al.pone.01673 73 42. Aksayli ND, Sala G, Gobet F (2019) The cognitive and academic benefits of Cogmed: a meta-analysis. Educ Res Rev 43. Anderson PJ, Lee KJ, Roberts G, Spencer-Smith MM, Thompson DK, Seal ML, Nosarti C, Grehan A, Josev EK, Gathercole S, Doyle LW, Pascoe L (2018) Long-term academic functioning following Cogmed working memory training for children born extremely preterm: a randomized controlled trial. J Pediatr 202:92–97.e94. https ://doi.org/10.1016/j.jpeds .2018.07.003 44. van Houdt CA, Oosterlaan J, van Wassenaer-Leemhuis AG, van Kaam AH, Aarnoudse-Moens CSH (2019) Executive function deficits in children born preterm or at low birthweight: a meta-analysis. Dev Med Child Neurol. https ://doi.org/10.1111/dmcn.14213 45. Mulder H, Pitchford NJ, Hagger MS, Marlow N (2009) Development of executive function and attention in preterm children: a systematic review. Dev Neuropsychol 34(4):393–421. https ://doi.org/10.1080/87565 64090 29645 24 46. Prins PJ, Brink ET, Dovis S, Ponsioen A, Geurts HM, De Vries M, Van Der Oord S (2013) “Braingame Brian”: toward an executive function training program with game elements for children with ADHD and cognitive control problems. Games Health Res DevClin Appl 2(1):44–49 47. van der Oord S, Ponsioen AJ, Geurts HM, Ten Brink EL, Prins PJ(2014) A pilot study of the efficacy of a computerized executive functioning remediation training with game elements for children with ADHD in an outpatient setting: outcome on parent- and teacher-rated executive functioning and ADHD behavior. J Atten Disord 18(8):699–712. https ://doi.org/10.1177/10870 54712 453167

48. Dovis S, Van der Oord S, Wiers RW, Prins PJ (2015) Improving executive functioning in children with ADHD: Training multiple executive functions within the context of a computer game. A randomized double-blind placebo controlled trial. PloS One 10 (4):e0121651 49. de Vries M, Prins PJ, Schmand BA, Geurts HM (2015) Working memory and cognitive flexibility-training for children with an autism spectrum disorder: a randomized controlled trial. J Child Psychol Psychiatry 56(5):566–576 50. Aarnoudse-Moens CSH, Twilhaar ES, Oosterlaan J, van Veen HG, Prins PJM, van Kaam A, van Wassenaer-Leemhuis AG (2018) Executive function computerized training in very preterm- born children: a pilot study. Games Health J. https ://doi.org/10.1089/g4h.2017.0038 51. Jaekel J, Eryigit-Madzwamuse S, Wolke D (2016) Preterm toddlers’ inhibitory control abilities predict attention regulation and academic achievement at age 8 years. J Pediatr 169:87–92.e81. https://doi.org/10.1016/j.jpeds .2015.10.029 52. Jaekel J, Wolke D (2014) Preterm birth and dyscalculia. J Pediatr 164(6):1327–1332. https://doi.org/10.1016/j.jpeds.2014.01.069 53. Jackson DC, Lin JJ, Chambers KL, Kessler-Jones A, Jones JE, Hsu DA, Stafstrom CE, Seidenberg M, Hermann BP (2014) Birth weight and cognition in children with epilepsy. Epilepsia 55(6):901–908. https ://doi.org/10.1111/epi.12622 54. Jaekel J, Wolke D, Bartmann P (2013) Poor attention rather than hyperactivity/impulsivity predicts academic achievement in very preterm and full-term adolescents. Psychol Med 43(1):183–196. https ://doi.org/10.1017/S0033 29171 20010 31 55. Verhulst FC, Van der Ende J (2013) Handleiding ASEBA-Vragenlijsten voor leeftijden 6 t/m 18 jaar: CBCL/6-18 YSR en TRF. ASEBA Nederland, Rotterdam 56. Hudziak JJ, Copeland W, Stanger C, Wadsworth M (2004) Screening for DSM-IV externalizing disorders with the child behavior checklist: a receiver-operating characteristic analysis. J Child Psychol Psychiatry 45(7):1299–1307 57. Swanson JM, Schuck S, Porter MM, Carlson C, Hartman CA, Sergeant JA, Clevenger W, Wasdell M, McCleary R, Lakes K, Wigal T (2012) Categorical and dimensional definitions and evaluations of symptoms of ADHD: history of the SNAP and the SWAN rating scales. Int J Educ Psychol Assess 10(1):51–70 58. Huizinga M, Smidts DP (2012) BRIEF Vragenlijst executive functies voor 5- tot 18-jarigen: handleiding. Hogrefe Uitgevers, Amsterdam 59. Sattler JM (1992) Assessment of children: WISC-III and WPPSI-R supplement. Assessment of children: WISC-III and WPPSI-R supplement. Jerome M. Sattler, San Diego 60. Nutley SB, Söderqvist S, Bryde S, Humphreys K, Klingberg T (2009) Measuring working memory capacity with greater precision in the lower capacity ranges. Dev Neuropsychol 35(1):81–95 61. Aarnoudse-Moens CSH, Duivenvoorden HJ, Weisglas-Kuperus N, Van Goudoever JB, Oosterlaan J (2012) The profile of executive function in very preterm children at 4 to 12 years. Dev Med Child Neurol 54(3):247–253. https ://doi.org/10.1111/j.1469-8749.2011.04150 .x 62. Königs M, Weeda WD, van Heurn L, Vermeulen RJ, Goslings JC, Luitse JS, Beelen A, van der Wees M, Kemps RJ, Catsman-Berrevoets CE (2017) Pediatric traumatic brain injury affects multisensory integration. Neuropsychology 31(2):137 63. de Vos T (2010) TempoTest Automatiseren: Handleiding en verantwording. Boom Testuitgevers, Amsterdam 64. Brus BT, Voeten MJM (1973) Eén-Mnuut-Test vorm A en B Verantwoording en Handleiding. Berkenhout Testmateriaal, Nijmegen 65. Van Houdt CA, Aarnoudse-Moens CS, van Wassenaer-Leemhuis AG, Laarman A, Koopman-Esseboom C, van Kaam AH, Oosterlaan J (2019) Effects of executive function training on attentional,

behavioral and emotional functioning and selfperceived competence in very preterm children: a randomized controlled trial. Front Psychol 10:2100 66. IBM C (2016) IBM SPSS statistics for windows, version 24.0. IBM Corp., Armonk 67. Ghosh D, Vogt A Outliers: an evaluation of methodologies 68. van Veen S, Aarnoudse-Moens CSH, Oosterlaan J, van Sonderen L, de Haan TR, van Kaam AH, van Wassenaer-Leemhuis AG (2018) Very preterm born children at early school age: healthcare therapies and educational provisions. Early Hum Dev 117:39–43. https ://doi.org/10.1016/j.earlh umdev .2017.12.010 69. Central Bureau of Statistics (2020) CBS Statline. https ://opendata.cbs.nl/statl ine/#/CBS/nl/datas et/82275 NED/table ?fromstatwe b. Accessed 19 Mar 2020 70. Klingberg T, Fernell E, Olesen PJ, Johnson M, Gustafsson P, Dahlstrom K, Gillberg CG, Forssberg H, Westerberg H (2005) Computerized training of working memory in children with ADHD—a randomized, controlled trial. J Am Acad Child Adolesc Psychiatry 44(2):177–186. https ://doi.org/10.1097/00004583-20050 2000-00010 71. Dunning DL, Holmes J, Gathercole SE (2013) Does working memory training lead to generalized improvements in children with low working memory? A randomized controlled trial. Dev Sci 16(6):915–925. https ://doi.org/10.1111/desc.12068 72. Hovik KT, Saunes BK, Aarlien AK, Egeland J (2013) RCT of working memory training in ADHD: long-term near-transfer effects. PLoS ONE 8(12):e80561. https ://doi.org/10.1371/journ al.pone.00805 61 73. Melby-Lervåg M, Hulme C (2013) Is working memory training effective? A meta-analytic review. Dev Psychol 49(2):270 74. Shipstead Z, Hicks KL, Engle RW (2012) Cogmed working memory training: Does the evidence support the claims? J Appl Res Memory Cognit 1(3):185–193 75. Murray AL, Thompson DK, Pascoe L, Leemans A, Inder TE, Doyle LW, Anderson JF, Anderson PJ (2016) White matter abnormalities and impaired attention abilities in children born very preterm. NeuroImage 124(Pt A):75–84. https ://doi.org/10.1016/j.neuro image .2015.08.044 76. Taylor HG, Clark CA (2016) Executive function in children born preterm: risk factors and implications for outcome. Semin Perinatol 40(8):520–529. https ://doi.org/10.1053/j.semperi.2016.09.004 77. de Kieviet JF, Heslenfeld DJ, Pouwels PJ, Lafeber HN, Vermeulen RJ, van Elburg RM, Oosterlaan J (2014) A crucial role for white matter alterations in interference control problems of very preterm children. Pediatr Res 75(6):731–737. https ://doi.org/10.1038/pr.2014.31 78. Krain AL, Castellanos FXJCpr (2006) Brain development and ADHD 26 (4):433–444 79. Lou HC (1996) Etiology and pathogenesis of attention-deficit hyperactivity disorder (ADHD): significance of prematurity and perinatal hypoxic-haemodynamic encephalopathy. Acta Paediatr (Oslo, Norway : 1992) 85 (11):1266–1271 80. Everts R, Murner-Lavanchy I, Schroth G, Steinlin M (2017) Neural change following different memory training approaches in very preterm born children—a pilot study. Dev Neurorehabil 20(1):14–24. https ://doi.org/10.3109/17518 423.2015.10270 10 81. Schaeffer DJ, Krafft CE, Schwarz NF, Chi L, Rodrigue AL, Pierce JE, Allison JD, Yanasak NE, Liu T, Davis CL, McDowell JE (2014) An 8-month exercise intervention alters frontotemporal white matter integrity in overweight children 51(8):728–733. https:doi.org/10.1111/psyp.12227 82. Kelly CE, Thompson DK, Chen J, Josev EK, Pascoe L, Spencer- Smith MM, Adamson C, Nosarti C, Gathercole S, Roberts G, Lee KJ, Doyle LW, Seal ML, Anderson PJ (2020) Working memory training and brain structure and function in extremely preterm or extremely low birth weight children. Hum Brain Mapp 41(3):684–696. https ://doi.org/10.1002/hbm.24832

83. Scionti N, Cavallero M, Zogmaister C, Marzocchi GM (2020) Is cognitive training effective for improving executive functions in preschoolers? A systematic review and meta-analysis. Front Psychol 10:2812–2812. https ://doi.org/10.3389/fpsyg .2019.02812 84. Green CS, Bavelier DJP, aging (2008) Exercising your brain: a review of human brain plasticity and training-induced learning 23 (4):692

Vol.:(0123456789)1 3

European Child & Adolescent Psychiatry https://doi.org/10.1007/s00787-020-01561-0

ORIGINAL CONTRIBUTION

Executive function training in very preterm children: a randomized controlled trial

Carolien A. van Houdt1,2 · Aleid G. van Wassenaer‑Leemhuis1 · Jaap Oosterlaan3,4 · Marsh Königs2 · Corine Koopman‑Esseboom5 · A. R. Céleste Laarman6 · Anton H. van Kaam1,6 · Cornelieke S. H. Aarnoudse‑Moens1,2,4,7

Received: 10 September 2019 / Accepted: 15 May 2020 © The Author(s) 2020

AbstractObjective of the current study was to assess whether game-formatted executive function (EF) training, is effective in improv-ing attention, EF and academic performance in very preterm and/or extremely low birthweight children aged 8–12 years. A multi-center, double-blind, placebo- and waitlist controlled randomized trial (NTR5365) in two academic hospitals in The Netherlands was performed. Eighty-five very preterm children with parent-rated attention problems on the Child Behavior Checklist were randomized to one of three treatment conditions: EF training, placebo training or waitlist condition. EF or placebo training was completed at home (6 weeks, 25 sessions of 30–45 min each). At baseline, 2 weeks after training or being on the waitlist, and five months after first follow-up visit, children underwent assessments of primary outcomes (parent and teacher ratings of attention) and secondary outcomes (parent and teacher ratings of daily-life EF, computerized EF tasks and academic performance). Linear mixed model analyses were performed for all outcome measures. There were no significant differences in improvement over time on parent- and teacher ratings of attention, parent- and teacher ratings of daily-life EF, computerized EF tasks, and academic performance (arithmetic and reading) between the EF training, placebo training and waitlist condition. In conclusion, game-formatted EF training does not improve attention, EF or academic performance in very preterm children with parent-rated attention problems.

Keywords Intervention · Premature · Attention · Behavior · Arithmetic · Reading

Introduction

In Western countries, 0.7–1.4% of all live born children are born very preterm (gestational age (GA) < 32 weeks) [1]. Due to advances in medical care, survival rates have increased and approximately 65% of children born extremely

Electronic supplementary material The online version of this article (https ://doi.org/10.1007/s0078 7-020-01561 -0) contains supplementary material, which is available to authorized users.

* Carolien A. van Houdt [email protected]

1 Department of Neonatology, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands

2 Emma Neuroscience Group, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands

3 Department of Pediatrics, Amsterdam UMC, University of Amsterdam, Emma Neuroscience Group at Emma Children’s Hospital, Amsterdam Reproduction and Development, Meibergdreef 9, Amsterdam, The Netherlands

4 Clinical Neuropsychology Section, Vrije Universiteit Amsterdam, Van der Boechorststraat 7, Amsterdam, The Netherlands

5 Department of Neonatology, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, The Netherlands

6 Department of Neonatology, Emma Children’s Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, de Boelelaan 1117, Amsterdam, The Netherlands

7 Psychosocial Department, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands

http://orcid.org/0000-0001-8830-6503

http://crossmark.crossref.org/dialog/?doi=10.1007/s00787-020-01561-0&domain=pdf

https://doi.org/10.1007/s00787-020-01561-0

European Child & Adolescent Psychiatry

1 3

preterm do not develop major disabilities [2]. However, more subtle problems in various domains are frequently encountered [3], which may have a significant negative impact on children’s and parents’ lives. One of the main and most persistent problems very preterm children encounter are problems in attentional functioning [4, 5]. Very preterm children have a two to four times higher risk of a diagnosis of Attention Deficit/Hyperactivity Disorder (ADHD) [6, 7], particularly the inattentive subtype [8], and an increased risk for an Autism Spectrum Disorder (ASD) diagnosis [8, 9]. Also in ASD, attentional problems are common [10] and several studies have shown high comorbidity rates of ADHD in children with ASD [11–15]. Although very preterm chil-dren’s behavioral attentional symptoms may resemble those of children with ADHD or ASD for some aspects, such as inattentive symptoms, the biological underpinnings seem to differ. For example, a recent study, comparing adolescents with ADHD and adolescents born preterm on electrophysi-ological measures associated with attentional and inhibitory processing, found that preterm adolescents showed both impairments overlapping with those found in adolescents with ADHD and impairments unique for the preterm ado-lescents [16]. Moreover, the clinical presentation is also dif-ferent. For example, the association between oppositional defiant disorder (ODD) and conduct disorder (CD) is much stronger in the general population than in children born extremely preterm [8]. Thus, interventions that were ineffec-tive in children with ADHD may be effective in very preterm children with attention problems and vice versa.

Deficits in executive functions (EFs) are considered to play an important role in the complex neuropsychology of both ADHD and ASD [17–26]. Executive functioning is an umbrella term for a set of higher-order cognitive functions that allow for top-down, goal-directed behavior, with core functions including working memory, inhibition and cogni-tive flexibility [27]. Research has indicated that poor EFs are strongly associated with the attentional problems of very preterm children as well [28–30]. Both ASD and ADHD are neurodevelopmental disorders that affect key fronto-striatal and fronto-parietal circuits that are important for EFs [31], and very preterm birth has been shown to affect white mat-ter network integrity and brain structures associated with EFs [32–39].

Computerized training interventions to improve EFs may therefore be one way to address the attentional prob-lems very preterm children encounter. Cogmed Working Memory Training (CWMT) is widely used in children with Attention Deficit/Hyperactivity Disorder (ADHD) [40]. It has been coined as a promising computerized EF train-ing for attentional problems [41], although more recent studies suggest that it might not be as effective as pre-viously thought [42]. In very preterm children, a recent randomized controlled trial showed no effects of CWMT

on any outcome measure, including attentional function-ing [43]. However, CWMT solely trains working memory, while very preterm children show problems in inhibition and cognitive flexibility as well [5, 44, 45]. Recently, the BrainGame Brian training was developed [46], targeting not only working memory, but also inhibition and cogni-tive flexibility. BrainGame Brian training further expands upon the CWMT by adding game elements and using strong and immediate reinforcements to optimize chil-dren’s motivational state. To date, effects of BrainGame Brian training have been assessed in three studies includ-ing children with clinically diagnosed ADHD and Autism Spectrum Disorder (ASD). These studies have consist-ently shown improvements in visuospatial working mem-ory, although without consistent effects on other EFs or other untrained functions [47–49]. Previously, our group showed in a small sized non-randomized pilot study that BrainGame Brian training was a feasible intervention for very preterm children. Clinically significant benefits for visuospatial working memory were found [50].

The current study examined, using a double-blind, ran-domized controlled design including both a placebo- and a waitlist condition, whether game-formatted EF training (i.e., BrainGame Brian training) improves attentional func-tioning in very preterm (GA < 30 weeks) and/or extremely low birthweight children (birthweight < 1000 g) aged 8 to 12 years. We also examined the effects of game-formatted EF training on secondary outcome measures. Because EF training is believed to improve attentional function-ing through improving EFs, we examined whether game-formatted EF training indeed improved EFs. Last, as both attentional problems and EF deficits are strongly linked to worse academic performance in very preterm children [28, 29, 51–54], we also investigated whether game-formatted EF training improves academic performance, more specifi-cally arithmetic and reading performance.

Methods

Trial design and ethical considerations

This multi-center, double-blind, placebo and waitlist con-trolled randomized trial was conducted in two academic hospitals in The Netherlands (Amsterdam University Medical Centers and University Medical Center Utrecht). Medical Ethical Committees in both centers approved the study protocol and execution of the study procedures was according to the Declaration of Helsinki. The trial was registered in the Dutch Trial Registry (NTR5365). CON-SORT guidelines were followed.


1 3

Participants

Parents of 7–12 year old children born very preterm and/or with extremely low birthweight (in short: very preterm chil-dren) who were admitted to the Neonatal Intensive Care Unit (NICU) in one of the two participating centers and who joined the neonatal follow-up program, were asked to complete the Dutch version of the Child Behavior Checklist (CBCL6-18 [55]). Children with parent-rated attention problems on the CBCL6-18 (T ≥ 55 on Attention Problems scale [56], as research has suggested this T-score is the optimal cut-off score for ADHD screening [56]) were eligible for this study as soon as they reached a minimum chronological age of 8 years. Exclusion criteria were estimated Intelligence Quo-tient (IQ) < 80, motor problems too profound to allow use of a computer and no Dutch language use in the home situation.

Randomization and blinding

Children meeting inclusion criteria were randomly assigned to one of three treatment conditions: training-, placebo- or wait-list condition. Allocation to treatment conditions was strati-fied by age (below or above 10.5 years of age) and severity of attention problems (Attention Problems T-score below or above 65), with equal proportions of children allocated to each condition within each stratum. To ensure blinding to train-ing- or placebo condition, parents were only informed about whether their child was randomized to either one of two train-ing conditions or the waitlist condition and in case more chil-dren from the same family were included in the study, one of those was randomized and the other was allocated to the same condition. A random number generator was used to gener-ate randomization lists. A researcher not otherwise involved in this study was responsible for randomization and handed the test assistant a sealed envelope with a note stating ‘wait-list’ or a login and password, which was opened by the child and parents after baseline assessment. All staff was blinded to training or placebo assignment, including the person involved in randomization. Test assistants that played the first training session with the child were deblinded because of differences in training tasks (see below) between training- and placebo condition and were not involved in follow-up assessments of these children. Parents, children and test administrators were aware of a child’s allocation to the waitlist condition. Data were analyzed blinded to treatment allocations.

Intervention

BrainGame Brian training

Braingame Brian is a game-formatted computerized EF training, performed by the child at home. An elaborate

description of the BrainGame Brian training can be found in Prins et al. [46]. BrainGame Brian is a game-world envi-ronment, in which three EF training tasks, one for each core EF, are embedded. In each of 25 training sessions, children have to help the main character, Brian, to solve problems for other game-world characters. To do so, they play the three EF training tasks, which leads to the creation of an invention that solves the problem. For example, Brian meets a character that has a problem shearing his sheep. By play-ing the three EF training tasks, a sheep-shearing machine is invented, which solves the problem and remains visible in the game-world throughout the rest of the sessions to opti-mize motivational state and self-control of the children. In each session, children play the three training tasks twice. In total, 25 sessions are played, and the child and parents were instructed to play the BrainGame Brian training 4 times a week (approximately 30–45 min per session). After each session, session data were saved to a database, which was accessible for researchers to monitor fidelity to the train-ing regimen. There was no additional support of researchers regarding motivation and/or feedback out of the computer game interface. For our randomized controlled trial, two ver-sions of the BrainGame Brian EF training were used: the BrainGame Brian EF training, and a placebo version of the BrainGame Brian EF training. In the placebo version of the BrainGame Brian EF training, everything is identical to the BrainGame Brain EF training, except that the EF training tasks were replaced by placebo versions of these tasks. See below for the descriptions of the training tasks for both ver-sions of the training.

Training tasks in EF training condition

In the working memory task, children are asked to repeat a sequence of dots on a 4 × 4 grid in a specific way (e.g., forwards, backwards). The instructions for this task change every five sessions to increase working memory demands. In the inhibition task, children are asked to press a button in a specific time window (target), but to refrain from pressing that button when a stop signal is presented. In the cognitive flexibility task, children are asked to sort objects according to one of two rules, with the sorting rule changing every three to five trials. After each block of all three training tasks, difficulty level of each task is automatically adjusted to the child’s performance.

Training tasks in placebo condition

In the placebo versions of the EF training tasks, the ele-ments actually training the EFs were removed, and difficulty level was set at the lowest difficulty level for all sessions regardless of the child’s performance. In the placebo version of the working memory task, children are asked to repeat


1 3

sequences in the same order as presented (which requires short-term memory, not working memory). This instruction remains the same throughout all training sessions. In the placebo version of the inhibition task, no stop signals are presented (thus children do not have to inhibit responses). In the placebo version of the cognitive flexibility task, the sorting rule never changes (thus no cognitive flexibility is required).

Waitlist condition

Children in the waitlist condition do not play the BrainGame Brian training and were instructed to perform the same activities in the waiting period as they normally do.

Procedure

After written informed consent was obtained from par-ents and, if applicable, children aged 12 years, and verbal informed consent was obtained from children below 12 years of age, participants completed a baseline neurocognitive assessment including measures of IQ, EF and academic functioning. Parents and teachers were asked to fill out ques-tionnaires on children’s attention and daily-life EF behav-ior. If children were randomized to the training- or placebo condition, a house visit was made to instruct children and parents and play the first session. In two follow-up visits, the neurocognitive assessment was repeated except for IQ, which was only administered at baseline. The first follow-up assessment (T1) was approximately two weeks after the last training session (approximately 2 months after baseline assessment for children in the waitlist condition) and the sec-ond follow-up assessment (T2) was approximately 5 months after the first follow-up assessment.

Measures

Primary outcome was parent- and teacher-rated attention as measured by the Strengths and Weaknesses of ADHD-symp-toms and Normal Behavior (SWAN) questionnaire [57]. Sec-ondary outcomes were (1) daily-life EF reported by parents and teachers as measured with the Behavior Rating Inven-tory of Executive Function (BRIEF) [58], (2) verbal working memory as measured using the Digit Span Backward subtest of the WISC-III-NL [59], (3) visuospatial working memory as measured using the Grid Task, backwards condition [60], (4) inhibition as measured with the Stop Signal Task [61], (5) cognitive flexibility as measured with the Multisensory Integration Test (MSIT) [62], (6) arithmetic as measured with the TempoTest Automatiseren (TTA) [63] and (7) Tech-nical reading as measured with the Brus Een Minuut Test (B-EMT) [64]. Detailed descriptions of tasks and outcome measures can be found in Supplementary Material 1. Other

secondary outcomes related to untrained functions were assessed as well, but were not included in the current paper on main outcome measures [65].

IQ, demographic characteristics and medical characteristics of neonatal period

IQ was estimated with a short-form of the Dutch Wechsler Intelligence Scale for Children, third edition (WISC-III-NL [59]), comprising the subtests Vocabulary and Block Design. Parents provided information on demographics. The Digit Span [59] and Grid Task [60] forwards conditions (repeat-ing a sequence of spoken digits or dots on a grid in forwards order, respectively), were administered to provide maximal forwards span length. Neonatal medical data were obtained from medical records.

Statistical analyses

Sample size calculations determined that, to detect a medium-sized intervention effect (Cohen’s d = 0.5) on our primary outcome measure with a within-subject correlation of 0.295 [50] with a power of 80% and a significance level of 0.05, 39 children in each intervention arm were needed.

IBM SPSS Statistics version 24 was used for the statis-tical analyses [66]. Outliers were winsorized at three SDs [67]. Data were missing for less than 5% of children, except for: the baseline assessments of the teacher SWAN (12.9%), teacher BRIEF (14.1%) and Stop Signal Task (9.4%); the first follow-up assessments of the teacher SWAN (30.1%), teacher BRIEF (30.1%), Grid Task Backwards (6.8%) and MSIT (9.6%); the second follow-up assessments of the teacher SWAN (44.9%), parent BRIEF (5.8%), teacher BRIEF (40.6%), Grid Task Backwards (17.4%), Stop Sig-nal Task (10.1%) and MSIT (7.2%). Missing data were not imputed.

Data were analyzed on intention-to-treat basis. To assess whether attrition from the study was selective, children that did and did not complete all assessments were compared on all demographic and neonatal medical characteristics with independent t tests and chi-square tests.

To assess whether BrainGame Brian training improves attention, EF and academic performance, linear mixed model analyses were run for all primary and secondary outcome measures with a random intercept to account for depend-ency in the data due to family bonds, and fixed factors for treatment condition (training, placebo or waitlist condition), time (baseline, first follow-up and second follow-up assess-ment) and the interaction between the two. All available data (also of participants with missing data) were used in the lin-ear mixed model analyses. Estimated marginal means were reported to aid interpretation of the results.


1 3

Results

Participants

Participants’ flow through the study process is depicted in Fig. 1. In short, 434 out of 1,019 parents returned the completed questionnaire. Main reasons not to return the questionnaire were no time or no interest. Of 234 children with elevated attention scores that were invited to partici-pate, 97 agreed. Reasons to not participate were: already busy schedules for the child and/or family, or no interest. Two children withdrew from the study before randomiza-tion. Ten children were excluded due to estimated IQ < 80. The remaining 85 children were randomized to a treatment condition (see Fig. 1). All children in the EF training and placebo training conditions that had at least one follow-up assessment, completed all 25 training sessions.

Randomization allocated 29 children to the training condition, 26 children to the placebo condition and 30 children to the waitlist condition. Twelve children with-drew from the study before the first follow-up visit and four withdrew before the second follow-up visit. Reasons for withdrawal were: not able to incorporate training ses-sions into busy schedule or child not wanting to com-plete training (n = 9), no time or willingness to schedule

follow-up visit(s) at appropriate time-point(s) (n = 5) or severe illness discovered (n = 2). Of the included children 81% completed all assessments. Attrition analyses showed no differences in demographic and neonatal medical char-acteristics between children that did and did not complete all assessments (all p values > 0.14). As no data from nonparticipating children could be assessed, we could not perform attrition analyses regarding the representa-tiveness of our sample. However, when compared to very preterm children included in previous cohort-studies of our research group, the GA and BW of the included chil-dren was similar (GA around 28 weeks and BW around 1000 g [3, 68]). Parental education level of our sample was high in 61% of children, compared to approximately 45% of the general Dutch population between 25–45 years of age being highly educated [69]. Assessments took place between October 2015 and September 2018. Demograph-ics and neonatal medical characteristics are presented in Table 1.

Primary and secondary outcome measures

There were no significant differences over time between the three treatment conditions for both parent and teacher SWAN questionnaires, indicating no beneficial effects of

Fig. 1 CONSORT flow diagram. CBCL child behavior checklist, IQ intelligence quotient, EF Executive function. Re-used from Van Houdt et al. [65]. Copyright 2019 by van Houdt, Aarnoudse-Moens, van Wassenaer-Leemhuis, Laarman, Koopman-Esseboom, van Kaam and Oosterlaan


1 3

the BrainGame Brian training as compared to the placebo or waitlist condition.

There were also no significant differences over time between the three treatment conditions for any of the EF measures, indicating no beneficial effects of the BrainGame Brian training as compared to the placebo or waitlist condition. Last, there were no significant differ-ences over time between the three treatment conditions for both the TTA and B-EMT, indicating no beneficial effects of the BrainGame Brian training as compared to the placebo or waitlist condition.

There were significant main effects of time for teacher BRIEF Working Memory and Total Score, Grid Task Backwards, Stop Signal Task, TTA and B-EMT, all indi-cating better performance over time. There were signifi-cant main effects of group for the Grid Task Backwards and MSIT, both indicating poorer performance in the pla-cebo training group than in the BrainGame Brian train-ing group and the waitlist group, with no difference in performance between the latter two (see Tables 2 and 3).

Discussion

The present study investigated whether game-formatted EF training improves attentional functioning in children born very preterm and/or with extremely low birthweight (in short: very preterm) with parent-rated attention problems. Additional outcomes included computerized EF tasks, parent- and teacher reported daily-life EF and academic performance. Results of our double-blind RCT provided no evidence for beneficial effects on any of the outcome measures assessed.

In children with ADHD, positive effects of both BrainGame Brian training and CWMT on working mem-ory performance have been found [48, 70–72]. Because behavioral symptoms of inattention in children born very preterm resemble those of children with ADHD, we expected positive effects in children born very pre-term. However, results of our study indicated no positive effects of the BrainGame Brian training in children born

Table 1 Demographic and neonatal medical characteristics for the three treatment groups

BGB BrainGame Brian, GA gestational age, BW birth weight, IQ intelligence quotient, CBCL child behav-ior check list, SGA small for gestational age, BPD broncho pulmonary dysplasia, PMA post menstrual age, IVH intra ventricular hemorrhage, PVL peri ventricular leukomalacia, M mean, SD standard deviation, n number

Measure BGB-Training (n = 29) BGB-Placebo (n = 26) Waitlist (n = 30)

Demographic characteristics: GA (M, SD) 28.2 (1.3) 28.0 (1.0) 27.8 (1.4) BW (gram; M, SD) 1026 (256) 1039 (179) 1049 (267) Age (years; M, SD) 10.2 (1.2) 10.2 (1.3) 10.3 (1.1) IQ (M, SD) 99.0 (13.6) 96.4 (11.7) 100.8 (11.1) CBCL attention T score (M, SD) 62.8 (6.9) 64.0 (7.6) 64.4 (7.0) Digit span forwards span length 5.1 (0.9) 5.1 (1.1) 5.1 (0.8) Grid task forwards span length 4.2 (1.2) 4.0 (1.3) 4.6 (1.2) Boys (n, %) 13 (45%) 16 (62%) 20 (67%)

Parental education level (n/total n) Low 6/29 4/25 1/28 Middle 3/29 5/25 11/28 High 20/29 16/25 16/28

Neonatal medical characteristics SGA (n, %) 8 (28%) 4 (15%) 4 (13%) Ventilator support (n, %) 20 (69%) 17 (65%) 23 (77%) BPD at 36 weeks PMA (n, %) 6 (21%) 4 (15%) 5 (17%) IVH I or II 9 (31%) 6 (23%) 8 (27%) IVH III or IV 0 (0%) 2 (8%) 1 (3%) PVL I 1 (3%) 2 (8%) 0 (0%) PVL II, III or IV 0 (0%) 0 (0%) 0 (0%) Open ductus botalli treated 3 (10%) 12 (46%) 13 (43%) Sepsis 17 (59%) 16 (62%) 20 (67%)


1 3

very preterm. Results of our study are in line with a rand-omized controlled trial investigating effects of CWMT in very preterm children, with no positive effects of CWMT on attentional functioning, working memory performance and academic performance [43]. Also, we recently ana-lyzed our other secondary outcome measures including behavioral and emotional functioning and self-perceived competence [65]. None of these untrained functions were improved by BrainGame Brian training either. Our results are also in line with previous meta-analyses investigating the effect of CWMT on far transfer measures in children with ADHD [41, 42, 73, 74]. Despite the behavioral paral-lels between ADHD and symptoms of inattention in chil-dren born very preterm, the neurobiological underpinnings of these symptoms may actually be different. A recent study, for instance, using electroencephalography (EEG) measures associated with attentional and inhibitory pro-cessing, demonstrated that adolescents born preterm show

unique patterns of aberrant neural activity as compared to adolescents with ADHD, suggestive of more generalized impairments in adolescents born preterm as compared to adolescents with ADHD [16]. This implies that interven-tions that are not effective in children with ADHD may be effective in very preterm children with attention problems and vice versa, and examining intervention effects in both populations instead of in one population and then gener-alizing the results to the other population, is extremely important.

An important prerequisite for improvement of EF and/or attentional functioning following EF training is plas-ticity of white matter networks and basal ganglia. In very preterm children, compromised white matter tract integ-rity and white matter abnormalities are associated with both EF- and attention problems [75–77]. Moreover, dam-age to the basal ganglia is also associated with attention problems [78] and is frequently observed in children born

Table 2 Baseline and follow-up data on the SWAN for the three intervention groups

SWAN strengths and weaknesses of ADHD-symptoms and normal behavior, BGB BrainGame Brian, M mean, SE standard error, T0 Time-point 0, i.e. baseline, T1 time-point 1, i.e. first follow-up visit, T2 time-point 2, i.e. second follow-up visit. See Fig. 1 for number of participants in each group at each time-point

Outcome measure T0 T1 T2 p value effect of intervention condi-tion

p value effect of time

p value interaction effect of intervention condition x time

SWAN parent Attention deficit (M, SE) .17 .18 .91 BGB-Training 40.1 (1.4) 39.9 (1.5) 38.9 (1.5) BGB-Placebo 42.2 (1.4) 43.1 (1.5) 42.0 (1.6) Waitlist 42.6 (1.3) 43.8 (1.4) 42.0 (1.4)

Hyperactivity/impulsivity (M, SE) .69 .12 .69 BGB-Training 38.1 (1.5) 38.7 (1.6) 36.6 (1.6) BGB-Placebo 40.6 (1.6) 38.9 (1.7) 38.7 (1.7) Waitlist 39.7 (1.4) 39.2 (1.5) 38.8 (1.5)

Total score (M, SE) .29 .06 .98 BGB-Training 78.4 (2.5) 79.3 (2.6) 75.5 (2.6) BGB-Placebo 82.9 (2.5) 82.9 (2.7) 80.7 (2.8) Waitlist 82.3 (2.3) 83.0 (2.4) 80.7 (2.4)

SWAN teacher Attention deficit (M, SE) .17 .05 .58 BGB-Training 37.7 (1.6) 37.7 (1.6) 37.0 (1.8) BGB-Placebo 40.6 (1.7) 40.6 (1.9) 39.0 (2.1) Waitlist 42.3 (1.5) 42.8 (1.6) 39.0 (1.7)

Hyperactivity/impulsivity (M, SE) .35 .81 .41 BGB-Training 34.1 (1.9) 32.2 (2.0) 33.9 (2.2) BGB-Placebo 36.4 (2.0) 34.6 (2.4) 36.3 (2.7) Waitlist 36.7 (1.8) 38.3 (2.0) 35.4 (2.1)

Total score (M, SE) .18 .42 .38 BGB-Training 71.8 (3.0) 70.0 (3.2) 70.9 (3.5) BGB-Placebo 76.9 (3.2) 75.2 (3.7) 75.5 (4.2) Waitlist 78.9 (2.9) 81.1 (3.1) 74.3 (3.3)


1 3

Table 3 Baseline and follow-up data on EF and academic performance for the three intervention groups




BRIEF parent working memory (M, SE)

.33 .06 .61

BGB-Training 57.45 (1.68) 56.09 (1.74) 54.12 (1.83) BGB-Placebo 56.56 (1.70) 57.47 (1.87) 54.79 (1.90) Waitlist 58.75 (1.58) 59.13 (1.60) 58.28 (1.62)

BRIEF parent inhibit (M, SE) .20 .27 .74 BGB-Training 51.23 (2.05) 49.70 (2.12) 48.65 (2.20) BGB-Placebo 54.98 (2.07) 52.93 (2.24) 53.94 (2.27) Waitlist 54.27 (1.92) 54.57 (1.95) 53.55 (1.96)

BRIEF parent cognitive flexibility (M, SE)

.57 .27 .64


BRIEF parent total (M, SE) .33 .54 .53 BGB-Training 52.41 (1.88) 51.57 (1.95) 49.75 (2.03) BGB-Placebo 52.75 (1.90) 53.48 (2.07) 53.99 (2.10) Waitlist 54.74 (1.77) 55.57 (1.79) 53.95 (1.81)

BRIEF teacher working memory (M, SE)

.63 .001* .96


BRIEF teacher inhibit (M, SE) .59 .67 .39 BGB-Training 49.43 (1.94) 48.79 (2.14) 51.02 (2.21) BGB-Placebo 53.08 (2.15) 52.00 (2.43) 51.03 (2.85) Waitlist 52.92 (1.88) 52.95 (2.03) 50.07 (2.12)

BRIEF teacher cognitive flexibil-ity (M, SE)

.83 .67 .96


BRIEF teacher total (M, SE) .59 .03* .27 BGB-Training 52.60 (2.25) 53.15 (2.40) 51.72 (2.45) BGB-Placebo 54.84 (2.46) 57.95 (2.67) 54.52 (3.00) Waitlist 55.81 (2.17) 55.60 (2.28) 50.65 (2.35)

Digit span backwards (M, SE) .67 .91 .94 BGB-Training 16.19 (1.75) 16.77 (1.88) 17.77 (1.91) BGB-Placebo 17.67 (1.81) 16.50 (2.03) 17.04 (2.12) Waitlist 15.79 (1.68) 15.31 (1.71) 15.31 (1.78)

Grid task backwards (M, SE) .02* .02* .33 BGB-Training 35.30 (5.40) 50.88 (6.26) 56.76 (6.94) BGB-Placebo 27.17 (5.54) 30.98 (6.39) 34.57 (6.96) Waitlist 38.39 (5.15) 48.24 (5.23) 40.10 (5.60)

Stop taskSSRT (M, SE) .99 .002* .49 BGB-Training 323.4 (30.8) 293.3 (31.9) 288.9 (32.2) BGB-Placebo 312.4 (31.4) 302.0 (34.6) 270.3 (33.5) Waitlist 310.3 (30.0) 316.3 (29.6) 263.6 (30.2)


1 3

very preterm [79]. Research has shown that EF training can induce neural changes in brain areas associated with atten-tion in very preterm children [80] and that exercise inter-vention can induce improvements in white matter integrity in children [81]. It thus seems that the very preterm brain does show the plasticity required for improvement of EF and/or attentional functioning. Possibly, the intensity and duration of the BrainGame Brian training and CWMT in its current forms are not sufficient to induce changes in EF in very preterm children. This is supported by the fact that all children in the EF training condition that had at least one follow-up assessment (24 out of 29, 83%) completed all training sessions, thereby ruling out that not finding any positive results was due to infidelity to the training regimen. Because we did not include brain measures, we cannot rule out that the BrainGame Brian training did induce changes in the brain that did not subsequently lead to changes in atten-tion, behavior or academic performance. However, a recent randomized controlled trial on CWMT in extremely pre-term children concluded that brain changes (both structural and functional) generally did not differ between CWMT and placebo conditions [82]. Thus, to induce changes in brain measures and attention, behavior or academic perfor-mance, it is likely that more intense and longer training is required. Furthermore, children’s motivation could play a role in the (absence of) training effects. In our study, we did

not measure this. However, in a previous pilot study of our group, it was reported that “the majority of parents were positive about BrainGame Brian, in that it is enjoyable and motivating” [50].

Given the growing evidence of ineffectiveness of EF training, alternative interventions should be investigated. One alternative that might come to mind is targeting lower-order cognitive skills with cognitive training, instead of EF (which are higher-order cognitive skills). However, the pla-cebo training condition may be considered as lower-order cognitive training: the child does not train EFs, but still has to remain alert and pay attention to the task in order to perform it correctly. If lower-order cognitive training would be effective, we would therefore expect to find larger improvements following placebo training than following EF training or waitlist condition, which was not the case. A recent meta-analysis on EF training in very preterm chil-dren at preschool-age specifically (3–6 years of age) con-cluded that EF training does have positive results in this population, especially when it is non-computerized and in a group setting [83]. Therefore, we suggest that focus should be directed towards training programs that target younger children, combine exercise and tasks demanding EFs and take place in group settings.

A limitation of the current study is not meeting the required numbers according to our power calculations. However,

BGB BrainGame Brian, BRIEF Behavior Rating Inventory of Executive Function, SSRT stop signal reaction time, MSIT multisensory integration task, B-EMT Brus-Een minuut test, TTA tempo test automatiseren, M mean, SE standard error, T0 time-point 0, i.e. baseline, T1 time-point 1, i.e. first follow-up visit, T2 time-point 2, i.e. second follow-up visit. See Fig. 1 for number of participants in each group at each time-point*Significant at alpha < .05

Table 3 (continued)




# errors (M, SE) .61 .01* .32 BGB-Training 5.21 (1.26) 3.08 (1.43) 3.93 (1.40) BGB-Placebo 6.06 (1.30) 3.41 (1.69) 3.41 (1.50) Waitlist 6.66 (1.21) 6.30 (1.19) 3.35 (1.27)

MSIT shifting accuracy loss (M, SE)

.002* .25 .35

BGB-Training 3.4% (2.1%) 3.2% (2.3%) 3.1% (2.4%) BGB-Placebo 14.4% (2.2%) 12.9% (2.7%) 7.4% (2.5%) Waitlist 3.9% (2.0%) 5.5% (2.0%) 4.1% (2.1%)

TTA (M, SE) .95 < . 001* .95 BGB-Training 90.3 (9.5) 97.6 (9.6) 101.3 (9.7) BGB-Placebo 93.0 (9.7) 103.1 (10.0) 105.9 (10.0) Waitlist 89.8 (9.0) 97.7 (9.0) 104.7 (9.1)

B-EMT (M, SE) .99 .001* .99 BGB-Training 59.6 (3.7) 61.5 (3.8) 64.5 (3.8) BGB-Placebo 60.8 (3.7) 61.3 (3.9) 65.7 (4.0) Waitlist 60.1 (3.5) 61.7 (3.5) 65.3 (3.5)


1 3

differences between groups over time were small and not clini-cally meaningful. Another limitation is that the current study included children with attention problems, and not necessarily children with EF problems. The rationale was that previous studies have shown that EF impairments play an important underlying role in the attention problems observed in very preterm children [28–30]. Last, despite substantial efforts, a large number of teacher questionnaires was missing, espe-cially at the second follow-up visit. However, additional analy-ses revealed that there were no significant differences in our teacher primary outcome measure at baseline between children with and without the teacher primary outcome measure at sec-ond follow-up visit, nor were there any significant differences in demographics between these children. Strengths of the pre-sent study are incorporation of both a placebo- and a waitlist control condition, intention-to-treat analyses, comprehensive assessment of a broad range of outcomes using multi-dimen-sional techniques (questionnaires and performance-based tests) and informants (parent and teacher questionnaires), and assess-ment of both direct effects and effects five months after the intervention ended.

Conclusion

Game-formatted EF training is not effective in improving attention, EF or academic functioning in very preterm chil-dren with attention problems. Future research may investigate whether alterations to EF training would make such training effective in very preterm children. For example, effectiveness may be enhanced with more ecologically valid and intrinsi-cally rewarding training tasks and/or with longer and more intensive training [84]. Parallel to this, research should also look beyond game-formatted training for interventions to improve EF and associated areas of functioning.

Funding Grants from the Stichting Kinderpostzegels Nederland, Cor-nelia Stichting, Stichting Zabawas and Stichting Elise Mathilde Fonds.

Compliance with ethical standards

Conflict of interest On behalf of all authors, the corresponding author states that there is no conflict of interest.

Ethical standards statement This study has been approved by the appropriate Medical Ethical Committees and has been performed in accordance with the ethical standards laid down in the 1964 Declara-tion of Helsinki and its later amendments. Parents of all children and, if applicable, children aged 12 years gave informed consent prior to inclusion in the study.

Open Access This article is licensed under a Creative Commons Attri-bution 4.0 International License, which permits use, sharing, adapta-tion, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are

included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/.

References

1. Delnord M, Hindori‐Mohangoo AD, Smith LK, Szamotulska K, Richards JL, Deb‐Rinker P, Rouleau J, Velebil P, Zile I, Sakkeus L (2017) Variations in very preterm birth rates in 30 high‐income countries: are valid international comparisons possible using routine data? BJOG Int J Obstet Gynaecol 124 (5):785–794

2. Lorenz JM (2011) Survival and long-term neurodevelopmental outcome of the extremely preterm infant. A systematic review. Saudi Med J 32(9):885–894

3. Potharst ES, van Wassenaer AG, Houtzager BA, van Hus JW, Last BF, Kok JH (2011) High incidence of multi-domain disabilities in very preterm children at five years of age. J Pediatr 159(1):79–85. https ://doi.org/10.1016/j.jpeds .2010.12.055

4. Shum D, Neulinger K, O’Callaghan M, Mohay H (2008) Atten-tional problems in children born very preterm or with extremely low birth weight at 7–9 years. Arch Clin Neuropsychol 23(1):103–112. https ://doi.org/10.1016/j.acn.2007.08.006

5. Aarnoudse-Moens CSH, Weisglas-Kuperus N, van Goudoever JB, Oosterlaan J (2009) Meta-analysis of neurobehavioral outcomes in very preterm and/or very low birth weight children. Pediatrics 124(2):717–728. https ://doi.org/10.1542/peds.2008-2816

6. Bhutta AT, Cleves MA, Casey PH, Cradock MM, Anand KJ (2002) Cognitive and behavioral outcomes of school-aged children who were born preterm: a meta-analysis. JAMA 288(6):728–737

7. Allotey J, Zamora J, Cheong-See F, Kalidindi M, Arroyo-Man-zano D, Asztalos E, van der Post J, Mol BW, Moore D, Birtles D, Khan KS, Thangaratinam S (2017) Cognitive, motor, behavioural and academic performances of children born preterm: a meta-analysis and systematic review involving 64 061 children. BJOG Int J Obstet Gynaecol. https ://doi.org/10.1111/1471-0528.14832

8. Johnson S, Hollis C, Kochhar P, Hennessy E, Wolke D, Marlow N (2010) Psychiatric disorders in extremely preterm children: longi-tudinal finding at age 11 years in the EPICure study. J Am Acad Child Adolesc Psychiatry 49(5):453–463.e451

9. Johnson S, Hollis C, Kochhar P, Hennessy E, Wolke D, Marlow N (2010) Autism spectrum disorders in extremely preterm chil-dren. J Pediatr 156(4):525–531.e522. https ://doi.org/10.1016/j.jpeds .2009.10.041

10. Sturm H, Fernell E, Gillberg C (2004) Autism spectrum disorders in children with normal intellectual levels: associated impairments and subgroups. Dev Med Child Neurol 46(7):444–447

11. Gadow KD, DeVincent CJ, Pomeroy J (2006) ADHD symptom subtypes in children with pervasive developmental disorder. J Autism Dev Disord 36(2):271–283. https ://doi.org/10.1007/s1080 3-005-0060-3

12. Holtmann M, Bolte S, Poustka F (2007) Attention deficit hyper-activity disorder symptoms in pervasive developmental disor-ders: association with autistic behavior domains and coexisting psychopathology. Psychopathology 40(3):172–177. https ://doi.org/10.1159/00010 0007

13. Lee DO, Ousley OY (2006) Attention-deficit hyperactivity disor-der symptoms in a clinic sample of children and adolescents with pervasive developmental disorders. J Child Adolesc Psychophar-macol 16(6):737–746. https ://doi.org/10.1089/cap.2006.16.737

http://creativecommons.org/licenses/by/4.0/

https://doi.org/10.1016/j.jpeds.2010.12.055

https://doi.org/10.1016/j.acn.2007.08.006

https://doi.org/10.1542/peds.2008-2816

https://doi.org/10.1111/1471-0528.14832



https://doi.org/10.1007/s10803-005-0060-3

https://doi.org/10.1007/s10803-005-0060-3

https://doi.org/10.1159/000100007

https://doi.org/10.1159/000100007

https://doi.org/10.1089/cap.2006.16.737


1 3

14. Simonoff E, Pickles A, Charman T, Chandler S, Loucas T, Baird G (2008) Psychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a population-derived sample. J Am Acad Child Adolesc Psychiatry 47(8):921–929. https ://doi.org/10.1097/CHI.0b013 e3181 79964 f

15. Yoshida Y, Uchiyama T (2004) The clinical necessity for assess-ing attention deficit/hyperactivity disorder (AD/HD) symptoms in children with high-functioning pervasive developmental disorder (PDD). Eur Child Adolesc Psychiatry 13(5):307–314. https ://doi.org/10.1007/s0078 7-004-0391-1

16. Rommel AS, James SN, McLoughlin G, Brandeis D, Banaschewski T, Asherson P, Kuntsi J (2017) Association of preterm birth with attention-deficit/hyperactivity disorder-like and wider-ranging neurophysiological impairments of attention and inhibition. J Am Acad Child Adolesc Psychiatry 56(1):40–50. https ://doi.org/10.1016/j.jaac.2016.10.006

17. Barkley RA (1997) Behavioral inhibition, sustained attention, and executive functions: constructing a unifying theory of ADHD. Psychol Bull 121(1):65–94

18. Pennington BF, Ozonoff S (1996) Executive functions and developmental psychopathology. J Child Psychol Psychiatry 37(1):51–87

19. Castellanos FX, Tannock R (2002) Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes. Nat Rev Neurosci 3(8):617–628. https ://doi.org/10.1038/nrn89 6

20. Schachar R, Mota VL, Logan GD, Tannock R, Klim P (2000) Confirmation of an inhibitory control deficit in attention-deficit/hyperactivity disorder. J Abnorm Child Psychol 28(3):227–235. https ://doi.org/10.1023/a:10051 40103 162

21. Willcutt EG, Doyle AE, Nigg JT, Faraone SV, Pennington BFJBp (2005) Validity of the executive function theory of atten-tion-deficit/hyperactivity disorder: a meta-analytic review 57 (11):1336–1346

22. Corbett BA, Constantine LJ, Hendren R, Rocke D, Ozonoff S (2009) Examining executive functioning in children with autism spectrum disorder, attention deficit hyperactivity disorder and typical development. Psychiatry Res 166(2–3):210–222. https ://doi.org/10.1016/j.psych res.2008.02.005

23. Ozonoff S, Cook I, Coon H, Dawson G, Joseph RM, Klin A, McMahon WM, Minshew N, Munson JA, Pennington BF, Rog-ers SJ, Spence MA, Tager-Flusberg H, Volkmar FR, Wrathall D (2004) Performance on Cambridge neuropsychological test automated battery subtests sensitive to frontal lobe function in people with autistic disorder: evidence from the collaborative programs of excellence in autism network. J Autism Dev Disord 34(2):139–150

24. Damasio AR, Maurer RG (1978) A neurological model for child-hood autism. Arch Neurol 35(12):777–786

25. Geurts HM, de Vries M, van den Bergh SFWM (2014) Execu-tive functioning theory and autism. In: Goldstein S, Naglieri JA (eds) Handbook of executive functioning. Springer, New York, pp 121–141. https ://doi.org/10.1007/978-1-4614-8106-5_8

26. Russell JE (1997) Autism as an executive disorder. Oxford Uni-versity Press, Oxford

27. Miyake A, Friedman NP, Emerson MJ, Witzki AH, Howerter A, Wager TD (2000) The unity and diversity of executive func-tions and their contributions to complex "frontal lobe" tasks: a latent variable analysis. Cogn Psychol 41(1):49–100. https ://doi.org/10.1006/cogp.1999.0734

28. Aarnoudse-Moens CSH, Weisglas-Kuperus N, Duivenvoorden HJ, van Goudoever JB, Oosterlaan J (2013) Executive function and IQ predict mathematical and attention problems in very preterm children. PLoS ONE 8(2):e55994. https ://doi.org/10.1371/journ al.pone.00559 94

29. Mulder H, Pitchford NJ, Marlow N (2010) Processing speed and working memory underlie academic attainment in very preterm children. Arch Dis Child Fetal Neonatal Ed 95(4):F267–272. https ://doi.org/10.1136/adc.2009.16796 5

30. de Kieviet JF, van Elburg RM, Lafeber HN, Oosterlaan J (2012) Attention problems of very preterm children compared with age-matched term controls at school-age. J Pediatr 161(5):824–829. https ://doi.org/10.1016/j.jpeds .2012.05.010

31. Craig F, Lamanna AL, Margari F, Matera E, Simone M, Mar-gari L (2015) Overlap between autism spectrum disorders and attention deficit hyperactivity disorder: searching for distinctive/common clinical features. Autism Res 8(3):328–337. https ://doi.org/10.1002/aur.1449

32. Inder TE, Wells SJ, Mogridge NB, Spencer C, Volpe JJ (2003) Defining the nature of the cerebral abnormalities in the premature infant: a qualitative magnetic resonance imaging study. J Pediatr 143(2):171–179. https ://doi.org/10.1067/s0022 -3476(03)00357 -3

33. Miller SP, Ferriero DM, Leonard C, Piecuch R, Glidden DV, Par-tridge JC, Perez M, Mukherjee P, Vigneron DB, Barkovich AJ (2005) Early brain injury in premature newborns detected with magnetic resonance imaging is associated with adverse early neu-rodevelopmental outcome. J Pediatr 147(5):609–616. https ://doi.org/10.1016/j.jpeds .2005.06.033

34. Cheong JL, Thompson DK, Wang HX, Hunt RW, Anderson PJ, Inder TE, Doyle LW (2009) Abnormal white matter signal on MR imaging is related to abnormal tissue microstructure. AJNR Am J Neuroradiol 30(3):623–628. https ://doi.org/10.3174/ajnr.A1399

35. Volpe JJ (2009) Brain injury in premature infants: a complex amal-gam of destructive and developmental disturbances. Lancet Neu-rol 8(1):110–124. https ://doi.org/10.1016/s1474 -4422(08)70294 -1

36. Stuss DT (2011) Functions of the frontal lobes: relation to execu-tive functions. J Int Neuropsychol Soc JINS 17(5):759–765. https ://doi.org/10.1017/s1355 61771 10006 95

37. Anderson V, Levin HS, Jacobs R (2002) Executive functions after frontal lobe injury: a developmental perspective. In: Principles of frontal lobe function. Oxford University Press, New York, pp 504–527. https ://doi.org/10.1093/acpro f:oso/97801 95134 971.003.0030

38. Hazy TE, Frank MJ, O’Reilly RC (2007) Towards an executive without a homunculus: computational models of the prefrontal cortex/basal ganglia system. Philos Trans R Soc Lond B Biol Sci 362(1485):1601–1613. https ://doi.org/10.1098/rstb.2007.2055

39. Miller EK, Cohen JD (2001) An integrative theory of prefron-tal cortex function. Annu Rev Neurosci 24:167–202. https ://doi.org/10.1146/annur ev.neuro .24.1.167

40. Söderqvist S, Nutley S (2016) Cogmed working memory training. Comput Softw

41. Spencer-Smith M, Klingberg T (2016) Correction: Ben-efits of a working memory training program for inattention in daily life: a systematic review and meta-analysis. PLoS ONE 11(11):e0167373. https ://doi.org/10.1371/journ al.pone.01673 73

42. Aksayli ND, Sala G, Gobet F (2019) The cognitive and academic benefits of Cogmed: a meta-analysis. Educ Res Rev

43. Anderson PJ, Lee KJ, Roberts G, Spencer-Smith MM, Thomp-son DK, Seal ML, Nosarti C, Grehan A, Josev EK, Gathercole S, Doyle LW, Pascoe L (2018) Long-term academic function-ing following Cogmed working memory training for children born extremely preterm: a randomized controlled trial. J Pediatr 202:92–97.e94. https ://doi.org/10.1016/j.jpeds .2018.07.003

44. van Houdt CA, Oosterlaan J, van Wassenaer-Leemhuis AG, van Kaam AH, Aarnoudse-Moens CSH (2019) Executive func-tion deficits in children born preterm or at low birthweight: a meta-analysis. Dev Med Child Neurol. https ://doi.org/10.1111/dmcn.14213

https://doi.org/10.1097/CHI.0b013e318179964f

https://doi.org/10.1007/s00787-004-0391-1

https://doi.org/10.1007/s00787-004-0391-1

https://doi.org/10.1016/j.jaac.2016.10.006

https://doi.org/10.1038/nrn896

https://doi.org/10.1038/nrn896

https://doi.org/10.1023/a:1005140103162

https://doi.org/10.1016/j.psychres.2008.02.005

https://doi.org/10.1016/j.psychres.2008.02.005

https://doi.org/10.1007/978-1-4614-8106-5_8

https://doi.org/10.1006/cogp.1999.0734

https://doi.org/10.1006/cogp.1999.0734

https://doi.org/10.1371/journal.pone.0055994


https://doi.org/10.1136/adc.2009.167965

https://doi.org/10.1136/adc.2009.167965


https://doi.org/10.1002/aur.1449

https://doi.org/10.1002/aur.1449

https://doi.org/10.1067/s0022-3476(03)00357-3



https://doi.org/10.3174/ajnr.A1399

https://doi.org/10.1016/s1474-4422(08)70294-1

https://doi.org/10.1016/s1474-4422(08)70294-1

https://doi.org/10.1017/s1355617711000695

https://doi.org/10.1017/s1355617711000695

https://doi.org/10.1093/acprof:oso/9780195134971.003.0030

https://doi.org/10.1093/acprof:oso/9780195134971.003.0030

https://doi.org/10.1098/rstb.2007.2055

https://doi.org/10.1146/annurev.neuro.24.1.167

https://doi.org/10.1146/annurev.neuro.24.1.167



https://doi.org/10.1111/dmcn.14213

https://doi.org/10.1111/dmcn.14213


1 3

45. Mulder H, Pitchford NJ, Hagger MS, Marlow N (2009) Develop-ment of executive function and attention in preterm children: a systematic review. Dev Neuropsychol 34(4):393–421. https ://doi.org/10.1080/87565 64090 29645 24

46. Prins PJ, Brink ET, Dovis S, Ponsioen A, Geurts HM, De Vries M, Van Der Oord S (2013) “Braingame Brian”: toward an executive function training program with game elements for children with ADHD and cognitive control problems. Games Health Res Dev Clin Appl 2(1):44–49

47. van der Oord S, Ponsioen AJ, Geurts HM, Ten Brink EL, Prins PJ (2014) A pilot study of the efficacy of a computerized executive functioning remediation training with game elements for children with ADHD in an outpatient setting: outcome on parent- and teacher-rated executive functioning and ADHD behavior. J Atten Disord 18(8):699–712. https ://doi.org/10.1177/10870 54712 45316 7

48. Dovis S, Van der Oord S, Wiers RW, Prins PJ (2015) Improving executive functioning in children with ADHD: Training multi-ple executive functions within the context of a computer game. A randomized double-blind placebo controlled trial. PloS One 10 (4):e0121651

49. de Vries M, Prins PJ, Schmand BA, Geurts HM (2015) Working memory and cognitive flexibility-training for children with an autism spectrum disorder: a randomized controlled trial. J Child Psychol Psychiatry 56(5):566–576

50. Aarnoudse-Moens CSH, Twilhaar ES, Oosterlaan J, van Veen HG, Prins PJM, van Kaam A, van Wassenaer-Leemhuis AG (2018) Executive function computerized training in very pre-term-born children: a pilot study. Games Health J. https ://doi.org/10.1089/g4h.2017.0038

51. Jaekel J, Eryigit-Madzwamuse S, Wolke D (2016) Preterm tod-dlers’ inhibitory control abilities predict attention regulation and academic achievement at age 8 years. J Pediatr 169:87–92.e81. https ://doi.org/10.1016/j.jpeds .2015.10.029

52. Jaekel J, Wolke D (2014) Preterm birth and dyscalculia. J Pediatr 164(6):1327–1332. https ://doi.org/10.1016/j.jpeds .2014.01.069

53. Jackson DC, Lin JJ, Chambers KL, Kessler-Jones A, Jones JE, Hsu DA, Stafstrom CE, Seidenberg M, Hermann BP (2014) Birth weight and cognition in children with epilepsy. Epilepsia 55(6):901–908. https ://doi.org/10.1111/epi.12622

54. Jaekel J, Wolke D, Bartmann P (2013) Poor attention rather than hyperactivity/impulsivity predicts academic achieve-ment in very preterm and full-term adolescents. Psychol Med 43(1):183–196. https ://doi.org/10.1017/S0033 29171 20010 31

55. Verhulst FC, Van der Ende J (2013) Handleiding ASEBA-Vra-genlijsten voor leeftijden 6 t/m 18 jaar: CBCL/6-18 YSR en TRF. ASEBA Nederland, Rotterdam

56. Hudziak JJ, Copeland W, Stanger C, Wadsworth M (2004) Screening for DSM-IV externalizing disorders with the child behavior checklist: a receiver-operating characteristic analysis. J Child Psychol Psychiatry 45(7):1299–1307

57. Swanson JM, Schuck S, Porter MM, Carlson C, Hartman CA, Sergeant JA, Clevenger W, Wasdell M, McCleary R, Lakes K, Wigal T (2012) Categorical and dimensional definitions and evaluations of symptoms of ADHD: history of the SNAP and the SWAN rating scales. Int J Educ Psychol Assess 10(1):51–70

58. Huizinga M, Smidts DP (2012) BRIEF Vragenlijst executive functies voor 5- tot 18-jarigen: handleiding. Hogrefe Uitgevers, Amsterdam

59. Sattler JM (1992) Assessment of children: WISC-III and WPPSI-R supplement. Assessment of children: WISC-III and WPPSI-R supplement. Jerome M. Sattler, San Diego

60. Nutley SB, Söderqvist S, Bryde S, Humphreys K, Klingberg T (2009) Measuring working memory capacity with greater

precision in the lower capacity ranges. Dev Neuropsychol 35(1):81–95

61. Aarnoudse-Moens CSH, Duivenvoorden HJ, Weisglas-Kupe-rus N, Van Goudoever JB, Oosterlaan J (2012) The profile of executive function in very preterm children at 4 to 12 years. Dev Med Child Neurol 54(3):247–253. https ://doi.org/10.1111/j.1469-8749.2011.04150 .x

62. Königs M, Weeda WD, van Heurn L, Vermeulen RJ, Goslings JC, Luitse JS, Beelen A, van der Wees M, Kemps RJ, Catsman-Berrevoets CE (2017) Pediatric traumatic brain injury affects multisensory integration. Neuropsychology 31(2):137

63. de Vos T (2010) TempoTest Automatiseren: Handleiding en verantwording. Boom Testuitgevers, Amsterdam

64. Brus BT, Voeten MJM (1973) Eén-Mnuut-Test vorm A en B Verantwoording en Handleiding. Berkenhout Testmateriaal, Nijmegen

65. Van Houdt CA, Aarnoudse-Moens CS, van Wassenaer-Leem-huis AG, Laarman A, Koopman-Esseboom C, van Kaam AH, Oosterlaan J (2019) Effects of executive function training on attentional, behavioral and emotional functioning and self-perceived competence in very preterm children: a randomized controlled trial. Front Psychol 10:2100

66. IBM C (2016) IBM SPSS statistics for windows, version 24.0. IBM Corp., Armonk

67. Ghosh D, Vogt A Outliers: an evaluation of methodologies 68. van Veen S, Aarnoudse-Moens CSH, Oosterlaan J, van Son-

deren L, de Haan TR, van Kaam AH, van Wassenaer-Leemhuis AG (2018) Very preterm born children at early school age: healthcare therapies and educational provisions. Early Hum Dev 117:39–43. https ://doi.org/10.1016/j.earlh umdev .2017.12.010

69. Central Bureau of Statistics (2020) CBS Statline. https ://opend ata.cbs.nl/statl ine/#/CBS/nl/datas et/82275 NED/table ?froms tatwe b. Accessed 19 Mar 2020

70. Klingberg T, Fernell E, Olesen PJ, Johnson M, Gustafsson P, Dahlstrom K, Gillberg CG, Forssberg H, Westerberg H (2005) Computerized training of working memory in children with ADHD—a randomized, controlled trial. J Am Acad Child Ado-lesc Psychiatry 44(2):177–186. https ://doi.org/10.1097/00004 583-20050 2000-00010

71. Dunning DL, Holmes J, Gathercole SE (2013) Does working memory training lead to generalized improvements in children with low working memory? A randomized controlled trial. Dev Sci 16(6):915–925. https ://doi.org/10.1111/desc.12068

72. Hovik KT, Saunes BK, Aarlien AK, Egeland J (2013) RCT of working memory training in ADHD: long-term near-transfer effects. PLoS ONE 8(12):e80561. https ://doi.org/10.1371/journ al.pone.00805 61

73. Melby-Lervåg M, Hulme C (2013) Is working memory training effective? A meta-analytic review. Dev Psychol 49(2):270

74. Shipstead Z, Hicks KL, Engle RW (2012) Cogmed working memory training: Does the evidence support the claims? J Appl Res Memory Cognit 1(3):185–193

75. Murray AL, Thompson DK, Pascoe L, Leemans A, Inder TE, Doyle LW, Anderson JF, Anderson PJ (2016) White mat-ter abnormalities and impaired attention abilities in children born very preterm. NeuroImage 124(Pt A):75–84. https ://doi.org/10.1016/j.neuro image .2015.08.044

76. Taylor HG, Clark CA (2016) Executive function in children born preterm: risk factors and implications for outcome. Semin Perinatol 40(8):520–529. https ://doi.org/10.1053/j.sempe ri.2016.09.004

77. de Kieviet JF, Heslenfeld DJ, Pouwels PJ, Lafeber HN, Ver-meulen RJ, van Elburg RM, Oosterlaan J (2014) A crucial role for white matter alterations in interference control problems of very preterm children. Pediatr Res 75(6):731–737. https ://doi.org/10.1038/pr.2014.31

https://doi.org/10.1080/87565640902964524

https://doi.org/10.1080/87565640902964524

https://doi.org/10.1177/1087054712453167

https://doi.org/10.1177/1087054712453167

https://doi.org/10.1089/g4h.2017.0038

https://doi.org/10.1089/g4h.2017.0038




https://doi.org/10.1111/epi.12622

https://doi.org/10.1017/S0033291712001031

https://doi.org/10.1111/j.1469-8749.2011.04150.x

https://doi.org/10.1111/j.1469-8749.2011.04150.x

https://doi.org/10.1016/j.earlhumdev.2017.12.010

https://opendata.cbs.nl/statline/#/CBS/nl/dataset/82275NED/table?fromstatweb



https://doi.org/10.1097/00004583-200502000-00010

https://doi.org/10.1097/00004583-200502000-00010

https://doi.org/10.1111/desc.12068



https://doi.org/10.1016/j.neuroimage.2015.08.044

https://doi.org/10.1016/j.neuroimage.2015.08.044

https://doi.org/10.1053/j.semperi.2016.09.004

https://doi.org/10.1053/j.semperi.2016.09.004

https://doi.org/10.1038/pr.2014.31

https://doi.org/10.1038/pr.2014.31


1 3

78. Krain AL, Castellanos FXJCpr (2006) Brain development and ADHD 26 (4):433–444

79. Lou HC (1996) Etiology and pathogenesis of attention-deficit hyperactivity disorder (ADHD): significance of prematurity and perinatal hypoxic-haemodynamic encephalopathy. Acta Paediatr (Oslo, Norway : 1992) 85 (11):1266–1271

80. Everts R, Murner-Lavanchy I, Schroth G, Steinlin M (2017) Neural change following different memory training approaches in very preterm born children—a pilot study. Dev Neurorehabil 20(1):14–24. https ://doi.org/10.3109/17518 423.2015.10270 10

81. Schaeffer DJ, Krafft CE, Schwarz NF, Chi L, Rodrigue AL, Pierce JE, Allison JD, Yanasak NE, Liu T, Davis CL, McDowell JE (2014) An 8-month exercise intervention alters frontotempo-ral white matter integrity in overweight children 51(8):728–733. https:doi.org/10.1111/psyp.12227

82. Kelly CE, Thompson DK, Chen J, Josev EK, Pascoe L, Spen-cer-Smith MM, Adamson C, Nosarti C, Gathercole S, Roberts G, Lee KJ, Doyle LW, Seal ML, Anderson PJ (2020) Working memory training and brain structure and function in extremely preterm or extremely low birth weight children. Hum Brain Mapp 41(3):684–696. https ://doi.org/10.1002/hbm.24832

83. Scionti N, Cavallero M, Zogmaister C, Marzocchi GM (2020) Is cognitive training effective for improving executive functions in preschoolers? A systematic review and meta-analysis. Front Psychol 10:2812–2812. https ://doi.org/10.3389/fpsyg .2019.02812

84. Green CS, Bavelier DJP, aging (2008) Exercising your brain: a review of human brain plasticity and training-induced learning 23 (4):692

https://doi.org/10.3109/17518423.2015.1027010

https://doi.org/10.1002/hbm.24832

https://doi.org/10.3389/fpsyg.2019.02812

Entrenamiento de la Función Ejecutiva en Niños Muy ...³n_ejecutiva.pdfEl objetivo del presente...

Documents

Transcript of Entrenamiento de la Función Ejecutiva en Niños Muy ...³n_ejecutiva.pdfEl objetivo del presente...