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Preventive interventions for ADHD: a neurodevelopmental perspective.

ABSTRACT: It is proposed that the time is ripe for the development of secondary preventive interventions for attention-deficit/hyperactivity disorder (ADHD). By targeting preschool children, a developmental stage during which ADHD symptoms first become evident in most children with the disorder, many of the adverse long-term consequences that typify the trajectory of ADHD may be avoided. A dynamic/interactive model of the biological and environmental factors that contribute to the emergence and persistence of ADHD throughout the lifespan is proposed. Based on this model, it is argued that environmental influences and physical exercise can be used to enhance neural growth and development, which in turn should have an enduring and long-term impact on the trajectory of ADHD. Central to this notion are 2 hypotheses: 1) environmental influences can facilitate structural and functional brain development, and 2) changes in brain structure and function are directly related to ADHD severity over the course of development and the degree to which the disorder persists or remits with time. We present experimental and correlational data supporting the first hypothesis and longitudinal data in individuals with ADHD supporting the second. The case is made for initiating such an intervention during the preschool years, when the brain is likely to be more "plastic" and perhaps susceptible to lasting modifications, and before complicating factors, such as comorbid psychiatric disorders, academic failure, and poor social and family relationships emerge, making successful treatment more difficult. Finally, we review recent studies in young children with ADHD that might fall under the umbrella of secondary prevention.

SUBMITTER: Halperin JM

PROVIDER: S-EPMC3441940 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:This study investigated the association between attention-deficit/hyperactivity disorder (ADHD) symptomatology in preschool-aged children who were born very preterm (<33 weeks) and cognitive outcomes, clinical risk and socio-demographic characteristics. 119 very preterm children who participated in the Evaluation of Preterm Imaging Study at term-equivalent age were assessed at a mean age of 4.5 years. Parents completed the ADHD Rating Scale IV, a norm-referenced checklist that evaluates ADHD symptomatology according to diagnostic criteria, and the Behavior Rating Inventory of Executive Function-Preschool version. Children completed the Wechsler Preschool and Primary Scales of Intelligence and the Forward Digit Span task. Longitudinal data including perinatal clinical, qualitative MRI classification, socio-demographic variables and neurodevelopmental disabilities were investigated in relation to ADHD symptomatology. All results were corrected for multiple comparisons using false discovery rate. Results showed that although the proportion of very preterm children with clinically significant ADHD did not differ from normative data after excluding those with neurodevelopmental disabilities, 32.7% met criteria for subthreshold ADHD inattentive type and 33.6% for combined type, which was higher than the expected 20% in normative samples. Higher ADHD symptom scores (all) were associated with greater executive dysfunction (inhibitory self-control, flexibility, and emergent metacognition, corrected p<0.001 for all tests). Higher inattentive ADHD symptom scores were associated with lower IQ (? = -0.245, p = 0.011) and higher perinatal clinical risk (more days on mechanical ventilation (? = 0.196, p = 0.032) and more days on parenteral nutrition (? = 0.222, p = 0.015). Higher hyperactive ADHD symptom scores instead were associated with lower socio-economic status (? = 0.259, p = 0.004). These results highlight the importance of monitoring and supporting the development of very preterm children throughout the school years, as subthreshold ADHD symptoms represent risk factors for psychosocial problems and for receiving a future clinical diagnosis of ADHD.

Project description:We describe an autosomal dominant disorder associated with loss-of-function variants in the Cell cycle associated protein 1 (CAPRIN1; MIM*601178). CAPRIN1 encodes a ubiquitous protein that regulates the transport and translation of neuronal mRNAs critical for synaptic plasticity, as well as mRNAs encoding proteins important for cell proliferation and migration in multiple cell types. We identified 12 cases with loss-of-function CAPRIN1 variants, and a neurodevelopmental phenotype characterized by language impairment/speech delay (100%), intellectual disability (83%), attention deficit hyperactivity disorder (82%) and autism spectrum disorder (67%). Affected individuals also had respiratory problems (50%), limb/skeletal anomalies (50%), developmental delay (42%) feeding difficulties (33%), seizures (33%) and ophthalmologic problems (33%). In patient-derived lymphoblasts and fibroblasts, we showed a monoallelic expression of the wild-type allele, and a reduction of the transcript and protein compatible with a half dose. To further study pathogenic mechanisms, we generated sCAPRIN1+/- human induced pluripotent stem cells via CRISPR-Cas9 mutagenesis and differentiated them into neuronal progenitor cells and cortical neurons. CAPRIN1 loss caused reduced neuronal processes, overall disruption of the neuronal organization and an increased neuronal degeneration. We also observed an alteration of mRNA translation in CAPRIN1+/- neurons, compatible with its suggested function as translational inhibitor. CAPRIN1+/- neurons also showed an impaired calcium signalling and increased oxidative stress, two mechanisms that may directly affect neuronal networks development, maintenance and function. According to what was previously observed in the mouse model, measurements of activity in CAPRIN1+/- neurons via micro-electrode arrays indicated lower spike rates and bursts, with an overall reduced activity. In conclusion, we demonstrate that CAPRIN1 haploinsufficiency causes a novel autosomal dominant neurodevelopmental disorder and identify morphological and functional alterations associated with this disorder in human neuronal models.

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Preventive interventions for ADHD: a neurodevelopmental perspective.

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