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Dr. Anna Penn uses a microscope

New model mimics persistent interneuron loss seen in prematurity

Dr. Anna Penn uses a microscope

Children’s research-clinicians created a novel preclinical model that mimics the persistent interneuron loss seen in preterm human infants, identifying interneuron subtypes that could become future therapeutic targets to prevent or lessen neurodevelopmental risks.

Research-clinicians at Children’s National Health System have created a novel preclinical model that mimics the persistent interneuron loss seen in preterm human infants, identifying interneuron subtypes that could become future therapeutic targets to prevent or lessen neurodevelopmental risks, the team reports Jan. 31, 2019, in eNeuro. The open access journal for Society for Neuroscience recognized the team’s paper as its “featured” article.

In the prefrontal cortex (PFC) of infants born preterm, there are decreased somatostatin and calbindin interneurons seen in upper cortical layers in infants who survived for a few months after preterm birth. This neuronal damage was mimicked in an experimental model of preterm brain injury in the PFC, but only when the newborn experimental models had first experienced a combination of prenatal maternal immune activation and postnatal chronic sublethal hypoxia. Neither neuronal insult on its own produced the pattern of interneuron loss in the upper cortical layers observed in humans, the research team finds.

“These combined insults lead to long-term neurobehavioral deficits that mimic what we see in human infants who are born extremely preterm,” says Anna Penn, M.D., Ph.D., a neonatologist in the Division of Neonatology and the Fetal Medicine Institute and a developmental neuroscientist at Children’s National Health System, and senior study author. “Future success in preventing neuronal damage in newborns relies on having accurate experimental models of preterm brain injury and well-defined outcome measures that can be examined in young infants and experimental models of the same developmental stage.”

According to the Centers for Disease Control and Prevention 1 in 10 infants is born preterm, before the 37th week of pregnancy. Many of these preterm births result from infection or inflammation in utero. After delivery, many infants experience other health challenges, like respiratory failure. These multi-hits can exacerbate brain damage.

Prematurity is associated with significantly increased risk of neurobehavioral pathologies, including autism spectrum disorder and schizophrenia. In both psychiatric disorders, the prefrontal cortex inhibitory circuit is disrupted due to alterations of gamma-aminobutyric acid (GABA) interneurons in a brain region involved in working memory and social cognition.

Cortical interneurons are created and migrate late in pregnancy and early infancy. That timing leaves them particularly vulnerable to insults, such as preterm birth.

In order to investigate the effects of perinatal insults on GABAergic interneuron development, the Children’s research team, led by Helene Lacaille, Ph.D., in Dr. Penn’s laboratory, subjected the new preterm encephalopathy experimental model to a battery of neurobehavioral tests, including working memory, cognitive flexibility and social cognition.

“This translational study, which examined the prefrontal cortex in age-matched term and preterm babies supports our hypothesis that specific cellular alterations seen in preterm encephalopathy can be linked with a heightened risk of children experiencing neuropsychiatric disorders later in life,” Dr. Penn adds. “Specific interneuron subtypes may provide specific therapeutic targets for medicines that hold the promise of preventing or lessening these neurodevelopmental risks.”

In addition to Dr. Penn and Lead Author Lacaille, Children’s co-authors include Claire-Marie Vacher; Dana Bakalar, Jiaqi J. O’Reilly and Jacquelyn Salzbank, all of Children’s Center for Neuroscience Research.

Financial support for research described in this post was provided by the National Institutes of Health under award R01HD092593, District of Columbia Intellectual Developmental Disabilities Research Center under award U54HD090257, Cerebral Palsy Alliance Research Foundation, Children’s National Board of Visitors, Children’s Research Institute and Fetal Medicine Institute.

In Brief- Fetal Medicine

Cognitive training exercises at home help kids with sickle cell boost visuospatial working memory

A team led by Children’s National Health System clinicians and research scientists attempted to identify novel approaches to boost working memory in children who suffer from sickle cell disease.

A team led by Children’s National Health System clinicians and research scientists attempted to identify novel approaches to boost working memory in children who suffer from sickle cell disease.

Youths with sickle cell disease who used hand-held computers to play game-like exercises that get harder as a user’s skill level rises improved their visuospatial working memory (WM). Children with sickle cell disease, however, completed fewer training sessions during an initial study compared with children with other disease-related WM deficits.

A team led by Children’s National Health System clinicians and research scientists attempted to identify novel approaches to boost WM in children who suffer from sickle cell disease. Kids who have this red blood cell disorder inherit abnormal hemoglobin genes from each parent. Rather than slipping through large and small vessels to ferry oxygen throughout the body, their stiff, sickle-shaped red blood cells stick to vessel walls, impeding blood supply and triggering sudden pain. Children with sickle cell disease have more difficulty completing tasks that place demands on one’s WM, the brain function responsible for temporarily remembering information and manipulating that information to facilitate learning and reasoning. As a result, they’re more likely to repeat a grade, require special academic services, and to have difficulty maintaining employment as adults.

Because computerized cognitive training programs have been used with success to boost WM for children with other health conditions, such as childhood cancer, the research team sought to examine the feasibility of using the technique for kids with sickle cell disease. “This small study highlights the challenges and opportunities of implementing a home-based cognitive training intervention with youths who have sickle cell disease,” says Steven J. Hardy, PhD, a pediatric psychologist in the Divisions of Hematology, Oncology, and Blood and Marrow Transplantation at Children’s National. “While a larger, randomized controlled clinical trial is needed to better characterize efficacy, our initial work indicates that Cogmed is acceptable and moderately feasible in this population.”

Children’s National is home to the Sickle Cell Disease (SCD) Program, one of the nation’s largest, most comprehensive pediatric programs that cares for 1,350 patients younger than 21 annually. Over 15 months, the team recruited youths aged 7 to 16 participating in the program who had an intelligence quotient of at least 70 and an absolute or relative memory deficit. Those who lacked access to a tablet computer were loaned an iPad Mini 2 loaded with Cogmed RM, an interactive audiovisual cognitive training program that consists of exercises that get progressively more challenging. A clinical psychologist provided coaching and moral support through weekly telephone calls to review progress and challenges, and to offer tips on how to optimize the youths’ progress.

Six of 12 eligible participants – all girls – completed by finishing at least 20 sessions of the program. The mean number of sessions completed was 15.83, and the kids spent a median of 725 minutes working actively on Cogmed exercises. “Participants who completed Cogmed indicated that they perceived greater levels of social support from teachers,” Hardy and colleagues write in the study, published by Pediatric Blood & Cancer. “[T]here was not a statistical difference in perceived parent support.”

Among those children who completed Cogmed, standard scores increased an average of 5.05 on a measure of visuospatial short-term memory, 19.72 on a measure of verbal WM, 27.53 on a measure of visuospatial short-term memory, and 23.82 on a measure of visuospatial WM. The researchers also observed a normalizing of memory functioning for those who finished Cogmed, as a significant portion of participants scored below the average range before using Cogmed and most scored in the average range or higher on memory tests after finishing the program.

“In this initial feasibility trial, adherence to Cogmed was lower than expected (50 percent completion) compared to adherence rates of other samples of children with medical histories, including patients with symptomatic epilepsy and youth treated for cancer,” Hardy and co-authors write. “Thus, additional modifications may be needed to achieve consistent delivery of the intervention to youth with SCD.”

Related Resources: Research at a Glance

Feasibility of home-based computerized WM training for sickle cell disease

What’s Known
Cognitive deficits are a common complication affecting about one-third of kids who have the higher risk sickle cell disease genotypes, HbSS and HbSβ0 thalassemia. While such deficits have been well-documented, no treatment has been proven to recover cognitive function for kids with sickle cell disease. Sickle cell disease is a group of red blood cell disorders in which abnormal genes that children inherit from parents cause their bodies to make sickle-shaped hemoglobin S. Kids with sickle cell disease are at heightened risk for neurocognitive deficits, which can have practical implications for their ability to learn and to succeed academically.

What’s New
Because home-based computerized cognitive training programs have helped to improve working memory (WM) for children with epilepsy and for childhood cancer survivors, a team led by Children’s National Health System researchers and clinicians sought to gauge the feasibility of using such an approach for a small number of children with sickle cell disease. The pilot study found that girls were more likely to complete the cognitive training exercises than boys. Additionally, children whose teachers showed a high level of support spent more time working on the exercises, completed more sessions, and were more likely to finish the program. The mean number of completed sessions was 15.83. Participants who reported experiencing fewer functional limitations as a result of sickle cell disease-related pain completed more sessions. Overall, children who completed Cogmed exercises showed improvements in verbal WM, and visuospatial short-term memory and WM.

Questions for Future Research
Q: Because sickle cell disease is often accompanied by sudden attacks of severe pain, would concurrent delivery of pain-management interventions impact children’s ability to complete cognitive training exercises?
Q: Would adding functional magnetic resonance imaging help to clarify the association between adaptive cognitive skills training and changes to physiological processes, such as alterations in prefrontal and parietal cortical activity, and functional connectivity?

Source: S.J. Hardy, K.K. Hardy, J.C. Schatz, A.L. Thompson, and E.R. Meier. Feasibility of Home-Based Computerized Working Memory Training With Children and Adolescents With Sickle Cell Disease.” Published online by Pediatric Blood & Cancer May 26, 2016.