Executive task-based brain function in children with type 1 diabetes: An observational study.

Background Optimal glycemic control is particularly difficult to achieve in children and adolescents with type 1 diabetes (T1D), yet the influence of dysglycemia on the developing brain remains poorly understood. Methods and findings Using a large multi-site study framework, we investigated activation patterns using functional magnetic resonance imaging (fMRI) in 93 children with T1D (mean age 11.5 +/- 1.8 years; 45.2% female) and 57 non-diabetic (control) children (mean age 11.8 +/- 1.5 years; 50.9% female) as they performed an executive function paradigm, the go/no-go task. Children underwent scanning and cognitive and clinical assessment at 1 of 5 different sites. Group differences in activation occurring during the contrast of "no-go > go" were examined while controlling for age, sex, and scan site. Results indicated that, despite equivalent task performance between the 2 groups, children with T1D exhibited increased activation in executive control regions (e.g., dorsolateral prefrontal and supramarginal gyri; p = 0.010) and reduced suppression of activation in the posterior node of the default mode network (DMN; p = 0.006). Secondary analyses indicated associations between activation patterns and behavior and clinical disease course. Greater hyperactivation in executive control regions in the T1D group was correlated with improved task performance (as indexed by shorter response times to correct "go" trials; r = -0.36, 95% CI -0.53 to -0.16, p < 0.001) and with better parent-reported measures of executive functioning (r values < -0.29, 95% CIs -0.47 to -0.08, p-values < 0.007). Increased deficits in deactivation of the posterior DMN in the T1D group were correlated with an earlier age of T1D onset (r = -0.22, 95% CI -0.41 to -0.02, p = 0.033). Finally, exploratory analyses indicated that among children with T1D (but not control children), more severe impairments in deactivation of the DMN were associated with greater increases in hyperactivation of executive control regions (T1D: r = 0.284, 95% CI 0.08 to 0.46, p = 0.006; control: r = 0.108, 95% CI -0.16 to 0.36, p = 0.423). A limitation to this study involves glycemic effects on brain function; because blood glucose was not clamped prior to or during scanning, future studies are needed to assess the influence of acute versus chronic dysglycemia on our reported findings. In addition, the mechanisms underlying T1D-associated alterations in activation are unknown. Conclusions These data indicate that increased recruitment of executive control areas in pediatric T1D may act to offset diabetes-related impairments in the DMN, ultimately facilitating cognitive and behavioral performance levels that are equivalent to that of non-diabetic controls. Future studies that examine whether these patterns change as a function of improved glycemic control are warranted. Author summaryWhy was this study done? Maintaining optimal levels of blood glucose in children with type 1 diabetes (T1D) is difficult. Because childhood and adolescence are periods of major neurodevelopmental change, there has been growing interest in whether T1D is associated with variations in the brain. No studies to date, to our knowledge, have examined brain function in children with T1D as they engaged in a cognitively demanding task. What did the researchers do and find? Brain function was examined in 150 children with or without T1D as they performed an executive function paradigm, the go/no-go task. This task requires that participants respond as quickly and accurately as possible, using a button press, to a high number of "go" stimuli (e.g., when they see any letter except "X"), and suppress a prepotent response on a smaller subset of "no-go" stimuli (e.g., when they see the letter "X"). Despite equivalent performance on the go/no-go task, children with T1D exhibited increased activation in task-positive networks (e.g., in executive control regions), as well as reduced suppression of activation in the default mode network (DMN). Increased hyperactivation in task-positive networks was associated with better executive functioning, improved go/no-go task performance, and reduced suppression of the DMN in children with T1D. Reduced suppression of the DMN, in turn, was associated with an earlier age of onset of T1D. What do these findings mean? These data indicate that increased recruitment of executive control areas in pediatric T1D may act to offset diabetes-related impairments in the DMN and cognitive function. Future studies that examine whether these patterns change as a function of improved glycemic control are warranted.