Compensatory Hyperconnectivity in Developing Brains of Young Children With Type 1 Diabetes

Saggar, Manish; Tsalikian, Eva; Mauras, Nelly; Mazaika, Paul K.; White, Neil H.; Weinzimer, Stuart A.; Buckingham, Bruce A.; Hershey, Tamara; Reiss, Allan L.

doi:10.2337/db16-0414

Cited by 31 publications

(35 citation statements)

References 29 publications

(53 reference statements)

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“…However, at the same time, our results also support the idea that under some circumstances the brains of T1D patients may develop some adaptations to prevent cognitive dysfunction, presenting different patterns of brain activity that could permit patients with diabetes to achieve the same levels of cognitive performance as healthy subjects. Other studies have supported this idea [18, 30, 65, 66]. However, more studies are needed to confirm this hypothesis and determine the variables responsible for these adaptations.…”

Section: Discussionmentioning

confidence: 87%

Effect of verbal task complexity in a working memory paradigm in patients with type 1 diabetes. A fMRI study

et al. 2017

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Type 1 diabetes (T1D) is commonly diagnosed in childhood and adolescence, and the developing brain has to cope with its deleterious effects. Although brain adaptation to the disease may not result in evident cognitive dysfunction, the effects of T1D on neurodevelopment could alter the pattern of BOLD fMRI activation. The aim of this study was to explore the neural BOLD activation pattern in patients with T1D versus that of healthy matched controls while performing two visuospatial working memory tasks, which included a pair of assignments administered through a block design. In the first task (condition A), the subjects were shown a trial sequence of 3 or 4 white squares positioned pseudorandomly around a fixation point on a black background. After a fixed delay, a second corresponding sequence of 3 or 4 red squares was shown that either resembled (direct, 50%) or differed from (50%) the previous stimulation order. The subjects were required to press one button if the two spatial sequences were identical or a second button if they were not. In condition B, the participants had to determine whether the second sequence of red squares appeared in inverse order (inverse, 50%) or not (50%) and respond by pressing a button. If the latter sequence followed an order distinct from the inverse sequence, the subjects were instructed to press a different button. Sixteen patients with normal IQ and without diabetes complications and 16 healthy control subjects participated in the study. In the behavioral analysis, there were no significant differences between the groups in the pure visuo-spatial task, but the patients with diabetes exhibited poorer performance in the task with verbal stimuli (p < .001). However, fMRI analyses revealed that the patients with T1D showed significantly increased activation in the prefrontal inferior cortex, subcortical regions and the cerebellum (in general p < .001). These different activation patterns could be due to adaptive compensation mechanisms that are devoted to improving efficiency while solving more complex cognitive tasks.

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Section: Discussionmentioning

confidence: 87%

Effect of verbal task complexity in a working memory paradigm in patients with type 1 diabetes. A fMRI study

et al. 2017

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“…The scatter plots in Fig. 3 of Sagger et al (10) seem to support the notion that there may be wide individual differences. Roughly half the T1D group had cognitive scores below the mean of the control subjects, but a majority of those patients had positive connectivity values, suggesting that their higher connectivity may not be sufficient to ensure fully normal performance.…”

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confidence: 65%

“…Increased functional connectivity, in reaction to T1D itself and/or structural damage caused by T1D, may serve as a moderator variable to reduce the otherwise adverse impact of diabetes onset on cognition. The solid lines indicate the pathways that have been studied previously or were studied by Sagger et al (10). The dashed lines are hypothesized pathways that warrant further study.…”

mentioning

confidence: 91%

“…Using both methods, Sagger et al (10) consistently showed increased functional connectivity in several brain networks in the T1D group, as compared with patterns of functional connectivity in healthy comparison subjects. This suggests that in response to having diabetes, the functional brain networks of these young patients undergo a "remodeling" or functional reorganization, perhaps as a compensatory reaction to diabetes-associated alterations occurring within the central nervous system (Fig.…”

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confidence: 97%

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Preserving Cognition in Children With Diabetes: Do Alterations in Functional Network Connectivity Play a Role?

Duinkerken

Ryan

2017

Diabetes

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Whether, and to what extent, type 1 diabetes (T1D) affects the brains of children and adolescents has been debated for more than 30 years. Early studies found that children and adolescents with T1D were more likely to perform somewhat poorer than their healthy peers on tasks of mental efficiency that required rapid responses and sustained attention, as well as on measures of executive functioning that required problem-solving and planning (1). It was assumed, but not proven, that these betweengroup differences were a consequence of differences in brain integrity. Only when researchers began using MRI techniques was there unequivocal evidence that diabetes in childhood is accompanied by gross structural changes to the brain, including relative reductions in gray matter density in multiple cortical regions and microstructural abnormalities in major white matter tracts (2,3). Furthermore, these effects were most pronounced in those who developed diabetes early in life and were evident within 2-4 years of disease onset (4-7).One might expect that a significant loss of neurons, accompanied by axonal damage relatively early in life, would lead to increasingly serious cognitive impairment over time in people with diabetes. Interestingly, that does not appear to be the case. Cross-sectional studies of children and young adults with T1D do not show a significant worsening of performance with increasing age or disease duration (8), nor were marked declines in cognition seen in the adolescents and adults participating in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study, despite more than 25 years of follow-up (9). One possible compensatory mechanism that could protect brain function in children with T1D has now been identified by Sagger et al. (10), who in this issue describe the first evidence of increased functional connectivity measured using resting-state functional MRI (rsfMRI) within a series of neuronal networks.rsfMRI is a tool that is commonly used to assess the functional connections of the brain. It provides a measure of spontaneous brain activity forming spatially distinct networks, such as the default mode (monitoring internal and self-referential processes), attention, visual, and motor networks (11). Although this brain activity is unrelated to any task, it has been shown to be related to specific cognitive functions. Altered connectivity in adulthood has been associated with a number of diseases, including diabetes (12). Adult T1D patients with complications show decreased visual and motor network connectivity, whereas adult patients without complications show higher connectivity in such networks (13).rsfMRI data can be analyzed in a data-driven way, i.e., by allowing software to identify spatially distinct resting-state networks. A commonly used method is independent component analysis. Originally used to identify artifacts in data, this method has also proved to be a useful tool in the detection of resting-state networks (11). This pro...

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“…Additionally, the within‐striatum increased FC may be a sign of functional re‐organization of the brain in response to chronic reduced glucose uptake. Such reorganization theoretically occurs by means of increased activation and/or synchronization of specific brain regions or networks (Saggar et al, ; Schoonheim, Geurts, & Barkhof, ). Sustained neuroglycopenia, as observed in GLUT1DS, might reinforce FC via neuroplasticity‐related mechanisms, representing an adaptive brain response.…”

Section: Discussionmentioning

confidence: 99%

The effect of chronic neuroglycopenia on resting state networks in GLUT1 syndrome across the lifespan

Vaudano

Olivotto

Ruggieri

et al. 2019

Human Brain Mapping

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Glucose transporter type I deficiency syndrome (GLUT1DS) is an encephalopathic disorder due to a chronic insufficient transport of glucose into the brain. PET studies in GLUT1DS documented a widespread cortico-thalamic hypometabolism and a signal increase in the basal ganglia, regardless of age and clinical phenotype. Herein, we captured the pattern of functional connectivity of distinct striatal, cortical, and cerebellar regions in GLUT1DS (10 children, eight adults) and in healthy controls (HC, 19 children, 17 adults) during rest. Additionally, we explored for regional connectivity differences in GLUT1 children versus adults and according to the clinical presentation. Compared to HC, GLUT1DS exhibited increase connectivity within the basal ganglia circuitries and between the striatal regions with the frontal cortex and cerebellum. The excessive connectivity was predominant in patients with movement disorders and in children compared to adults, suggesting a correlation with the clinical phenotype and age at fMRI study. Our findings highlight the primary role of the striatum in the GLUT1DS pathophysiology and confirm the dependency of symptoms to the patients' chronological age. Despite the reduced chronic glucose uptake, GLUT1DS exhibit increased connectivity changes in regions highly sensible to glycopenia. Our results may portrait the effect of neuroprotective brain strategy to overcome the chronic poor energy supply during vulnerable ages. K E Y W O R D S basal ganglia, cerebellum, children, functional connectivity, GLUT1DS, neuroglycopenia, striatum

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Compensatory Hyperconnectivity in Developing Brains of Young Children With Type 1 Diabetes

Cited by 31 publications

References 29 publications

Effect of verbal task complexity in a working memory paradigm in patients with type 1 diabetes. A fMRI study

Effect of verbal task complexity in a working memory paradigm in patients with type 1 diabetes. A fMRI study

Preserving Cognition in Children With Diabetes: Do Alterations in Functional Network Connectivity Play a Role?

The effect of chronic neuroglycopenia on resting state networks in GLUT1 syndrome across the lifespan

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