“Neurocognitive Deficits in Pediatric Obesity”
Introduction
In the United States, 20.5% of adolescents (12-19 years) and 17.5% of children (6-11 years) meet criteria for obesity and 7.8% of adolescents and 5.6% of children meet criteria for severe obesity1. Pediatric obesity is associated with a series of deleterious consequences spanning medical, psychosocial, cognitive, and academic outcomes2-4, resulting in a quality of life equivalent to that of pediatric cancer for adolescents with severe obesity5. Pediatric obesity is associated with an additional $19,000 of lifetime direct medical costs6, which results in a cumulative increase costs of $17-$25 billion in direct medical costs for the approximately 4 million 5th graders in the United States7. Thus, with 55% of children and 80% of adolescents with obesity continuing to meet criteria for obesity after the age of 308, it is clear that understanding the causes and consequences of obesity is not only important for pediatric health and development, but also for the future health and productivity of the United States.
The complexity of the etiology of obesity becomes clear when considering all the possible reasons why some children fail to regulate their energy balance and obesogenic behaviors (e.g., emotional eating, consuming energy dense foods, sedentary behavior) while others do so successfully. Risk for obesogenic behaviors includes characteristics related to neighborhoods (e.g., food deserts and safety), schools (e.g., physical education and school lunch quality), families (e.g., parental obesity, education and socio-economic status), and the individual (e.g., psychosocial and cognitive functioning and psychopathology)9. Despite the importance of environmental, social, and familial characteristics in the development of pediatric obesity, creating a model of the causes and consequences of obesity pertaining to the individual is critical for prevention and intervention.
This dissertation proposes a model of pediatric obesity that integrates feed-forward individual risk factors for obesogenic behaviors and feedback consequences that result from the development of obesity (e.g., medical comorbidities). Poor executive, reward, and mnemonic functioning may predispose children to engage in fewer protective health related behaviors while also increasing the likelihood of engaging in obesogenic behavior, potentially leading to a habitual energy imbalance and weight gain. Chronic, systemic inflammation, that develops along with obesity, potentially extends to the brain. It is hypothesized that neuro-inflammation influences the maintenance and promotion of obesity through two pathways: 1) hypothalamic inflammation leads to local leptin and insulin resistance, disrupting appetite suppressing signaling; and 2) non-hypothalamic inflammation may alter neuronal structure and function, resulting in worse neurocognitive function. Thus, the inflammatory consequences of obesity contribute to a feedback cycle that reinforces the maintenance of obesity though neuronal and behavioral pathways. As this cycle is maintained, development of other comorbidities such as insulin resistance, metabolic syndrome, and sleep apnea may compound the effects of neuro inflammation on neurocognitive function. The goal of this dissertation was to help elucidate the feed-forward components of the proposed model in order to examine the breadth and specificity of neurocognitive deficits in pediatric obesity.
Methods
This dissertation examined neurocognitive deficits associated with pediatric obesity in order to further clarify the roles of reward, executive, and mnemonic function in pediatric obesity. Known risk factors (e.g., SES, IQ) and comorbidities (e.g., psychopathology) of pediatric obesity were also examined to determine their influence on neurocognitive deficits. Understanding what modulates the association between obesity and neurocognitive function is critically important to the identification of potential causal pathways and the development of prevention and treatment programs. A series of three studies were completed using different methodological approaches: 1) a meta-analytic review of the literature; 2) a behavioral study using performance-based and parent-reported assessments; and 3) a functional magnetic resonance imaging (fMRI) study. The cross-modal, multi-method approach of this dissertation provided novel findings that specified the nature of neurocognitive deficits associated with pediatric obesity in higher resolution than in the past and began to identify potential targets for prevention and intervention.
The meta-analysis of 68 studies from 1978-2016 was conducted in compliance with PRISMA guidelines and aimed to 1) estimate the effect of pediatric obesity on component processes of executive function and reward-related decision making and 2) evaluate how the observed effects of obesity were moderated by sample (e.g., age, gender, intelligence, and socio economic status – SES) and study/task characteristics (e.g., categorical/continuous variable, food stimuli). The review was limited to studies including children and adolescents without known medical comorbidities related to pediatric obesity in order to eliminate their potential confounding effects. This was the first quantitative review of executive function and reward related decision-making deficits in pediatric obesity that not only estimated the overall effect of obesity, but also examined factors that may moderate the negative effect of obesity (revision under review at Childhood Obesity).
The behavioral study in 7-18 year-old children (N=112) with either healthy weight or obesity with no known medical comorbidities aimed to test 1) component processes of executive functioning with laboratory tasks (e.g., working memory and response inhibition) and parent reported of everyday behavior; 2) reward-related decision-making with a Bayesian decision making model and 3) sleep health and parent-reported psychopathology as potential mediators of observed deficits in pediatric obesity. This study was the first to test the independent mediating effects of sleep health and psychopathology on the association between cognitive deficits and pediatric obesity and use a computational modeling approach to reward-related decision making in pediatric obesity (Childhood Obesity, 2018, 10.1089/chi.2017.0281).
The fMRI study in 14-19 year-old adolescents (N=62) with healthy weight or severe obesity who were candidates for bariatric surgery aimed to 1) examine the neural underpinnings of working memory load, a core process of executive function, response to increasing value of anticipated monetary reward, and encoding-related activation for subsequently remembered pictures and 2) replicate behavioral findings from the second study for executive function and reward-related decision making. This study was the first brain imaging study to examine all three processes in the same individuals at baseline (i.e., without evoking activation with food stimuli) and was the first to probe mnemonic function in adolescents with obesity.
Results
Study 1: Meta-Analysis. Small-to-moderate deleterious effects of obesity were observed on executive and reward-related performance but not on reported impulsivity, with larger effects on inhibitory task performance in older and predominantly female samples. This study showed for the first time that although obesity was associated with lower IQ and SES, these variables did not predict the observed effects. Together, these findings replicate an earlier meta-analysis10 by showing negative effects of obesity on inhibitory control and reward-related decision making but no effect of obesity on parental/self-report measures of impulsivity. This study also provided the first meta-analytic evidence for 1) negative effects of obesity on working memory and cognitive flexibility/shifting and 2) age and gender as moderators of inhibition such that the performance gap between children with and without obesity was larger for older than younger children and for females than males on inhibition tasks. Largely consistent findings across the current and previous meta-analyses10 underscores the stability of executive and reward dysfunction, and therefore, their importance for behaviors that promote obesity in children and adolescents. Additionally, sensitivity analyses suggest cognitive and demographic intervention targets for prevention and mitigation of obesogenic behavior.
Study 2: Behavioral Study. Pediatric obesity was associated with impairment in select components of reward related decision-making and executive functioning with everyday executive deficits mediated by poorer sleep health and greater risk of internalizing psychopathology. Children with obesity did not differ in reward related decision-making outcomes or sensitivity to monetary reward (?), but showed reduced ability to adapt behavior to changing reward contingencies (?). While inhibitory performance did not differ, children with obesity showed executive dysfunction under higher working memory demands and in everyday behavioral regulation and metacognition. Parents reported that children with obesity had poorer sleep health, despite equal sleep durations, and four times greater risk (odds ratio=4.27) for experiencing internalizing psychopathology. Importantly, sleep health and internalizing symptoms mediated the deleterious effect of obesity on everyday behavioral regulation and metacognitive abilities but not on decision-making and working memory performance. Our results highlight significant vulnerabilities for cognitive, sleep, and mental health of children with obesity, while elucidating a potential path through which obesity impacts everyday executive behaviors.
Study 3: fMRI Study. Adolescents with obesity, relative to those without, had greater prefrontal, parietal, and caudate activation during working memory, which suggests greater effort in light of less accurate working memory performance in adolescents with obesity. During anticipation of reward, adolescents without obesity increased activation in posterior cingulate cortex (PCC) in response to monetary value whereas adolescents with obesity did not, suggesting reduced sensitivity to differences in reward value. Additionally, reduced ability to adapt behavior to changing reward contingencies during reward related decision-making replicated findings from Study 2. During encoding of subsequently remembered pictures, adolescents with obesity, relative those without, showed reduced hippocampal activation suggesting atypical mnemonic function despite no differences in recognition memory performance. These results, for the first time, showed alterations in functional neural circuitry subserving executive, reward, and mnemonic function.
Discussion
Overall, this dissertation provided evidence for the association between pediatric obesity and alterations in neurocognitive processes that are pertinent to obesogenic behavior. The proposed model posited that executive, reward, and mnemonic deficits represent feed-forward risk-factors for pediatric obesity due to their influence on food-related behaviors. Evidence in support of this model was obtained without the use of food stimuli, which suggests more pervasive neurocognitive dysfunction in obesity. Direct examination of whether the observed neurocognitive alterations promote food-related or obesogenic behaviors is an important next step. Clarifying the role and specificity of neurocognitive deficits in pediatric obesity is an important step in identifying targets for prevention and intervention.
In addition to the identification of pertinent neurocognitive factors, these studies suggest an important modulatory role for demographic, health, and psychological factors that are potential targets for intervention and prevention. Study 1 showed that inhibitory deficits were moderated by age and gender, potentially indicating that obesity has differential effects on inhibition through development and puberty. Similarly, Study 2 showed that sleep health and psychopathology fully mediated the association between obesity and everyday executive abilities. Together, these findings suggest demographic and health related characteristics modulate obesity associated executive deficits but not reward related decision-making. Therefore, future prevention efforts may have greater success targeting executive functions in younger children, while intervention efforts may see larger effects in children and adolescents with obesity when sleep hygiene training and treatment of internalizing symptoms are incorporated.
Despite promising findings related to feed-forward components of the proposed model, it is unclear whether neurocognitive deficits were a cause or consequence of pediatric obesity. However, a pilot study using a sample of adolescents from Study 3 provided the first evidence for neuroplasticity after weight loss such that patterns of activation became more similar to those seen in adolescents without obesity after bariatric surgery12. Although the mechanisms behind weight-loss induced neural plasticity are unknown, this finding provides initial evidence for the feed-back component of the proposed model and suggests that obesity may have deleterious effects on neurocognitive processing.
A promising mechanism for improved neurocognitive function after weight loss is inflammation for three reasons: 1) the onset of low grade inflammation occurs before the onset of more serious obesity related co-morbidities13; 2) it is sensitive to changes in weight and health status; and 3) initial evidence suggests it may lead to neuro-inflammatory processes that impact neurocognitive function14,15. If changes in systemic inflammation track changes in neurocognitive function after surgical or other weight loss interventions it will provide initial evidence for its role as a feedback mechanism in pediatric obesity. Examining individual differences in neurocognitive function and inflammation within children and adolescents with obesity is crucial to the identification of mechanism and paths through which obesity develops and is maintained. The proposed model provides a framework for future empirical studies to identify and test targets for early prevention and treatment of pediatric obesity.
References
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