Abstract
Evidence indicates that pediatric chronic health conditions (CHCs) often impair executive functioning (EF) and impaired EF undermines pediatric CHC management. This bidirectional relationship likely occurs due to biobehavioral and social-structural factors that serve to maintain this feedback loop. Specifically, biobehavioral research suggests that inflammation may sustain a feedback loop that links together increased CHC severity, challenges with EF, and lower engagement in health promoting behaviors. Experiencing social and environmental inequity also maintains pressure on this feedback loop as experiencing inequities is associated with greater inflammation, increased CHC severity, as well as challenges with EF and engagement in health promoting behaviors. Amidst this growing body of research, a model of biobehavioral and social-structural factors that centers inflammation and EF is warranted to better identify individual and structural targets to ameliorate the effects of CHCs on children, families, and society at large. This paper proposes this model, reviews relevant literature, and delineates actionable research and clinical implications.
Keywords: Executive Function, Systemic Inequity, Chronic Health Conditions, Inflammation, Pediatric Psychology, Health Behavior
Introduction
Pediatric Chronic Health Conditions
Pediatric chronic health conditions (CHCs) affect approximately 1 in 5 children, and the presence of one or more CHCs significantly reduces quality of life for both the affected child and their parents (Hall et al., 2019; Newacheck & Stoddard, 1994). Children with one or more CHCs have higher prevalence of developmental delay, mental health conditions, activity limitations, and hospitalizations than those with no CHCs (King-Dowling et al., 2019; Newacheck & Stoddard, 1994). Children with CHCs also experience increased school absences, days in bed, and contacts with physicians (Newacheck & Stoddard, 1994). Further, CHCs have been associated with decreased family quality of life and increased parental stress (Cousino & Hazen, 2013; Golics et al., 2013). Pediatric CHCs also represent a financial burden to the family (Zan & Scharff, 2015).
In addition to impacts to the individual and family, pediatric CHCs represent a financial burden to the health care system. Pediatric health care is estimated to cost between $50-100 billion annually (Cohen et al., 2012; Lassman et al., 2014; Neff et al., 2004). For example, pediatric obesity and type 1 diabetes are CHCs with substantial financial burden, accounting for greater than $14 billion each in United States (U.S.) spending per year (Finkelstein et al., 2014; Hammond & Levine, 2010; Tao et al., 2010). Notably, improved management of CHCs (e.g. decreased disease severity, increased medication adherence) has been associated with decreases in associated health-care spending in adults and children (Choudhary et al., 2019; Gibson et al., 2014; Hommel et al., 2017; McEwan et al., 2018). These significant personal, familial, financial, and societal impacts of CHCs point to the importance of better understanding how to promote more optimal CHC outcomes.
Proposed Biobehavioral and Socio-Structural Model
Pediatric CHC outcomes may be best understood through a biobehavioral and social-structural perspective that integrates physiological and neurodevelopmental changes with the impacts of social-structural exposures to systemic inequalities and oppression, all of which effect health behavior and CHC severity. In particular, inflammation may be a critical physiological mechanism that links together a core neurodevelopmental domain, executive function (EF), with experience of systemic inequity, health behavior engagement, and CHC severity (see Figure 1). First, greater CHC severity may be linked with increased systemic inflammation, both directly (for proinflammatory conditions) and indirectly through increased distress (Baumeister et al., 2016; Hoffman et al., 2016; Marsland et al., 2017; Shields et al., 2021). Second, increased systemic inflammation is known to impair EF, and greater impairment in EF may impede engagement in key health behaviors involved in the management of CHCs (Castaneda et al., 2013; Chen et al., 2021; Miller & Spencer, 2014; Piasecki et al., 2016; Reinert et al., 2013; Yamasaki et al., 2020). Impaired EF development may be particularly detrimental in the context of pediatric CHC’s (Arain et al., 2013) since EF is responsible for tasks that are critical to CHC management, such as planning, organization, attention, and problem solving, and is actively developing across childhood and adolescence (Anderson, 2002). Suboptimal management of CHCs can, in turn, further worsen CHC severity (McGrady & Hommel, 2013), creating a feedback loop that maintains and exacerbates challenges in CHC severity, inflammation, EF, and health behavior engagement. Third, more frequent exposure to social-structural inequity (e.g., food insecurity, discrimination) is also associated with greater inflammation, problems with EF, lower health behavior engagement, and greater CHC severity (Hackman et al., 2015; Kalichman & Grebler, 2010; Muscatell et al., 2020; Waldrop-Valverde et al., 2010). However, limited research has integrated across all five domains of this literature to propose a biobehavioral and social-structural model for inflammation and pediatric CHCs. Thus, this paper proposes a conceptual model of inflammatory, executive, behavioral, and social systemic processes contributing to pediatric CHC outcomes and explores this model in the context of two common CHC’s: pediatric obesity and type 1 diabetes.
Figure 1.
Biobehavioral and Contextual Model of Inflammation and EF in Pediatric Chronic Health Conditions
Methods
The goal of this review is to build a new conceptual model through identifying previously unexplored connections between constructs to build a theoretical framework to predict relationships (Jaakkola, 2020). This approach allows for exploring emerging concepts where few published studies are available and contributes to the literature by providing a roadmap for understanding the entities in question to guide future study (Jaakkola, 2020). The present review builds on the biopsychosocial model of pediatric CHCs. Although the biopsychosocial model broadly posits that medical conditions must be conceptualized in the setting of and interaction with psychological, behavioral, and social influences (Engel, 1977), the connections between inflammation, EF, health behaviors, and social structural inequity have yet to be explicitly connected. That said, EF deficits, chronic inflammation, health behavior engagement, and social structural inequity in the context of CHCs have seen increased attention in the literature over the past decade, though research on the transactional links between these constructs are only emerging. Thus, we are proposing a conceptual model that can provide a framework for testing these transactional associations and related targets for individual and structural intervention in the future.
Overview: A Biobehavioral and Social-Structural Model of Inflammation and Executive Function in Pediatric CHCs
CHCs and Inflammation
Biobehavioral evidence in CHC literature suggests that inflammation may drive a feedback loop that links together increased CHC severity, challenges with EF, and lower engagement in health promoting behaviors. First, CHC severity is linked with systemic inflammation, which can result from various sources of pathophysiology and stress (e.g., physiological, social). Inflammation is the activation of the immune system via pro-inflammatory cytokines, typically in response to harmful stimuli to aid in the healing process (Pahwa, Goyal, Bansal, and Jialal, 2018). Acute inflammation occurs rapidly in response to tissue damage, such as infection or injury and lasts up to a few days. Chronic, low-level, systemic inflammation occurs more slowly often without a clear, persistent stimuli, lasts for months to years, and can have harmful effects on the body including, pain, fatigue, gastrointestinal symptoms, frequent infections, and mental health concerns (Pahwa et al., 2018). Many CHCs are proinflammatory, meaning that disease activity is associated with heightened chronic inflammation. For example, for youths with type 1 diabetes, suboptimal glycemic levels have been linked with increased systemic inflammation (Hoffman et al., 2016). In pediatric obesity, higher fat mass has been associated with greater levels of chronic inflammation (Shields et al., 2021). In addition to the direct effect of CHC status and severity on levels on chronic inflammation, higher severity CHC and CHC status alone places extra stress on the body, both physically and psychologically (Baumeister et al., 2016; Marsland et al., 2017). Chronic physical and psychological stress can lead to consistently elevated levels of a cortisol, a glucocorticoid hormone. The body’s adaptation to high levels of cortisol can lead to glucocorticoid resistance and impairment in the downregulation of the inflammatory response of pro-inflammatory cytokines contributing to chronic inflammation (Cohen et al., 2012). This stress-inflammatory pathway then further exacerbates the pro-inflammatory impacts of CHCs.
CHCs and Executive Function
Second, CHC severity is linked with EF. Literature in the fields of pediatric obesity, asthma, cystic fibrosis, HIV, diabetes, and inflammatory bowel disease (IBD) document that children with CHCs show more deficits in EF than their control counterparts without a chronic illness (Castaneda et al., 2013; Chen et al., 2021; Miller & Spencer, 2014; Piasecki et al., 2016; Reinert et al., 2013; Yamasaki et al., 2020). For example, pediatric patients with cystic fibrosis (CF) compared to individuals without CF performed significantly poorer on a test of cognitive flexibility (Piasecki et al., 2016). In pediatric allergic airway diseases, increased difficulties in memory and concentration were identified compared with individuals without allergic airway diseases (Yamasaki et al., 2020). These deficits appear to occur in adulthood as well with a meta-analysis demonstrating that adults with IBD have poorer functioning in attention, cognitive flexibility, and working memory when compared with patients without IBD (Hopkins et al., 2021). Further, increased severity and longer length of CHC duration correspond with higher rates of EF deficits (Castaneda et al., 2013; Zayyad & Spudich, 2015). Given the ubiquity of EF deficits observed in CHCs, literature has begun to investigate physiological mechanisms of this effect, with inflammation a key candidate mechanism.
Inflammation and EF in CHCs
Third, chronic inflammation likely contributes to EF deficits in pediatric CHCs. Chronic, systemic inflammation circulates throughout the body and can lead to neuroinflammation through the blood-brain barrier, choroid plexus, or the vagus nerve connecting the brain and the gut, depending on the CHC pathophysiology (Guillemot-Legris & Muccioli, 2017). Neuroinflammation can then lead to neuronal damage directly and via glial cell activation (Guillemot-Legris & Muccioli, 2017). Broadly, increased inflammatory biomarkers have been associated with deficits in EF, including inhibitory control and cognitive flexibility (Cullen et al., 2017; Peters et al., 2019). In children with and without indication of psychopathological symptoms, higher chronic inflammation was found to be associated with lower scores in inhibition, switching, and verbal fluency, (Cullen et al., 2017). More specifically, CHC, inflammation, and EF associations have been found across multiple condition populations including pediatric obesity, type 1 diabetes, sickle cell disease, preterm birth, acute lymphoblastic leukemia survivors, and psychopathology (Allred et al., 2017; Andreotti et al., 2015; Broadley et al., 2017; Chen et al., 2021; Cheung et al., 2017; Cullen et al., 2017). For example, in children with sickle cell disease, several inflammatory cytokines (Interleukin-4, -5, -8, and -13) were negatively associated with tests of EF, such that higher levels of inflammatory markers correspond with poorer performance in inhibition, cognitive flexibility, and fluency (Andreotti et al., 2015). In pediatric type 1 diabetes, there is evidence that neuroinflammation links diabetic ketoacidosis, a severe disease state, with impairments in EF, including working memory (Ghetti et al., 2020). Taken together, this literature supports that CHC severity and associated increases in inflammation may contribute to EF impairments found in pediatric CHCs.
CHCs, Inflammation, EF, and Health Behavior
Fourth, as CHC severity drives inflammation, and inflammation exacerbates challenges with EF, the biobehavioral system becomes self-sustaining via impairments in health behavior engagement. A downstream effect of challenges with EF is decreased engagement in health behaviors that might otherwise alleviate CHC severity and reduce inflammation. Executive dysfunction negatively affects health behavior engagement, such as disrupting medical adherence, physical activity, and healthy eating behavior (Duke & Harris, 2014). For example, consistently following medical recommendations can limit the impact of CHCs, reducing inflammation and slowing impairments in EF, while decreased engagement in following medical recommendations for CHC management exacerbates these effects (McGrady & Hommel, 2013). Likewise, consistently engaging in health promoting behaviors, including eating a balanced diet, getting high quality sleep, and getting regular physical activity, may reduce both CHC severity and inflammation, providing protective effects for EF and increasing capacity for treatment engagement (Allan et al., 2016; Jirout et al., 2019). Thus, a feedback loop is likely perpetuated whereby intact EF sustains adherence, disease management, and reduces inflammation, while EF deficits lead to decreased engagement in medical recommendations, increased CHC severity and increased inflammation, further worsening EF and related health behavior challenges.
CHCs, Inflammation, EF, and Social-Structural Systems
Lastly, moving beyond the biobehavioral system, more frequent exposure to social and environmental inequity is also associated with greater CHC severity and challenges with health behavior engagement, as well as greater inflammation and problems with EF. Exposure to social and environmental inequity, such as environmental pollution and toxin exposure, is associated with greater CHC severity (e.g., greater risk and morbidity of asthma; Barnthouse & Jones, 2019). Additionally, social-structural factors such as disparities in treatment options and specialist referrals for minoritized populations compared to non-minoritized populations contribute to worse CHC prognosis (Hannaway et al., 2005; Mahdavinia et al., 2017; Shah et al., 2014; Taylor-Black & Wang, 2012). Similarly, social-structural inequity can diminish family engagement in health promoting behaviors, including how poverty (Kalichman & Grebler, 2010; Waldrop-Valverde et al., 2010), underfunded health insurance systems (Bengiamin, 2010), and built environments can impair diet quality, physical activity, access to medical supplies, and time availability for CHC care (Carroll-Scott et al., 2013; Qato et al., 2014). Moreover, given the links between pediatric CHC severity and inflammation, children with CHCs and greater exposure to social systemic inequities may experience more sustained or elevated inflammation via the impact of social-systemic inequities on CHC severity and health behavior engagement.
Finally, the impacts of social-structural inequity on CHC severity and related inflammation likely also extend to and exacerbate challenges in EF development, that make changes in health behavior engagement more challenging. First, social-systemic inequities outside of the context of a CHC are alone linked with greater inflammation. For example, a recent meta-analysis documented that low socioeconomic status (SES) was related to higher levels of inflammation (for both CRP and Interleukin-6) in non-patient populations (Muscatell et al., 2020). Racial discrimination among Black adolescents predicts elevated inflammation at 22 years of age (Brody et al., 2015), potentially via upregulation of the hypothalamic–pituitary–adrenal axis increasing systemic stress and inflammation (Goosby et al., 2018). In a sample of children living in the U.S., Hispanic and Black children with parents who immigrated to the U.S. compared to children with U.S.-born parents also experience greater inflammation (Schmeer & Tarrence, 2018). Second, exposure to social and environmental inequity is also associated with deficits in EF. Lower SES is associated with poorer EF by 54 months of age and changes in SES across childhood are positively associated with changes in EF (Hackman et al., 2015) into adulthood (Campanholo et al., 2017). Rural residency status and exposure to environmental toxins (e.g. lead, manganese) independently lead to decreased EF (Nascimento et al., 2016). And, discrimination may be associated with decreased EF (Zahodne et al., 2020). Exposure to higher levels of social-structural inequity may thus increase inflammation and impair EF, which places further pressure on the feedback loop between greater CHC severity, lower health behavior engagement, and greater inflammation (Shields et al., 2021). The public health effects of social-structural inequity are such that each of these influences compound to increase the prevalence of cost-intensive CHCs. By modeling the social-structural and biobehavioral contexts that maintain this cycle of CHC severity, intervention science can better understand targets to prevent and ameliorate the impact of pediatric CHCs.
Pediatric Obesity and Type 1 Diabetes as Exemplars of the Biobehavioral and Social-Structural Model of Inflammation and EF in Pediatric CHCs
The proposed biobehavioral and social-structural model of inflammation and EF in pediatric CHCs lays out important implications for expected associations between CHC severity, inflammation, EF, health behavior engagement, and social-structural inequity, with inflammation acting as a keystone in linking together these systems in a self-sustaining feedback loop. Applying this model within specific CHCs illustrates these connections and highlights new avenues for intervention. Next, we explore this model and intervention insights in two common CHCs, pediatric obesity and type 1 diabetes. The exemplars of obesity and type 1 diabetes were selected due to several factors: the involvement of inflammation in the pathophysiology of both diseases, the high demands placed on health behavior engagement to treat these conditions (e.g. diet and physical activity changes in obesity, diet and glucose monitoring in addition to medication adherence in type I diabetes), and a growing literature documentation of executive function deficits and socio-structural inequality within in these disease populations.
Pediatric Obesity
Obesity, Inflammation, and EF
Research in pediatric obesity suggests robust relations among inflammation, EF, health behavior, disease outcomes, and social-systemic inequities that influence long-term disease outcomes and treatment (See Figure 2). Obesity is a pro-inflammatory disease, and greater disease severity is associated with greater inflammation (Epingeac et al., 2020), whereby systemic inflammation arises due to an excess of adipocytes. Obesity is also linked with impaired EF and that association is, in part, mediated by inflammation. Neurobiological evidence suggests that obesity-related cognitive deficits occur secondary to neuronal damage via inflammation as well as due to metabolic effects linked with obesity-associated inflammation such as insulin resistance, hyperlipidemia, and hypertension (Spyridaki et al., 2016). A recent pilot study supporting the proposed conceptual model demonstrated that elevated C-reactive protein mediated the association between adiposity and global EF (King et al., 2022). This finding indicated that higher percent body fat as measured by Dual X-Ray Absorptiometry was associated with higher levels of C-reactive protein, which corresponded with more executive dysfunction (King, 2022). Similarly, higher adiposity in school-age children predicts higher inflammation and in turn, poorer working memory in adolescents (Shields et al., 2021). Consistent with the theorized feedback loop in the biobehavioral and social-structural model between CHC severity, inflammation, and EF, poorer working memory also in turn predicted higher adiposity at a third time point (Shields et al., 2021). In the pediatric obesity context, inflammation from disease pathophysiology likely contributes not only to CHC severity but also to disruptions in the development of EF that may have lasting impacts across the lifespan.
Figure 2.
Biobehavioral and Contextual Model of Inflammation and EF in Pediatric Obesity
Obesity, EF, Inflammation and Health Behavior
Obesity-associated inflammation and EF impairments are also known to impact health behaviors, such as eating behavior and physical activity, that are critical to obesity treatment and may further exacerbate disease severity. First, eating behavior is influenced by both inflammation and EF, and dysregulated eating behavior can worsen obesity severity and in turn exacerbate further inflammation and challenges in EF. For example, after controlling for changes in BMI, decreases in inflammation secondary to gastric surgery were associated with improvement regulation of eating behavior (Capuron et al., 2011). It is theorized that changes in gut inflammation modify gut-brain signaling around appetite and reward associated with eating highly palatable foods (Moran & Thapaliya, 2021). Regulation of eating behavior is also associated with EF, for example, youth who experience episodic over-eating have greater problems with behavior regulation and youth experiencing binge eating have greater problems with both behavior regulation and metacognition (Gowey et al., 2018). Thus, inflammation and EF may be worsened by early adiposity, which in turn contributes to dysregulation of eating behavior and diet quality, which then further worsens disease severity across childhood and adolescence. This feedback loop also points to a potential focus of interventions to target gut inflammation to help disrupt this feedback loop driving obesity severity.
Second, physical activity (PA) represents another mechanism by which the feedback loop of inflammation, EF and obesity severity is perpetuated. PA has been repeatedly documented to benefit EF. A meta-analysis examining the effect of PA on cognition in children analyzed effect sizes from 36 studies, finding significant pooled effects for physical activity on EFs globally, as well as specifically on working memory, attention/inhibition, and metacognition (Alvarez-Bueno et al., 2017). PA also improves some aspects of inflammation (Ertek & Cicero, 2012; Peres et al., 2019). For example, interleukin-6 (IL-6) was down-modulated, or decreased, by PA training in girls ages 7-17 playing volleyball (Peres et al., 2019). At the same time, impairments in EF are known to contribute to challenges with increasing physical activity in youth. For example, low EF dampens the link between behavioral intention and engagement in PA (Hall et al., 2008). Thus, youths with early adiposity may experience increases in inflammation and challenges with EF that drive decreases in physical activity, in turn worsening obesity severity. Developing interventions that are tailored to target not only PA behavior but also reduce inflammation might help improve EF skills needed to sustain physical activity behavior change across time.
Obesity and Social-Structural Systems
Finally, exposure to social-structural inequity that includes oppression, discrimination, and stigma is known to lead to greater severity in pediatric obesity. For example, SES is inversely associated with adiposity, and this association is strongest among those aged 5-11 (Shrewsbury & Wardle, 2008). Further, increased experiences of racial discrimination show a similar pattern of effects in pediatric obesity. In Black adolescents, experiencing discrimination predicts higher BMI in late adolescence and insulin resistance in emerging adulthood (Brody et al., 2018). This link between social-structural inequities and obesity might be maintained by the additional impact of inequities on inflammation, challenges in EF, and health behavior engagement For example, although social-structural inequities impact the food and built environment leading to changes in diet and physical activity that drive obesity severity, lower SES has also been associated with greater risk of obesity in part due to increased inflammation (Muscatell et al., 2020). Though the mechanism of SES-related inflammation’s effect on obesity risk has yet to be identified, evidence suggests that EF and health behavior may represent mediators of this process. Given evidence of how social-structural inequity is also associated with greater challenges with EF, it may be that for youth with excess adiposity, exposure to social-structural inequity reifies a feedback loop. This feedback loop links together inflammation and challenges in EF that further impact eating behavior and PA and worsened obesity outcomes. This suggests that multi-level interventions that address social-structural inequalities, in addition to individual or family behavior, will be essential to reducing the severity of obesity in youths.
Type 1 Diabetes
Diabetes, Inflammation, and EF
Type 1 diabetes is an autoimmune disease that commonly impacts children and adolescents and requires a complex daily medical regimen to manage the symptoms of the disease and prevent short and long-term morbidity and mortality. In type 1 diabetes there are robust associations between disease severity and inflammation, EF, health behaviors, and social-systemic factors that suggest disease outcomes may be best explained by a biobehavioral and social-structural model (See Figure 3). First, challenges with EF are bidirectionally linked with worse disease severity and may be driven by diabetes-related pathophysiology including increased inflammation. For example, type 1 diabetes pathophysiology has been linked to decreases in brain-derived neurotrophic factor (BDNF), a protein involved in learning and memory, which has been associated with poorer EF (Chen et al., 2021). In addition, diabetes severity may increase inflammatory cytokines (e.g., Interleukin-6 and Tumor Necrosis Factor alpha), increasing cerebrovascular lesions, which may exacerbate EF deficits (Sato & Morishita, 2013; Shalimova et al., 2019). These pathophysiological pathways are consistent with a plethora of studies that link worse disease severity, i.e., suboptimal glycemic levels, with impaired cognitive performance (Chen et al., 2021; Ferguson et al., 2005; He et al., 2018; Strudwick et al., 2005). Studies have also found that specific EF deficits (namely processing speed and visuospatial construction) in individuals with type 1 diabetes may also be mediated by associated microvascular diseases, such as proliferative retinopathy (Wessels et al., 2007). Further, chronic systemic inflammation may contribute to that microvascular disease (Recio-Mayoral et al., 2009). Additional research supports that these deficits in EF persist into young adulthood where youths with type 1 diabetes continue to show impairments in multiple areas of EF, including cognitive flexibility, inhibition, and problem-solving abilities (Reid, 2017) making this a critical area for intervention in pediatrics to prevent long-term diabetes-related morbidity and mortality.
Figure 3.
Biobehavioral and Social-Structural Model of Inflammation and EF in Pediatric Type I Diabetes
Diabetes, Inflammation, EF, and Health Behavior
Health behaviors, including diabetes treatment engagement, physical activity, and improved sleep, have been linked to decreased type 1 diabetes disease severity, improved EF, and more optimal disease management in type 1 diabetes. For example, the association between disease severity and EF is also bidirectional whereby impaired EF also predicts challenges in diabetes-related behavior regulation (Suchy et al., 2017) and, in turn, worse disease severity, as measured by suboptimal glycemic levels (Nylander et al., 2017). This evidence is consistent with a biobehavioral model of disease outcomes whereby disease onset increases inflammation which contributes to EF deficits that further disrupt diabetes-related behavior regulation and worsening of disease severity. Extending to broader health promoting behaviors, Tonoli and colleagues (2015) found that increased physical activity led to more optimal glycemic levels in addition to increased brain-derived neurotrophic factor levels, improving EF. In addition to physical activity improving EF and disease severity, physical activity also reduces inflammation (Viana et al., 2014) which may further benefit improvements in EF and health behavior regulation. Sleep also plays an important role in diabetes disease severity, EF, and more optimal disease management. The nature of type 1 diabetes management interferes with sleep quality, given that individuals with type 1 diabetes often need to check their blood glucose levels during the night (Larcher et al., 2015). Higher sleep variability, operationalized by sleep deprivation and shifts in circadian cycles, has been linked to suboptimal glycemic levels, which is known to increase inflammation (Chontong et al., 2016; Patel et al., 2018). In addition, reduced sleep quality can also contribute to further EF deficits (Perez et al., 2018). Finally, sleep restriction has also been associated with increased insulin resistance and increased inflammation (Leproult et al., 2014). Thus, consistent with the theorized biobehavioral feedback loop, youths with type 1 diabetes and greater challenges in glucose regulation may experience more frequent disruptions in disease management tasks, sleep, and regulation of physical activity, which further drive impairments in EF and inflammation and worsen disease severity.
Type 1 Diabetes and Social Structural Systems
Lastly, it is important to contextualize the diabetes, EF, inflammation, and health behavior feedback loop within social-structural inequities, such as systemic racism and SES. For example, Carter et al (2008) found both ethnicity (a proxy for systemic and everyday discrimination) and SES independently effected glycemic control. These findings are similar to results from Willi and colleagues, who found that after adjusting for SES, there were still disparities in type 1 diabetes treatment outcomes for Black (race also represents a proxy for discrimination) and Hispanic youth compared to White youth (Willi et al., 2015). Further, minoritized youth experiencing low SES also reported higher diabetes distress, which has been linked to increased glycemic levels (Fegan-Bohm et al., 2020; Hessler et al., 2017). Neighborhood disadvantage has also been linked to increased inflammation and suboptimal glycemic levels (Coulon et al., 2017). These data support the link between social structural inequity and type 1 diabetes outcomes, implying that these inequities may amplify the effects of the biobehavioral feedback loop in type 1 diabetes. The biobehavioral and social-structural model as applied in pediatric type 1 diabetes also suggests multiple key avenues for potential interventions: (1) interventions that target reducing inflammation may benefit EF and disease outcomes long-term, this includes changes in diet, physical activity, and sleep quality that may exacerbate inflammation ; and (2) interventions will need to be multi-level and target not only individual and family but also social-systemic factors that may reify the biobehavioral feedback loop including limited access to high quality medical care and diabetes medical supplies, experiencing discrimination, and lower quality food and built environments for everyday living.
Discussion
The present paper proposes a biobehavioral and social systemic model of inflammation and EF in pediatric CHCs that links together inflammation with changes in CHC severity, EF, health behavior engagement, and exposure to social-systemic inequities. First, the effects of CHC status and severity on inflammation, both directly through CHC pathophysiology and due to increased physical and psychological stress placed on humans by CHCs were described. Then, the model was expanded to include research connecting CHC status and severity to EF, in part through the effects of chronic inflammation and the role of compromised EF in inhibiting successful engagement with health promoting behaviors, further hindering CHC management and exacerbating inflammation and executive dysfunction. Finally, evidence was reviewed that detailed the deleterious effects of social-systemic inequities, such as those experienced by persons with low SES, minoritized race or ethnicity, or immigrant status on CHC status and severity, inflammation, EF, and health behavior engagement. These inequities further compromise effective CHC management and increase CHC burden on children, families, schools, and the healthcare system at large. Examples of how this model can be applied in pediatric obesity and type 1 diabetes were elaborated and potential avenues for intervention discussed. Overall, this biobehavioral and social-structural model of inflammation and EF in pediatric CHCs serves to identify factors perpetuating negative cycles of CHC management that can be targeted and addressed to reduce CHC burden.
This model is the first to delineate specific, inflammation and EF mechanistic processes integrating social-systemic, biological, cognitive, and behavioral factors in a CHC-general fashion among pediatric CHCs. It builds upon a robust literature of biopsychosocial models of child and adult health, unique to specific diseases or specific health behaviors. Existing biopsychosocial models excellently describe the multifactorial psychological and social influences on health, and this research has paved the way for existing multidisciplinary research in clinical settings (Crosby et al., 2015; Goetz & Caron, 1999; John et al., 2020; Peyrot et al., 1999; Stempel et al., 2019). Although these models emphasize the importance of biological and psychosocial factors, few have delineated pathways and proposed directionality by which inflammation and EF are interrelated with CHC severity, health behaviors, and social-structural inequity (Lämmle et al., 2011). For example, rarely do existing biopsychosocial models address EF and its bidirectional relationship with CHC severity, nor the role of inflammation and social-structural inequity in that relationship. Further, given that childhood and adolescence is a key period for EF development that is known to then impact health and behavior across the lifespan, the specific inclusion of EF related pathways is critical to ameliorate long-term pediatric CHC burdens. For example, Appelhans and colleagues (2021) show that pre-existing EF-deficits measured in adolescence predicted detrimental changes in physical activity and diet during COVID-19 for individuals who were then young adults. Thus, the current model extends upon prior research to propose mechanistic pathways linking inflammation, EF, health behavior, inequity, and CHC outcomes as well as discuss the cyclical nature of CHCs, inflammation and EF deficits, an area saturated with potential to intervene and improve pediatric disease management.
The biobehavioral and social-systemic model of inflammation and EF in pediatric CHCs lays groundwork for both additional research and potential clinical innovation. First, immediate implications for research include the need for studies designed to further evaluate these proposed mechanistic pathways, particularly longitudinally. Much of the research described in the present paper evaluated linear associations between two of the many constructs implicated by this model. Fewer studies examined mediation models where one of the model’s constructs served as a mechanism linking two other constructs. Of studies that did examine mediation models, very few reported on longitudinal data. No studies reviewed here evaluated these relations via complex systems modeling that might capture the transactional relations between factors. The proposed conceptual model of these constructs in the present paper supports further complex systems research across inflammation, EF, health behavior, and social-structural inequalities in CHCs. Second, another direction for future research involves translating this model to additional CHC populations, beyond pediatric obesity and type 1 diabetes. Based on the literature reviewed, this model could be applied to allergic diseases, pulmonary diseases such as asthma and cystic fibrosis, HIV, hematologic conditions, and inflammatory bowel disease, to name a few. Each of these CHCs has unique pathophysiology including impacts on inflammation and health behaviors required in treatment that can be compromised by impaired EF and social-structural inequalities. Future research should conceptualize how other pediatric CHCs exhibit similar cycles to inform clinical targets and downstream areas of research needing additional disease-specific attention. Finally, given that inflammation may link together challenges with CHC severity, EF, health behaviors, and exposure to social-structural inequity, greater clarity on how existing and novel interventions modify inflammation is critical. For example, more research is needed on what types of biobehavioral and social system interventions are most important for reducing inflammation both directly (e.g., improving sleep to reduce inflammation, modifying food access to reduce inflammatory food consumption, medications that reduce inflammation) and indirectly through improvements in CHC severity.
In addition, the proposed biobehavioral and social-structural model of inflammation and EF in pediatric CHCs has implications for clinical settings and clinical research. Based on the literature reviewed, future clinical research or quality improvement efforts may wish to implement and evaluate the utility of screening for and intervening on both social determinants of health and EF deficits in pediatric CHCs. Indications for EF and social determinants of health screening may include patients with a new diagnosis, those with worsening disease activity or higher levels of CHC severity, those demonstrating difficulty with following medical recommendations and implementation of health-promoting behaviors, those with known cognitive concerns, or those reporting social or systemic stressors. The practice of screening in general is only recommended when there are avenues of treatment that can be provided should screening detect difficulties. Thus, this model also suggests the need to advocate for increased access to and funding for healthcare professionals trained in therapeutic modalities specific to EF challenges or social-structural supports and policy changes, such as psychologists, counselors, or social workers and health policy workers. For settings with access to these resources, social determinants of health may be targeted by involving social work on CHC care teams and through efforts such as housing interventions, food-related resources, and connecting patients with other local resources (Findley et al., 2014; Sandel et al., 2010). Health systems or clinics should also implement programs to reduce discrimination and stigma in the clinic setting and advance policy changes that reduce systemic oppression. Further, EF can be improved through treatments such as parent training, behavior schedules and rewards, routine and habit formation, timers and alarms, planning and organizational training, and cognitive remediation to address EF deficits (Barkley, 2013; Langberg, 2008, Murdaugh, 2019). These treatments generally are short-term and have the potential to ameliorate CHC burden, particularly when directed at improving the family’s management of the child’s CHC and reducing social-structural inequity.
Although the proposed biobehavioral and social-systemic model of inflammation and EF in pediatric CHCs offers innovative concepts and rich directions for future research and intervention, it also has inherent limitations. This model, as described, did not explicitly capture aspects of stress outside of the stress of social and environmental inequity and distress from CHC management such as SES, discrimination, environmental safety, and diabetes distress. In particular, the role of psychopathology is not extensively discussed as it is considered outside of the scope of this initial model that aimed to focus on social-structural inequity more specifically. However, we acknowledge the key role psychopathology will likely play in the processes discussed and in further reifying the connections between CHC severity, inflammation, EF, and health behaviors across the lifespan. We recommend that as the literature builds upon this model, the role of psychopathology should be further evaluated and incorporated. Additionally, limited research currently exists to inform some of the specific mechanistic relations and directionality proposed by the model across pediatric CHC disease groups. As discussed, these gaps in the literature revealed by the current model are important areas for future research to pave the way for more complex modeling and clinical research examining how CHC severity, inflammation, EF, health behaviors, psychopathology, and social-structural inequity are connected across childhood and intro emerging adulthood. As this model is evaluated holistically in future research and sufficient evidence comes available, it will also be important to follow-up this conceptual review with a systematic review to synthesize progress in the development and evaluation of this model. As this model is evaluated holistically in future research and sufficient evidence comes available, it will also be important to follow-up this conceptual review with a systematic review to synthesize progress in the development and evaluation of this model. Finally, given the breadth of components in this model that needed to be reviewed, the depth of discussion in some areas of work was more limited and, in particular, there is extensive research on how social-structural inequities impact CHC severity that can be readily integrated into this framework and expand multi-level intervention opportunities.
Conclusion
The biobehavioral and social structural model of inflammation and EF in pediatric CHCs proposes that social-structural inequities increase risk of chronic inflammation, CHC onset and severity, and EF difficulties. These biobehavioral and structural factors are related in a feedback loop wherein heightened CHC severity compromises EF in part through the effects of chronic inflammation, wherein EF negatively affects CHC severity through its negative influence on health behavior engagement. This model extends upon existing biopsychosocial models through its proposal of specific mechanistic, directional pathways for inflammation and EF, and its applicability across pediatric CHCs. Future research applying this model to additional pediatric CHC populations and evaluating clinical targets suggested by this model could pave the way for more effective pediatric CHC management and decreased pediatric CHC burden on patients, families, and society at large.
Acknowledgements:
This work was supported by the University of Alabama at Birmingham Nutrition Obesity Research Center and National Institute of Diabetes and Digestive and Kidney Diseases under grants P30DK056336 and T32DK062710 and the National Institute of General Medical Sciences under grant P20GM103644. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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