PACE: a Novel Eating Behavior Phenotype to Assess Risk for Obesity in Middle Childhood.

BACKGROUND: Behavioral phenotypes that predict future weight gain are needed to identify children susceptible to obesity. OBJECTIVES: This prospective study developed an eating behavior risk score to predict change in adiposity over 1 y in children. METHODS: Data from 6 baseline visits (Time 1, T1) and a 1-y follow-up visit (Time 2, T2) were collected from 76, 7- to 8-y-old healthy children recruited from Central Pennsylvania. At T1, children had body mass index (BMI) percentiles <90 and were classified with either high (n = 33; maternal BMI ≥30 kg/m2) or low (n = 43; maternal BMI ≤25 kg/m2) familial risk for obesity. Appetitive traits and eating behaviors were assessed at T1. Adiposity was measured at T1 and T2 using dual-energy x-ray absorptiometry, with a main outcome of fat mass index (FMI; total body fat mass divided by height in meters squared). Hierarchical linear regressions determined which eating measures improved prediction of T2 FMI after adjustment for covariates in the baseline model (T1 FMI, sex, income, familial risk, and Tanner stage). RESULTS: Four eating measures-Portion susceptibility, Appetitive traits, loss of control eating, and eating rate-were combined into a standardized summary score called PACE. PACE improved the baseline model to predict 80% variance in T2 FMI. PACE was positively associated with the increase in FMI in children from T1 to T2, independent of familial risk (r = 0.58, P < 0.001). Although PACE was higher in girls than boys (P < 0.05), it did not differ by familial risk, income, or education. CONCLUSIONS: PACE represents a cumulative eating behavior risk score that predicts adiposity gain over 1 y in middle childhood. If PACE similarly predicts adiposity gain in a cohort with greater racial and socioeconomic diversity, it will inform the development of interventions to prevent obesity. This trial was registered at clinicaltrials.gov as NCT03341247.

The Cerebellar Response to Visual Portion Size Cues Is Associated with the Portion Size Effect in Children.

The neural mechanisms underlying susceptibility to eating more in response to large portions (i.e., the portion size effect) remain unclear. Thus, the present study examined how neural responses to portion size relate to changes in weight and energy consumed as portions increase. Associations were examined across brain regions traditionally implicated in appetite control (i.e., an appetitive network) as well as the cerebellum, which has recently been implicated in appetite-related processes. Children without obesity (i.e., BMI-for-age-and-sex percentile < 90; N = 63; 55% female) viewed images of larger and smaller portions of food during fMRI and, in separate sessions, ate four meals that varied in portion size. Individual-level linear and quadratic associations between intake (kcal, grams) and portion size (i.e., portion size slopes) were estimated. The response to portion size in cerebellar lobules IV-VI was associated with the quadratic portion size slope estimated from gram intake; a greater response to images depicting smaller compared to larger portions was associated with steeper increases in intake with increasing portion sizes. Within the appetitive network, neural responses were not associated with portion size slopes. A decreased cerebellar response to larger amounts of food may increase children's susceptibility to overeating when excessively large portions are served.

Does 'portion size' matter? Brain responses to food and non-food cues presented in varying amounts.

Larger portions of food elicit greater intake than smaller portions of food, particularly when foods are high in energy density (kcal/g; ED). The neural mechanisms underlying this effect remain unclear. The present study used fMRI to assess brain activation to food (higher-ED, lower-ED) and non-food (office supplies) images presented in larger and smaller (i.e., age-appropriate) amounts in 61, 7-8-year-olds (29 male, 32 female) without obesity. Larger amounts of food increased activation in bilateral visual and right parahippocampal areas compared to smaller amounts; greater activation to food amount (larger > smaller) in this cluster was associated with smaller increases in food intake as portions increased. Activation to amount (larger > smaller) was stronger for food than office supplies in primary and secondary visual areas, but, for office supplies only, extended into bilateral parahippocampus, inferior parietal cortex, and additional visual areas (e.g., V7). Activation was greater for higher-vs. lower-ED food images in ventromedial prefrontal cortex for both larger and smaller amounts of food; however, this activation extended into left lateral orbital frontal cortex for smaller amounts only. Activation to food cues did not differ by familial risk for obesity. These results highlight potentially distinct neural pathways for encoding food energy content and quantity.

Children with lower ratings of executive functions have a greater response to the portion size effect.

Deficits in executive functions (EFs), a set of cognitive processes related to self-regulation, are associated with the development of obesity. Prior studies from our group showed that lower food-cue related activation in brain regions implicated in self-regulation was related to a larger portion size effect. We tested the hypothesis that lower EFs in children would be positively related to the portion size effect. Healthy weight children aged 7-8 y (n = 88), who varied by maternal obesity status, participated in a prospective study. At baseline, the parent primarily in charge of feeding completed the Behavior Rating Inventory of Executive Function (BRIEF2) to assess child EFs, including Behavioral (BRI), Emotional (ERI), and Cognitive (CRI) indices. At 4 baseline sessions, children consumed meals in which the portion sizes of foods (pasta, chicken nuggets, broccoli, and grapes) varied by visit (total meal weight of 769, 1011, 1256, or 1492g). Intake increased with increasing portions in a linear trajectory (p < 0.001). EFs moderated the portion size effect such that lower BRI (p = 0.003) and ERI (p = 0.006) were associated with steeper increases in intake as portions increased. As amount of food increased, children in the lowest functioning tertiles for BRI and ERI increased intake by 35% and 36%, respectively, compared to children in the higher tertiles. Increases in intake among children with lower EFs were for higher- but not lower-energy-dense foods. Thus, in healthy weight children who varied by obesity risk, lower parentally reported EFs were associated with a larger portion size effect, and these results were independent of child and parent weight status. Therefore, EFs may be target behaviors that could be strengthened to help children moderate excess intake in response to large portions of energy-dense foods.

Loss of control eating in children is associated with altered cortical and subcortical brain structure.

Introduction: Loss of control (LOC) eating is the perceived inability to control how much is eaten, regardless of actual amount consumed. Childhood LOC-eating is a risk factor for the development of binge-eating disorder (BED), but its neurobiological basis is poorly understood. Studies in children with BED have shown both increased gray matter volume in regions related to top-down cognitive control (e.g., dorsolateral prefrontal cortex) and reward-related decision making (e.g., orbital frontal cortex) relative to healthy controls. However, no studies have examined brain structure in children with LOC-eating. To identify potential neurobiological precursors of BED, we conducted secondary analysis of five studies that conducted T1 MPRAGE scans. Methods: A total of 143, 7-12-year-old children (M = 8.9 years, 70 boys) were included in the study, 26% of which (n = 37) reported LOC-eating (semi-structured interview). Age, sex, and obesity status did not differ by LOC-eating. Differences between children with and without LOC were examined for gray matter volume, cortical thickness, gyrification, sulci depth, and cortical complexity after adjusting for age, sex, total intercranial volume, weight status, and study. Results: Children with LOC, relative to those without, had greater gray matter volume in right orbital frontal cortex but lower gray matter volume in right parahippocampal gyrus, left CA4/dentate gyrus, and left cerebellar lobule VI. While there were no differences in cortical thickness or gyrification, children with LOC-eating had great sulci depth in left anterior cingulate cortex and cuneus and greater cortical complexity in right insular cortex. Discussion: Together, this indicates that children with LOC-eating have structural differences in regions related to cognitive control, reward-related decision-making, and regulation of eating behaviors.

The role of reinforcement learning and value-based decision-making frameworks in understanding food choice and eating behaviors.

The obesogenic food environment includes easy access to highly-palatable, energy-dense, "ultra-processed" foods that are heavily marketed to consumers; therefore, it is critical to understand the neurocognitive processes the underlie overeating in response to environmental food-cues (e.g., food images, food branding/advertisements). Eating habits are learned through reinforcement, which is the process through which environmental food cues become valued and influence behavior. This process is supported by multiple behavioral control systems (e.g., Pavlovian, Habitual, Goal-Directed). Therefore, using neurocognitive frameworks for reinforcement learning and value-based decision-making can improve our understanding of food-choice and eating behaviors. Specifically, the role of reinforcement learning in eating behaviors was considered using the frameworks of (1) Sign-versus Goal-Tracking Phenotypes; (2) Model-Free versus Model-Based; and (3) the Utility or Value-Based Model. The sign-and goal-tracking phenotypes may contribute a mechanistic insight on the role of food-cue incentive salience in two prevailing models of overconsumption-the Extended Behavioral Susceptibility Theory and the Reactivity to Embedded Food Cues in Advertising Model. Similarly, the model-free versus model-based framework may contribute insight to the Extended Behavioral Susceptibility Theory and the Healthy Food Promotion Model. Finally, the value-based model provides a framework for understanding how all three learning systems are integrated to influence food choice. Together, these frameworks can provide mechanistic insight to existing models of food choice and overconsumption and may contribute to the development of future prevention and treatment efforts.

Heterogeneity in PFC-amygdala connectivity in middle childhood, and concurrent interrelations with inhibitory control and anxiety symptoms.

The prefrontal cortex (PFC) is a key brain area in considering adaptive regulatory behaviors. This includes regulatory projections to regions of the limbic system such as the amygdala, where the nature of functional connections may confer lower risk for anxiety disorders. The PFC is also associated with behaviors like executive functioning. Inhibitory control is a behavior encompassed by executive functioning and is generally viewed favorably for adaptive socioemotional development. Yet, some research suggests that high levels of inhibitory control may actually be a risk factor for some maladaptive developmental outcomes, like anxiety disorders. In a sample of 51 children ranging from 7 to 9 years old, we examined resting state functional connectivity between regions of the PFC and the amygdala. We used Subgrouping Group Iterative Multiple Model Estimation (S-GIMME) to identify and characterize data-driven subgroups of individuals with similar networks of connectivity between these brain regions. Generated subgroups were collapsed into children characterized by the presence or absence of recovered connections between the PFC and amygdala. For subsets of children with available data (N = 38-44), we then tested whether inhibitory control, as measured by a stop signal task, moderated the relation between these subgroups and child-reported anxiety symptoms. We found an inverse relation between stop-signal reaction times and reported count of anxiety symptoms when covarying for connectivity group, suggesting that greater inhibitory control was actually related to greater anxiety symptoms, but only when accounting for patterns of PFC-amygdala connectivity. These data suggest that there is a great deal of heterogeneity in the nature of functional connections between the PFC and amygdala during this stage of development. The findings also provide support for the notion of high levels of inhibitory control as a risk factor for anxiety, but trait-level biopsychosocial factors may be important to consider in assessing the nature of risk.

Influence of exclusive breastfeeding on hippocampal structure, satiety responsiveness, and weight status.

Longer exclusive breastfeeding duration has been associated with differences in neural development, better satiety responsiveness, and decreased risk for childhood obesity. Given hippocampus sensitivity to diet and potential role in the integration of satiety signals, hippocampus may play a role in these relationships. We conducted a secondary analysis of 149, 7-11-year-olds (73 males) who participated in one of five studies that assessed neural responses to food cues. Hippocampal grey matter volume was extracted from structural scans using CAT12, weight status was assessed using age- and sex-adjusted body mass index (%BMIp85 ), and parents reported exclusive breastfeeding duration and satiety responsiveness (Children's Eating Behaviour Questionnaire). Separate path models for left and right hippocampus tested: (1) the direct effect of exclusive breastfeeding on satiety responsiveness and its indirect effect through hippocampal grey matter volume; (2) the direct effect of hippocampal grey matter volume on %BMIp85 and its indirect effect through satiety responsiveness. %BMIp85 was adjusted for maternal education, yearly income, and premature birth while hippocampal grey matter volume was adjusted for total intercranial volume, age, and study from which data were extracted. Longer exclusive breastfeeding duration was associated with greater bilateral hippocampal grey matter volumes. In addition, better satiety responsiveness and greater left hippocampal grey matter volume were both associated with lower %BMIp85 . However, hippocampal grey matter volumes were not associated with satiety responsiveness. Although no relationship was found between breastfeeding and child weight status, these results highlight the potential impact of exclusive breastfeeding duration on the hippocampal structure.

Decision-Making Processes Related to Perseveration Are Indirectly Associated With Weight Status in Children Through Laboratory-Assessed Energy Intake.

Decision-making contributes to what and how much we consume, and deficits in decision-making have been associated with increased weight status in children. Nevertheless, the relationships between cognitive and affective processes underlying decision-making (i.e., decision-making processes) and laboratory food intake are unclear. We used data from a four-session, within-subjects laboratory study to investigate the relationships between decision-making processes, food intake, and weight status in 70 children 7-to-11-years-old. Decision-making was assessed with the Hungry Donkey Task (HDT), a child-friendly task where children make selections with unknown reward outcomes. Food intake was measured with three paradigms: (1) a standard ad libitum meal, (2) an eating in the absence of hunger (EAH) protocol, and (3) a palatable buffet meal. Individual differences related to decision-making processes during the HDT were quantified with a reinforcement learning model. Path analyses were used to test whether decision-making processes that contribute to children's (a) expected value of a choice and (b) tendency to perseverate (i.e., repeatedly make the same choice) were indirectly associated with weight status through their effects on intake (kcal). Results revealed that increases in the tendency to perseverate after a gain outcome were positively associated with intake at all three paradigms and indirectly associated with higher weight status through intake at both the standard and buffet meals. Increases in the tendency to perseverate after a loss outcome were positively associated with EAH, but only in children whose tendency to perseverate persistedacross trials. Results suggest that decision-making processes that shape children's tendencies to repeat a behavior (i.e., perseverate) are related to laboratory energy intake across multiple eating paradigms. Children who are more likely to repeat a choice after a positive outcome have a tendency to eat more at laboratory meals. If this generalizes to contexts outside the laboratory, these children may be susceptible to obesity. By using a reinforcement learning model not previously applied to the study of eating behaviors, this study elucidated potential determinants of excess energy intake in children, which may be useful for the development of childhood obesity interventions.

Intrinsic connections between thalamic sub-regions and the lateral prefrontal cortex are differentially impacted by acute methylphenidate.

BACKGROUND: The thalamus is a major target of dopaminergic projections and is densely connected with the prefrontal cortex. A better understanding of how dopamine changes thalamo-cortical communication may shed light on how dopamine supports cognitive function. Methylphenidate has been shown to facilitate cognitive processing and reduce connectivity between the thalamus and lateral prefrontal cortex. AIMS: The thalamus is a heterogeneous structure, and the present study sought to clarify how the intrinsic connections of thalamic sub-regions are differentially impacted by acute dopamine transporter blockade. METHODS: Sixty healthy volunteers were orally administered either 20 mg of methylphenidate (N = 29) or placebo (N = 31) in a double-blind, randomized, between-subject design. Multi-echo fMRI was used to assess intrinsic functional connectivity of sub-regions of the thalamus during a resting state scan. An N-back working-memory paradigm provided a measure of cognitive performance. RESULTS: Acute methylphenidate significantly reduced connectivity of the lateral prefrontal cortex with the motor and somatosensory sub-regions of the thalamus and reduced connectivity with the parietal and visual sub-regions at a trend level. Connectivity with the premotor, prefrontal, and temporal sub-regions was not impacted. The intrinsic connectivity between the thalamus and the lateral prefrontal cortex was not associated with working-memory performance. CONCLUSIONS: Methylphenidate decreases functional connections between the lateral prefrontal cortex and thalamus broadly, while sparing intrinsic connectivity with thalamic sub-regions involved with working-memory and language related processes. Collectively, our results suggest that the dopamine transporter regulates functional connections between the prefrontal cortex and non-cognitive areas of the thalamus.

Resting-state connectivity of the bed nucleus of the stria terminalis and the central nucleus of the amygdala in clinical anxiety

Background: The central nucleus of the amygdala and bed nucleus of the stria terminalis are involved primarily in phasic and sustained aversive states. Although both structures have been implicated in pathological anxiety, few studies with a clinical population have specifically focused on them, partly because of their small size. Previous work in our group used high-resolution imaging to map the restingstate functional connectivity of the bed nucleus of the stria terminalis and the central nucleus of the amygdala in healthy subjects at 7 T, confirming and extending structural findings in humans and animals, while providing additional insight into cortical connectivity that is potentially unique to humans. Methods: In the current follow-up study, we contrasted resting-state functional connectivity in the bed nucleus of the stria terminalis and central nucleus of the amygdala at 7 T between healthy volunteers (n = 30) and patients with generalized and/or social anxiety disorder (n = 30). Results: Results revealed significant voxel-level group differences. Compared with healthy volunteers, patients showed stronger resting-state functional connectivity between the central nucleus of the amygdala and the lateral orbitofrontal cortex and superior temporal sulcus. They also showed weaker resting-state functional connectivity between the bed nucleus of the stria terminalis and the dorsolateral prefrontal cortex and occipital cortex. Limitations: These findings depart from a previous report of resting-state functional connectivity in the central nucleus of the amygdala and bed nucleus of the stria terminalis under sustained threat of shock in healthy volunteers. Conclusion: This study provides functional MRI proxies of the functional dissociation of the bed nucleus of the stria terminalis and central nucleus of the amygdala, and suggests that resting-state functional connectivity of key structures in the processing of defensive responses do not recapitulate changes related to induced state anxiety. Future work needs to replicate and further probe the clinical significance of these findings.

A Biopsychosocial Model of Sex Differences in Children's Eating Behaviors.

The prevalence of obesity and eating disorders varies by sex, but the extent to which sex influences eating behaviors, especially in childhood, has received less attention. The purpose of this paper is to critically discuss the literature on sex differences in eating behavior in children and present new findings supporting the role of sex in child appetitive traits and neural responses to food cues. In children, the literature shows sex differences in food acceptance, food intake, appetitive traits, eating-related compensation, and eating speed. New analyses demonstrate that sex interacts with child weight status to differentially influence appetitive traits. Further, results from neuroimaging suggest that obesity in female children is positively related to neural reactivity to higher-energy-dense food cues in regions involved with contextual processing and object recognition, while the opposite was found in males. In addition to differences in how the brain processes information about food, other factors that may contribute to sex differences include parental feeding practices, societal emphasis on dieting, and peer influences. Future studies are needed to confirm these findings, as they may have implications for the development of effective intervention programs to improve dietary behaviors and prevent obesity.

Impact of induced anxiety on neural responses to monetary incentives.

Previous research demonstrates that aversive stimuli can interrupt appetitive processing and that brain regions involved with the processing of potential rewards, such as the ventral striatum (VS), also respond to threatening information. Potential losses can likewise activate the VS and, thus, the full extent to which threat can impact neural responses during incentive processing remains unclear. Here, unpredictable threat of shock was used to induce anxiety while participants performed the monetary incentive delay (MID) task during functional magnetic resonance imaging (fMRI). During anticipation, anxiety impacted neural responses within the bilateral VS and distributed regions of the occipital cortex. Anxiety enhanced activity within the VS to both gain and loss trials. Furthermore, anxiety enhanced activity to both gain and loss trials within dorsal areas of BA19. However, anxiety only enhanced activity during gain, but not loss trials, within ventral areas of BA19. These results suggest that during anticipation, induced anxiety enhanced VS activity to incentives generally, which might reflect changes in the subjective salience of gains and losses. Collectively, these results suggest that the impact of induced anxiety on responses to monetary incentives depend on the neural region, type of incentive, and stage of processing.