Converging evidence on neural substrates of abnormal food intake and obesity has implicated somewhat overlapping but distinct neural circuits related to hunger/satiety, reward, and self-control. Our results extend these findings and suggest unique patterns of brain activation in these regions in two groups of individuals with different types of obesity: one group with a genetic syndrome and phenotype that includes extreme overeating (PWS), the other with (idiopathic) OB. Specifically, we report hyperactivations in response to visual food stimuli in individuals with PWS compared to BMI-matched OB subjects in subcortical regions (hypothalamus, hippocampus) depending on appetitive state. Altered function in the amygdala in PWS vs. OB was unaffected by state, with hyperactivation both before and after meal consumption. In particular, post-meal abnormalities in the amygdala resulted from failure to demonstrate decreased activation, which could be one factor affecting disruption of satiety mechanisms in PWS. More strikingly, individuals with PWS displayed significant hypoactivity in prefrontal cortical regions (posterior/lateral OFC, DLPFC) post-meal. The brain activation patterns distinguishing these groups map well onto the differences observed between PWS and OB in eating behavior (extreme hyperphagia versus moderate overeating), energy expenditure (very low versus moderately low), and appetite-regulatory peptide levels (hyperghrelinemia versus low ghrelin), and thus support the conceptualization of PWS as a model of extreme obesity.
Pre-meal subcortical hyperactivation in response to visual food stimuli and to glucose ingestion has been documented previously in OB1
in comparison to healthy-weight controls, and post-meal in OB4
and in PWS30,39,40
. These regions (hypothalamus, amygdala, hippocampus), which are densely populated with ghrelin receptors41–46
, are involved in basic hunger and satiety signaling45
, reward and approach behaviors related to food47–50
, and emotion-modulated memory processes involved with food51
, respectively. Our results replicate and extend these findings by demonstrating that subcortical reward circuitry hyperactivation in response to food stimuli is a hallmark of obesity and disorders of obesity (i.e., PWS), and is independent of appetitive state.
The most noteworthy finding in this study relates to post-meal differences between PWS and simple OB in putative cortical inhibitory regions (DLPFC, OFC) with significant effect sizes in the range of 0.75 to 1.0 full standard deviation from the mean. We note the paradigm used in the current study did not directly manipulate inhibitory demands or measure inhibition outside of the scanner. However, the DLPFC is well-established as a critical inhibitory region, associated with suppression of motor responses52
and higher-level cognitive processes such as self-control in goal-directed behavior and decision-making53,54
, including issues involving food intake. Evidence for this role includes greater DLPFC activation in response to: meal consumption in successful dieters compared with non-dieting obese individuals55
, food pictures15
for obese children15
and adult males56
in comparison to healthy-weight counterparts, self-control trials for high-self-controllers versus non-self-controllers13
, inhibitory control in a food go/no-go task in lean compared with overweight adolescents57
, and tasting palatable food14
for individuals with high dietary restraint scores. Thus, based on previous findings of activation in this region during tasks requiring inhibition58–60
, one possible interpretation of the current DLPFC hypoactivation in PWS is that it reflects deficits in inhibitory control. Hypoactivation in similar frontal regions in a task-switching paradigm has also been reported in PWS, providing additional evidence of prefrontal circuitry deficits related to executive functioning61
. This hypothesis should be more directly tested in future studies. Further, genetic variability related to subtle differences in behavioral profiles in PWS62
was significantly associated with differential activation of DLPFC post-meal39
, suggesting a genetic basis for abnormal activation in this cortical region associated with inhibitory control in obesity. Failure of DLPFC recruitment in PWS may result from abnormalities in GABAA
receptors in the frontal cortex63
, likely related to deletion of GABA receptor subunit genes from the ~6-Mb PWS region of chromosome 1518
. Our work to further define the brain phenotype in PWS will help direct molecular genetics studies to identify additional genes and polymorphisms on chromosome 15 associated with specific brain abnormalities. This may, in turn, contribute to understanding genes associated with brain circuitry implicated in OB.
Our findings suggest that hyperactivation of the DLPFC post-meal might be associated with either the greater ability or heightened need to inhibit food-related behaviors and intake, reflecting the necessity of additional top-down inhibition in the presence of high-reward food stimuli. In light of these results, we suggest that hyperactivation of DLPFC in OB versus PWS post-meal might reflect successful recruitment (i.e., ability to activate the DLPFC in a situation requiring inhibition) of this important inhibitory self-control region in individuals who overeat moderately, and unsuccessful activation of DLPFC in PWS, contributing to hyperphagia and excessive overeating.
PWS is associated with intellectual disability, including deficits in abstract reasoning and executive functioning, domains which are also governed substantially by DLPFC. Thus, to parse out what might be driving hypoactivation in this region, we explored the relationships between DLPFC activation and specific executive functioning and general cognitive ability. PWS hypoactivation in DLPFC was unrelated to memory for food items and moderately associated with general IQ, which is not surprising, given that the DLPFC is involved in multiple executive processes. However, we argue that global intellectual deficits were not driving the DLPFC effects of inhibition around food, given the strongest correlation (although not significant) was between DLPFC activation and TFEQ, suggesting the most substantial link was between deficits in this area and food-related behaviors. Based on these findings, inability to recruit the DLPFC in response to food cues after eating may represent what distinguishes PWS from OB.
In addition to hypoactivation of DLPFC in the current study, PWS exhibited lower activation post-meal compared with OB in left posterior-lateral OFC, a region associated with evaluation of simple stimuli (such as food images) in the context of punishment leading to behavior changes64
. OFC hypoactivation in response to food stimuli post-meal has previously been associated with higher BMI10,11
, including in individuals with fewer striatal dopamine receptors7
. Further, dysfunction in the amygdala’s modulation of OFC was reported in OB65
, and OFC volume was specifically decreased in PWS compared with healthy controls66
We hypothesize that concurrent dysfunction in OFC and DLPFC in PWS might significantly impair the ability to effectively inhibit food intake during states of low appetite (post-meal, when consumption would be primarily for hedonic purposes rather than energy balance maintenance). We argue that subcortical hyperactivation combined with cortical hypoactivation contributes importantly to the phenotype of excessive hunger, uncontrollable food seeking behavior, and hyperphagia in PWS as distinct from OB, in which more intact functioning in these regions results in a less extreme behavioral profile.
In the current investigation, we replicated previous findings from fMRI studies comparing PWS versus HWC28,29,39
and OB versus HWC1,3,10
, with results suggesting hyperactivation in subcortical and cortical food motivation regions in the OB and PWS groups both pre- and post-meal. To date, our study includes the largest sample in an fMRI study of BMI-matched PWS and OB groups; thus inconsistencies between previous studies may be resolved given increased statistical power of our tests. In addition to these strengths, we note the following limitations of this study. Rather than match meal sizes to each subject’s corresponding caloric homeostatic needs, we developed our meal size according to the restricted diets that are characteristic for PWS, which may have influenced the level to which each individual felt satiated and affected patterns of activation. However, given that our OB and PWS groups were matched on BMI, this was unlikely to be a confounder. We did not assess hunger level before and after the meal, which might have assisted in validating the satiating effect of the meal across groups. Future studies should incorporate hunger ratings that can be used with individuals with and without intellectual disabilities. In our sample, the PWS group likely had a significantly lower mean IQ than the other groups. However, behavioral results indicated greater-than-chance accuracy on the recognition memory test in all groups, suggesting that all subjects were able to perform the task. The original design of this study did not include neurobehavioral testing in OB and HWC, so we were unable to explore relationships between brain activity and other cognitive/behavioral functioning which may contribute to understanding differences between PWS and OB. In our PWS sample, data acquired under slightly different TEs were included reflecting inter-instrumental differences. The minimal effect (~3%) on the contrast-to-noise ratio was less than the expected experimental variation. Indeed, sub-analysis of the KUMC data yielded similar findings (data not shown), indicating that site and TE differences did not affect our results. Finally, there are significant sex differences in obesity67
, and several of our ROIs are sexually dimorphic68
. Given that the majority of our participants were female, especially in the PWS group, it was not possible to conduct an analysis of sex differences. However, analysis of females and males found qualitatively similar results.
In summary, this study demonstrates dysfunction in dual circuits which are involved in the regulation of food reward and in putative decision-making processes regarding food intake in individuals with PWS, a putative model of extreme obesity compared with OB. In a post-meal state, PWS compared to OB demonstrated hyperactivations in the subcortical regions associated with hunger and food motivation and hypoactivations in cortical regions involved in self-control during food-related decision-making. These findings provide evidence of distinct neural patterns that correspond with group differences in eating behavior (degree of overeating) despite similar BMI levels, and suggest neural pathways that can be targeted in future studies of the treatment of obesity and related conditions.