Michael Michaelides, PhD, is a research associate, Medical Department, Brookhaven National Laboratory, Upton, NY; and a postdoctoral fellow, Departments of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY. Panayotis K. Thanos, PhD, is a guest scientist, Medical Department, Brookhaven National Laboratory, Upton, NY; a staff scientist, Laboratory of Neuroimaging, National Institute for Alcohol Abuse and Alcoholism, Bethesda, MD; and an associate research professor, Departments of Psychology and Neuroscience, Stony Brook University, Stony Brook, NY. Nora D. Volkow, MD, is the Director, National Institute on Drug Abuse, Bethesda, MD; and a staff scientist, Laboratory of Neuroimaging, National Institute for Alcohol Abuse and Alcoholism, Bethesda, MD. Gene-Jack Wang, MD, is a senior scientist and the Chairman, Medical Department, Brookhaven National Laboratory, Upton, NY; and a professor, Department of Psychiatry, Mount Sinai School of Medicine, New York, NY.
The project is supported in part by NIH: 5T32DA007135 (Dr. Michaelides), Z01AA000550 (Dr. Volkow) and R01DA06278 (Dr. Wang).
Drs. Michaelides, Thanos, Volkow, and Wang have disclosed no relevant financial relationships.
Address correspondence to: Gene-Jack Wang, MD, 30 Bell Ave., Building 490, Medical Department, Brookhaven National Laboratory, Upton, NY 11973; fax: 631-344-2358; email: firstname.lastname@example.org.
Obesity is a growing community health problem. The dramatic rise in childhood cases of obesity and type-2 diabetes in recent years is especially alarming.1,2 Similar increases in pediatric cases of depression have also been reported.3 These escalating trends foreshadow future increases in physical and mental health problems,4 which in turn necessitate the use of novel methods to understand and treat obesity and its related comorbidities.4
While obesity traditionally has been considered a disease of the body, the brain’s contribution in mediating dietary choices, initiating exercise, and influencing metabolism cannot be overstated. Functional neuroimaging of brain activity in both normal weight and obese individuals during basal conditions, as well as during food chemosensory stimulation, gastric manipulations, periods of cravings, and post-bariatric surgery in obese patients have revealed more about how obesity is affected by the brain.5–8
Obesity is characterized by functional impairment within discrete brain regions and neurotransmitter circuits that have well-described roles in mood, motivation, reward, memory, and inhibitory control. Several of the activated brain regions and circuits play important roles in psychiatric disorders such as depression, anxiety, attention-deficit/hyperactivity disorder (ADHD), addiction, and eating disorders.
Positron Emission Tomography
Positron emission tomography (PET) is a noninvasive molecular imaging modality that uses positron-emitting radio-tracers to visualize and quantify their respective uptake in biological tissue. PET is a valuable tool for clinical research because it allows within-subject monitoring of radiotracer uptake dynamically (within one imaging session) and longitudinally (within multiple imaging sessions). PET has been used for studying neurobiological markers in obesity.
Among these, [15O]-water, used to measure regional cerebral blood flow; the glucose analog 2-deoxy-2-(18F)fluoro-D-glucose (FDG), used to measure brain metabolic activity; and the dopamine (DA) D2 receptor (D2R) antagonist [11C] raclopride have been used to observe the connection between meal ingestion, food presentation, and obesity.
Both brain uptake of [15O]-water and FDG are used as markers of brain activation while [11C]raclopride, which binds with regional selectively to D2R in the striatum (a component of the basal ganglia heavily implicated in reward), is used as a marker of brain DA function.
Notable strengths of PET include its minimal invasiveness (ie, venous and arterial catheterizations), high sensitivity and reproducibility, as well as its ability to study discrete molecular targets and mechanisms. Minimal invasiveness and molecular specificity allow PET to be used for disease prevention (assuming the use of established biomarkers); high sensitivity and reproducibility allow detection of disease progression. These features make PET a very promising imaging modality for use in both clinical and research settings.
In the clinical setting, PET can aid in disease diagnosis and response to treatment. In the research setting, PET can aid in the discovery of disease biomarkers.
Aside from these strengths, PET has several weaknesses. The most notable weaknesses include radiation exposure for patients and staff, as well as logistical capacity for radiotracer design and production. In most cases, radiation exposure is low, since PET detection sensitivity is high and most radiotracers are labeled with short-lived radioisotopes. Nevertheless, this is still a limiting factor in its prevalence of use, especially in children, adolescents, and during pregnancy.
Another limitation is its relatively low spatial resolution when compared to other modalities. Dual modality PET/CT (computed tomography) and PET/MRI (magnetic resonance imaging) scanners have significantly enhanced the localization accuracy of radiotracer accumulation in tissues.
Other limitations include radiotracer availability due to unique kinetic properties in tissue (slow-acting, fast-acting, etc); pharmacology (target affinity, specific versus non-specific binding profile, etc); and side effects (physiological effects of radio-tracer administration). The term “tracer” denotes the presence of “trace” amounts of the radiolabeled compound being administered. This is not a critical shortcoming, but should be considered.
Radiotracer kinetics can be modulated by metabolism, and since obese patients are characterized by altered metabolic states, it is important to take into account certain physiological variables (ie, blood pressure, heart rate, body weight, adiposity, and circulating glucose, etc) during scanning, for purposes of normalization between patients.
For example, FDG is taken up by both the brain as well as skeletal muscle (albeit significantly less in muscle than brain). Because obese people are characterized by lower skeletal muscle mass, such factors may need to be taken into account. Furthermore, circulating glucose directly competes with FDG uptake.9 Because obese patients are frequently hyperinsulinemic/insulin-resistant (thus have high-circulating glucose concentrations) or have type 2 diabetes (low insulin/high glucose), such patients need to be carefully screened; circulating glucose content should be used to normalize FDG uptake in brain.
Therefore, it is imperative that FDG PET studies in obese patients take both physiological and metabolic variables into account during scanning and recognize that the high plasma glucose levels may interfere with absolute estimates of regional glucose metabolism. Aside from direct physiological and metabolic effects on radiotracer uptake in tissue and brain, indirect effects due to the cognitive state of patients during scanning may also affect PET radiotracer kinetics and target occupancy.10 Such effects would be particularly important and would need to be taken into account in studies that are aimed at elucidating cognitive mechanisms associated with obesity and psychiatric disease.
Brain Response to Food Presentation and Taste
Food is essential for survival, and therefore, brain activity is expected to be highly sensitive to food stimuli and tightly coupled to energy status (ie, starvation, overweight). Indeed, food presentation with and without taste has been shown to preferentially activate the brain.11,12 Using the radiotracer [15O]-water, which measures regional cerebral blood flow (rCBF), taste stimulation increased rCBF in temporal cortex, thalamus, cingulate cortex, striatum, and hippocampus in normal-weight patients.11 Similar preferential changes in brain metabolic activity with FDG during food presentation (without taste) were localized to cortical regions (temporal cortex, insula, orbitofrontal cortex). Increased brain metabolism in the orbitofrontal cortex in particular was correlated with both hunger and desire for the presented food.12
During food presentation in both studies, the areas that showed greatest activation were not subcortical areas that are expected to be primarily involved in physiological aspects related to feeding (ie, hypothalamus, thalamus, brainstem, etc) but cortical areas that are associated with higher-order cognitive functions (decision-making, memory, etc). These findings showed the involvement of the orbitofrontal cortex and striatum, as well as limbic regions such as the amygdala and hippocampus in mediating brain activity in these regions during food presentation. These regions have been implicated in emotional regulation, conditioning, and motivation.
Patients also were asked to inhibit their craving through will power during food presentation. Men were found to better suppress the activation of the orbitofrontal cortex during cognitive inhibition of craving brought upon by food presentation. These results suggest a mechanism by which cognitive capacity to inhibit craving decreases the desire for food and that this mechanism differs with gender.13
Associations between being overweight and having decreased frontal activity in obese people has been suggested to underlie impairments in cognitive tasks of executive function.14 Neuroimaging studies on obesity suggest that the human brain is hardwired to respond with a distinct neural signature to taste, as well as food cues and the extent of this response may reflect the degree of related physiological, cognitive, and emotional states such as hunger, satiation, stress, and so on.
The implication of orbitofrontal cortex and caudate (striatum) involvement in brain responses to food is particularly intriguing given their well-defined roles in decision-making, impulsivity, reward, as well as in mood and anxiety disorders.15,16 Orbitofrontal cortex involvement has been implicated in obsessive compulsive disorder17 and hoarding disorders;18 psychiatric behavioral manifestations that may have roots in evolutionary feeding behaviors.
Somatosensory Cortex Activation in Obesity
Research has established that obese, relative to normal-weight, people are characterized by increased brain activity, specifically in oral sensory processing-related brain areas (oral somatosensory cortex).19 This finding generalizes to the notion that feeding, and perhaps learned food cues, might elicit a notable response in the areas of the brain that encode oral somatosensory function (sensory input from mouth, lips, etc) in obesity.
It is, therefore, possible that impaired chemosensory processing of food may potentially predispose an individual to overeating due to a lack of hedonic/pleasure derived during eating, or to impaired homeostatic and nutrient-sensing interoceptive feedback mechanisms relating to satiety. Maladaptive decisions regarding food choices (ie, impaired taste leading to consuming food with high salt, fat or sugar content) can also lead to obesity.
Gastric Distention Activates Brain Circuitry in Obesity
Our recent findings of impaired interoceptive feedback mechanisms in obesity support the notion that impaired brain-gut interoceptive processing of food facilitates the propensity to overeat. Our group has recently implicated the involvement of interoceptive signals (ie, afferent signals originating in the gut during digestion) in food-related satiety and reward. In particular, we assessed the effects of implantable gastric stimulation (IGS) on brain metabolism using FDG and PET in obese humans.20
IGS is a surgical manipulation used for clinical obesity management and relies on implanting a device that electrically stimulates the enteric nervous system, disrupting gastric motility.20 This intervention showed some effectiveness in decreasing food consumption, blood pressure and body weight in obese humans,21 leading to the hypothesis that therapeutic efficacy of IGS involves modulation of food satiety signals similar to postprandial signals to the brain originating from the vagus nerve. IGS in obese patients led to increased brain metabolism in parts of the brain associated with memory (hippocampus); reward and goal directed behaviors (striatum); motor function/coordination (cerebellum); and inhibitory control/decision-making/mood (orbitofrontal cortex). Increased brain activity in the above brain areas during IGS was related to concurrent decreases in “emotional eating” scores.
Such findings demonstrate that interoceptive signals related to feeding and potentially to satiety, concurrently activate brain areas involved in feeding; these activations may be related to emotional aspects of feeding. This implies a strong connection between brain function, emotionality, and feeding-related physiology. It also reinforces the recent epidemiological findings of increased prevalence of mood and anxiety disorders in obese people.1 This view is supported by another study in which gastric distention and its effects on brain activity (rCBF) was also demonstrated in normal-weight women with PET and [15O]-water during gastric balloon inflection and deflection. This study showed gastric distention increased rCBF in frontal cortical areas (left inferior frontal gyrus; bilateral insula; and anterior cingulate cortex), as well as in the dorsal brain stem (where afferent gut signals project).22
Brain Dopamine in Obesity and Binge-Eating Disorder
One of the brain mechanisms that may be involved in mediating brain responses to feeding is dopamine (DA). Brain DA in the striatum, a component of the basal ganglia (the brain’s “reward center”) has been implicated in both food motivation and obesity. One of our first studies using [11C]raclopride demonstrated that obese people show decreased striatal D2R.23 Similar findings using another D2R radiotracer ([11C]FLB 457) that binds to extrastriatal D2R were also reported with D2R in the amygdala being correlated with the personality trait of harm avoidance.24
Using the D2R antagonist [11C]raclopride in conjunction with methylphenidate (which blocks the DA transporters and enhances the synaptic levels of DA), we showed that elevated synaptic DA levels in the striatum correlated with self-reports of hunger and the desire to consume food in normal-weight people.25 In a more recent study using the same imaging approach, we found that food presentation increased striatal DA in obese patients with binge-eating disorder (BED) but not in non-BED obese patients; these increases correlated with binge-eating scores.26
These findings suggest that striatal DA signaling is involved in food motivation, and thus, deficits in such signaling may predispose to eating disorders, overweight, and obesity (Figure, see page 498). By combining [11C]raclopride with FDG, we showed that decreased D2R in the striatum in obesity positively correlated with brain activity in prefrontal, orbitofrontal, cingulate gyrus, and somatosensory cortices.27
Figure. Images of positron emission tomography scans with [11C]raclopride showing that both cocaine and food cues are capable of eliciting similar increases in dopamine in the striatum of chronic cocaine abusers and obese binge-eaters respectively, suggesting that increases in striatal dopamine may commonly subserve conditioned reinforcement related to drugs, food, and perhaps other stimuli in psychiatric disorders. Source: Wang GJ, adapted from Wang GJ, et al. Obesity (Silver Spring). 2011;19(8):1601–1608; and Volkow ND, et al. Bioessays. 2010;32(9):748–755.
Other findings we have reported involve interactions between psychosocial and striatal DA deficits, which presumably may lead to feeding deficits. Such studies have shown that DA responses in the striatum were positively correlated with restraint behavior during food presentation.28
In the same study, emotionality and D2R binding were inversely related, suggesting that D2R deficits may coincide with susceptibility to emotional imbalances, factors that might be involved in overeating, since the affective state strongly influences feeding behavior.29 Prefrontal cortical and striatal connections comprise a circuit involved in inhibitory control, saliency attribution, and mood regulation, and these results suggest that functional interactions between frontal and striatal DA circuitry may act to regulate overeating, in part through their modulation of emotional reactivity.
Obese people are at increased risk for certain psychiatric disorders (ie, depression, eating disorders, ADHD)30,31 and bariatric surgery worsens psychiatric symptoms in certain patients.31,32 Indeed, two studies to date have reported effects of gastric bypass surgery on D2R binding with PET. Dunn and colleagues report decreased D2R binding 7 weeks after surgery,33 whereas Steele and colleagues report increased D2R binding 6 weeks after surgery.34 D2R binding with PET varies considerably between patients, and although surgical and imaging procedures from both studies were similar, the low sample size (n = 5 for each) does not allow robust generalizations to be made, and further studies are needed to address this issue.
Functional neuroimaging studies in obesity have shed light on the brain’s involvement obesity, and combined with neuropsychological testing and behavioral observations, have implicated an important role for the brain in mediating factors involved in cognitive and emotional regulation of feeding. Such studies have shown that preferential brain activation occurs in circuits and neurotransmitter systems involved in motivation, reward, memory, emotion, decision-making, sensory representation, and interoception during feeding and exposure to food cues and that this activation differs in obese and normal-weight people.
Therefore, overweight and obesity may be brought on by disturbances in one or more of these behaviors. More importantly, overweight and obesity may coincide with psychiatric disorders such as eating disorders, depression, anxiety disorders, and ADHD. In treating obesity, clinicians would benefit their patients by taking such factors into account during the design of appropriate treatments and therapeutic interventions.
- Faith MS, Butryn M, Wadden TA, Fabricatore A, Nguyen AM, Heymsfield SB. Evidence for prospective associations among depression and obesity in population-based studies. Obes Rev. 2011;12(5):e438–e453. doi:10.1111/j.1467-789X.2010.00843.x [CrossRef]
- Ogden CL, Carroll MD, Curtin LR, Lamb MM, Flegal KM. Prevalence of high body mass index in US children and adolescents, 2007–2008. JAMA. 2010;303(3):242–249. doi:10.1001/jama.2009.2012 [CrossRef]
- Collishaw S, Maughan B, Goodman R, Pickles A. Time trends in adolescent mental health. J Child Psychol Psychiatry. 2004;45(8):1350–1362. doi:10.1111/j.1469-7610.2004.00335.x [CrossRef]
- Puder JJ, Munsch S. Psychological correlates of childhood obesity. Int J Obes (Lond). 2010;34Suppl 2:S37–S43. doi:10.1038/ijo.2010.238 [CrossRef]
- Tomasi D, Wang GJ, Wang R, Backus W, Geliebter A, Telang F, Jayne MC, Wong C, Fowler JS, Volkow ND. Association of body mass and brain activation during gastric distention: implications for obesity. PLoS One. 2009;4(8):e6847. doi:10.1371/journal.pone.0006847 [CrossRef]
- Ochner CN, Kwok Y, Conceição E, Pantazatos SP, Puma LM, Carnell S, Teixeira J, Hirsch J, Geliebter A. Selective reduction in neural responses to high calorie foods following gastric bypass surgery. Ann Surg. 2011;253(3):502–507. doi:10.1097/SLA.0b013e318203a289 [CrossRef]
- Ng J, Stice E, Yokum S, Bohon C. An fMRI study of obesity, food reward, and perceived caloric density. Does a low-fat label make food less appealing?Appetite. 2011;57(1):65–72. doi:10.1016/j.appet.2011.03.017 [CrossRef]
- Wang G-J, Volkow ND, Fowler JS, Thanos PK. Neuroimaging of Obesity. In: Understanding Neuropsychiatric Disorder: Insight From Neuroimaging. Shenton ME, Turetsky BI, eds. Cambridge University Press, 2011. Chapter 34: 487–509.
- Wienhard K. Measurement of glucose consumption using [(18)F]fluorodeoxyglucose. Methods. 2002;27(3):218–225. doi:10.1016/S1046-2023(02)00077-4 [CrossRef]
- Yoder KK, Kareken DA, Morris ED. What were they thinking? Cognitive states may influence [11C]raclopride binding potential in the striatum. Neurosci Lett. 2008;430(1):38–42. doi:10.1016/j.neulet.2007.10.017 [CrossRef]
- Gautier JF, Chen K, Uecker A, et al. Regions of the human brain affected during a liquid-meal taste perception in the fasting state: a positron emission tomography study. Am J Clin Nutr. 1999;70(5):806–810.
- Wang GJ, Volkow ND, Telang F, et al. Exposure to appetitive food stimuli markedly activates the human brain. Neuroimage. 2004;21(4):1790–1797. doi:10.1016/j.neuroimage.2003.11.026 [CrossRef]
- Wang GJ, Volkow ND, Telang F, et al. Evidence of gender differences in the ability to inhibit brain activation elicited by food stimulation. Proc Natl Acad Sci U S A. 2009;106(4):1249–1254. doi:10.1073/pnas.0807423106 [CrossRef]
- Volkow ND, Wang GJ, Telang F, et al. Inverse association between BMI and prefrontal metabolic activity in healthy adults. Obesity (Silver Spring). 2009;17(1):60–65. doi:10.1038/oby.2008.469 [CrossRef]
- Blair RJ. Neuroimaging of psychopathy and antisocial behavior: a targeted review. Curr Psychiatry Rep. 2010;12(1):76–82. doi:10.1007/s11920-009-0086-x [CrossRef]
- Krishnan V, Nestler EJ. Linking molecules to mood: new insight into the biology of depression. Am J Psychiatry. 2010;167(11):1305–1320. doi:10.1176/appi.ajp.2009.10030434 [CrossRef]
- Aouizerate B, Guehl D, Cuny E, et al. Pathophysiology of obsessive-compulsive disorder: a necessary link between phenomenology, neuropsychology, imagery and physiology. Prog Neurobiol. 2004;72(3):195–221. doi:10.1016/j.pneurobio.2004.02.004 [CrossRef]
- Tolin DF, Kiehl KA, Worhunsky P, Book GA, Maltby N. An exploratory study of the neural mechanisms of decision making in compulsive hoarding. Psychol Med. 2009;39(2):325–336. doi:10.1017/S0033291708003371 [CrossRef]
- Wang GJ, Volkow ND, Felder C, et al. Enhanced resting activity of the oral somatosensory cortex in obese subjects. Neuroreport. 2002;13(9):1151–1155. doi:10.1097/00001756-200207020-00016 [CrossRef]
- Wang GJ, Yang J, Volkow ND, et al. Gastric stimulation in obese subjects activates the hippocampus and other regions involved in brain reward circuitry. Proc Natl Acad Sci U S A. 2006;103(42):15641–15645. doi:10.1073/pnas.0601977103 [CrossRef]
- Cigaina V. Long-term follow-up of gastric stimulation for obesity: the Mestre 8-year experience. Obes Surg. 2004;14Suppl 1:S14–S22. doi:10.1381/0960892041978953 [CrossRef]
- Stephan E, Pardo JV, Faris PL, et al. Functional neuroimaging of gastric distention. J Gastrointest Surg. 2003;7(6):740–749. doi:10.1016/S1091-255X(03)00071-4 [CrossRef]
- Wang GJ, Volkow ND, Logan J, et al. Brain dopamine and obesity. Lancet. 2001;357(9253):354–357. doi:10.1016/S0140-6736(00)03643-6 [CrossRef]
- Yasuno F, Suhara T, Sudo Y, et al. Relation among dopamine D(2) receptor binding, obesity and personality in normal human subjects. Neurosci Lett. 2001;300(1):59–61. doi:10.1016/S0304-3940(01)01552-X [CrossRef]
- Volkow ND, Wang GJ, Fowler JS, et al. “Non-hedonic” food motivation in humans involves dopamine in the dorsal striatum and methylphenidate amplifies this effect. Synapse. 2002;44(3):175–180. doi:10.1002/syn.10075 [CrossRef]
- Wang GJ, Geliebter A, Volkow ND, et al. Enhanced striatal dopamine release during food stimulation in binge eating disorder. Obesity (Silver Spring). 2011;19(8):1601–1608. doi:10.1038/oby.2011.27 [CrossRef]
- Volkow ND, Wang GJ, Telang F, et al. Low dopamine striatal D2 receptors are associated with prefrontal metabolism in obese subjects: possible contributing factors. Neuroimage. 2008;42(4):1537–1543. doi:10.1016/j.neuroimage.2008.06.002 [CrossRef]
- Volkow ND, Wang GJ, Maynard L, et al. Brain dopamine is associated with eating behaviors in humans. Int J Eat Disord. 2003;33(2):136–142. doi:10.1002/eat.10118 [CrossRef]
- Shin AC, Zheng H, Berthoud HR. An expanded view of energy homeostasis: neural integration of metabolic, cognitive, and emotional drives to eat. Physiol Behav. 2009;97(5):572–580. doi:10.1016/j.physbeh.2009.02.010 [CrossRef]
- Pagoto SL, Curtin C, Lemon SC, et al. Association between adult attention deficit/hyperactivity disorder and obesity in the US population. Obesity (Silver Spring). 2009;17(3):539–544. doi:10.1038/oby.2008.587 [CrossRef]
- Wadden TA, Sarwer DB, Fabricatore AN, Jones L, Stack R, Williams NS. Psychosocial and behavioral status of patients undergoing bariatric surgery: what to expect before and after surgery. Med Clin North Am. 2007;91(3):451–469, xi–xii. doi:10.1016/j.mcna.2007.01.003 [CrossRef]
- Rusch MD, Andris D. Maladaptive eating patterns after weight-loss surgery. Nutr Clin Pract. 2007;22(1):41–49. doi:10.1177/011542650702200141 [CrossRef]
- Dunn JP, Cowan RL, Volkow ND, et al. Decreased dopamine type 2 receptor availability after bariatric surgery: preliminary findings. Brain Res. 2010;1350:123–130. doi:10.1016/j.brainres.2010.03.064 [CrossRef]
- Steele KE, Prokopowicz GP, Schweitzer MA, et al. Alterations of central dopamine receptors before and after gastric bypass surgery. Obes Surg. 2010;20(3):369–374. doi:10.1007/s11695-009-0015-4 [CrossRef]