Megan E. Shott

Anorexia Nervosa and Obesity are Associated with Opposite Brain Reward Response

Anorexia nervosa (AN) is a severe psychiatric disorder associated with food avoidance and malnutrition. In this study, we wanted to test whether we would find brain reward alterations in AN, compared with individuals with normal or increased body weight. We studied 21 underweight, restricting-type AN (age M 22.5, SD 5.8 years), 19 obese (age M 27.1, SD 6.7 years), and 23 healthy control women (age M 24.8, SD 5.6 years), using blood oxygen level-dependent functional magnetic resonance brain imaging together with a reward-conditioning task. This paradigm involves learning the association between conditioned visual stimuli and unconditioned taste stimuli, as well as the unexpected violation of those learned associations. The task has been associated with activation of brain dopamine reward circuits, and it allows the comparison of actual brain response with expected brain activation based on established neuronal models. A group-by-task condition analysis (family-wise-error-corrected P<0.05) indicated that the orbitofrontal cortex differentiated all three groups. The dopamine model reward-learning signal distinguished groups in the anteroventral striatum, insula, and prefrontal cortex (P<0.001, 25 voxel cluster threshold), with brain responses that were greater in the AN group, but lesser in the obese group, compared with controls. These results suggest that brain reward circuits are more responsive to food stimuli in AN, but less responsive in obese women. The mechanism for this association is uncertain, but these brain reward response patterns could be biomarkers for the respective weight state.

Alterations in Brain Structures Related to Taste Reward Circuitry in Ill and Recovered Anorexia Nervosa and in Bulimia Nervosa

OBJECTIVE The pathophysiology of anorexia nervosa remains obscure, but structural brain alterations could be functionally important biomarkers. The authors assessed taste pleasantness and reward sensitivity in relation to brain structure, which may be related to food avoidance commonly seen in eating disorders. METHOD The authors used structural MR imaging to study gray and white matter volumes in women with current restricting-type anorexia nervosa (N=19), women recovered from restricting-type anorexia nervosa (N=24), women with bulimia nervosa (N=19), and healthy comparison women (N=24). RESULTS All eating disorder groups exhibited increased gray matter volume of the medial orbitofrontal cortex (gyrus rectus). Manual tracing confirmed larger gyrus rectus volume, and volume predicted taste pleasantness ratings across all groups. Analyses also indicated other morphological differences between diagnostic categories. Antero-ventral insula gray matter volumes were increased on the right side in the anorexia nervosa and recovered anorexia nervosa groups and on the left side in the bulimia nervosa group relative to the healthy comparison group. Dorsal striatum volumes were reduced in the recovered anorexia nervosa and bulimia nervosa groups and predicted sensitivity to reward in all three eating disorder groups. The eating disorder groups also showed reduced white matter in right temporal and parietal areas relative to the healthy comparison group. The results held when a range of covariates, such as age, depression, anxiety, and medications, were controlled for. CONCLUSION Brain structure in the medial orbitofrontal cortex, insula, and striatum is altered in eating disorders and suggests altered brain circuitry that has been associated with taste pleasantness and reward value.

Heightened sensitivity to reward and punishment in anorexia nervosa

OBJECTIVE The objective of this study is to test whether females with anorexia nervosa (AN) have increased sensitivity to punishing or rewarding stimuli, behaviors that could drive high self-control and anxious, avoidant behaviors. METHOD Sixty-four females completed the study: 33 control females (CFs, mean age 19.7 years) and 31 females with AN (mean age 19.6 years). Participants completed diagnostic exams, questionnaires for eating disorder severity and personality, and the Sensitivity to Punishment/Sensitivity to Reward Questionnaire (SPSRQ). RESULTS Females with AN scored higher than CFs on SPSRQ sensitivity to punishment (p < 0.00001) and sensitivity to reward (p = 0.005). Females with AN without anxiety or depression continued to have increased SPSRQ scores compared to CFs. DISCUSSION This is the first study comparing the SPSRQ in females with AN and CFs. Results suggest that reward and punishment sensitivity are increased in females with AN and could be potential trait markers. It is possible that harm-avoidant, anxious behaviors in females with AN are related to this heightened sensitivity.

Altered temporal difference learning in bulimia nervosa.

BACKGROUND The neurobiology of bulimia nervosa (BN) is poorly understood. Recent animal literature suggests that binge eating is associated with altered brain dopamine (DA) reward function. In this study, we wanted to investigate DA-related brain reward learning in BN. METHODS Ill BN (n = 20, age: mean = 25.2, SD = 5.3 years) and healthy control women (CW) (n = 23, age: mean = 27.2, SD = 6.4 years) underwent functional magnetic resonance brain imaging together with application of a DA-related reward learning paradigm, the temporal difference (TD) model. That task involves association learning between conditioned visual and unconditioned taste stimuli, as well as unexpected violation of those learned associations. Study participants also completed the Sensitivity to Reward and Punishment Questionnaire. RESULTS Bulimia nervosa individuals showed reduced brain response compared with CW for unexpected receipt and omission of taste stimuli, as well as reduced brain regression response to the TD computer model generated reward values, in insula, ventral putamen, amygdala, and orbitofrontal cortex. Those results were qualitatively similar in BN individuals who were nondepressed and unmedicated. Binge/purge frequency in BN inversely predicted reduced TD model response. Bulimia nervosa individuals showed significantly higher Sensitivity to Reward and Punishment compared with CW. CONCLUSIONS This is the first study that relates reduced brain DA responses in BN to the altered learning of associations between arbitrary visual stimuli and taste rewards. This attenuated response is related to frequency of binge/purge episodes in BN. The brain DA neurotransmitter system could be an important treatment target for BN.

Altered fimbria-fornix white matter integrity in anorexia nervosa predicts harm avoidance

The eating disorder anorexia nervosa (AN) is associated with high anxiety. The brain mechanisms that drive those behaviors are unknown. In this study we wanted to test whether brain white matter (WM) integrity is altered in AN, and related to heightened anxiety. Sixteen adult women with AN (mean age 24 ± 7 years) and 17 healthy control women (CW, mean age 25 ± 4 years) underwent diffusion tensor imaging (DTI) of the brain. The DTI brain images were used to calculate the fractional anisotropy (FA) of WM tracts, which is a measure for WM integrity. AN individuals compared to CW showed clusters of significantly reduced FA (p<0.05, corrected) in the bilateral fimbria-fornix and the fronto-occipital fasciculus, as well as the posterior cingulum WM. In the AN group, Harm Avoidance was predicted by FA in the left and right fimbria-fornix. Those findings were not due to WM volume deficits in AN. This study indicates that WM integrity is abnormal in AN in limbic and association pathways, which could contribute to disturbed feeding, emotion processing and body perception in AN. The prediction of Harm Avoidance in AN by fimbria-fornix WM integrity suggests that this pathway may be mechanistically involved in high anxiety in AN.

Heightened fear of uncertainty in anorexia and bulimia nervosa.

OBJECTIVE To test whether intolerance of uncertainty (IU) is related to eating disorder (ED) pathology. METHOD Thirty individuals with anorexia nervosa (AN), 19 with bulimia nervosa (BN), and 28 healthy control women (CW) completed the Intolerance of Uncertainty Scale (IUS). RESULTS AN and BN groups showed higher IU compared with CW. In AN and BN, Harm Avoidance and Depression scores were positively correlated with IU. In AN but not BN, IU was related positively to Drive for Thinness and Body Dissatisfaction. DISCUSSION Elevated IU is associated with AN and BN. Anxious traits may be inherent in EDs and IU could be a developmental factor contributing to anxiety, mood, and ED behavior in AN and BN.

Orbitofrontal Cortex Volume and Brain Reward Response in Obesity

Background/objectives:What drives overconsumption of food is poorly understood. Alterations in brain structure and function could contribute to increased food seeking. Recently, brain orbitofrontal cortex (OFC) volume has been implicated in dysregulated eating but little is known how brain structure relates to function.Subjects/methods:We examined obese (n=18, age=28.7±8.3 years) and healthy control women (n=24, age=27.4±6.3 years) using a multimodal brain imaging approach. We applied magnetic resonance and diffusion tensor imaging to study brain gray and white matter volume as well as white matter (WM) integrity, and tested whether orbitofrontal cortex volume predicts brain reward circuitry activation in a taste reinforcement-learning paradigm that has been associated with dopamine function.Results:Obese individuals displayed lower gray and associated white matter volumes (P<0.05 family-wise error (FWE)- small volume corrected) compared with controls in the orbitofrontal cortex, striatum and insula. White matter integrity was reduced in obese individuals in fiber tracts including the external capsule, corona radiata, sagittal stratum, and the uncinate, inferior fronto-occipital, and inferior longitudinal fasciculi. Gray matter volume of the gyrus rectus at the medial edge of the orbitofrontal cortex predicted functional taste reward-learning response in frontal cortex, insula, basal ganglia, amygdala, hypothalamus and anterior cingulate cortex in control but not obese individuals.Conclusions:This study indicates a strong association between medial orbitofrontal cortex volume and taste reinforcement-learning activation in the brain in control but not in obese women. Lower brain volumes in the orbitofrontal cortex and other brain regions associated with taste reward function as well as lower integrity of connecting pathways in obesity (OB) may support a more widespread disruption of reward pathways. The medial orbitofrontal cortex is an important structure in the termination of food intake and disturbances in this and related structures could contribute to overconsumption of food in obesity.

Cognitive set-shifting in anorexia nervosa.

OBJECTIVE Adult anorexia nervosa (AN) is associated with inefficient cognitive flexibility and set-shifting. Whether such inefficiencies also characterize adolescent AN is an important area of research. METHOD Adolescents with AN and matched controls were administered a computerized task that required initial learning of an explicit rule using corrective feedback and learning of a new rule after a set number of trials. Adult patients with AN and controls were also examined. RESULTS Adolescents with AN did not differ from matched controls with respect to set-shifting cost (decrease in performance after rule change), whereas adults with AN had significantly greater set-shifting cost compared with controls. DISCUSSION This study suggests that set-shifting inefficiencies may not be a vulnerability factor for AN development in adolescents with AN, but might become an important aspect of the disorder at later age, and could point towards developmental neurobiologic brain changes that could affect AN at different ages.

Greater Insula White Matter Fiber Connectivity in Women Recovered from Anorexia Nervosa

Anorexia nervosa is a severe psychiatric disorder associated with reduced drive to eat. Altered taste-reward circuit white matter fiber organization in anorexia nervosa after recovery could indicate a biological marker that alters the normal motivation to eat. Women recovered from restricting-type anorexia (Recovered AN, n=24, age=30.3±8.1 years) and healthy controls (n=24, age=27.4±6.3 years) underwent diffusion weighted imaging of the brain. Probabilistic tractography analyses calculated brain white matter connectivity (streamlines) as an estimate of fiber connections in taste-reward-related white matter tracts, and microstructural integrity (fractional anisotropy, FA) was assessed using tract-based spatial statistics. Recovered AN showed significantly (range P<0.05–0.001, Bonferroni corrected) greater white matter connectivity between bilateral insula regions and ventral striatum, left insula and middle orbitofrontal cortex (OFC), and right insula projecting to gyrus rectus and medial OFC. Duration of illness predicted connectivity of tracts projecting from the insula to ventral striatum and OFC. Microstructural integrity was lower in Recovered AN in most insula white matter tracts, as was whole-brain FA in parts of the anterior corona radiata, external capsule, and cerebellum (P<0.05, family-wise error-corrected). This study indicates higher structural white matter connectivity, an estimate of fibers connections, in anorexia after recovery in tracts that connect taste-reward processing regions. Greater connectivity together with less-fiber integrity could indicate altered neural activity between those regions, which could interfere with normal food-reward circuit function. Correlations between connectivity and illness duration suggest that connectivity could be a marker for illness severity. Whether greater connectivity can predict prognosis of the disorder requires further study.

White matter integrity is reduced in bulimia nervosa.

OBJECTIVE To investigate brain white matter (WM) functionality in bulimia nervosa (BN) in relation to anxiety. METHOD Twenty-one control women (CW, mean age 27 ± 7 years) and 20 BN women (mean age 25 ± 5 years) underwent brain diffusion tensor imaging to measure fractional anisotropy (FA; an indication of WM axon integrity) and the apparent diffusion coefficient (ADC; reflecting WM cell damage). RESULTS FA was decreased in BN in the bilateral corona radiata extending into the posterior limb of the internal capsule, the corpus callosum, the right sub-insular WM, and right fornix. In CW but not BN, trait anxiety correlated negatively with fornix, corpus callosum, and left corona radiata FA. ADC was increased in BN compared with CW in the bilateral corona radiata, corpus callosum, inferior fronto-occipital, and uncinate fasciculus. Alterations in BN WM functionality were not due to structural brain alterations. DISCUSSION WM integrity is disturbed in BN, especially in the corona radiata, which has been associated with taste and brain reward processing. Whether this is a premorbid condition or an effect from the illness is yet uncertain. The relationships between WM FA and trait anxiety in CW but not BN may suggest that altered WM functionality contributes to high anxious traits in BN.