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Valuation and Cognitive Circuitry in Anorexia Nervosa: Disentangling Appetite from the Effort to Obtain a Reward
Commentary
Biological Psychiatry
Valuation and Cognitive Circuitry in Anorexia Nervosa: Disentangling Appetite from the Effort to Obtain a Reward Laura M. Holsen and Jill M. Goldstein Motivation is classically defined as the amount of effort one is willing to expend to acquire a reward. In humans, rewards may range from basic or primary (e.g., drugs of abuse, sex, money, palatable food) to more complex, personal ones (e.g., social engagement or reciprocity, entertainment, hobbies), and working toward those rewards, whether immediate or distant, often guides the choices we make daily. Findings in healthy populations have identified key neural regions involved in anticipation, evaluation, and decision making during reward processing and demonstrated the impact of internal states modulating these, including stress (1) and sleep (2), among others. Disruption in these circuits underlies the pathophysiology of several neuropsychiatric conditions (i.e., addiction to substances, sex, and gambling; eating disorders; major depression and anxiety; autism). Of these conditions, anorexia nervosa (AN), marked by a refusal to consume adequate nutrients in a state of severe starvation, is one of the most difficult to treat and deadly (3). This fact owes largely to the necessity of the primary reward in question (food) to sustain health and, ultimately, life. Mounting evidence of neurohormonal dysfunction contributes to aberrant food reward and appetite in AN, but there is little clinical application of these findings to treatment. A study by Wierenga et al. (4) in this issue of Biological Psychiatry may have implications for enhancing efficacy of treatment for AN. Their study focuses on the impact of internal appetitive drive on brain activity during decision making for monetary cues in women remitted from AN (RAN) compared with healthy control (HC) women. This clever and wellformulated design sidesteps numerous potential confounders in identifying brain activity deficits in AN. In particular, rather than food cues, the authors used a robust delay discounting paradigm to assess immediate versus future valuation of monetary rewards; this design avoids the use of stimuli which commonly elicits anxiety in this population. The task simultaneously evokes neural response to reward and cognitive control, both of which are abnormal in AN. In a group of subjects (23 RAN women, 17 HC women) who were carefully phenotyped and medication-free, one of the novel features of the design was the counterbalanced task administration across two states of appetitive motivation: hunger (after 16-hour fast) and satiety (meal consumption 2 hours before the scan). The authors showed enhanced activity to immediate rewards in valuation circuitry (ventral striatum, dorsal caudate, anterior cingulate cortex) during hunger in HC women compared with satiety but no differences across appetitive states in RAN women, who tended to show hyperactivity in these regions during satiation compared with HC women. The opposite trend emerged in HC women during decision making, with
heightened activity for cognitive control (i.e., insula, ventrolateral prefrontal cortex) during satiety compared with hunger, but here, too, RAN women failed to demonstrate variable activity in these regions in response to appetitive state. No behavioral differences in choice behavior were observed, suggesting that brain activity differences were not due to variation in the ability to perform the task, but rather that the same behavioral outcome resulted from altered circuitry involvement in RAN women. The authors concluded that abnormal reward processing in RAN women stems from failure to exhibit adequate sensitivity to reward under a highly motivational state (hunger), in combination with increased and excessive recruitment of executive control regions during satiety. These findings parallel previous reports of deficits in valuation and cognitive circuitry under other physiologic states, such as nicotine administration during temporal discounting (6). They also support our prior functional magnetic resonance imaging findings in a study of food reward processing of increased reward and limbic circuitry activity in response to food cues during hunger compared with satiation in healthy individuals (5). However, they are in contrast to the RAN women and women with active AN in this previous study (5). That is, RAN women compared with HC women demonstrated less activity in food valuation circuitry (hypothalamus, amygdala, insula) in response to palatable, high-reward foods during a state of hunger (with no differences during satiation). In RAN women, we also observed hunger-elicited activity (i.e., greater activity during hunger than satiety) in orbitofrontal and anterior cingulate cortices and satiety-elicited activity (i.e., greater activity during satiety than hunger) in the insula. Our findings suggest at least some degree of modulation of food reward valuation by internal appetitive motivation in RAN. Although there are methodologic differences between our studies that include task-related variation (passive viewing vs. delay discounting) and length of delay between food intake and scanning for the satiation scan (immediate vs. 2 hours), we suggest that the inconsistencies in results derive primarily from the use of contrasting stimuli: money versus food. Although seemingly disparate, one interpretation could be that although persistent abnormalities exist in reward/valuation circuitry in RAN women, remission requires the ability to mount at least a partially appropriate response to food stimuli to enable food intake during times of high appetitive motivation (i.e., hunger). In contrast, appetite-mediated activity to monetary rewards in valuation regions may be less critical for immediate recovery. From a clinical viewpoint, the findings of Wierenga et al. may offer some unique insights into potential markers of
SEE CORRESPONDING ARTICLE ON PAGE 642 & 2015 Society of Biological Psychiatry Biological Psychiatry April 1, 2015; 77:604–606 www.sobp.org/journal
604
ISSN: 0006-3223
Biological Psychiatry
Commentary
relapse and treatment strategies. For instance, Kishinevsky et al. (7) reported that brain activity in cognitive control regions during monetary delay discounting predicted weight gain in obese women. As noted by the authors, food-related stimuli often elicit anxiety in individuals with AN, making their use during treatment regimens potentially counterproductive. Perhaps cognitive therapies related to nonfood rewards across varying motivational states would attenuate anxiety-eliciting properties of the stimulus set and facilitate a more rapid and broadly grounded treatment course. One surprising trend in the data reported by Wierenga et al. can be observed in the plots of percent signal change in reward and valuation regions, in which activity appeared to be higher in RAN women than HC women during satiation and enhanced compared with a hungry state. The authors commented that this trend may be indicative of abnormal motivation during satiety in RAN women, yet it is difficult to unconfound whether this pattern resulted as a consequence of previous acute phases of self-starvation or emerged with recovery. Future studies might investigate variable stages of the disorder by incorporating a prospective longitudinal design (from before onset in at-risk youth to individuals with active AN and individuals remitted AN). Although a focus on women remitted from AN avoids the confounders associated with chronic starvation–induced effects on reward circuitry, comparison of activity in these regions across prodromal, acute state, and trait phases of AN is critical for full understanding of the disorder and neural biomarkers contributing to recovery. Finally, but importantly, the impact of prior and current depression in AN is a persistent issue in unconfounding the underlying pathophysiology related to eating disorders, to depression, or to both, particularly given the shared neural circuitry between reward circuits implicated in these conditions (for
example, as represented by food reward and monetary reward, respectively; Figure 1) (10). For example, there is a substantial comorbidity between major depressive disorder and obesity in women both of which have been hypothesized to stem partly from altered functioning in overlapping reward regions, and appetite dysregulation symptoms (hypophagia/hyperphagia) often occur during an episode of major depression. In the study by Wierenga et al., a significant proportion (74%) of RAN women endorsed a lifetime history of major depressive disorder—higher than most samples in prior neuroimaging studies in AN. Although the authors controlled for depression history in their analyses, there were few RAN women without depression and no statistical power to unconfound the two. Current level of depression severity was not assessed or reported, although evidence suggests that beyond history of past depression, levels of anhedonia are significantly and inversely related to delay discounting rate (8), independent of impulsivity. Future studies could address this important issue by adequate designs of RAN women with and without history of major depression. Finally, this comorbidity is particularly salient in studies investigating circuitry implicated in monetary reward processing, given that monetary reward in major depression is significantly disrupted (9), and deficits in reward circuitry are present in the face of stressful stimuli, even in remitted cases (10). In a complementary fashion, it would be informative in future studies to incorporate delay discounting tasks with monetary and food reward, allowing the examination of valuation and cognitive circuitry functioning across a spectrum of salient cues. Combined, these additional experimental design approaches would begin to disentangle whether findings relate more to eating or mood-related symptoms in RAN. In conclusion, the elegant study by Wierenga et al. reveals novel insights into the breadth of reward and executive circuitry dysfunction in AN and hints at the enduring insensitivity to salient motivational factors in individuals remitted from AN. That is, the effort these individuals are willing to exert to obtain a reward (food, money, or otherwise) has little to do with the timing of their last meal. The challenge for studies that build on these data will be to determine the specificity of the findings to eating disorders and the extent to which use of monetary reward paradigms can provide insights into enhancing treatment efficacy and prevention of relapse.
Acknowledgments and Disclosures This work was supported by National Institute of Mental Health Grant No. K01 MH091222 (LMH) and the Connors Center for Women’s Health and Gender Biology at Brigham & Women’s Hospital (JMG). The authors report no biomedical financial interests or potential conflicts of interest.
Article Information Figure 1. Overlapping neural circuitry involved in food reward and monetary reward, often implicated in eating disorders and depression, respectively. Although not exhaustive, regions commonly active during valuation of food-related and money-related stimuli (shown in green) include the ventral striatum (VS), amygdala (AMYG), insula, orbitofrontal cortex (OFC), and ventromedial prefrontal cortex (VMPFC). Food-related valuation paradigms additionally recruit the ventral tegmental area (VTA) and hypothalamus (HYPO) (shown in yellow), whereas monetary reward paradigms also involve the anterior cingulate cortex (ACC) and caudate (shown in blue).
From the Department of Psychiatry (LMH, JMG), Harvard Medical School; Connors Center for Women’s Health and Gender Biology (LMH, JMG), Division of Women’s Health, Department of Medicine, and Department of Psychiatry (LMH, JMG), Brigham & Women’s Hospital, Boston; and Athinoula A. Martinos Center (JMG), Massachusetts General Hospital and Massachusetts Institute of Technology, Charlestown, Massachusetts. Address correspondence to Jill M. Goldstein, Ph.D., Division of Women’s Health, Brigham & Women’s Hospital, One Brigham Circle, 1620 Tremont Street, Boston, MA 02120; E-mail: [email protected]. Received Feb 9, 2015; accepted Feb 10, 2015.
Biological Psychiatry April 1, 2015; 77:604–606 www.sobp.org/journal
605
Biological Psychiatry
Commentary
References 1. 2.
3.
4.
5.
606
Porcelli AJ, Lewis AH, Delgado MR (2012): Acute stress influences neural circuits of reward processing. Front Neurosci 6:157. Mullin BC, Phillips ML, Siegle GJ, Buysse DJ, Forbes EE, Franzen PL (2013): Sleep deprivation amplifies striatal activation to monetary reward. Psychol Med 43:2215–2225. Arcelus J, Mitchell AJ, Wales J, Nielsen S (2011): Mortality rates in patients with anorexia nervosa and other eating disorders. A metaanalysis of 36 studies. Arch Gen Psychiatry 68:724–731. Wierenga CE, Bischoff-Grethe A, Melrose AJ, Irvine Z, Torres L, Bailer UF, et al. (2015): Hunger does not motivate reward in women remitted from anorexia nervosa. Biol Psychiatry 77:642–652. Holsen LM, Lawson EA, Blum J, Ko E, Makris N, Fazeli PK, et al. (2012): Food motivation circuitry hypoactivation related to hedonic and nonhedonic aspects of hunger and satiety in women with active anorexia nervosa and weight-restored women with anorexia nervosa. J Psychiatry Neurosci 37:322–332.
6.
7.
8.
9.
10.
Biological Psychiatry April 1, 2015; 77:604–606 www.sobp.org/journal
Kobiella A, Ripke S, Kroemer NB, Vollmert C, Vollstadt-Klein S, Ulshofer DE, et al. (2014): Acute and chronic nicotine effects on behaviour and brain activation during intertemporal decision making. Addict Biol 19:918–930. Kishinevsky FI, Cox JE, Murdaugh DL, Stoeckel LE, Cook EW 3rd, Weller RE (2012): fMRI reactivity on a delay discounting task predicts weight gain in obese women. Appetite 58:582–592. Lempert KM, Pizzagalli DA (2010): Delay discounting and futuredirected thinking in anhedonic individuals. J Behav Ther Exp Psychiatry 41:258–264. Pizzagalli DA (2014): Depression, stress, and anhedonia: Toward a synthesis and integrated model. Annu Rev Clin Psychol 10: 393–423. Admon R, Holsen LM, Aizley H, Remington A, Whitfield-Gabrieli S, Goldstein JM, et al. (2014): Striatal hypersensitivity during stress in remitted individuals with recurrent depression [published online ahead of print Oct 2]. Biol Psychiatry.
Biological Psychiatry
Valuation and Cognitive Circuitry in Anorexia Nervosa: Disentangling Appetite from the Effort to Obtain a Reward Laura M. Holsen and Jill M. Goldstein Motivation is classically defined as the amount of effort one is willing to expend to acquire a reward. In humans, rewards may range from basic or primary (e.g., drugs of abuse, sex, money, palatable food) to more complex, personal ones (e.g., social engagement or reciprocity, entertainment, hobbies), and working toward those rewards, whether immediate or distant, often guides the choices we make daily. Findings in healthy populations have identified key neural regions involved in anticipation, evaluation, and decision making during reward processing and demonstrated the impact of internal states modulating these, including stress (1) and sleep (2), among others. Disruption in these circuits underlies the pathophysiology of several neuropsychiatric conditions (i.e., addiction to substances, sex, and gambling; eating disorders; major depression and anxiety; autism). Of these conditions, anorexia nervosa (AN), marked by a refusal to consume adequate nutrients in a state of severe starvation, is one of the most difficult to treat and deadly (3). This fact owes largely to the necessity of the primary reward in question (food) to sustain health and, ultimately, life. Mounting evidence of neurohormonal dysfunction contributes to aberrant food reward and appetite in AN, but there is little clinical application of these findings to treatment. A study by Wierenga et al. (4) in this issue of Biological Psychiatry may have implications for enhancing efficacy of treatment for AN. Their study focuses on the impact of internal appetitive drive on brain activity during decision making for monetary cues in women remitted from AN (RAN) compared with healthy control (HC) women. This clever and wellformulated design sidesteps numerous potential confounders in identifying brain activity deficits in AN. In particular, rather than food cues, the authors used a robust delay discounting paradigm to assess immediate versus future valuation of monetary rewards; this design avoids the use of stimuli which commonly elicits anxiety in this population. The task simultaneously evokes neural response to reward and cognitive control, both of which are abnormal in AN. In a group of subjects (23 RAN women, 17 HC women) who were carefully phenotyped and medication-free, one of the novel features of the design was the counterbalanced task administration across two states of appetitive motivation: hunger (after 16-hour fast) and satiety (meal consumption 2 hours before the scan). The authors showed enhanced activity to immediate rewards in valuation circuitry (ventral striatum, dorsal caudate, anterior cingulate cortex) during hunger in HC women compared with satiety but no differences across appetitive states in RAN women, who tended to show hyperactivity in these regions during satiation compared with HC women. The opposite trend emerged in HC women during decision making, with
heightened activity for cognitive control (i.e., insula, ventrolateral prefrontal cortex) during satiety compared with hunger, but here, too, RAN women failed to demonstrate variable activity in these regions in response to appetitive state. No behavioral differences in choice behavior were observed, suggesting that brain activity differences were not due to variation in the ability to perform the task, but rather that the same behavioral outcome resulted from altered circuitry involvement in RAN women. The authors concluded that abnormal reward processing in RAN women stems from failure to exhibit adequate sensitivity to reward under a highly motivational state (hunger), in combination with increased and excessive recruitment of executive control regions during satiety. These findings parallel previous reports of deficits in valuation and cognitive circuitry under other physiologic states, such as nicotine administration during temporal discounting (6). They also support our prior functional magnetic resonance imaging findings in a study of food reward processing of increased reward and limbic circuitry activity in response to food cues during hunger compared with satiation in healthy individuals (5). However, they are in contrast to the RAN women and women with active AN in this previous study (5). That is, RAN women compared with HC women demonstrated less activity in food valuation circuitry (hypothalamus, amygdala, insula) in response to palatable, high-reward foods during a state of hunger (with no differences during satiation). In RAN women, we also observed hunger-elicited activity (i.e., greater activity during hunger than satiety) in orbitofrontal and anterior cingulate cortices and satiety-elicited activity (i.e., greater activity during satiety than hunger) in the insula. Our findings suggest at least some degree of modulation of food reward valuation by internal appetitive motivation in RAN. Although there are methodologic differences between our studies that include task-related variation (passive viewing vs. delay discounting) and length of delay between food intake and scanning for the satiation scan (immediate vs. 2 hours), we suggest that the inconsistencies in results derive primarily from the use of contrasting stimuli: money versus food. Although seemingly disparate, one interpretation could be that although persistent abnormalities exist in reward/valuation circuitry in RAN women, remission requires the ability to mount at least a partially appropriate response to food stimuli to enable food intake during times of high appetitive motivation (i.e., hunger). In contrast, appetite-mediated activity to monetary rewards in valuation regions may be less critical for immediate recovery. From a clinical viewpoint, the findings of Wierenga et al. may offer some unique insights into potential markers of
SEE CORRESPONDING ARTICLE ON PAGE 642 & 2015 Society of Biological Psychiatry Biological Psychiatry April 1, 2015; 77:604–606 www.sobp.org/journal
604
ISSN: 0006-3223
Biological Psychiatry
Commentary
relapse and treatment strategies. For instance, Kishinevsky et al. (7) reported that brain activity in cognitive control regions during monetary delay discounting predicted weight gain in obese women. As noted by the authors, food-related stimuli often elicit anxiety in individuals with AN, making their use during treatment regimens potentially counterproductive. Perhaps cognitive therapies related to nonfood rewards across varying motivational states would attenuate anxiety-eliciting properties of the stimulus set and facilitate a more rapid and broadly grounded treatment course. One surprising trend in the data reported by Wierenga et al. can be observed in the plots of percent signal change in reward and valuation regions, in which activity appeared to be higher in RAN women than HC women during satiation and enhanced compared with a hungry state. The authors commented that this trend may be indicative of abnormal motivation during satiety in RAN women, yet it is difficult to unconfound whether this pattern resulted as a consequence of previous acute phases of self-starvation or emerged with recovery. Future studies might investigate variable stages of the disorder by incorporating a prospective longitudinal design (from before onset in at-risk youth to individuals with active AN and individuals remitted AN). Although a focus on women remitted from AN avoids the confounders associated with chronic starvation–induced effects on reward circuitry, comparison of activity in these regions across prodromal, acute state, and trait phases of AN is critical for full understanding of the disorder and neural biomarkers contributing to recovery. Finally, but importantly, the impact of prior and current depression in AN is a persistent issue in unconfounding the underlying pathophysiology related to eating disorders, to depression, or to both, particularly given the shared neural circuitry between reward circuits implicated in these conditions (for
example, as represented by food reward and monetary reward, respectively; Figure 1) (10). For example, there is a substantial comorbidity between major depressive disorder and obesity in women both of which have been hypothesized to stem partly from altered functioning in overlapping reward regions, and appetite dysregulation symptoms (hypophagia/hyperphagia) often occur during an episode of major depression. In the study by Wierenga et al., a significant proportion (74%) of RAN women endorsed a lifetime history of major depressive disorder—higher than most samples in prior neuroimaging studies in AN. Although the authors controlled for depression history in their analyses, there were few RAN women without depression and no statistical power to unconfound the two. Current level of depression severity was not assessed or reported, although evidence suggests that beyond history of past depression, levels of anhedonia are significantly and inversely related to delay discounting rate (8), independent of impulsivity. Future studies could address this important issue by adequate designs of RAN women with and without history of major depression. Finally, this comorbidity is particularly salient in studies investigating circuitry implicated in monetary reward processing, given that monetary reward in major depression is significantly disrupted (9), and deficits in reward circuitry are present in the face of stressful stimuli, even in remitted cases (10). In a complementary fashion, it would be informative in future studies to incorporate delay discounting tasks with monetary and food reward, allowing the examination of valuation and cognitive circuitry functioning across a spectrum of salient cues. Combined, these additional experimental design approaches would begin to disentangle whether findings relate more to eating or mood-related symptoms in RAN. In conclusion, the elegant study by Wierenga et al. reveals novel insights into the breadth of reward and executive circuitry dysfunction in AN and hints at the enduring insensitivity to salient motivational factors in individuals remitted from AN. That is, the effort these individuals are willing to exert to obtain a reward (food, money, or otherwise) has little to do with the timing of their last meal. The challenge for studies that build on these data will be to determine the specificity of the findings to eating disorders and the extent to which use of monetary reward paradigms can provide insights into enhancing treatment efficacy and prevention of relapse.
Acknowledgments and Disclosures This work was supported by National Institute of Mental Health Grant No. K01 MH091222 (LMH) and the Connors Center for Women’s Health and Gender Biology at Brigham & Women’s Hospital (JMG). The authors report no biomedical financial interests or potential conflicts of interest.
Article Information Figure 1. Overlapping neural circuitry involved in food reward and monetary reward, often implicated in eating disorders and depression, respectively. Although not exhaustive, regions commonly active during valuation of food-related and money-related stimuli (shown in green) include the ventral striatum (VS), amygdala (AMYG), insula, orbitofrontal cortex (OFC), and ventromedial prefrontal cortex (VMPFC). Food-related valuation paradigms additionally recruit the ventral tegmental area (VTA) and hypothalamus (HYPO) (shown in yellow), whereas monetary reward paradigms also involve the anterior cingulate cortex (ACC) and caudate (shown in blue).
From the Department of Psychiatry (LMH, JMG), Harvard Medical School; Connors Center for Women’s Health and Gender Biology (LMH, JMG), Division of Women’s Health, Department of Medicine, and Department of Psychiatry (LMH, JMG), Brigham & Women’s Hospital, Boston; and Athinoula A. Martinos Center (JMG), Massachusetts General Hospital and Massachusetts Institute of Technology, Charlestown, Massachusetts. Address correspondence to Jill M. Goldstein, Ph.D., Division of Women’s Health, Brigham & Women’s Hospital, One Brigham Circle, 1620 Tremont Street, Boston, MA 02120; E-mail: [email protected]. Received Feb 9, 2015; accepted Feb 10, 2015.
Biological Psychiatry April 1, 2015; 77:604–606 www.sobp.org/journal
605
Biological Psychiatry
Commentary
References 1. 2.
3.
4.
5.
606
Porcelli AJ, Lewis AH, Delgado MR (2012): Acute stress influences neural circuits of reward processing. Front Neurosci 6:157. Mullin BC, Phillips ML, Siegle GJ, Buysse DJ, Forbes EE, Franzen PL (2013): Sleep deprivation amplifies striatal activation to monetary reward. Psychol Med 43:2215–2225. Arcelus J, Mitchell AJ, Wales J, Nielsen S (2011): Mortality rates in patients with anorexia nervosa and other eating disorders. A metaanalysis of 36 studies. Arch Gen Psychiatry 68:724–731. Wierenga CE, Bischoff-Grethe A, Melrose AJ, Irvine Z, Torres L, Bailer UF, et al. (2015): Hunger does not motivate reward in women remitted from anorexia nervosa. Biol Psychiatry 77:642–652. Holsen LM, Lawson EA, Blum J, Ko E, Makris N, Fazeli PK, et al. (2012): Food motivation circuitry hypoactivation related to hedonic and nonhedonic aspects of hunger and satiety in women with active anorexia nervosa and weight-restored women with anorexia nervosa. J Psychiatry Neurosci 37:322–332.
6.
7.
8.
9.
10.
Biological Psychiatry April 1, 2015; 77:604–606 www.sobp.org/journal
Kobiella A, Ripke S, Kroemer NB, Vollmert C, Vollstadt-Klein S, Ulshofer DE, et al. (2014): Acute and chronic nicotine effects on behaviour and brain activation during intertemporal decision making. Addict Biol 19:918–930. Kishinevsky FI, Cox JE, Murdaugh DL, Stoeckel LE, Cook EW 3rd, Weller RE (2012): fMRI reactivity on a delay discounting task predicts weight gain in obese women. Appetite 58:582–592. Lempert KM, Pizzagalli DA (2010): Delay discounting and futuredirected thinking in anhedonic individuals. J Behav Ther Exp Psychiatry 41:258–264. Pizzagalli DA (2014): Depression, stress, and anhedonia: Toward a synthesis and integrated model. Annu Rev Clin Psychol 10: 393–423. Admon R, Holsen LM, Aizley H, Remington A, Whitfield-Gabrieli S, Goldstein JM, et al. (2014): Striatal hypersensitivity during stress in remitted individuals with recurrent depression [published online ahead of print Oct 2]. Biol Psychiatry.