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New insights into symptoms and neurocircuit function of anorexia nervosa

Nature Reviews Neuroscience volume 10, pages 573–584 (2009)Cite this article

Key Points

  • Individuals with anorexia nervosa (AN) exhibit an ego-syntonic resistance to eating and a powerful pursuit of weight loss, yet are paradoxically preoccupied with food and eating rituals to the point of obsession. Moreover, these individuals have a distorted body image and, even when emaciated, tend to see themselves as 'fat', express denial of being underweight and compulsively over-exercise.

  • Premorbid, childhood personality and temperament traits, which are thought to be genetically-determined, are thought to contribute to a vulnerability to develop AN. These include negative emotionality, harm avoidance, perfectionism, inhibition, a drive for thinness, altered interoceptive awareness and obsessive-compulsive personality traits.

  • Individuals with AN seem to have a paradoxical response to eating; they engage in dietary restraint in order to reduce anxiety, because eating stimulates dysphoric mood. Several lines of evidence raise the possibility that altered serotonin (5-HT) function contributes to anxiety in subjects with AN, and starvation is a means of diminishing 5-HT functional activity.

  • Individuals with AN might have a trait towards an imbalance between serotonin and dopamine pathways, which may have a role in an altered interaction between ventral (limbic) neurocircuits, which are important for identifying the emotional significance of stimuli and for generating an affective response to these stimuli, and dorsal (cognitive) neurocircuits that modulate selective attention, planning and effortful regulation of affective states.

  • Recent functional MRI studies support the possibility that individuals with AN might be less able to precisely modulate affective responses to immediately salient stimuli but have increased activity in neurocircuits concerned with planning and consequences.

  • Coding the awareness of pleasant sensation from the taste experience through the anterior insula might be altered in individuals with AN, tipping the balance of striatal processes away from normal, automatic reward responses mediated by the ventral striatum and towards a more 'strategic' approach mediated by the dorsal striatum.

  • Perfectionism and obsessional personality traits could be related to exaggerated cognitive control by the dorsal lateral prefrontal cortex (which may have excessive inhibitory activity and thus dampen information processing through reward pathways) or to compensation for primary deficits in limbic function. When there are deficits in emotional regulation, overdependence upon cognitive rules is a reasonable strategy of self-management.

  • The temperament and personality traits that create a vulnerability to develop AN also persist after recovery. After recovery, these traits tend to have positive aspects, including attention to detail, concern about consequences and a drive to accomplish and succeed.

Abstract

Individuals with anorexia nervosa have a relentless preoccupation with dieting and weight loss that results in severe emaciation and sometimes death. It is controversial whether such symptoms are secondary to psychosocial influences, are a consequence of obsessions and anxiety or reflect a primary disturbance of brain appetitive circuits. New brain imaging technology provides insights into ventral and dorsal neural circuit dysfunction — perhaps related to altered serotonin and dopamine metabolism — that contributes to the puzzling symptoms found in people with eating disorders. For example, altered insula activity could explain interoceptive dysfunction, and altered striatal activity might shed light on altered reward modulation in people with anorexia nervosa.

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Figure 1: The time course and phenomenology of anorexia nervosa.
Figure 2: The role of serotonin neural function in anorexia nervosa.
Figure 3: Cortical-striatal pathways with a focus on taste.
Figure 4: Impaired balance between interoceptive and reward processing.

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References

  1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 4th edn (American Psychiatric Association, Washington, DC 1994).

  2. Lilenfeld, L. R. et al. A controlled family study of anorexia nervosa and bulimia nervosa: psychiatric disorders in first-degree relatives and effects of proband comorbidity. Arch. Gen. Psychiatry 55, 603–610 (1998).

    CAS  PubMed  Google Scholar 

  3. Walters, E. E. & Kendler, K. S. Anorexia nervosa and anorexic-like syndromes in a population-based female twin sample. Am. J. Psychiatry 152, 64–71 (1995).

    CAS  PubMed  Google Scholar 

  4. Berrettini, W. Genetics of psychiatric disease. Annu. Rev. Med. 51, 465–479 (2000).

    CAS  PubMed  Google Scholar 

  5. Bulik, C. et al. Prevalence, heritability and prospective risk factors for anorexia nervosa. Arch. Gen. Psychiatry 63, 305–312 (2006).

    PubMed  Google Scholar 

  6. Wade, T., Martin, N. G. & Tiggemann, M. Genetic and environmental risk factors for the weight and shape concerns characteristic of bulimia nervosa. Psychol. Med. 28, 761–771 (1998).

    CAS  PubMed  Google Scholar 

  7. Rutherford, J., McGuffin, P., Katz, R. J. & Murray, R. M. Genetic influences on eating attitudes in a normal female twin population. Psychol. Med. 23, 425–436.

  8. Bulik, C., Slof-Op't Landt M, van Furth, E. & Sullivan, P. The genetics of anorexia nervosa. Ann. Rev. Nutr. 27, 263–275 (2007).

    CAS  Google Scholar 

  9. Strober, M., Freeman, R., Lampert, C., Diamond, J. & Kaye, W. Controlled family study of anorexia nervosa and bulimia nervosa: evidence of shared liability and transmission of partial syndromes. Am. J. Psychiatry 157, 393–401.

  10. Lilenfeld, L., Wonderlich, S., Riso, L. P., Crosby, R. & Mitchell, J. Eating disorders and personality: a methodological and empirical review. Clin. Psychol. Rev. 26, 299–320 (2006). This paper, which reviews the relationship between personality and eating disorders, shows that negative emotionality, perfectionism, drive for thinness, poor interoceptive awareness, ineffectiveness and obsessive-compulsive personality traits are probable predisposing factors for AN and BN.

    PubMed  Google Scholar 

  11. Stice, E. Risk and maintenance factors for eating pathology: a meta-analytic review. Psychopharm. Bull. 128, 825–848 (2002).

    Google Scholar 

  12. Anderluh, M. B., Tchanturia, K., Rabe-Hesketh, S. & Treasure, J. Childhood obsessive-compulsive personalitiy traits in adult women with eating disorders: defining a broader eating disorder phenotype. Am. J. Psychiatry. 160, 242–247 (2003). One of the first studies to find that childhood traits reflecting obsessive-compulsive personality seem to be important risk factors for the development of eating disorders. Such traits may represent markers of a broader phenotype for a specific subgroup of patients with AN.

    PubMed  Google Scholar 

  13. Bulik, C. et al. Genetic epidemiology, endophenotypes, and eating disorder classification. Int. J. Eat. Disord. 40, S52–S60 (2007).

    PubMed  Google Scholar 

  14. Pollice, C., Kaye, W. H., Greeno, C. G. & Weltzin, T. E. Relationship of depression, anxiety, and obsessionality to state of illness in anorexia nervosa. Int. J. Eat. Disord. 21, 367–376 (1997).

    CAS  PubMed  Google Scholar 

  15. Katzman, D. K. et al. Cerebral gray matter and white matter volume deficits in adolescent girls with anorexia nervosa. J. Pediat. 129, 794–803 (1996).

    CAS  PubMed  Google Scholar 

  16. Kaye, W., Wagner, A., Frank, G., U. F. Review of brain imaging in anorexia and bulimia nervosa in Annual Review of Eating Disorders, Part 2 (eds Wonderlich, S., Mitchell, J., De Zwann, M. & Steiger, H.) 113–130 (Radcliffe Publishing Ltd, Abingdon UK, 2006).

    Google Scholar 

  17. Boyar, R. K. et al. Anorexia nervosa. Immaturity of the 24-hour luteinizing hormone secretory pattern. N. Engl. J. Med. 291, 861–865 (1974).

    CAS  PubMed  Google Scholar 

  18. Schwartz, M. W., Woods, S. C., Porte, D. Jr, Seeley, R. J. & Baskin, D. G. Central nervous system control of food intake. Nature 404, 661–671 (2000).

    CAS  PubMed  Google Scholar 

  19. Inui, A. Eating behavior in anorexia nervosa—an excess of both orexigenic and anorexigenic signalling? Mol. Psychiatry. 6, 620–624 (2001).

    CAS  PubMed  Google Scholar 

  20. Jimerson, D., Wolfe, B. Psychobiology of eating disorders in Annual Review of Eating Disorders, Part 2 (eds Wonderlich, S., Mitchell, J., De Zwann, M. & Steiger, H.) 1–15 (Radcliffe Publishing Ltd, Abingdon UK, 2006).

    Google Scholar 

  21. Kaye, W. H. et al. Elevated cerebrospinal fluid levels of immunoreactive corticotropin-releasing hormone in anorexia nervosa: relation to state of nutrition, adrenal function, and intensity of depression. J. Clin. Endocrinol. Metab. 64, 203–208 (1987).

    CAS  PubMed  Google Scholar 

  22. Godart, N. et al. Comorbidity studies of eating disorders and mood disorders. Critical review of the literature. J. Affect. Disord. 97, 37–49 (2007).

    CAS  PubMed  Google Scholar 

  23. Kaye, W. et al. Comorbidity of anxiety disorders with anorexia and bulimia nervosa. Am. J. Psychiatry 161, 2215–2221 (2004).

    PubMed  Google Scholar 

  24. Wagner, A. et al. Personality traits after recovery from eating disorders: do subtypes differ? Int. J. Eat. Disord. 39, 276–284 (2006).

    PubMed  Google Scholar 

  25. Steinhausen, H. C. The outcome of anorexia nervosa in the 20th century. Am. J. Psychiatry 159, 1284–1293 (2002).

    PubMed  Google Scholar 

  26. Strober, M., Freeman, R. & Morrell, W. The long-term course of severe anorexia nervosa in adolescents: survival analysis of recovery, relapse, and outcome predictors over 10–15 years in a prospective study. Int. J. Eat. Disord. 22, 339–360 (1997).

    CAS  PubMed  Google Scholar 

  27. Casper, R. C. Personality features of women with good outcome from restricting anorexia nervosa. Psychosom. Med. 52, 156–170 (1990).

    CAS  PubMed  Google Scholar 

  28. Srinivasagam, N. M. et al. Persistent perfectionism, symmetry, and exactness after long-term recovery from anorexia nervosa. Am. J. Psychiatry 152, 1630–1634 (1995).

    CAS  PubMed  Google Scholar 

  29. Phillips, M., Drevets, W. R. & Rauch, S. L. Neurobiology of emotion perception II: implications for major psychiatric disorders Biol. Psych. 54, 515–528 (2003).

    Google Scholar 

  30. Phillips, M., Drevets, W. R., Rauch S. L. & Lane, R. Neurobiology of emotion perception I: The neural basis of normal emotion perception Biol. Psych. 54, 504–514 (2003). References 29 and 30 provide an outstanding synthesis of neural processes underlying emotional perception, as well as how distinct patterns of structural and functional abnormalities in neural systems important for emotion processing are associated with specific symptoms of schizophrenia and bipolar and major depressive disorder.

    Google Scholar 

  31. Gordon, I., Lask, B., Bryant-Waugh, R., Christie, D. & Timimi, S. Childhood-onset anorexia nervosa: towards identifying a biological substrate. Int. J. Eat. Disord. 22, 159–165 (1997).

    CAS  PubMed  Google Scholar 

  32. Rastam, M. et al. Regional cerebral blood flow in weight-restored anorexia nervosa: a preliminary study. Dev. Med. Child. Neurol. 43, 239–242 (2001).

    CAS  PubMed  Google Scholar 

  33. Uher, R. et al. Recovery and chronicity in anorexia nervosa: brain activity associated with differential outcomes. Biol. Psychiatry 54, 934–942 (2003). One of the first neuroimaging studies to identify neural correlates of food stimuli that underlie trait and state characteristics of AN.

    PubMed  Google Scholar 

  34. Drevets, W. R. et al. Serotonin-1A receptor imaging in recurrent depression: replication and literature review. Nucl. Med. Biol. 34, 865–877 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Lanzenberger, R. et al. Reduced serotonin-1A receptor binding in social anxiety disorder. Biol. Psychiatry 61, 1081–1089 (2007).

    CAS  PubMed  Google Scholar 

  36. Neumeister, A. et al. Reduced serotinin type 1A receptor binding in panic disorder. J. Neurosci. 24, 589–591 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Tiihonen, J. et al. Brain serotonin 1A receptor binding in bulimia nervosa. Biol. Psychiatry 55, 871–873 (2004).

    CAS  PubMed  Google Scholar 

  38. Galusca, B. et al. Organic background of restrictive-type anorexia nervosa suggested by increased serotonin1A receptor binding in right frontotemporal cortex of both lean and recovered patients: [18F]MPPF PET scan study. Biol. Psychiatry 64, 1009–1013 (2008).

    CAS  PubMed  Google Scholar 

  39. Bailer, U. F. et al. Exaggerated 5-HT1A but normal 5-HT2A receptor activity in individuals ill with anorexia nervosa. Biol. Psychiatry 61, 1090–1099 (2007).

    CAS  PubMed  Google Scholar 

  40. Bailer, U. F. et al. Altered brain serotonin 5-HT1A receptor binding after recovery from anorexia nervosa measured by positron emission tomography and [Carbonyl11C]WAY-100635. Arch. Gen. Psychiatry 62, 1032–1041 (2005).

    CAS  PubMed  Google Scholar 

  41. Simansky, K. J. Serotonergic control of the organization of feeding and satiety. Behav. Brain Res. 73, 37–42 (1996).

    CAS  PubMed  Google Scholar 

  42. Soubrie, P. Reconciling the role of central serotonin neurons in human and animal behavior. Beh. Brain Sci. 9, 319–364 (1986).

    Google Scholar 

  43. Fairbanks, L., Melega, W., Jorgensen, M., Kaplan, J. & McGuire, M. Social impulsivity inversely associated with CSF 5-HIAA and fluoxetine exposure in vermet monkeys. Neuropsychopharmacology 24, 370–378 (2001).

    CAS  PubMed  Google Scholar 

  44. Lesch, K., Merschdorf, U. Impulsivity, aggression, and serotonin: a molecular psychobiological perspective. Behav. Sci. Law 185, 581–604 (2000).

    Google Scholar 

  45. Mann, J. J. Role of the serotonergic system in the pathogenesis of major depression and suicidal behavior. Neuropsychopharmacology 21, S99–S105 (1999).

    Google Scholar 

  46. Brewerton, T. D., Brandt, H. A., Lessem, M. D., Murphy, D. L., Jimerson, D. C. Serotonin in eating disorders in Serotonin in Major Psychiatric Disorders (Progress in Psychiatry). (eds Coccaro, E. F. & Murphy, D. L.) 155–184 (American Psychiatric Press, Washington DC, 1990).

    Google Scholar 

  47. Kaye, W. H., Frank, G., Bailer, U. F. & Henry, S. Neurobiology of anorexia nervosa: clinical implications of alterations of the function of serotonin and other neuronal systems. Int. J. Eat. Disord. 37, S15–S19 (2005).

    PubMed  Google Scholar 

  48. Stanley, M., Traskman-Bendz, L. & Dorovini-Zis, K. Correlations between aminergic metabolites simultaneously obtained from human CSF and brain. Life Sci. 37, 1279–1286 (1985).

    CAS  PubMed  Google Scholar 

  49. Frank, G. K. et al. Reduced 5-HT2A receptor binding after recovery from anorexia nervosa. Biol. Psychiatry 52, 896–906 (2002).

    CAS  PubMed  Google Scholar 

  50. Bailer, U. F. et al. Altered 5-HT2A receptor binding after recovery from bulimia-type anorexia nervosa: relationships to harm avoidance and drive for thinness. Neuropsychopharmacology 29, 1143–1155 (2004).

    CAS  PubMed  Google Scholar 

  51. Audenaert, K. et al. Decreased 5-HT2a receptor binding in patients with anorexia nervosa. J. Nucl. Med. 44, 163–169 (2003).

    CAS  PubMed  Google Scholar 

  52. Frank, G. K. et al. Altered response to meta-chlorophenylpiperazine in anorexia nervosa: support for a persistent alteration of serotonin activity after short-term weight restoration. Int. J. Eat. Disord. 30, 57–68 (2001).

    CAS  PubMed  Google Scholar 

  53. Kaye, W. H. et al. Anxiolytic effects of acute tryptophan depletion in anorexia nervosa. Int. J. Eat. Disord. 33, 257–267 (2003).

    PubMed  Google Scholar 

  54. Cloninger, C. R., Przybeck, T. R., Svrakic, D. M., Wetzel, R. D. in The temperament and character inventory (TCI): a guide to its development and use. (Center for Psychobiology of Personality, Washington University, St Louis, Missouri, USA, 1994).

    Google Scholar 

  55. File, S. E., Kenny, P. J. & Cheeta, S. The role of the dorsal hippocampal serotonergic and cholinergic systems in the modulation of anxiety. Pharmacol. Biochem. Behav. 66, 65–72 (2000).

    CAS  PubMed  Google Scholar 

  56. Tauscher, J. et al. Inverse relationship between serotonin 5-HT1A receptor binding and anxiety: a [11C]WAY-100635 PET investigation in healthy volunteers. Am. J. Psychiatry 158, 1326–1328 (2001).

    CAS  PubMed  Google Scholar 

  57. Weisstaub, N. et al. Cortical 5-HT2A receptor signaling modulates anxiety-like behaviors in mice. Science 313, 536–540 (2006).

    CAS  PubMed  Google Scholar 

  58. Moresco, F. M. et al. In vivo serotonin 5HT2A receptor binding and personality traits in healthy subjects: A positron emission tomography study. NeuroImage 17, 1470–1478 (2002).

    CAS  PubMed  Google Scholar 

  59. Amargos-Bosch, M. et al. Co-expression and in vivo interaction of serotonin1A and serotonin2A receptors in pyramidal neurons of prefrontal cortex. Cereb. Cortex 14, 281–299 (2004).

    PubMed  Google Scholar 

  60. Varnas, K., Halldin, C. & Hall, H. Autoradiographic distribution of serotonin transporters and receptor subtypes in human brain. Hum. Brain Mapp. 22, 246–260 (2004).

    PubMed  PubMed Central  Google Scholar 

  61. Santana, N., Bortolozzi, A., Serrats, J., Mengod, G. & Artigas, F. Expression of serotoinin1A and serotonin2A receptor in pyramidal and GABAergic neurons of the rat prefrontal cortex. Cereb. Cortex. 14, 1100–1109 (2004).

    PubMed  Google Scholar 

  62. Carli, M., Baviera, M., Invernizzi, R. & Balducci, C. Dissociable contribution of 5-HT1A and 5-HT2A receptors in the medial prefrontal cortex to different aspects of executive control such as impulsivity and compulsive perseveration in rats Neuropsychopharmacology 31, 757–767 (2006).

    CAS  PubMed  Google Scholar 

  63. Winstanley, C. A. et al. Intra-prefrontal 8-OH-DPAT and M100907 improve visuospatial attention and decrease impulsivity on the five-choice serial reaction time task in rats. Psypchopharmacology (Berl.) 167, 304–314 (2003).

    CAS  Google Scholar 

  64. Krebs-Thomson, K. & Geyer, M. A. Evidence for a functional interaction between 5-HT1A and 5-HT2A receptors in rats. Psychopharmacology (Berl.) 140, 69–74 (1998).

    CAS  Google Scholar 

  65. Strober, M. Family-genetic perspectives on anorexia nervosa and bulimia nervosa. in Eating Disorders and Obesity - A Comprehensive Handbook (eds Brownell, K. & Fairburn, C.) 212–218 (The Guilford Press, New York,1995).

    Google Scholar 

  66. Vitousek, K. & Manke, F. Personality variables and disorders in anorexia nervosa and bulimia nervosa. J. Abnorm. Psychol. 103, 137–147 (1994).

    CAS  PubMed  Google Scholar 

  67. Fernstrom, J. D. & Wurtman, R. J. Brain serotonin content: physiological regulation by plasma neutral amino acids. Science 178, 414–416 (1972).

    CAS  PubMed  Google Scholar 

  68. Kaye, W. H., Gwirtsman, H. E., George, D. T. & Ebert, M. H. Altered serotonin activity in anorexia nervosa after long-term weight restoration. Does elevated cerebrospinal fluid 5-hydroxyindoleacetic acid level correlate with rigid and obsessive behavior? Arch. Gen. Psychiatry 48, 556–562 (1991).

    CAS  PubMed  Google Scholar 

  69. Simansky, K. J. et al. A 5-HT2C agonist elicits hyperactivity and oral dyskinesia with hypophagia in rabbits. Physiol. Behav. 82, 97–107 (2004).

    CAS  PubMed  Google Scholar 

  70. Young, S. N. & Gauthier, S. Effect of tryptophan administration on tryptophan, 5- hydroxyindoleacetic acid and indoleacetic acid in human lumbar and cisternal cerebrospinal fluid. J. Neurol. Neurosurg. Psychiatry 44, 323–327 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Anderson, I. M., Parry-Billings, M., Newsholme, E. A., Fairburn, C. G. & Cowen, P. J. Dieting reduces plasma tryptophan and alters brain 5-HT function in women. Psychol. Med. 20, 785–791 (1990).

    CAS  PubMed  Google Scholar 

  72. Schweiger, U., Warnhoff, M., Pahl, J. & Pirke, K. M. Effects of carbohydrate and protein meals on plasma large neutral amino acids, glucose, and insulin plasma levels of anorectic patients. Metabolism 35, 938–943 (1986).

    CAS  PubMed  Google Scholar 

  73. Attia, E., Wolk, S., Cooper, T., Glasofer, D. & Walsh, B. Plasma tryptophan during weight restoration in patients with anorexia nervosa. Biol. Psychiatry 57, 674–678 (2005).

    CAS  PubMed  Google Scholar 

  74. Kaye, W. H., Gwirtsman, H. E., George, D. T., Jimerson, D. C. & Ebert, M. H. CSF 5-HIAA concentrations in anorexia nervosa: reduced values in underweight subjects normalize after weight gain. Biol. Psychiatry 23, 102–105 (1988).

    CAS  PubMed  Google Scholar 

  75. Klump, K. et al. Personality characteristics of women before and after recovery from an eating disorder. Psych. Med. 34, 1407–1418 (2004).

    Google Scholar 

  76. Frank, G. et al. Increased dopamine D2/D3 receptor binding after recovery from anorexia nervosa measured by positron emission tomography and [11C]raclopride. Biol. Psychiatry 58, 908–912 (2005).

    CAS  PubMed  Google Scholar 

  77. Kaye, W. H., Frank, G. K. & McConaha, C. Altered dopamine activity after recovery from restricting-type anorexia nervosa. Neuropsychopharmacology 21, 503–506 (1999).

    CAS  PubMed  Google Scholar 

  78. Bergen, A. et al. Association of multiple DRD2 polymorphisms with anorexia nervosa. Neuropsychopharmacology 30, 1703–1710 (2005).

    CAS  PubMed  Google Scholar 

  79. Lawrence, A. Impaired visual discrimination learning in anorexia nervosa. Appetite 20, 85–89 (2003).

    Google Scholar 

  80. Montague, R., Hyman, S. & Cohen, J. Computational roles for dopamine in behavioural control. Nature 431, 760–767 (2004).

    CAS  PubMed  Google Scholar 

  81. Schultz, W. Neural coding of basic reward terms of animal learning theory, game theory, microeconomics and behavioural ecology. Science 14, 139–147 (2004). This is an excellent summary of the new approach proposed by Schultz and others as to the function of dopamine in learning and reward. Specifically, it implicates dopamine as a key learning signal that functions to alter relative preferences among available choices.

    CAS  Google Scholar 

  82. Wagner, A. et al. Altered reward processing in women recovered from anorexia nervosa. Am. J. Psych. 164, 1842–1849 (2007).

    Google Scholar 

  83. Delgado, M., Nystrom, L., Fissel, C., Noll, D. & Fiez, J. Tracking the hemodynamic responses to reward and punishment in the striatum. J. Neurophysiol. 84, 3072–3077 (2000).

    CAS  PubMed  Google Scholar 

  84. Berridge, K. & Robinson, T. What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Res. 28, 309–369 (1998).

    CAS  Google Scholar 

  85. Halmi, K. et al. Predictors of treatment acceptance and completion in anorexia nervosa. Arch. Gen. Psychiatry 62, 776–781 (2005).

    PubMed  Google Scholar 

  86. Tricomi, E. M., Delgado, M. R. & Fiez, J. A. Modulation of caudate activity by action contingency. Neuron 41, 281–292 (2004).

    CAS  PubMed  Google Scholar 

  87. Lopez, C. et al. An examination of the concept of central coherence in women with anorexia nervosa. Int. J. Eat. Disord. 41, 143–152 (2008).

    PubMed  Google Scholar 

  88. Zastrow, A. et al. Neural correlates of impaired cognitive-behavioral flexibility in anorexia nervosa. Am. J. Psychiatry 166, 608–616 (2009). This paper shows that impaired behavioural response shifting in AN is associated with hypoactivation in the ventral anterior cingulate-striato-thalamic loop that is involved in motivation-related behaviour. By contrast, subjects with AN have predominant activation of frontoparietal networks that is indicative of effortful and supervisory cognitive control during task performance.

    PubMed  Google Scholar 

  89. Daw, N. D., Kakade, S. & Dayan, P. Opponent interactions between serotonin and dopamine. Neural Networks 15, 603–616 (2002).

    PubMed  Google Scholar 

  90. Cools, R., Roberts, A. & Robbins, T. Serotoninergic regulation of emotional and behavioural control processes. Trends Cogn. Sci. 12, 31–40 (2008).

    PubMed  Google Scholar 

  91. De Deurwaerdere, P., Navailles, S., Berg, K., Clarke, W. & Spampinato, U. Constitutive activity of the serotonin2C receptor inhibits in vivo dopamine release in the rat striatum and nucleus accumbens. J. Neurosci. 24, 3235–3241 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Di Matteo, V., Di Giovanni, G., Di Mascio, M. & Esposito, E. Biochemical and electrophysiological evidence that RO 60–0175 inhibits mesolimbic dopaminergic function through serotonin2C receptors. Brain Res. 865, 85–90 (2000).

    CAS  PubMed  Google Scholar 

  93. Schweighofer, N., Tanaka, S. & Doya, K. Serotonin and the evaluation of future rewards: theory, experiments, and possible neural mechanisms. Ann. NY Acad. Sci. 1104, 289–300 (2007).

    CAS  PubMed  Google Scholar 

  94. McClure, S., Laibson, D., Loewenstein, G. & Cohen, J. Separate neural systems value immediate and delayed monetary rewards. Science 306, 503–507 (2004). A study in which the authors propose that two competing systems, that is, the prefrontal cortex and the subcortical striatum, underlie the computation of the immediate and delayed value.

    CAS  PubMed  Google Scholar 

  95. Westergaard, G. et al. Physiological correlates of aggression and impulsivity in free-ranging female primates. Neuropsychopharmacology 28, 1045–1055 (2003).

    CAS  PubMed  Google Scholar 

  96. Attia, E., Schroeder, L. Pharmacologic treatment of anorexia nervosa: where do we go from here? Int. J. Eat. Disord. 37, S60–S63 (2005).

    PubMed  Google Scholar 

  97. Tollefson, G. D. Selective serotonin reuptake inhibitors. in Textbook of Psychopharmacology. (Schatzberg, A. F. & Nemeroff, C. B.) 161–182 (American Psychiatric Press, Inc. Washington DC,1995).

    Google Scholar 

  98. Blier P, de Montigny, C. Serotonin and drug-induced therapeutic responses in major depression, obsessive-compulsive and panic disorders. Neuropsychopharmacology 21, S91–S98 (1999).

    Google Scholar 

  99. Bissada, H., Tasca, G. A., Barber, A. M. & Bradwejn, J. Olanzapine in the treatment of low body weight and obsessive thinking in women with anorexia nervosa: a randomized, double-blind, placebo-controlled trial. Am. J. Psych. 165, 1281–1288 (2008).

    Google Scholar 

  100. Elman, I., Borsook, D. & Lukas, S. E. Food intake and reward mechanisms in patients with schizophrenia: implications for metabolic disturbances and treatment with second-generation antipsychotic agents. Neuropsychopharmacology 31, 2091–2120 (2006).

    CAS  PubMed  Google Scholar 

  101. Kelley, A. E. Ventral striatal control of appetite motivation: role in ingestive behavior and reward-related learning. Neurosci. Biobehav. Rev. 27, 765–776 (2004).

    PubMed  Google Scholar 

  102. Saper, C. B., Chou, T. C., Elmquist, J. K. The need to feed: homeostatic and hedonic control of eating. Neuron 36:199–211 (2002).

    CAS  PubMed  Google Scholar 

  103. Fernstrom, M. H., Weltzin, T. E., Neuberger, S., Srinivasagam, N. & Kaye, W. H. Twenty-four-hour food intake in patients with anorexia nervosa and in healthy control subjects. Biol. Psychiatry 36, 696–702 (1994).

    CAS  PubMed  Google Scholar 

  104. Drewnowski, A., Pierce, B. & Halmi, K. A. Fat aversion in eating disorders. Appetite 10, 119–131 (1988).

    CAS  PubMed  Google Scholar 

  105. Garfinkel, P., Moldofsky, H. & Garner, D. M. The stability of perceptual disturbances in anorexia nervosa. Psychol. Med. 9, 703–708 (1979).

    CAS  PubMed  Google Scholar 

  106. Santel, S., Baving, L., Krauel, K., Münte, T. & Rotte, M. Hunger and satiety in anorexia nervosa: fMRI during cognitive processing of food pictures. Brain Res. 1114, 138–148 (2006).

    CAS  PubMed  Google Scholar 

  107. Small, D. Central gustatory processing in humans. Adv. Otorhinolaryngol. 63, 191–220 (2006).

    PubMed  Google Scholar 

  108. Chandraskekar, J., Hoon, M., Ryba, N. & Zuker, C. The receptors and cells for mammalian taste. Nature 444, 288–294 (2006).

    Google Scholar 

  109. Ogawa, H. Gustatory cortex of primates: anatomy and physiology. Neurosci. Res. 20, 1–13 (1994).

    CAS  PubMed  Google Scholar 

  110. Scott, T. R., Yaxley, S., Sienkiewicz, Z. & Rolls, E. Gustatory responses in the frontal opercular cortex of the alert cynomolgus monkey. J. Neurophysiol. 56, 876–890 (1986).

    CAS  PubMed  Google Scholar 

  111. Yaxley, S., Rolls, E. & Sienkiewicz, Z. Gustatory responses of single neurons in the insula of the macaque monkey. J. Neurophysiol. 63, 689–700 (1990).

    CAS  PubMed  Google Scholar 

  112. Faurion, A. et al. Human taste cortical areas studied with functional magnetic resonance imaging: evidence of functional lateralization related to handedness. Neurosci. Lett. 277, 189–192 (1999).

    CAS  PubMed  Google Scholar 

  113. Schoenfeld, M. et al. Functional magnetic resonance tomography correlates of taste perception in the human primary taste cortex. Neuroscience 127, 347–353 (2004).

    CAS  PubMed  Google Scholar 

  114. O'Doherty, J., Kringelbach, M. L., Rolls, E. T., Hornak, J. & Andrews, C. Abstract reward and punishment representations in the human orbitofrontal cortex. Nature Neuroscience 4, 95–102 (2001).

    CAS  PubMed  Google Scholar 

  115. Schultz, W., Tremblay, L. & Hollerman, J. R. Reward processing in primate orbitofrontal cortex and basal ganglia. Cereb. Cortex 10, 272–284 (2000).

    CAS  PubMed  Google Scholar 

  116. Small, D. Toward an understanding of the brain substrates of reward in humans. Neuron 22, 668–671 (2002).

    Google Scholar 

  117. Small, D. M., Zatorre, R. J., Dagher, A., Evans, A. C. & Jones-Gotman, M. Changes in brain activity related to eating chocolate: from pleasure to aversion. Brain 124, 1720–1733 (2001).

    CAS  PubMed  Google Scholar 

  118. Freedman, L. J., Insel, T. R. & Smith, Y. Subcortical projections of area 25 (subgenual cortex) of the macaque monkey. J. Comp. Neurol. 421, 172–188 (2000).

    CAS  PubMed  Google Scholar 

  119. Ongur, D., An, X. & Price, J. Prefrontal cortical projections to the hypothalamus in macaque monkeys. J. Comp. Neurol. 401, 480–505 (1998).

    CAS  PubMed  Google Scholar 

  120. Carter, C. S., Botvinick, M. M. & Cohen, J. D. The contribution of the anterior cingulate cortex to executive processes in cognition. Rev. Neurosci. 10, 49–57 (1999).

    CAS  PubMed  Google Scholar 

  121. Critchley, H. D., Mathias, C. J. & Dolan, R. J. Neural activity in the human brain relating to uncertainty and arousal during anticipation. Neuron 29, 537–545 (2001).

    CAS  PubMed  Google Scholar 

  122. Critchley, H. D. et al. Human cingulate cortex and autonomic control: converging neuroimaging and clinical evidence. Brain 126, 2139–2152 (2003).

    PubMed  Google Scholar 

  123. Furuyashiki, T., Holland, P. & Gallagher, M. Rat orbitofrontal cortex separately encodes response and outcome information during performance of goal-directed behavior. J. Neurosci. 28, 5127–5138 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Gottfried, J., O'Doherty, J. & Dolan, R. Encoding predictive reward value in human amygdala and orbitofrontal cortex. Science 301, 1104–1107 (2003).

    CAS  PubMed  Google Scholar 

  125. Hare, T. A., O'Doherty, J., Camerer, C. F., Schultz, W. & Rangel, A. Dissociating the role of the orbitofrontal cortex and the striatum in the computation of goal values and prediction errors. J. Neurosci. 28, 5623–5630 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Roberts, A. Primate orbitofrontal cortex and adaptive behaviour. Trends Cogn. Sci. 10, 83–90 (2006).

    CAS  PubMed  Google Scholar 

  127. Tataranni, P. A. et al. Neuroanatomical correlates of hunger and satiation in humans using positron emission tomography. Proc. Natl Acad. Sci. USA 96, 4569–4574 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Morris, J. S. & Dolan, R. J. Involvement of human amygdala and orbitofrontal cortex in hunger-enhanced memory for food stimuli. J. Neurosc. 21, 5304–5310 (2001).

    CAS  Google Scholar 

  129. Kringelbach, M. L., O'Doherty, J., Rolls, E. & Andrews, C. Activation of the human orbitofrontal cortex to a liquid food stimulus is correlated with its subjective pleasantness. Cereb. Cortex 13, 1064–1071 (2003).

    CAS  PubMed  Google Scholar 

  130. Uher, R., Treasure, J., Heining, M., Brammer, M. C. & Campbell I. C. Cerebral processing of food-related stimuli: effects of fasting and gender. Behav. Brain Res. 169, 111–119 (2006).

    CAS  PubMed  Google Scholar 

  131. Chikama, M., McFarland, N., Amaral, D. H. & Haber S. N. Insular cortical projections to functional regions of the striatum correlate with cortical cytoarchitectonic organization in the primate. J. Neurosci. 17, 9686–9705 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Fudge, J., Breitbart, M., Danish, M. & Pannoni, V. Insular and gustatory inputs to the caudal ventral striatum in primates. J. Comp. Neurol. 490, 101–118 (2005).

    PubMed  PubMed Central  Google Scholar 

  133. Wagner, A. et al. Altered insula response to a taste stimulus in individuals recovered from restricting-type anorexia nervosa. Neuropsychopharmacology 33, 513–523 (2008).

    PubMed  Google Scholar 

  134. Ellison, Z. et al. Functional anatomy of calorie fear in anorexia nervosa. Lancet 352, 1192 (1998).

    CAS  PubMed  Google Scholar 

  135. Gordon, C. M. et al. Neural substrates of anorexia nervosa: a behavioral challenge study with positron emission tomography. J. Pediatr. 139, 51–57 (2001).

    CAS  PubMed  Google Scholar 

  136. Naruo, T. et al. Characteristic regional cerebral blood flow patterns in anorexia nervosa patients with binge/purge behavior. Am. J. Psychiatry 157, 1520–1522 (2000).

    CAS  PubMed  Google Scholar 

  137. Nozoe, S. et al. Changes in regional cerebral blood flow in patients with anorexia nervosa detected through single photon emission tomography imaging. Biol. Psychiatry 34, 578–580 (1993).

    CAS  PubMed  Google Scholar 

  138. Uher, R. et al. Medial prefrontal cortex activity associated with symptom provocation in eating disorders. Am. J. Psychiatry. 161, 1238–1246 (2004).

    PubMed  Google Scholar 

  139. Devinsky, O., Morrell, M. J. & Vogt, B. A. Contributions of anterior cingulate cortex to behaviour. Brain 118, 279–306 (1995).

    PubMed  Google Scholar 

  140. Critchley, H., Wiens, S., Rotshtein, P., Ohman, A. & Dolan, R. Neural systems supporting interoceptive awareness. Nature Neurosci. 7, 189–195 (2004). One of the first neuroimaging studies to demonstrate a direct association between interoceptive awareness and perceived emotions. In a paradigm that asked subjects to detect their heartbeat as accurately as possible, activation of an 'interoceptive' circuit involving the anterior insula/frontal operculum (AI/FO) was identified. AI/FO activation predicted accuracy in heartbeat detection, which in turn correlated with indices of negative emotional experience.

    CAS  PubMed  Google Scholar 

  141. Paulus, M. & Stein, M. B. An insular view of anxiety. Biol. Psychiatry 60, 383–387 (2006).

    PubMed  Google Scholar 

  142. Craig, A. How do you feel — now? The anterior insula and human awareness. Nature Rev. Neurosci. 10, 59–70 (2008).

    Google Scholar 

  143. Craig, A. D. How do you feel? Interoception: the sense of the physiological condition of the body. Nature Rev. Neurosci. 3, 655–666 (2002). This paper reviews the afferent neural system in non-human and human primates that represents all aspects of the physiological condition of the physical body. This system constitutes a representation of 'the material me', and thus might provide a foundation for subjective feelings, emotion and self-awareness.

    CAS  Google Scholar 

  144. Craig, A. Human feelings: why are some more aware than others? Trends Cogn. Sci. 8, 239–241 (2004).

    PubMed  Google Scholar 

  145. Damasio, A. et al. Subcortical and cortical brain activity during the feeling of self-generated emotions. Nature Neurosci. 3, 1049–1056 (2000).

    CAS  PubMed  Google Scholar 

  146. Bruch, H. Perceptual and conceptual disturbances in anorexia nervosa. Psychosom. Med. 24, 187–194 (1962).

    CAS  PubMed  Google Scholar 

  147. Fassino, S., Piero, A., Gramaglia, C. & Abbate-Daga, G. Clinical, psychopathological and personality correlates of interoceptive awareness in anorexia nervosa, bulimia nervosa and obesity. Psychopathology 37, 168–174 (2004).

    PubMed  Google Scholar 

  148. Garner, D. M., Olmstead, M. P. & Polivy, J. Development and validation of a multidimensional eating disorder inventory for anorexia and bulimia nervosa. Int. J. Eat. Disord. 2, 15–34 (1983).

    Google Scholar 

  149. Pollatos, O. et al. Reduced perception of bodily signals in anorexia nervosa. Eat. Behav. 9, 381–388 (2008).

    PubMed  Google Scholar 

  150. Preuschoff, K., Quartz, S. & Bossaerts, P. Human insula activation reflects risk prediction errors as well as risk. J. Neurosci. 28, 2745–2752 (2008). This study uses an elegant design to disambiguate the role of the insular cortex in risk-related processing. In particular, the authors suggest that the insula is important for both generating prediction errors and risk (variance) related processing.

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Carter, C. S. et al. Parsing executive processes: strategic vs. evaluative functions of the anterior cingulate cortex. Proc. Natl Acad. Sci. USA 97, 1944–1948 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Ongur, D. & Price, J. L. Organization of networks within the orbital and medial prefrontal cortex of rats, monkeys, and humans. Cereb. Cortex 10, 206–219 (2000).

    CAS  PubMed  Google Scholar 

  153. Rolls, E. T. The orbitofrontal cortex. Philos. Trans. R. Soc. Lond. B Biol. Sci. 351, 1433–1443 (1996).

    CAS  PubMed  Google Scholar 

  154. Kerns, J. et al. Anterior cingulate conflict monitoring and adjustments in control. Science 303, 1023–1026 (2004).

    CAS  PubMed  Google Scholar 

  155. Redish, A. Addiction as a computational process gone awry. Science 306, 1944–1947 (2004).

    CAS  PubMed  Google Scholar 

  156. Volkow, N. D., Wise, R. A. How can drug addiction help us understand obesity? Nature Neurosci. 8, 555–560 (2005).

    CAS  PubMed  Google Scholar 

  157. Chambers, R., Taylor, J. & Potenza, M. Developmental neurocircuitry of motivation in adolescence: a critical period of addiction vulnerability. Am. J. Psych. 160, 1041–1052 (2003).

    Google Scholar 

  158. Connan, F., Campbell, I., Katzman, M., Lightman, S. & Treasure, J. A neurodevelopmental model for anorexia nervosa. Physiol. Behav. 79, 13–24 (2003). This excellent synthesis integrates genetic, biological, cognitive and psychosocial factors, and interpersonal stress, to generate a neurodevelopmental hypothesis for the aetiology of AN.

    CAS  PubMed  Google Scholar 

  159. Kirby, K., Petry, N. & Bickel, W. Heroin addicts have higher discount rates for delayed rewards than non-drug-using controls. J. Exp. Psychol. Gen. 128, 78–87 (1999).

    CAS  PubMed  Google Scholar 

  160. Kaye, W., Wisniewski, L. Vulnerability to substance abuse in eating disorders. NIDA Res. Monogr. 159, 269–311 (1996).

    CAS  PubMed  Google Scholar 

  161. Huttenlocher, P. & Dabholkar, A. Regional differences in synaptogenesis in human cerebral cortex. J. Comp. Neurol. 387, 167–178 (1997).

    CAS  PubMed  Google Scholar 

  162. Jacobi, C., Hayward C, de Zwaan, M., Kraemer, H. & Agras, W. Coming to terms with risk factors for eating disorders: application of risk terminology and suggestions for a general taxonomy. Psych. Bull. 130, 19–65 (2004).

    Google Scholar 

  163. Klump, K., Burt, S., McGue, M. & Iacono, W. Changes in genetic and environmental influences on disordered eating across adolescence. A longitudinal twin study. Arch. Gen. Psychiatry 64, 1409–1415 (2007). The authors of this study present data from the first longitudinal twin studies in eating disorders. Findings highlight the transition from early to mid adolescence as a crucial time for the emergence of a genetic diathesis for disordered eating. The increase in genetic effects during this developmental stage corroborates previous research implicating puberty in the genetic aetiology of eating disorders.

    PubMed  Google Scholar 

  164. Rubinow, D. R., Schmidt, P. J. & Roca, C. A. Estrogen-serotonin interactions: implications for affective regulation. Biol. Psychiatry 44, 839–850.

  165. Torpy, D. J., Papanicolaou, D. A. & Chrousos, G. P. Sexual dismorphism of the human stress response may be due to estradiol-mediated stimulation of hypothalamic corticotropin-releasing hormone synthesis. J. Clin. Endocrinol. Metab. 82, 982 (1997).

    CAS  PubMed  Google Scholar 

  166. Kaye, W. H. et al. Reduced cerebrospinal fluid levels of immunoreactive pro- opiomelanocortin related peptides (including beta-endorphin) in anorexia nervosa. Life Sci. 41, 2147–2155 (1987).

    CAS  PubMed  Google Scholar 

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Acknowledgements

Much of the research incorporated into this Review was supported for W.H.K. by the National Institute of Mental Health (NIMH) (046001, 042984, 066122 and 001894) and the Price Foundation, for J.L.F. by the NIMH (063291) and for M.P. by the National Institute on Drug Abuse (016663, 018307 and 020687) and the Center of Excellence in Stress and Mental Health.

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Authors and Affiliations

  1. Department of Psychiatry, Eating Disorder Treatment & Research Program, University of California, San Diego, La Jolla Village Professional Center, 8950 Villa La Jolla Drive, Suite C-207, La Jolla, 92037, California, USA

    Walter H. Kaye

  2. Psychiatry & Neurobiology and Anatomy, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, 14642, New York, USA

    Julie L. Fudge

  3. Department of Psychiatry, Laboratory of Biological Dynamics and Theoretical Medicine, University of California, San Diego, 8939 Villa La Jolla Dr. Suite 200, La Jolla, 92037-0985, California, USA

    Martin Paulus

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Correspondence to Walter H. Kaye.

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Glossary

Interoception

The sensing and integrating of afferent proprioceptive and visceroceptive information, resulting in feeling the 'inner state' of the body, which is important for allocating attention, evaluating context and planning actions.

Hedonic

A sensation related to or characterized by pleasure

Visceroception

A sensation originating from the internal organs.

Proprioception

A sensation originating from the joints and the subcutaneous tissues.

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Kaye, W., Fudge, J. & Paulus, M. New insights into symptoms and neurocircuit function of anorexia nervosa. Nat Rev Neurosci 10, 573–584 (2009). https://doi.org/10.1038/nrn2682

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