Skip to main content
    • Aa
    • Aa

Impaired probabilistic reversal learning in youths with mood and anxiety disorders

  • D. P. Dickstein (a1), E. C. Finger (a1), M. A. Brotman (a1), B. A. Rich (a1), D. S. Pine (a1), J. R. Blair (a1) and E. Leibenluft (a1)...

From an affective neuroscience perspective, our understanding of psychiatric illness may be advanced by neuropsychological test paradigms probing emotional processes. Reversal learning is one such process, whereby subjects must first acquire stimulus/reward and stimulus/punishment associations through trial and error and then reverse them. We sought to determine the specificity of previously demonstrated reversal learning impairments in youths with bipolar disorder (BD) by now comparing BD youths to those with severe mood dysregulation (SMD), major depressive disorder (MDD), anxiety (ANX), and healthy controls.


We administered the probabilistic response reversal (PRR) task to 165 pediatric participants aged 7–17 years with BD (n=35), SMD (n=35), ANX (n=42), MDD (n=18) and normal controls (NC; n=35). Our primary analysis compared PRR performance across all five groups matched for age, sex and IQ.


Compared to typically developing controls, probabilistic reversal learning was impaired in BD youths, with a trend in those with MDD (p=0.07).


Our results suggest that reversal learning deficits are present in youths with BD and possibly those with MDD. Further work is necessary to elucidate the specificity of neural mechanisms underlying such behavioral deficits.

Corresponding author
*Address for correspondence: D. P. Dickstein, M.D., EP Bradley Hospital, Bradley/Hasbro Children's Research Center, 1 Hoppin Street, Coro West 2nd Floor, Providence, RI 02903, USA. (Email:
Hide All
Abler B, Greenhouse I, Ongur D, Walter H, Heckers S (2008). Abnormal reward system activation in mania. Neuropsychopharmacology 33, 22172227.
Bellebaum C, Koch B, Schwarz M, Daum I (2008). Focal basal ganglia lesions are associated with impairments in reward-based reversal learning. Brain 131, 829841.
Ben Pazi H, Gross-Tsur V, Bergman H, Shalev RS (2003). Abnormal rhythmic motor response in children with attention-deficit-hyperactivity disorder. Developmental Medicine and Child Neurology 45, 743745.
Birmaher B, Axelson DA, Monk K, Kalas C, Clark DB, Ehmann M, Bridge J, Heo J, Brent DA (2003). Fluoxetine for the treatment of childhood anxiety disorders. Journal of the American Academy of Child and Adolescent Psychiatry 42, 415423.
Blair RJ (2004). The roles of orbital frontal cortex in the modulation of antisocial behavior. Brain and Cognition 55, 198208.
Blair RJ, Cipolotti L (2000). Impaired social response reversal. A case of ‘acquired sociopathy’. Brain 123, 11221141.
Blair RJ, Colledge E, Mitchell DG (2001). Somatic markers and response reversal: is there orbitofrontal cortex dysfunction in boys with psychopathic tendencies? Journal of Abnormal Child Psychology 29, 499511.
Blair RJR (2009). Psychopathy, frustration, and reactive aggression: the role of ventromedial prefrontal cortex. British Journal of Psychology. Published online: 24 March 2009. doi: 10.1348/000712609X418480.
Blumberg HP, Charney DS, Krystal JH (2002). Frontotemporal neural systems in bipolar disorder. Seminars in Clinical Neuropsychiatry 7, 243254.
Blumberg HP, Martin A, Kaufman J, Leung HC, Skudlarski P, Lacadie C, Fulbright RK, Gore JC, Charney DS, Krystal JH, Peterson BS (2003). Frontostriatal abnormalities in adolescents with bipolar disorder: preliminary observations from functional MRI. American Journal of Psychiatry 160, 13451347.
Brotman MA, Kassem L, Reising MM, Guyer AE, Dickstein DP, Rich BA, Towbin KE, Pine DS, McMahon FJ, Leibenluft E (2007). Parental diagnoses in youth with narrow phenotype bipolar disorder or severe mood dysregulation. American Journal of Psychiatry 164, 12381241.
Brotman MA, Schmajuk M, Rich BA, Dickstein DP, Guyer AE, Costello EJ, Egger HL, Angold A, Pine DS, Leibenluft E (2006). Prevalence, clinical correlates, and longitudinal course of severe mood dysregulation in children. Biological Psychiatry 60, 991997.
Budhani S, Marsh AA, Pine DS, Blair RJ (2007). Neural correlates of response reversal: considering acquisition. NeuroImage 34, 17541765.
Budhani S, Richell RA, Blair RJ (2006). Impaired reversal but intact acquisition: probabilistic response reversal deficits in adult individuals with psychopathy. Journal of Abnormal Psychology 115, 552558.
Carlson GA (1998). Mania and ADHD: comorbidity or confusion. Journal of Affective Disorders 51, 177187.
Chamberlain SR, Menzies L, Hampshire A, Suckling J, Fineberg NA, del Campo N, Aitken M, Craig K, Owen AM, Bullmore ET, Robbins TW, Sahakian BJ (2008). Orbitofrontal dysfunction in patients with obsessive-compulsive disorder and their unaffected relatives. Science 321, 421422.
Chamberlain SR, Muller U, Blackwell AD, Clark L, Robbins TW, Sahakian BJ (2006). Neurochemical modulation of response inhibition and probabilistic learning in humans. Science 311, 861863.
Clark L, Cools R, Robbins TW (2004). The neuropsychology of ventral prefrontal cortex: decision-making and reversal learning. Brain and Cognition 55, 4153.
Cools R, Clark L, Owen AM, Robbins TW (2002). Defining the neural mechanisms of probabilistic reversal learning using event-related functional magnetic resonance imaging. Journal of Neuroscience 22, 45634567.
Cools R, Clark L, Robbins TW (2004). Differential responses in human striatum and prefrontal cortex to changes in object and rule relevance. Journal of Neuroscience 24, 11291135.
Devido J, Jones M, Geraci M, Hollon N, Blair RJ, Pine DS, Blair K (2008). Stimulus-reinforcement-based decision making and anxiety: impairment in generalized anxiety disorder (GAD) but not in generalized social phobia (GSP). Psychological Medicine 39, 11531161.
Dickstein DP, Nelson EE, McClure EB, Grimley ME, Knopf L, Brotman MA, Rich BA, Pine DS, Leibenluft E (2007 a). Cognitive flexibility in phenotypes of pediatric bipolar disorder. Journal of the American Academy of Child and Adolescent Psychiatry 46, 341355.
Dickstein DP, Rich BA, Roberson-Nay R, Berghorst L, Vinton D, Pine DS, Leibenluft E (2007 b). Neural activation during encoding of emotional faces in pediatric bipolar disorder. Bipolar Disorders 9, 679692.
Dickstein DP, Treland JE, Snow J, McClure EB, Mehta MS, Towbin KE, Pine DS, Leibenluft E (2004). Neuropsychological performance in pediatric bipolar disorder. Biological Psychiatry 55, 3239.
Doyle AE (2006). Executive functions in attention-deficit/hyperactivity disorder. Journal of Clinical Psychiatry 67 (Suppl. 8), 2126.
Drevets WC (2000). Functional anatomical abnormalities in limbic and prefrontal cortical structures in major depression. Progress in Brain Research 126, 413431.
Eysenck MW, Derakshan N, Santos R, Calvo MG (2007). Anxiety and cognitive performance: attentional control theory. Emotion 7, 336353.
Fellows LK, Farah MJ (2003). Ventromedial frontal cortex mediates affective shifting in humans: evidence from a reversal learning paradigm. Brain 126, 18301837.
Finger EC, Marsh AA, Mitchell DG, Reid ME, Sims C, Budhani S, Kosson DS, Chen G, Towbin KE, Leibenluft E, Pine DS, Blair JR (2008). Abnormal ventromedial prefrontal cortex function in children with psychopathic traits during reversal learning. Archives of General Psychiatry 65, 586594.
Geller B, Williams M, Zimerman B, Frazier J, Beringer L, Warner KL (1998). Prepubertal and early adolescent bipolarity differentiate from ADHD by manic symptoms, grandiose delusions, ultra-rapid or ultradian cycling. Journal of Affective Disorders 51, 8191.
Gorrindo T, Blair RJ, Budhani S, Dickstein DP, Pine DS, Leibenluft E (2005). Deficits on a probabilistic response-reversal task in patients with pediatric bipolar disorder. American Journal of Psychiatry 162, 19751977.
Guyer AE, McClure EB, Adler AD, Brotman MA, Rich BA, Kimes AS, Pine DS, Ernst M, Leibenluft E (2007). Specificity of facial expression labeling deficits in childhood psychopathology. Journal of Child Psychology and Psychiatry 48, 863871.
Huettel SA (2006). Behavioral, but not reward, risk modulates activation of prefrontal, parietal, and insular cortices. Cognitive, Affective and Behavioral Neuroscience 6, 141151.
Izquierdo A, Murray EA (2004). Combined unilateral lesions of the amygdala and orbital prefrontal cortex impair affective processing in rhesus monkeys. Journal of Neurophysiology 91, 20232039.
Kaufman J, Birmaher B, Brent D, Rao U, Flynn C, Moreci P, Williamson D, Ryan N (1997). Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL): initial reliability and validity data. Journal of the American Academy of Child and Adolescent Psychiatry 36, 980988.
Kempton S, Vance A, Maruff P, Luk E, Costin J, Pantelis C (1999). Executive function and attention deficit hyperactivity disorder: stimulant medication and better executive function performance in children. Psychological Medicine 29, 527538.
Knutson B, Westdorp A, Kaiser E, Hommer D (2000). FMRI visualization of brain activity during a monetary incentive delay task. NeuroImage 12, 2027.
Krain AL, Gotimer K, Hefton S, Ernst M, Castellanos FX, Pine DS, Milham MP (2008). A functional magnetic resonance imaging investigation of uncertainty in adolescents with anxiety disorders. Biological Psychiatry 63, 563568.
Kyte ZA, Goodyer IM, Sahakian BJ (2005). Selected executive skills in adolescents with recent first episode major depression. Journal of Child Psychology and Psychiatry 46, 995–1005.
Leibenluft E, Charney DS, Towbin KE, Bhangoo RK, Pine DS (2003). Defining clinical phenotypes of juvenile mania. American Journal of Psychiatry 160, 430437.
Leibenluft E, Rich BA, Vinton DT, Nelson EE, Fromm SJ, Berghorst LH, Joshi P, Robb A, Schachar RJ, Dickstein DP, McClure EB, Pine DS (2007). Neural circuitry engaged during unsuccessful motor inhibition in pediatric bipolar disorder. American Journal of Psychiatry 164, 5260.
McClure EB, Monk CS, Nelson EE, Parrish JM, Adler A, Blair RJ, Fromm S, Charney DS, Leibenluft E, Ernst M, Pine DS (2007). Abnormal attention modulation of fear circuit function in pediatric generalized anxiety disorder. Archives of General Psychiatry 64, 97–106.
Milham MP, Nugent AC, Drevets WC, Dickstein DS, Leibenluft E, Ernst M, Charney D, Pine DS (2005). Selective reduction in amygdala volume in pediatric anxiety disorders: a voxel-based morphometry investigation. Biological Psychiatry 57, 961966.
Mitchell DG, Rhodes RA, Pine DS, Blair RJ (2008). The contribution of ventrolateral and dorsolateral prefrontal cortex to response reversal. Behavioural Brain Research 187, 8087.
Monk CS, Nelson EE, McClure EB, Mogg K, Bradley BP, Leibenluft E, Blair RJ, Chen G, Charney DS, Ernst M, Pine DS (2006). Ventrolateral prefrontal cortex activation and attentional bias in response to angry faces in adolescents with generalized anxiety disorder. American Journal of Psychiatry 163, 10911097.
Nelson EE, Vinton DT, Berghorst L, Towbin KE, Hommer RE, Dickstein DP, Rich BA, Brotman MA, Pine DS, Leibenluft E (2007). Brain systems underlying response flexibility in healthy and bipolar adolescents: an event-related fMRI study. Bipolar Disorders 9, 810819.
NIMH (2001). National Institute of Mental Health research roundtable on prepubertal bipolar disorder. Journal of the American Academy of Child and Adolescent Psychiatry 40, 871878.
O'Doherty J, Dayan P, Schultz J, Deichmann R, Friston K, Dolan RJ (2004). Dissociable roles of ventral and dorsal striatum in instrumental conditioning. Science 304, 452454.
Paulus MP, Hozack N, Zauscher B, McDowell JE, Frank L, Brown GG, Braff DL (2001). Prefrontal, parietal, and temporal cortex networks underlie decision-making in the presence of uncertainty. NeuroImage 13, 91–100.
Pavuluri MN, O'Connor MM, Harral E, Sweeney JA (2007). Affective neural circuitry during facial emotion processing in pediatric bipolar disorder. Biological Psychiatry 62, 158167.
Pavuluri MN, O'Connor MM, Harral EM, Sweeney JA (2008). An fMRI study of the interface between affective and cognitive neural circuitry in pediatric bipolar disorder. Psychiatry Research 162, 244255.
Pfeifer JC, Welge J, Strakowski SM, Adler CM, DelBello MP (2008). Meta-analysis of amygdala volumes in children and adolescents with bipolar disorder. Journal of the American Academy of Child and Adolescent Psychiatry 47, 12891298.
Poznanski EO, Freeman LN, Mokros HB (1985). Children's Depression Rating Scale-Revised. Psychopharmacology Bulletin 21, 979984.
Ramnani N, Elliott R, Athwal BS, Passingham RE (2004). Prediction error for free monetary reward in the human prefrontal cortex. NeuroImage 23, 777786.
Rich BA, Grimley ME, Schmajuk M, Blair KS, Blair RJ, Leibenluft E (2008). Face emotion labeling deficits in children with bipolar disorder and severe mood dysregulation. Development and Psychopathology 20, 529546.
Rich BA, Vinton DT, Roberson-Nay R, Hommer RE, Berghorst LH, McClure EB, Fromm SJ, Pine DS, Leibenluft E (2006). Limbic hyperactivation during processing of neutral facial expressions in children with bipolar disorder. Proceedings of the National Academy of Sciences USA 103, 89008905.
Robbins TW, James M, Owen AM, Sahakian BJ, Lawrence AD, McInnes L, Rabbitt PM (1998). A study of performance on tests from the CANTAB battery sensitive to frontal lobe dysfunction in a large sample of normal volunteers: implications for theories of executive functioning and cognitive aging. Cambridge Neuropsychological Test Automated Battery. Journal of the International Neuropsychological Society 4, 474490.
Roberson-Nay R, McClure EB, Monk CS, Nelson EE, Guyer AE, Fromm SJ, Charney DS, Leibenluft E, Blair J, Ernst M, Pine DS (2006). Increased amygdala activity during successful memory encoding in adolescent major depressive disorder: an fMRI study. Biological Psychiatry 60, 966973.
Rosenberg DR, MacMaster FP, Mirza Y, Smith JM, Easter PC, Banerjee SP, Bhandari R, Boyd C, Lynch M, Rose M, Ivey J, Villafuerte RA, Moore GJ, Renshaw P (2005). Reduced anterior cingulate glutamate in pediatric major depression: a magnetic resonance spectroscopy study. Biological Psychiatry 58, 700704.
RUPP (2001). Fluvoxamine for the treatment of anxiety disorders in children and adolescents. The Research Units on Pediatric Psychopharmacology Anxiety Study Group. New England Journal of Medicine 344, 12791285.
RUPP (2002). The Pediatric Anxiety Rating Scale (PARS): development and psychometric properties. The Research Units on Pediatric Psychopharmacology Anxiety Study Group. Journal of the American Academy of Child and Adolescent Psychiatry 41, 10611069.
Shaffer D, Gould MS, Brasic J, Ambrosini P, Fisher P, Bird H, Aluwahlia S (1983). A Children's Global Assessment Scale (CGAS). Archives of General Psychiatry 40, 12281231.
Stemme A, Deco G, Busch A, Schneider WX (2005). Neurons and the synaptic basis of the fMRI signal associated with cognitive flexibility. NeuroImage 26, 454470.
Thomas KM, Drevets WC, Dahl RE, Ryan ND, Birmaher B, Eccard CH, Axelson D, Whalen PJ, Casey BJ (2001). Amygdala response to fearful faces in anxious and depressed children. Archives of General Psychiatry 58, 10571063.
Xue G, Ghahremani DG, Poldrack RA (2008). Neural substrates for reversing stimulus-outcome and stimulus-response associations. Journal of Neuroscience 28, 1119611204.
Young RC, Biggs JT, Ziegler VE, Meyer DA (1978). A rating scale for mania: reliability, validity and sensitivity. British Journal of Psychiatry 133, 429435.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Psychological Medicine
  • ISSN: 0033-2917
  • EISSN: 1469-8978
  • URL: /core/journals/psychological-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Altmetric attention score

Full text views

Total number of HTML views: 9
Total number of PDF views: 49 *
Loading metrics...

Abstract views

Total abstract views: 340 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 20th October 2017. This data will be updated every 24 hours.