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Altered functioning of reward circuitry in youth offspring of parents with bipolar disorder

  • A. Manelis (a1), C. D. Ladouceur (a1), S. Graur (a1), K. Monk (a1), L. K. Bonar (a1), M. B. Hickey (a1), A. C. Dwojak (a1), D. Axelson (a2), B. I. Goldstein (a3), T. R. Goldstein (a1), G. Bebko (a1), M. A. Bertocci (a1), M. K. Gill (a1), B. Birmaher (a1) and M. L. Phillips (a1)...

Abstract

Background.

Offspring of parents with bipolar disorder (BD) (BO) are at higher risk of BD than offspring of parents with non-BD psychopathology (NBO), although both groups are at higher risk than offspring of psychiatrically healthy parents (HC) for other affective and psychiatric disorders. Abnormal functioning in reward circuitry has been demonstrated previously in individuals with BD. We aimed to determine whether activation and functional connectivity in this circuitry during risky decision-making differentiated BO, NBO and HC.

Method.

BO (n = 29; mean age = 13.8 years; 14 female), NBO (n = 28; mean age = 13.9 years; 12 female) and HC (n = 23; mean age = 13.7 years; 11 female) were scanned while performing a number-guessing reward task. Of the participants, 11 BO and 12 NBO had current non-BD psychopathology; five BO and four NBO were taking psychotropic medications.

Results.

A 3 (group) × 2 (conditions: win-control/loss-control) analysis of variance revealed a main effect of group on right frontal pole activation: BO showed significantly greater activation than HC. There was a significant main effect of group on functional connectivity between the bilateral ventral striatum and the right ventrolateral prefrontal cortex (Z > 3.09, cluster-p < 0.05): BO showed significantly greater negative functional connectivity than other participants. These between-group differences remained after removing youth with psychiatric disorders and psychotropic medications from analyses.

Conclusions.

This is the first study to demonstrate that reward circuitry activation and functional connectivity distinguish BO from NBO and HC. The fact that the pattern of findings remained when comparing healthy BO v. healthy NBO v. HC suggests that these neuroimaging measures may represent trait-level neurobiological markers conferring either risk for, or protection against, BD in youth.

Copyright

Corresponding author

* Address for correspondence: A. Manelis, Department of Psychiatry, Western Psychiatric Institute and Clinic, 121 Meyran Avenue, Loeffler Building, Room 205, Pittsburgh, PA 15213, USA. (Email: anna.manelis@gmail.com)

References

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Alloy, LB, Bender, RE, Whitehouse, WG, Wagner, CA, Liu, RT, Grant, DA, Jager-Hyman, S, Molz, A, Choi, JY, Harmon-Jones, E, Abramson, LY (2012). High Behavioral Approach System (BAS) sensitivity, reward responsiveness, and goal-striving predict first onset of bipolar spectrum disorders: a prospective behavioral high-risk design. Journal of Abnormal Psychology 121, 339351.
Altshuler, L, Bookheimer, S, Townsend, J, Proenza, MA, Sabb, F, Mintz, J, Cohen, MS (2008). Regional brain changes in bipolar I depression: a functional magnetic resonance imaging study. Bipolar Disorders 10, 708717.
Andersson, JLR, Jenkinson, M, Smith, S (2007). Non-linear registration aka spatial normalisation. Technical Report FMRIB Technical Report TR07JA2. FMRIB Centre: Oxford.
Angold, A, Prendergast, M, Cox, A, Harrington, R, Simonoff, E, Rutter, M (1995). The Child and Adolescent Psychiatric Assessment (CAPA). Psychological Medicine 25, 739753.
Baxter, MG, Murray, EA (2002). The amygdala and reward. Nature Reviews Neuroscience 3, 563573.
Bebko, G, Bertocci, MA, Fournier, JC, Hinze, AK, Bonar, L, Almeida, JRC, Perlman, SB, Versace, A, Schirda, C, Travis, M, Gill, MK, Demeter, C, Diwadkar, VA, Ciuffetelli, G, Rodriguez, E, Olino, T, Forbes, E, Sunshine, JL, Holland, SK, Kowatch, RA, Birmaher, B, Axelson, D, Horwitz, SM, Arnold, LE, Fristad, MA, Youngstrom, EA, Findling, RL, Phillips, ML (2014). Parsing dimensional vs diagnostic category-related patterns of reward circuitry function in behaviorally and emotionally dysregulated youth in the longitudinal assessment of Manic Symptoms Study. JAMA Psychiatry 71, 7180.
Bermpohl, F, Kahnt, T, Dalanay, U, Hgele, C, Sajonz, B, Wegner, T, Stoy, M, Adli, M, Krger, S, Wrase, J, Strhle, A, Bauer, M, Heinz, A (2010). Altered representation of expected value in the orbitofrontal cortex in mania. Human Brain Mapping 31, 958969.
Birmaher, B, Axelson, D, Goldstein, B, Monk, K, Kalas, C, Obreja, M, Hickey, MB, Iyengar, S, Brent, D, Shamseddeen, W, Diler, R, Kupfer, D (2010). Psychiatric disorders in preschool offspring of parents with bipolar disorder: the Pittsburgh Bipolar Offspring Study (BIOS). American Journal of Psychiatry 167, 321330.
Birmaher, B, Axelson, D, Monk, K, Kalas, C, Goldstein, B, Hickey, MB, Obreja, M, Ehmann, M, Iyengar, S, Shamseddeen, W, Kupfer, D, Brent, D (2009). Lifetime psychiatric disorders in school-aged offspring of parents with bipolar disorder: the Pittsburgh Bipolar Offspring study. Archives of General Psychiatry 66, 287296.
Birmaher, B, Khetarpal, S, Brent, D, Cully, M, Balach, L, Kaufman, J, Neer, SM (1997). The Screen for Child Anxiety Related Emotional Disorders (SCARED): scale construction and psychometric characteristics. Journal of the American Academy of Child and Adolescent Psychiatry 36, 545553.
Boorman, ED, Behrens, TEJ, Woolrich, MW, Rushworth, MFS (2009). How green is the grass on the other side? Frontopolar cortex and the evidence in favor of alternative courses of action. Neuron 62, 733743.
Burgess, PW, Gilbert, SJ, Dumontheil, I (2007). Function and localization within rostral prefrontal cortex (area 10). Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 362, 887899.
Burgund, ED, Kang, HC, Kelly, JE, Buckner, RL, Snyder, AZ, Petersen, SE, Schlaggar, BL (2002). The feasibility of a common stereotactic space for children and adults in fMRI studies of development. NeuroImage 17, 184200.
Cardoso de Almeida, JR, Phillips, ML (2013). Distinguishing between unipolar depression and bipolar depression: current and future clinical and neuroimaging perspectives. Biological Psychiatry 73, 111118.
Caseras, X, Lawrence, NS, Murphy, K, Wise, RG, Phillips, ML (2013). Ventral striatum activity in response to reward: differences between bipolar I and II disorders. American Journal of Psychiatry 170, 533541.
Chase, HW, Nusslock, R, Almeida, JR, Forbes, EE, Labarbara, EJ, Phillips, ML (2013). Dissociable patterns of abnormal frontal cortical activation during anticipation of an uncertain reward or loss in bipolar versus major depression. Bipolar Disorders 15, 839854.
Cremers, HR, Veer, IM, Spinhoven, P, Rombouts, SARB, Roelofs, K (2014). Neural sensitivity to social reward and punishment anticipation in social anxiety disorder. Frontiers in Behavioral Neuroscience 8, 439.
Croxson, PL, Walton, ME, O'Reilly, JX, Behrens, TEJ, Rushworth, MFS (2009). Effort-based cost–benefit valuation and the human brain. Journal of Neuroscience 29, 45314541.
Del Arco, A, Mora, F (2009). Neurotransmitters and prefrontal cortex–limbic system interactions: implications for plasticity and psychiatric disorders. Journal of Neural Transmission 116, 941952.
Elman, I, Lowen, S, Frederick, BB, Chi, W, Becerra, L, Pitman, RK (2009). Functional neuroimaging of reward circuitry responsivity to monetary gains and losses in posttraumatic stress disorder. Biological Psychiatry 66, 10831090.
Ernst, M, Dickstein, DP, Munson, S, Eshel, N, Pradella, A, Jazbec, S, Pine, DS, Leibenluft, E (2004). Reward-related processes in pediatric bipolar disorder: a pilot study. Journal of Affective Disorders 82 (Suppl. 1), S89S101.
Findling, RL, Youngstrom, EA, Fristad, MA, Birmaher, B, Kowatch, RA, Arnold, LE, Frazier, TW, Axelson, D, Ryan, N, Demeter, CA, Gill, MK, Fields, B, Depew, J, Kennedy, SM, Marsh, L, Rowles, BM, Horwitz, SM (2010). Characteristics of children with elevated symptoms of mania: the Longitudinal Assessment of Manic Symptoms (LAMS) study. Journal of Clinical Psychiatry 71, 16641672.
First, M, Spitzer, R, Gibbon, M, Williams, J (2002). Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Non-patient Edition (SCID-I/NP). Biometrics Research, New York State Psychiatric Institute: New York.
FitzGerald, THB, Friston, KJ, Dolan, RJ (2012). Action-specific value signals in reward-related regions of the human brain. Journal of Neuroscience 32, 1641716423a.
Forbes, EE, Brown, SM, Kimak, M, Ferrell, RE, Manuck, SB, Hariri, AR (2009). Genetic variation in components of dopamine neurotransmission impacts ventral striatal reactivity associated with impulsivity. Molecular Psychiatry 14, 6070.
Friston, KJ, Buechel, C, Fink, GR, Morris, J, Rolls, E, Dolan, RJ (1997). Psychophysiological and modulatory interactions in neuroimaging. NeuroImage 6, 218229.
Gerson, AC, Gerring, JP, Freund, L, Joshi, PT, Capozzoli, J, Brady, K, Denckla, MB (1996). The Children's Affective Lability Scale: a psychometric evaluation of reliability. Psychiatry Research 65, 189198.
Goldstein, BI, Shamseddeen, W, Axelson, DA, Kalas, C, Monk, K, Brent, DA, Kupfer, DJ, Birmaher, B (2010). Clinical, demographic, and familial correlates of bipolar spectrum disorders among offspring of parents with bipolar disorder. Journal of the American Academy of Child and Adolescent Psychiatry 49, 388396.
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.
Greenberg, T, Chase, HW, Almeida, JR, Stiffler, R, Zevallos, CR, Aslam, HA, Deckersbach, T, Weyandt, S, Cooper, C, Toups, M, Carmody, T, Kurian, B, Peltier, S, Adams, P, McInnis, MG, Oquendo, MA, McGrath, PJ, Fava, M, Weissman, M, Parsey, R, Trivedi, MH, Phillips, ML (2015). Moderation of the relationship between reward expectancy and prediction error-related ventral striatal reactivity by anhedonia in unmedicated major depressive disorder: findings from the EMBARC study. American Journal of Psychiatry 172, 881891.
Guyer, AE, Choate, VR, Detloff, A, Benson, B, Nelson, EE, Perez-Edgar, K, Fox, NA, Pine, DS, Ernst, M (2012). Striatal functional alteration during incentive anticipation in pediatric anxiety disorders. American Journal of Psychiatry 169, 205212.
Haber, SN, Knutson, B (2010). The reward circuit: linking primate anatomy and human imaging. Neuropsychopharmacology 35, 426.
Hollingshead, AA (1975). Four Factor Index of Social Status. Yale University Department of Sociology: New Haven, CT.
Horwitz, SM, Demeter, CA, Pagano, ME, Youngstrom, EA, Fristad, MA, Arnold, LE, Birmaher, B, Gill, MK, Axelson, D, Kowatch, RA, Frazier, TW, Findling, RL (2010). Longitudinal Assessment of Manic Symptoms (LAMS) study: background, design, and initial screening results. Journal of Clinical Psychiatry 71, 15111517.
Ibanez, A, Cetkovich, M, Petroni, A, Urquina, H, Baez, S, Gonzalez-Gadea, ML, Kamienkowski, JE, Torralva, T, Torrente, F, Strejilevich, S, Teitelbaum, J, Hurtado, E, Guex, R, Melloni, M, Lischinsky, A, Sigman, M, Manes, F (2012). The neural basis of decision-making and reward processing in adults with euthymic bipolar disorder or attention-deficit/hyperactivity disorder (ADHD). PLOS ONE 7, e37306.
Jenkinson, M (2003). Fast, automated, N-dimensional phase-unwrapping algorithm. Magnetic Resonance in Medicine 49, 193197.
Jenkinson, M, Bannister, P, Brady, M, Smith, S (2002). Improved optimization for the robust and accurate linear registration and motion correction of brain images. NeuroImage 17, 825841.
Jenkinson, M, Smith, S (2001). A global optimisation method for robust affine registration of brain images. Medical Image Analysis 5, 143156.
Kang, HC, Burgund, ED, Lugar, HM, Petersen, SE, Schlaggar, BL (2003). Comparison of functional activation foci in children and adults using a common stereotactic space. NeuroImage 19, 1628.
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.
Knutson, B, Adams, CM, Fong, GW, Hommer, D (2001). Anticipation of increasing monetary reward selectively recruits nucleus accumbens. Journal of Neuroscience 21, RC159.
Koechlin, E, Hyafil, A (2007). Anterior prefrontal function and the limits of human decision-making. Science 318, 594598.
Kumar, P, Waiter, G, Ahearn, T, Milders, M, Reid, I, Steele, JD (2008). Abnormal temporal difference reward-learning signals in major depression. Brain 131, 20842093.
Kurniawan, IT, Seymour, B, Talmi, D, Yoshida, W, Chater, N, Dolan, RJ (2010). Choosing to make an effort: the role of striatum in signaling physical effort of a chosen action. Journal of Neurophysiology 104, 313321.
Mason, L, O'Sullivan, N, Blackburn, M, Bentall, R, El-Deredy, W (2012). I want it now! Neural correlates of hypersensitivity to immediate reward in hypomania. Biological Psychiatry 71, 530537.
Nusslock, R, Almeida, JR, Forbes, EE, Versace, A, Frank, E, Labarbara, EJ, Klein, CR, Phillips, ML (2012). Waiting to win: elevated striatal and orbitofrontal cortical activity during reward anticipation in euthymic bipolar disorder adults. Bipolar Disorders 14, 249260.
O'Doherty, JP (2004). Reward representations and reward-related learning in the human brain: insights from neuroimaging. Current Opinion in Neurobiology 14, 769776.
Oldfield, RC (1971). The assessment and analysis of handedness: the Edinburgh Inventory. Neuropsychologia 9, 97113.
Olsavsky, AK, Brotman, MA, Rutenberg, JG, Muhrer, EJ, Deveney, CM, Fromm, SJ, Towbin, K, Pine, DS, Leibenluft, E (2012). Amygdala hyperactivation during face emotion processing in unaffected youth at risk for bipolar disorder. Journal of the American Academy of Child and Adolescent Psychiatry 51, 294303.
Pagnoni, G, Zink, CF, Montague, PR, Berns, GS (2002). Activity in human ventral striatum locked to errors of reward prediction. Nature Neuroscience 5, 9798.
Phillips, ML, Kupfer, DJ (2013). Bipolar disorder diagnosis: challenges and future directions. Lancet 381, 16631671.
Phillips, ML, Swartz, HA (2014). A critical appraisal of neuroimaging studies of bipolar disorder: toward a new conceptualization of underlying neural circuitry and a road map for future research. American Journal of Psychiatry 171, 829843.
Ramnani, N, Owen, AM (2004). Anterior prefrontal cortex: insights into function from anatomy and neuroimaging. Nature Reviews Neuroscience 5, 184194.
Rich, BA, Schmajuk, M, Perez-Edgar, KE, Pine, DS, Fox, NA, Leibenluft, E (2005). The impact of reward, punishment, and frustration on attention in pediatric bipolar disorder. Biological Psychiatry 58, 532539.
Rushworth, MFS, Noonan, MP, Boorman, ED, Walton, ME, Behrens, TE (2011). Frontal cortex and reward-guided learning and decision-making. Neuron 70, 10541069.
Russo, SJ, Nestler, EJ (2013). The brain reward circuitry in mood disorders. Nature Reviews Neuroscience 14, 609625.
Schultz, W, Tremblay, L, Hollerman, JR (2000). Reward processing in primate orbitofrontal cortex and basal ganglia. Cerebral Cortex 10, 272284.
Singh, MK, Chang, KD, Kelley, RG, Cui, X, Sherdell, L, Howe, ME, Gotlib, IH, Reiss, AL (2013). Reward processing in adolescents with bipolar I disorder. Journal of the American Academy of Child and Adolescent Psychiatry 52, 6883.
Singh, MK, Kelley, RG, Howe, ME, Reiss, AL, Gotlib, IH, Chang, KD (2014). Reward processing in healthy offspring of parents with bipolar disorder. JAMA Psychiatry 71, 11481156.
Smith, SM (2002). Fast robust automated brain extraction. Human Brain Mapping 17, 143155.
Tachibana, Y, Hikosaka, O (2012). The primate ventral pallidum encodes expected reward value and regulates motor action. Neuron 76, 826837.
Tanaka, SC, Doya, K, Okada, G, Ueda, K, Okamoto, Y, Yamawaki, S (2004). Prediction of immediate and future rewards differentially recruits cortico-basal ganglia loops. Nature Neuroscience 7, 887893.
Trost, S, Diekhof, EK, Zvonik, K, Lewandowski, M, Usher, J, Keil, M, Zilles, D, Falkai, P, Dechent, P, Gruber, O (2014). Disturbed anterior prefrontal control of the mesolimbic reward system and increased impulsivity in bipolar disorder. Neuropsychopharmacology 39, 19141923.
Walton, ME, Behrens, TEJ, Noonan, MP, Rushworth, MFS (2011). Giving credit where credit is due: orbitofrontal cortex and valuation in an uncertain world. Annals of the New York Academy of Sciences 1239, 1424.
Walton, ME, Kennerley, SW, Bannerman, DM, Phillips, PEM, Rushworth, MFS (2006). Weighing up the benefits of work: behavioral and neural analyses of effort-related decision making. Neural Networks 19, 13021314.
Wechsler, D (1999). Wechsler Abbreviated Scale of Intelligence. The Psychological Corporation: San Antonio, TX.
Worsley, K (2001). Statistical analysis of activation images. In Functional MRI: an Introduction to Methods (ed. Jezzard, P., Matthews, P. M. and Smith, S. M.), pp. 251270. Oxford University Press: New York.
Yoshida, W, Ishii, S (2006). Resolution of uncertainty in prefrontal cortex. Neuron 50, 781789.
Youngstrom, EA, Frazier, TW, Demeter, C, Calabrese, JR, Findling, RL (2008). Developing a 10-item mania scale from the Parent General Behavior Inventory for children and adolescents. Journal of Clinical Psychiatry 69, 831839.

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