Skip to main content Accessibility help

Behavioral and emotional dysregulation trajectories marked by prefrontal–amygdala function in symptomatic youth

  • M. A. Bertocci (a1), G. Bebko (a1), T. Olino (a1), J. Fournier (a1), A. K. Hinze (a1), L. Bonar (a1), J. R. C. Almeida (a1) (a2), S. B. Perlman (a1), A. Versace (a1), M. Travis (a1), M. K. Gill (a1), C. Demeter (a3), V. A. Diwadkar (a4), R. White (a4), C. Schirda (a1), J. L. Sunshine (a3), L. E. Arnold (a5), S. K. Holland (a6), R. A. Kowatch (a7), B. Birmaher (a1), D. Axelson (a5), E. A. Youngstrom (a8), R. L. Findling (a3) (a9), S. M. Horwitz (a10), M. A. Fristad (a5) and M. L. Phillips (a1)...



Neuroimaging measures of behavioral and emotional dysregulation can yield biomarkers denoting developmental trajectories of psychiatric pathology in youth. We aimed to identify functional abnormalities in emotion regulation (ER) neural circuitry associated with different behavioral and emotional dysregulation trajectories using latent class growth analysis (LCGA) and neuroimaging.


A total of 61 youth (9–17 years) from the Longitudinal Assessment of Manic Symptoms study, and 24 healthy control youth, completed an emotional face n-back ER task during scanning. LCGA was performed on 12 biannual reports completed over 5 years of the Parent General Behavior Inventory 10-Item Mania Scale (PGBI-10M), a parental report of the child's difficulty regulating positive mood and energy.


There were two latent classes of PGBI-10M trajectories: high and decreasing (HighD; n = 22) and low and decreasing (LowD; n = 39) course of behavioral and emotional dysregulation over the 12 time points. Task performance was >89% in all youth, but more accurate in healthy controls and LowD versus HighD (p < 0.001). During ER, LowD had greater activity than HighD and healthy controls in the dorsolateral prefrontal cortex, a key ER region, and greater functional connectivity than HighD between the amygdala and ventrolateral prefrontal cortex (p's < 0.001, corrected).


Patterns of function in lateral prefrontal cortical–amygdala circuitry in youth denote the severity of the developmental trajectory of behavioral and emotional dysregulation over time, and may be biological targets to guide differential treatment and novel treatment development for different levels of behavioral and emotional dysregulation in youth.


Corresponding author

* Address for correspondence: M. A. Bertocci, Ph.D., Department of Psychiatry, University of Pittsburgh School of Medicine, 3811 O'Hara Street, Loeffler Building, Room 203, Pittsburgh, PA 15213, USA. (Email:


Hide All
Axelson, DA, Birmaher, B, Brent, DA, Wassick, S, Hoover, C, Bridge, J, Ryan, ND (2003). A preliminary study of the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children mania rating scale for children and adolescents. Journal of Child and Adolescent Psychopharmacology 13, 463470.
Bebko, G, Bertocci, MA, Fournier, JC, Hinze, AK, Bonar, L, Almeida, JR, 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 (2013). 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. Published online 27 November 2013 . doi:10.1001/jamapsychiatry.2013.2870.
Birmaher, B, Brent, DA, Chiappetta, L, Bridge, J, Monga, S, Baugher, M (1999). Psychometric properties of the Screen for Child Anxiety Related Emotional Disorders (SCARED): a replication study. Journal of the American Academy of Child and Adolescent Psychiatry 38, 12301236.
Brotman, M, Schmajuk, M, Rich, B, Dickstein, D, Guyer, A, Costello, E, Egger, H, Angold, A, Pine, D, Leibenluft, E (2006). Prevalence, clinical correlates, and longitudinal course of severe mood dysregulation in children. Biological Psychiatry 60, 991997.
Charney, DS, Babich, KS (2002). Foundation for the NIMH strategic plan for mood disorders research. Biological Psychiatry 52, 455456.
Cusi, A, Nazarov, A, Holshausen, K, Macqueen, G, McKinnon, M (2012). Systematic review of the neural basis of social cognition in patients with mood disorders. Journal of Psychiatry Neuroscience 37, 154169.
Desmond, J, Glover, G (2002). Estimating sample size in functional MRI (fMRI) neuroimaging studies: statistical power analyses. Journal of Neuroscience Methods 118, 115128.
Eklund, A, Andersson, M, Josephson, C, Johannesson, M, Knutsson, H (2012). Does parametric fMRI analysis with SPM yield valid results? An empirical study of 1484 rest datasets. NeuroImage 61, 565578.
Findling, RL, Jo, B, Frazier, TW, Youngstrom, EA, Demeter, CA, Fristad, MA, Birmaher, B, Kowatch, RA, Arnold, E, Axelson, DA, Ryan, N, Hauser, JC, Brace, DJ, Marsh, LE, Gill, MK, Depew, J, Rowles, BM, Horwitz, SM (2013). The 24-month course of manic symptoms in children. Bipolar Disorders 15, 669679.
Findling, RL, Youngstrom, EA, Fristad, M, Birmaher, B, Kowatch, R, Arnold, LE, Frazier, TW, Axelson, DA, Ryan, ND, Demeter, C, Gill, MK, Fields, B, Depew, J, Kennedy, S, Marsh, L, Rowles, B, 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.
Frazier, TW, Youngstrom, EA, Horwitz, SM, Demeter, C, Fristad, M, Arnold, LE, Birmaher, B, Kowatch, R, Axelson, DA, Ryan, ND, Gill, MK, Findling, RL (2011). Relationship of persistent manic symptoms to the diagnosis of pediatric bipolar spectrum disorders. Journal of Clinical Psychiatry 72, 846853.
Friedman, L, Glover, G (2006). Report on a multicenter fMRI quality assurance protocol. Journal of Magnetic Resonance Imaging 23, 827839.
Friedman, L, Glover, G; fBIRN Consortium (2006). Reducing interscanner variability of activation in a multicenter fMRI study: controlling for signal-to-fluctuation-noise-ratio (SFNR) differences. NeuroImage 33, 471481.
Gee, D, Karlsgodt, K, van Erp, T, Bearden, C, Lieberman, M, Belger, A, Perkins, D, Olvet, D, Cornblatt, B, Constable, T, Woods, S, Addington, J, Cadenhead, K, McGlashan, T, Seidman, L, Tsuang, M, Walker, E, Cannon, T (2012). Altered age-related trajectories of amygdala–prefrontal circuitry in adolescents at clinical high risk for psychosis: a preliminary study. Schizophrenia Research 134, 19.
Halari, R, Simic, M, Pariante, C, Papadopoulos, A, Cleare, A, Brammer, M, Fombonne, E, Rubia, K (2009). Reduced activation in lateral prefrontal cortex and anterior cingulate during attention and cognitive control functions in medication-naive adolescents with depression compared to controls. Journal of Child Psychology and Psychiatry 50, 307316.
Hasler, G, Drevets, WC, Gould, TD, Gottesman, II, Manji, HK (2006). Toward constructing an endophenotype strategy for bipolar disorders. Biological Psychiatry 60, 93105.
Haxby, J, Ungerleider, L, Horwitz, B, Rapoport, S, Grady, C (1995). Hemispheric differences in neural systems for face working memory: a PET-rCBF study. Human Brain Mapping 3, 6882.
Horwitz, SM, Demeter, C, Pagano, M, Youngstrom, EA, Fristad, M, Arnold, LE, Birmaher, B, Gill, MK, Axelson, DA, Kowatch, R, Frazier, T, Findling, RL (2010). Longitudinal Assessment of Manic Symptoms (LAMS) study: background, design, and initial screening results. Journal of Clinical Psychiatry 71, 15111517.
Hulvershorn, L, Cullen, K, Anand, A (2011). Toward dysfunctional connectivity: a review of neuroimaging findings in pediatric major depressive disorder. Brain Imaging Behavior 5, 307328.
Insel, T, Cuthbert, B, Garvey, M, Heinssen, R, Pine, D, Quinn, K, Sanislow, C, Wang, P (2010). Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. American Journal of Psychiatry 167, 748751.
Kaufman, J, Birmaher, B, Brent, DA, Rao, U, Flynn, C, Moreci, P, Williamson, D, Ryan, ND (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.
Ladouceur, C, Silk, JS, Dahl, RE, Ostapenko, L, Kronhaus, DM, Phillips, ML (2009 a). Fearful faces influence attentional control processes in anxious youth and adults. Emotion 9, 855864.
Ladouceur, CD, Farchione, T, Diwadkar, V, Pruitt, P, Radwan, J, Axelson, D, Birmaher, B, Phillips, ML (2011). Differential patterns of abnormal activity and connectivity in the amygdala–prefrontal circuitry in bipolar-I and bipolar-NOS youth. Journal of the American Academy of Child and Adolescent Psychiatry 50, 12751289.
Ladouceur, CD, Silk, JS, Dahl, RE, Ostapenko, L, Kronhaus, D, Phillips, ML (2009 b). Fearful faces influence attentional control processes in anxious youth and adults. Emotion 9, 855864.
Lewinsohn, P, Klein, D, Seeley, J (2000). Bipolar disorder during adolescence and young adulthood in a community sample. Bipolar Disorders 2, 281293.
Magnotta, V, Friedman, L (2006). Measurement of signal-to-noise and contrast-to-noise in the fBIRN multicenter imaging study. Journal of Digital Imaging 19, 140147.
Maldjian, JA, Laurienti, PJ, Kraft, RA, Burdette, JH (2003). An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. Neuroimage 19, 12331239.
Morgan, J, Olino, TM, McMakin, D, Ryan, ND, Forbes, EE (2013). Neural response to reward as a predictor of increases in depressive symptoms in adolescence. Neurobiological Disorders 52, 6674.
Muthén, LK, Muthén, BO (1998–2011). Mplus User's Guide, sixth edn. Muthén & Muthén: Los Angeles, CA.
Nylund, KL, Asparouhov, T, Muthén, BO (2007). Deciding on the number of classes in latent class analysis and growth mixture modeling: a Monte Carlo simulation study. Structural Equation Modeling 14, 535569.
Ochsner, KN, Gross, JJ (2005). The cognitive control of emotion. Trends in Cognitive Sciences 9, 242249.
Passarotti, A, Ellis, J, Wegbreit, E, Stevens, M, Pavuluri, M (2012). Reduced functional connectivity of prefrontal regions and amygdala within affect and working memory networks in pediatric bipolar disorder. Brain Connectivity 2, 320334.
Passarotti, A, Sweeney, J, Pavuluri, M (2010 a). Emotion processing influences working memory circuits in pediatric bipolar disorder and attention-deficit/hyperactivity disorder. Journal of the American Academy of Child and Adolescent Psychiatry 49, 10641080.
Passarotti, A, Sweeney, J, Pavuluri, M (2010 b). Neural correlates of response inhibition in pediatric bipolar disorder and attention deficit hyperactivity disorder. Psychiatry Research: Neuroimaging 181, 3643.
Pavuluri, M, O'Connor, M, Harral, E, Sweeney, J (2008). An fMRI study of the interface between affective and cognitive neural circuitry in pediatric bipolar disorder. Psychiatry Research: Neuroimaging 162, 244255.
Perlman, G, Simmons, A, Wu, J, Hahn, K, Tapert, S, Max, J, Paulus, M, Brown, G, Frank, G, Campbell-Sills, L, Yang, T (2012). Amygdala response and functional connectivity during emotion regulation: a study of 14 depressed adolescents. Journal of Affective Disorders 139, 7584.
Phillips, M, Ladouceur, C, Drevets, W (2008). A neural model of voluntary and automatic emotion regulation: implications for understanding the pathophysiology and neurodevelopment of bipolar disorder. Molecular Psychiatry 13, 833857.
Phillips, ML, Frank, E (2006). Redefining bipolar disorder: toward DSM5. American Journal of Psychiatry 163, 11351136.
Rich, B, Carver, F, Holroyd, T, Rosen, H, Mendoza, J, Cornwell, B, Fox, N, Pine, D, Coppola, R, Leibenluft, E (2011). Different neural pathways to negative affect in youth with pediatric bipolar disorder and severe mood dysregulation. Journal of Psychiatry Research 45, 12831294.
Rich, B, Fromm, S, Berghorst, L, Dickstein, D, Brotman, M, Pine, D, Leibenluft, E (2008). Neural connectivity in children with bipolar disorder: impairment in the face emotion processing circuit. Journal of Child Psychology and Psychiatry 49, 8896.
Rygula, R, Walker, S, Clarke, H, Robbins, T, Roberts, A (2010). Differential contributions of the primate ventrolateral prefrontal and orbitofrontal cortex to serial reversal learning. Journal of Neuroscience 30, 1455214559.
Segall, J, Turner, J, van Erp, T, White, T, Bockholt, H, Gollub, R, Ho, B, Magnotta, V, Jung, R, McCarley, R, Schulz, S, Lauriello, J, Clark, V, Voyvodic, J, Diaz, M, Calhoun, V (2009). Voxel-based morphometric multisite collaborative study on schizophrenia. Schizophrenia Bulletin 35, 8295.
Stringaris, A, Goodman, R (2009). Mood lability and psychopathology in youth. Psychological Medicine 39, 12371245.
Youngstrom, EA, Frazier, T, Demeter, C, Calabrese, J, 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.
Youngstrom, EA, Meyers, O, Demeter, C, Youngstrom, J, Morello, L, Piiparinen, R, Feeny, N, Calabrese, J, Findling, RL (2005). Comparing diagnostic checklists for pediatric bipolar disorder in academic and community mental health settings. Bipolar Disorders 7, 507517.


Type Description Title
Supplementary materials

Bertocci Supplementary Material
Supplementary Material

 Word (62 KB)
62 KB


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed