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Decoupling of the amygdala to other salience network regions in adolescent-onset recurrent major depressive disorder

  • R. H. Jacobs (a1), A. Barba (a1), J. R. Gowins (a1), H. Klumpp (a1), L. M. Jenkins (a1), B. J. Mickey (a2), O. Ajilore (a1), M. Peciña (a2), M. Sikora (a2), K. A. Ryan (a2), D. T. Hsu (a2) (a3), R. C. Welsh (a2) (a4), J.-K. Zubieta (a2) (a4), K. L. Phan (a1) (a5) and S. A. Langenecker (a1)...

Recent meta-analyses of resting-state networks in major depressive disorder (MDD) implicate network disruptions underlying cognitive and affective features of illness. Heterogeneity of findings to date may stem from the relative lack of data parsing clinical features of MDD such as phase of illness and the burden of multiple episodes.


Resting-state functional magnetic resonance imaging data were collected from 17 active MDD and 34 remitted MDD patients, and 26 healthy controls (HCs) across two sites. Participants were medication-free and further subdivided into those with single v. multiple episodes to examine disease burden. Seed-based connectivity using the posterior cingulate cortex (PCC) seed to probe the default mode network as well as the amygdala and subgenual anterior cingulate cortex (sgACC) seeds to probe the salience network (SN) were conducted.


Young adults with remitted MDD demonstrated hyperconnectivity of the left PCC to the left inferior frontal gyrus and of the left sgACC to the right ventromedial prefrontal cortex (PFC) and left hippocampus compared with HCs. Episode-independent effects were observed between the left PCC and the right dorsolateral PFC, as well as between the left amygdala and right insula and caudate, whereas the burden of multiple episodes was associated with hypoconnectivity of the left PCC to multiple cognitive control regions as well as hypoconnectivity of the amygdala to large portions of the SN.


This is the first study of a homogeneous sample of unmedicated young adults with a history of adolescent-onset MDD illustrating brain-based episodic features of illness.

Corresponding author
* Address for correspondence: S. A. Langenecker, Ph.D., Department of Psychiatry, University of Illinois at Chicago, 1601 W. Taylor Street, M/C 912, Chicago, IL 60612, USA. (Email:
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Alexopoulos GS, Hoptman MJ, Kanellopoulos D, Murphy CF, Lim KO, Gunning FM (2012). Functional connectivity in the cognitive control network and the default mode network in late-life depression. Journal of Affective Disorders 139, 5665.
Aron AR, Durston S, Eagle DM, Logan GD, Stinear CM, Stuphorn V (2007). Converging evidence for a fronto-basal-ganglia network for inhibitory control of action and cognition. Journal of Neuroscience 27, 1186011864.
Behzadi Y, Restom K, Liau J, Liu TT (2007). A component based noise correction method (CompCor) for BOLD and perfusion based fMRI. NeuroImage 37, 90101.
Bluhm RL, Clark CR, McFarlane AC, Moores KA, Shaw ME, Lanius RA (2011). Default network connectivity during a working memory task. Human Brain Mapping 32, 10291035.
Bressler SL, Menon V (2010). Large-scale brain networks in cognition: emerging methods and principles. Trends in Cognitive Sciences 14, 277290.
Briceño EM, Weisenbach SL, Rapport LJ, Hazlett KE, Bieliauskas LA, Haase BD, Ransom MT, Brinkman ML, Pecina M, Schteingart DE, Starkman MN, Giordani B, Welsh RC, Noll DC, Zubieta J-K, Langenecker SA (2013). Shifted inferior frontal laterality in women with major depressive disorder is related to emotion-processing deficits. Psychological Medicine 43, 14331445.
Crowther A, Smoski MJ, Minkel J, Moore T, Gibbs D, Petty C, Bizzell J, Schiller CE, Sideris J, Carl H, Dichter GS (2015). Resting-state connectivity predictors of response to psychotherapy in major depressive disorder. Neuropsychopharmacology 40, 16591673.
de Kwaasteniet BP, Rive MM, Ruhé HG, Schene AH, Veltman DJ, Fellinger L, van Wingen GA, Denys D (2015). Decreased resting-state connectivity between neurocognitive networks in treatment resistant depression. Frontiers in Psychiatry 6, 28.
Dichter GS, Gibbs D, Smoski MJ (2015). A systematic review of relations between resting-state functional-MRI and treatment response in major depressive disorder. Journal of Affective Disorders 172, 817.
Drevets WC, Price JL, Furey ML (2008). Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression. Brain Structure and Function 213, 93118.
Fox MD, Snyder AZ, Vincent JL, Corbetta M, Van Essen DC, Raichle ME (2005). The human brain is intrinsically organized into dynamic, anticorrelated functional networks. Proceedings of the National Academy of Sciences USA 102, 96739678.
Fox MD, Zhang D, Snyder AZ, Raichle ME (2009). The global signal and observed anticorrelated resting state brain networks. Journal of Neurophysiology 101, 32703283.
Gabbay V, Ely BA, Qingyang L, Bangaru SD, Panzer AM, Alonso CM, Castellanos FX, Milham MP (2013). Striatum-based circuitry of adolescent depression and anhedonia. Journal of the American Academy of Child and Adolescent Psychiatry 52, 628641.
Hamilton JP, Etkin A, Furman DJ, Lemus MG, Johnson RF, Gotlib IH (2012). Functional neuroimaging of major depressive disorder: a meta-analysis and new integration of base line activation and neural response data. American Journal of Psychiatry 169, 693703.
Hamilton JP, Farmer M, Fogelman P, Gotlib IH (2015). Depressive rumination, the default-mode network, and the dark matter of clinical science. Biological Psychiatry 78, 224230.
Hamilton M (1960). A rating scale for depression. Journal of Neurology, Neurosurgery and Psychiatry 23, 5662.
Harrison BJ, Pujol J, Ortiz H, Fornito A, Pantelis C, Yücel M (2008). Modulation of brain resting-state networks by sad mood induction. PLoS ONE 3, e1794.
Jacobs RH, Jenkins LM, Gabriel LB, Barba A, Ryan KA, Weisenbach SL, Verges A, Baker AM, Peters AT, Crane NA, Gotlib IH, Zubieta J-K, Phan KL, Langenecker SA (2014). Increased coupling of intrinsic networks in remitted depressed youth predicts rumination and cognitive control. PLOS ONE 9, e104366.
Jo HJ, Gotts SJ, Reynolds RC, Bandettini PA, Martin A, Cox RW, Saad ZS (2013). Effective preprocessing procedures virtually eliminate distance-dependent motion artifacts in resting state fMRI. Journal of Applied Mathematics 2013, 10.1155/2013/935154.
Kaiser RH, Andrews-Hanna JR, Wager TD, Pizzagalli DA (2015). Large-scale network dysfunction in major depressive disorder: a meta-analysis of resting-state functional connectivity. JAMA Psychiatry 72, 603611.
Keller MB, Trivedi MH, Thase ME, Shelton RC, Kornstein SG, Nemeroff CB, Friedman ES, Gelenberg AJ, Kocsis JH, Dunner DL, Hirschfeld RM, Rothschild AJ, Ferguson JM, Schatzberg AF, Zajecka JM, Pedersen RD, Yan B, Ahmed S, Musgnung J, Ninan PT (2007). The Prevention of Recurrent Episodes of Depression with Venlafaxine for Two Years (PREVENT) Study: outcomes from the 2-year and combined maintenance phases. Journal of Clinical Psychiatry 68, 12461256.
Kelly AMC, Di Martino A, Uddin LQ, Shehzad Z, Gee DG, Reiss PT, Margulies DS, Castellanos FX, Milham MP (2009). Development of anterior cingulate functional connectivity from late childhood to early adulthood. Cerebral Cortex 19, 640657.
Kerestes R, Bhagwagar Z, Nathan PJ, Meda SA, Ladouceur CD, Maloney K, Matuskey D, Ruf B, Saricicek A, Wang F, Pearlson GD, Phillips ML, Blumberg HP (2012). Prefrontal cortical response to emotional faces in individuals with major depressive disorder in remission. Psychiatry Research 202, 3037.
Langenecker SA, Briceño EM, Hamid NM, Nielson KA (2007). An evaluation of distinct volumetric and functional MRI contributions toward understanding age and task performance: a study in the basal ganglia. Brain Research 1135, 5868.
Lee RSC, Hermens DF, Porter MA, Redoblado-Hodge A (2012). A meta-analysis of cognitive deficits in first-episode major depressive disorder. Journal of Affective Disorders 140, 113124.
Majer M, Nater UM, Lin JM, Capuron L, Reeves WC (2010). Association of childhood trauma with cognitive function in healthy adults: a pilot study. BMC Neurology 10, 61.
Margulies DS, Kelly AMC, Uddin LQ, Biswal BB, Castellanos FX, Milham MP (2007). Mapping the functional connectivity of anterior cingulate cortex. NeuroImage 37, 579588.
Mayberg HS, Liotti M, Brannan SK, McGinnis S, Mahurin RK, Jerabek PA, Silva JA, Tekell JL, Martin CC, Lancaster JL, Fox PT (1999). Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. American Journal of Psychiatry 156, 675682.
McCabe C, Mishor Z (2011). Antidepressant medications reduce subcortical-cortical resting-state functional connectivity in healthy volunteers. NeuroImage 57, 13171323.
Menon V (2011). Large-scale brain networks and psychopathology: a unifying triple network model. Trends in Cognitive Sciences 15, 483506.
Menon V, Uddin LQ (2010). Saliency, switching, attention and control: a network model of insula function. Brain Structure and Function 214, 655667.
Pannekoek JN, Veer IM, van Tol MJ, van der Werff SJA, Demenescu LR, Aleman A, Veltman DJ, Zitman FG, Rombouts SARB, van der Wee NJA (2013). Aberrant limbic and salience network resting-state functional connectivity in panic disorder without comorbidity. Journal of Affective Disorders 145, 2935.
Perlman SB, Almeida JRC, Kronhaus DM, Versace A, LaBarbara EJ, Klein CR, Phillips ML (2012). Amygdala activity and prefrontal cortex-amygdala effective connectivity to emerging emotional faces distinguish remitted and depressed mood states in bipolar disorder. Bipolar Disorders 14, 162174.
Pizzagalli D (2011). Frontocingulate dysfunction in depression: toward biomarkers of treatment response. Neuropsychopharmacology 36, 183206.
Price JL, Drevets WC (2010). Neurocircuitry of mood disorders. Neuropsychopharmacology 35, 192216.
Rogosch FA, Cicchetti D, Aber JL (1995). The role of child maltreatment in early deviations in cognitive and affective processing abilities and later peer relationship problems. Development and Psychopathology 7, 591609.
Seeley WW, Menon V, Schatzberg AF, Keller J, Glover GH, Kenna H, Reiss AL, Greicius MD (2007). Dissociable intrinsic connectivity networks for salience processing and executive control. Journal of Neuroscience 27, 23492356.
Sheline YI, Barch DM, Price JL, Rundle MM, Vaishnavi SN, Snyder AZ, Mintun MA, Wang S, Coalson RS, Raichle ME (2009). The default mode network and self-referential processes in depression. Proceedings of the National Academy of Sciences USA 106, 19421947.
Sheline YI, Price JL, Yan Z, Mintun MA (2010). Resting-state functional MRI in depression unmasks increased connectivity between networks via the dorsal nexus. Proceedings of the National Academy of Sciences USA 107, 1102011025.
Spann MN, Mayes LC, Kalmar JH, Guiney J, Womer FY, Pittman B, Mazure CM, Sinha R, Blumberg HP (2012). Childhood abuse and neglect and cognitive flexibility in adolescents. Child Neuropsychology 18, 182189.
Sundermann B, Beverborg MOL, Pfleiderer B (2014). Toward literature-based feature selection for diagnostic classification: a meta-analysis of resting-state fMRI in depression. Frontiers in Human Neuroscience 8, 692.
Versace A, Ladouceur CD, Romero S, Birmaher B, Axelson DA, Kupfer DJ, Phillips ML (2010). Altered development of white matter in youth at high familial risk for bipolar disorder: a diffusion tensor imaging study. Journal of the American Academy of Child and Adolescent Psychiatry 49, 12491259.
Weisenbach SL, Kassel MT, Rao J, Weldon AL, Avery ET, Briceño EM, Ajilore O, Mann M, Kales HC, Welsh RC, Zubieta J-K, Langenecker SA (2014). Differential prefrontal and subcortical circuitry engagement during encoding of semantically related words in patients with late-life depression. International Journal of Geriatric Psychiatry 29, 11041115.
Whitfield-Gabrieli S, Ford JM (2012). Default mode network activity and connectivity in psychopathology. Annual Review of Clinical Psychology 8, 4976.
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