Affect Regulation–Related Emergent Brain Network Properties Differentiate Depressed Bipolar Disorder From Major Depression and Track Risk for Bipolar Disorder

Published:October 09, 2021DOI:



      Individuals with or at risk for bipolar disorder (BD) often present initially for the treatment of depressive symptoms. Unfortunately, pharmacological treatments for major depressive disorder (MDD) can be iatrogenic, precipitating mania that may not have otherwise occurred. Current diagnostic procedures rely solely on self-reported/observable symptoms, and thus alternative data sources, such as brain network properties, are needed to supplement current self-report/observation–based indices of risk for mania.


      Brain connectivity during affect maintenance/regulation was examined in a large (N = 249), medication-free sample of currently depressed patients with BD (n = 50) and MDD (n = 116) and healthy control subjects (n = 83). BD risk was categorized in a subset of patients with MDD. We used graph theory to identify emergent network properties that differentiated between patients with BD and MDD and between patients with MDD at high and low risk for BD.


      BD and MDD differed in the extent to which the rostral anterior cingulate cortex was embedded in the local network, amount of influence the hippocampus exerted over global network communication, and clarity of orbitofrontal cortex communication. Patients with MDD at high risk for BD showed a pattern of local network clustering around the right amygdala that was similar to the pattern observed in healthy control subjects, whereas patients with MDD at low risk for BD deviated from this pattern.


      BD and MDD differed in emergent network mechanisms subserving affect regulation, and amygdala properties tracked BD risk in patients with MDD. If replicated, our findings may be combined with other markers to assess the presence of BD and/or BD risk in individuals presenting with depressive symptoms to prevent the use of iatrogenic treatments.


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        • Whiteford H.A.
        • Ferrari A.J.
        • Degenhardt L.
        • Feigin V.
        • Vos T.
        The global burden of mental, neurological and substance use disorders: An analysis from the Global Burden of Disease Study 2010.
        PLoS One. 2015; 10e0116820
        • Kessler R.C.
        • Petukhova M.
        • Sampson N.A.
        • Zaslavsky A.M.
        • Wittchen H.-U.
        Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States.
        Int J Methods Psychiatr Res. 2012; 21: 169-184
        • Perugi G.
        • Micheli C.
        • Akiskal H.S.
        • Madaro D.
        • Socci C.
        • Quilici C.
        • Musetti L.
        Polarity of the first episode, clinical characteristics, and course of manic depressive illness: A systematic retrospective investigation of 320 bipolar I patients.
        Compr Psychiatry. 2000; 41: 13-18
        • Ghaemi S.N.
        • Boiman E.E.
        • Goodwin F.K.
        Diagnosing bipolar disorder and the effect of antidepressants: A naturalistic study.
        J Clin Psychiatry. 2000; 61 (quiz 809): 804-808
        • Hirschfeld R.M.A.
        • Lewis L.
        • Vornik L.A.
        Perceptions and impact of bipolar disorder: How far have we really come? Results of the national depressive and manic-depressive association 2000 survey of individuals with bipolar disorder.
        J Clin Psychiatry. 2003; 64: 161-174
        • Chun B.J.D.H.
        • Dunner D.L.
        A review of antidepressant-induced hypomania in major depression: Suggestions for DSM-V.
        Bipolar Disord. 2004; 6: 32-42
        • Strawn J.R.
        • Adler C.M.
        • McNamara R.K.
        • Welge J.A.
        • Bitter S.M.
        • Mills N.P.
        • et al.
        Antidepressant tolerability in anxious and depressed youth at high risk for bipolar disorder: A prospective naturalistic treatment study.
        Bipolar Disord. 2014; 16: 523-530
        • Chen C.H.
        • Suckling J.
        • Lennox B.R.
        • Ooi C.
        • Bullmore E.T.
        A quantitative meta-analysis of fMRI studies in bipolar disorder.
        Bipolar Disord. 2011; 13: 1-15
        • Houenou J.
        • Frommberger J.
        • Carde S.
        • Glasbrenner M.
        • Diener C.
        • Leboyer M.
        • Wessa M.
        Neuroimaging-based markers of bipolar disorder: Evidence from two meta-analyses.
        J Affect Disord. 2011; 132: 344-355
        • Groenewold N.A.
        • Opmeer E.M.
        • de Jonge P.
        • Aleman A.
        • Costafreda S.G.
        Emotional valence modulates brain functional abnormalities in depression: Evidence from a meta-analysis of fMRI studies.
        Neurosci Biobehav Rev. 2013; 37: 152-163
        • Delvecchio G.
        • Fossati P.
        • Boyer P.
        • Brambilla P.
        • Falkai P.
        • Gruber O.
        • et al.
        Common and distinct neural correlates of emotional processing in bipolar disorder and major depressive disorder: A voxel-based meta-analysis of functional magnetic resonance imaging studies.
        Eur Neuropsychopharmacol. 2012; 22: 100-113
        • Bullmore E.
        • Sporns O.
        Complex brain networks: Graph theoretical analysis of structural and functional systems [published correction appears in Nat Rev Neurosci 2009; 10:312].
        Nat Rev Neurosci. 2009; 10: 186-198
        • He H.
        • Yu Q.
        • Du Y.
        • Vergara V.
        • Victor T.A.
        • Drevets W.C.
        • et al.
        Resting-state functional network connectivity in prefrontal regions differs between unmedicated patients with bipolar and major depressive disorders.
        J Affect Disord. 2016; 190: 483-493
        • Wang Y.
        • Wang J.
        • Jia Y.
        • Zhong S.
        • Zhong M.
        • Sun Y.
        • et al.
        Topologically convergent and divergent functional connectivity patterns in unmedicated unipolar depression and bipolar disorder.
        Transl Psychiatry. 2017; 7: e1165
        • Anand A.
        • Grandhi J.
        • Karne H.
        • Spielberg J.M.
        Intrinsic functional connectivity during continuous maintenance and suppression of emotion in bipolar disorder.
        Brain Imaging Behav. 2020; 14: 1747-1757
        • Campos J.J.
        • Walle E.A.
        • Dahl A.
        • Main A.
        Reconceptualizing emotion regulation.
        Emot Rev. 2011; 3: 26-35
        • Hollenstein T.
        This time, it’s real: Affective flexibility, time scales, feedback loops, and the regulation of emotion.
        Emot Rev. 2015; 7: 308-315
        • Saramäki J.
        • Kivelä M.
        • Onnela J.P.
        • Kaski K.
        • Kertész J.
        Generalizations of the clustering coefficient to weighted complex networks.
        Phys Rev E Stat Nonlin Soft Matter Phys. 2007; 75027105
        • Cunningham W.A.
        • Brosch T.
        Motivational salience: Amygdala tuning from traits, needs, values, and goals.
        Curr Dir Psychol Sci. 2012; 21: 54-59
        • Nurnberger Jr., J.I.
        • McInnis M.
        • Reich W.
        • Kastelic E.
        • Wilcox H.C.
        • Glowinski A.
        • et al.
        A high-risk study of bipolar disorder. Childhood clinical phenotypes as precursors of major mood disorders.
        Arch Gen Psychiatry. 2011; 68: 1012-1020
        • Angst J.
        • Gamma A.
        • Benazzi F.
        • Ajdacic V.
        • Eich D.
        • Rössler W.
        Toward a re-definition of subthreshold bipolarity: Epidemiology and proposed criteria for bipolar-II, minor bipolar disorders and hypomania.
        J Affect Disord. 2003; 73: 133-146
        • Fiedorowicz J.G.
        • Endicott J.
        • Leon A.C.
        • Solomon D.A.
        • Keller M.B.
        • Coryell W.H.
        Subthreshold hypomanic symptoms in progression from unipolar major depression to bipolar disorder.
        Am J Psychiatry. 2011; 168: 40-48
        • Merikangas K.R.
        • Jin R.
        • He J.P.
        • Kessler R.C.
        • Lee S.
        • Sampson N.A.
        • et al.
        Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative.
        Arch Gen Psychiatry. 2011; 68: 241-251
        • Zimmermann P.
        • Brückl T.
        • Nocon A.
        • Pfister H.
        • Lieb R.
        • Wittchen H.U.
        • et al.
        Heterogeneity of DSM-IV major depressive disorder as a consequence of subthreshold bipolarity.
        Arch Gen Psychiatry. 2009; 66: 1341-1352
        • Koirala P.
        • Hu B.
        • Altinay M.
        • Li M.
        • DiVita A.L.
        • Bryant K.A.
        • et al.
        Sub-threshold bipolar disorder in medication-free young subjects with major depression: Clinical characteristics and antidepressant treatment response.
        J Psychiatr Res. 2019; 110: 1-8
        • Lang P.J.
        • Bradley M.M.
        • Cuthbert B.N.
        International Affective Picture System (IAPS): Technical Manual and Affective Ratings.
        NIMH Center for the Study of Emotion and Attention, 1997
        • Spielberg J.M.
        • McGlinchey R.E.
        • Milberg W.P.
        • Salat D.H.
        Brain network disturbance related to posttraumatic stress and traumatic brain injury in veterans.
        Biol Psychiatry. 2015; 78: 210-216
        • Blair R.C.
        • Higgins J.J.
        Tests of hypotheses for unbalanced factorial designs under various regression/coding method combinations.
        Educ Psychol Meas. 1978; 38: 621-631
        • Wise T.
        • Radua J.
        • Via E.
        • Cardoner N.
        • Abe O.
        • Adams T.M.
        • et al.
        Common and distinct patterns of grey-matter volume alteration in major depression and bipolar disorder: Evidence from voxel-based meta-analysis.
        Mol Psychiatry. 2017; 22: 1455-1463
        • Benjamini Y.
        • Hochberg Y.
        Controlling the false discovery rate: A practical and powerful approach to multiple testing.
        J R Stat Soc B. 1995; 57: 289-300
        • Di X.
        • Huang J.
        • Biswal B.B.
        Task modulated brain connectivity of the amygdala: A meta-analysis of psychophysiological interactions.
        Brain Struct Funct. 2017; 222: 619-634
        • Anand A.
        • Li Y.
        • Wang Y.
        • Wu J.
        • Gao S.
        • Bukhari L.
        • et al.
        Activity and connectivity of brain mood regulating circuit in depression: A functional magnetic resonance study.
        Biol Psychiatry. 2005; 57: 1079-1088
        • Anand A.
        • Li Y.
        • Wang Y.
        • Lowe M.J.
        • Dzemidzic M.
        Resting state corticolimbic connectivity abnormalities in unmedicated bipolar disorder and unipolar depression.
        Psychiatry Res. 2009; 171: 189-198
        • Ranganath C.
        Binding items and contexts: The cognitive neuroscience of episodic memory.
        Curr Dir Psychol Sci. 2010; 19: 131-137
        • McLaughlin K.A.
        • Nolen-Hoeksema S.
        Rumination as a transdiagnostic factor in depression and anxiety.
        Behav Res Ther. 2011; 49: 186-193
        • Padoa-Schioppa C.
        • Cai X.
        The orbitofrontal cortex and the computation of subjective value: Consolidated concepts and new perspectives.
        Ann N Y Acad Sci. 2011; 1239: 130-137
        • Bylsma L.M.
        • Morris B.H.
        • Rottenberg J.
        A meta-analysis of emotional reactivity in major depressive disorder.
        Clin Psychol Rev. 2008; 28: 676-691
        • Spielberg J.M.
        • Matyi M.A.
        • Karne H.
        • Anand A.
        Lithium monotherapy associated longitudinal effects on resting state brain networks in clinical treatment of bipolar disorder.
        Bipolar Disord. 2019; 21: 361-371
        • Joslyn C.
        • Hawes D.J.
        • Hunt C.
        • Mitchell P.B.
        Is age of onset associated with severity, prognosis, and clinical features in bipolar disorder? A meta-analytic review.
        Bipolar Disord. 2016; 18: 389-403