Advertisement

Abnormal Left and Right Amygdala-Orbitofrontal Cortical Functional Connectivity to Emotional Faces: State Versus Trait Vulnerability Markers of Depression in Bipolar Disorder

      Background

      Amygdala-orbitofrontal cortical (OFC) functional connectivity (FC) to emotional stimuli and relationships with white matter remain little examined in bipolar disorder individuals (BD).

      Methods

      Thirty-one BD (type I; n = 17 remitted; n = 14 depressed) and 24 age- and gender-ratio-matched healthy individuals (HC) viewed neutral, mild, and intense happy or sad emotional faces in two experiments. The FC was computed as linear and nonlinear dependence measures between amygdala and OFC time series. Effects of group, laterality, and emotion intensity upon amygdala-OFC FC and amygdala-OFC FC white matter fractional anisotropy (FA) relationships were examined.

      Results

      The BD versus HC showed significantly greater right amygdala-OFC FC (p ≤ .001) in the sad experiment and significantly reduced bilateral amygdala-OFC FC (p = .007) in the happy experiment. Depressed but not remitted female BD versus female HC showed significantly greater left amygdala-OFC FC (p = .001) to all faces in the sad experiment and reduced bilateral amygdala-OFC FC to intense happy faces (p = .01). There was a significant nonlinear relationship (p = .001) between left amygdala-OFC FC to sad faces and FA in HC. In BD, antidepressants were associated with significantly reduced left amygdala-OFC FC to mild sad faces (p = .001).

      Conclusions

      In BD, abnormally elevated right amygdala-OFC FC to sad stimuli might represent a trait vulnerability for depression, whereas abnormally elevated left amygdala-OFC FC to sad stimuli and abnormally reduced amygdala-OFC FC to intense happy stimuli might represent a depression state marker. Abnormal FC measures might normalize with antidepressant medications in BD. Nonlinear amygdala-OFC FC–FA relationships in BD and HC require further study.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Murray C.J.L.
        • Lopez A.D.
        Evidence-based health policy—lessons from the global burden of disease study.
        Science. 1996; 274: 740-743
        • Brooks J.O.
        • Hoblyn J.C.
        • Woodard S.A.
        • Rosen A.C.
        • Ketter T.A.
        Corticolimbic metabolic dysregulation in euthymic older adults with bipolar disorder.
        Biol Psychiatry. 2008; 63 (181S–181S)
        • Goodwin F.K.
        • Jamison K.R.
        • Ghaemi S.N.
        Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression.
        Oxford University Press, New York2007
        • Robinson J.L.
        • Monkul E.S.
        • Tordesillas-Gutierrez D.
        • Franklin C.
        • Bearden C.E.
        • Fox P.T.
        • et al.
        Fronto-limbic circuitry in euthymic bipolar disorder: Evidence for prefrontal hyperactivation.
        Psychiatry Res Neuroimaging. 2008; 164: 106-113
        • Adolphs R.
        • Tranel D.
        Impaired judgments of sadness but not happiness following bilateral amygdala damage.
        J Cogn Neurosci. 2004; 16: 453-462
        • Adolphs R.
        • Gosselin F.
        • Buchanan T.W.
        • Tranel D.
        • Schyns P.
        • Damasio A.R.
        A mechanism for impaired fear recognition after amygdala damage.
        Nature. 2005; 433: 68-72
        • Baxter M.G.
        • Parker A.
        • Lindner C.C.
        • Izquierdo A.D.
        • Murray E.A.
        Control of response selection by reinforcer value requires interaction of amygdala and orbital prefrontal cortex.
        J Neurosci. 2000; 20: 4311-4319
        • Bechara A.
        • Tranel D.
        • Damasio H.
        • Adolphs R.
        • Rockland C.
        • Damasio A.R.
        Double dissociation of conditioning and declarative knowledge relative to the amygdala and hippocampus in humans.
        Science. 1995; 269: 1115-1118
        • Gallagher M.
        • McMahan R.W.
        • Schoenbaum G.
        Orbitofrontal cortex and representation of incentive value in associative learning.
        J Neurosci. 1999; 19: 6610-6614
        • Gur R.C.
        • Schroeder L.
        • Turner T.
        • McGrath C.
        • Chan R.M.
        • Turetsky B.I.
        • et al.
        Brain activation during facial emotion processing.
        Neuroimage. 2002; 16: 651-662
        • Izquierdo A.
        • Suda R.K.
        • Murray E.A.
        Bilateral orbital prefrontal cortex lesions in rhesus monkeys disrupt choices guided by both reward value and reward contingency.
        J Neurosci. 2004; 24: 7540-7548
        • Pickens C.L.
        • Saddoris M.P.
        • Setlow B.
        • Gallagher M.
        • Holland P.C.
        • Schoenbaum G.
        Different roles for orbitofrontal cortex and basolateral amygdala in a reinforcer devaluation task.
        J Neurosci. 2003; 23: 11078-11084
        • Delamater A.R.
        The role of the orbitofrontal cortex in sensory-specific encoding of associations in Pavlovian and instrumental conditioning.
        in: Schoenbaum G. Gottfried J.A. Murray E.A. Ramus S.J. Linking Affect to Action: Critical Contributions of the Orbitofrontal Cortex. Wiley, New York2007: 152-173
        • Highley J.R.
        • Walker M.A.
        • Esiri M.M.
        • Crow T.J.
        • Harrison P.J.
        Asymmetry of the uncinate fasciculus: A post-mortem study of normal subjects and patients with schizophrenia.
        Cereb Cortex. 2002; 12: 1218-1224
        • Dannlowski U.
        • Ohrmann P.
        • Konrad C.
        • Bauer J.
        • Kugel H.
        • Schoning S.
        • et al.
        Reduced amygdala-prefrontal connectivity is associated with symptom severity in major depression.
        Pharmacopsychiatry. 2007; 40 (206–206)
        • Habel U.
        • Windischberger C.
        • Derntl B.
        • Robinson S.
        • Kryspin-Exner I.
        • Gur R.C.
        • et al.
        Amygdala activation and facial expressions: Explicit emotion discrimination versus implicit emotion processing.
        Neuropsychologia. 2007; 45: 2369-2377
        • Todorov A.
        • Engell A.D.
        The role of the amygdala in implicit evaluation of emotionally neutral faces.
        Soc Cogn Affect Neurosci. 2008; 3: 303-312
        • Phillips M.
        • Ladouceur C.
        • Drevets W.
        A neural model of voluntary and automatic emotion regulation: Implications for understanding the pathophysiology and neurodevelopment of bipolar disorder.
        Mol Psychiatry. 2008; 13: 833-857
        • Phillips M.L.
        • Vieta E.
        Identifying functional neuroimaging biomarkers of bipolar disorder: toward DSM-V.
        Schizophr Bull. 2007; 33: 893-904
        • Abler B.
        • Greenhouse I.
        • Ongur D.
        • Walter H.
        • Heckers S.
        Abnormal reward system activation in mania.
        Neuropsychopharmacology. 2008; 33: 2217-2227
        • Green M.J.
        • Cahill C.M.
        • Malhi G.S.
        The cognitive and neurophysiological basis of emotion dysregulation in bipolar disorder.
        J Affect Disord. 2007; 103: 29-42
        • Houenou J.
        • Wessa M.
        • Douaud G.
        • Leboyer M.
        • Chanraud S.
        • Perrin M.
        • et al.
        Increased white matter connectivity in euthymic bipolar patients: Diffusion tensor tractography between the subgenual cingulate and the amygdalo-hippocampal complex.
        Mol Psychiatry. 2007; 12: 1001-1010
        • Kafantaris V.
        • Kingsley P.
        • Ardekant B.
        • Saito E.
        • Lencz T.
        • Lim K.
        • et al.
        Lower orbital frontal white matter integrity in adolescents with bipolar I disorder.
        J Am Acad Child Adolesc Psychiatry. 2009; 48: 79-86
        • Mahon K.
        • Wu J.
        • Malhotra A.K.
        • Burdick K.E.
        • Derosse P.
        • Ardekani B.A.
        • Szeszko P.R.
        A voxel-based diffusion tensor imaging study of white matter in bipolar disorder.
        Neuropsychopharmacology. 2009; 34: 1590-1600
        • McIntosh A.M.
        • Maniega S.M.
        • Lymer G.K.S.
        • McKirdy J.
        • Hall J.
        • Sussmann J.E.D.
        • et al.
        White matter tractography in bipolar disorder and schizophrenia.
        Biol Psychiatry. 2008; 64: 1088-1092
        • Sussmann J.E.
        • Lymer G.K.S.
        • McKirdy J.
        • Moorhead T.W.J.
        • Maniega S.M.
        • Job D.
        • et al.
        White matter abnormalities in bipolar disorder and schizophrenia detected using diffusion tensor magnetic resonance imaging.
        Bipolar Disord. 2009; 11: 11-18
        • Versace A.
        • Almeida J.R.C.
        • Hassel S.
        • Walsh N.D.
        • Novelli M.
        • Klein C.R.
        • et al.
        Elevated left and reduced right orbitomedial prefrontal fractional anisotropy in adults with bipolar disorder revealed by tract-based spatial statistics.
        Arch Gen Psychiatry. 2008; 65: 1041-1052
        • Friston K.J.
        • Frith C.D.
        • Fletcher P.
        • Liddle P.F.
        • Frackowiak R.S.J.
        Functional topography: Multidimensional scaling and functional connectivity in the brain.
        Cereb Cortex. 1996; 6: 156-164
        • Foland L.C.
        • Altshuler L.L.
        • Bookheimer S.Y.
        • Eisenberger N.
        • Townsend J.
        • Thompson P.M.
        Evidence for deficient modulation of amygdala response by prefrontal cortex in bipolar mania.
        Psychiatry Res Neuroimaging. 2008; 162: 27-37
        • Almeida J.R.C.
        • Mechelli A.
        • Hassel S.
        • Versace A.
        • Walsh N.
        • Kupfer D.J.
        • et al.
        Increased functional connectivity in the paralimbic-ventral prefrontal cortical system during emotion processing in bipolar disorder: A dynamic causal modelling approach.
        Biol Psychiatry. 2008; 63 (148S–148S)
        • Wang F.
        • Kalmar J.H.
        • He Y.
        • Jackowski M.
        • Chepenik L.G.
        • Edmiston E.E.
        • et al.
        Functional and structural connectivity between the Perigenual anterior cingulate and amygdala in bipolar disorder.
        Biol Psychiatry. 2009; 66: 516-521
        • Irwin W.
        • Anderle M.J.
        • Abercrombie H.C.
        • Schaefer S.M.
        • Kalin N.H.
        • Davidson R.J.
        Amygdalar interhemispheric functional connectivity differs between the non-depressed and depressed human brain.
        Neuroimage. 2004; 21: 674-686
        • Almeida J.R.
        • Versace A.
        • Mechelli A.
        • Hassel S.
        • Quevedo K.
        • Kupfer D.J.
        • et al.
        Abnormal amygdala-prefrontal effective connectivity to happy faces differentiates bipolar from major depression.
        Biol Psychiatry. 2009; 66: 451-459
        • Lange K.
        • Williams L.M.
        • Young A.W.
        • Bullmore E.T.
        • Brammer M.J.
        • Williams S.C.R.
        • et al.
        Task instructions modulate neural responses to fearful facial expressions 1.
        Biol Psychiatry. 2003; 53: 226-232
        • Lawrence N.S.
        • Williams A.M.
        • Surguladze S.
        • Giampietro V.
        • Brammer M.J.
        • Andrew C.
        • et al.
        Subcortical and ventral prefrontal cortical neural responses to facial expressions distinguish patients with bipolar disorder and major depression.
        Biol Psychiatry. 2004; 55: 578-587
        • Surguladze S.
        • Brammer M.J.
        • Keedwell P.
        • Giampietro V.
        • Young A.W.
        • Travis M.J.
        • et al.
        A differential pattern of neural response toward sad versus happy facial expressions in major depressive disorder.
        Biol Psychiatry. 2005; 57: 201-209
        • Granger C.W.J.
        • Lin J.L.
        Causality in the long-run.
        Econ Theory. 1995; 11: 530-536
        • Salvador R.
        • Suckling J.
        • Schwarzbauer C.
        • Bullmore E.
        Undirected graphs of frequency-dependent functional connectivity in whole brain networks.
        Philos Trans R Soc Lond B Biol Sci. 2005; 360: 937-946
        • Zhou D.
        • Thompson W.K.
        • Siegle G.
        MATLAB toolbox for functional connectivity.
        Neuroimage. 2009; 47: 1590-1607
        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders.
        American Psychiatric Press, Washington, DC1994
        • First M.B.
        • Spitzer R.L.
        • Gibbon M.L.
        • Williams J.B.W.
        Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition.
        Biometrics Research. New York State Psychiatric Institute, New York2002
        • Young R.C.
        • Biggs J.T.
        • Ziegler V.E.
        • Meyer D.A.
        A rating scale for mania: Reliability, validity and sensitivity.
        Br J Psychiatry. 1978; 133: 429-435
        • Hamilton M.
        A rating scale for depression.
        J Neurol Neurosurg Psychiatry. 1960; 23: 56-62
        • Annett M.
        A classification of hand preference by association analysis.
        Br J Psychol. 1970; 61: 303-321
        • Folstein M.F.
        • Folstein S.E.
        • McHugh P.R.
        “Mini-mental state”.
        J Psychiatr Res. 1975; 12: 189-198
        • Nelson H.E.
        • Willison J.R.
        The Revised National Adult Reading Test—Test Manual.
        Nfer-Nelson, Windsor, United Kingdom1991
        • Hassel S.
        • Almeida J.R.C.
        • Kerr N.
        • Nau S.
        • Ladouceur C.D.
        • Fissell K.
        • et al.
        Elevated striatal and decreased dorsolateral prefrontal cortical activity in response to emotional stimuli in euthymic bipolar disorder: No associations with psychotropic medication load.
        Bipolar Disord. 2008; 10: 916-927
        • Sun F.T.
        • Miller L.M.
        • D'Esposito M.
        Measuring interregional functional connectivity using coherence and partial coherence analyses of fMRI data.
        Neuroimage. 2004; 21: 647-658
        • Blackhart G.C.
        • Minnix J.A.
        • Kline J.P.
        Can EEG asymmetry patterns predict future development of anxiety and depression?.
        Biol Psychol. 2006; 72: 46-50
        • Henriques J.B.
        • Davidson R.J.
        Regional brain electrical asymmetries discriminate between previously depressed and healthy control subjects.
        J Abnorm Psychol. 1990; 99: 22-31
        • Elliott R.
        • Rubinsztein J.S.
        • Sahakian B.J.
        • Dolan R.J.
        The neural basis of mood-congruent processing biases in depression.
        Arch Gen Psychiatry. 2002; 59: 597-604
        • Keedwell P.A.
        • Andrew C.
        • Williams S.C.R.
        • Brammer M.J.
        • Phillips M.L.
        A double dissociation of ventromedial prefrontal cortical responses to sad and happy stimuli in depressed and healthy individuals.
        Biol Psychiatry. 2005; 58: 495-503
        • Liotti M.
        • Mayberg H.S.
        • McGinnis S.
        • Brannan S.L.
        • Jerabek P.
        Unmasking disease-specific cerebral blood flow abnormalities: Mood challenge in patients with remitted unipolar depression.
        Am J Psychiatry. 2002; 159: 1830-1840
        • Van der Gucht E.
        • Morriss R.
        • Lancaster G.
        • Kinderman P.
        • Bentall R.P.
        Psychological processes in bipolar affective disorder: Negative cognitive style and reward processing.
        Br J Psychiatry. 2009; 194: 146-151
        • Altshuler L.
        • Bookheimer S.
        • Townsend J.
        • Proenza M.A.
        • Sabb F.
        • Mintz J.
        • et al.
        Regional brain changes in bipolar I depression: A functional magnetic resonance imaging study.
        Bipolar Disord. 2008; 10: 708-717
        • Almeida J.R.C.
        • Versace A.
        • Hassel S.
        • Kupfer D.J.
        • Phillips M.L.
        Elevated amygdala activity to sad facial expressions: A state marker of bipolar but not unipolar depression.
        Biol Psychiatry. 2009; ([published online ahead of print November 20])
        • Peterson C.K.
        • Harmon-Jones E.
        Proneness to hypomania predicts EEG coherence between left motor cortex and left prefrontal cortex.
        Biol Psychol. 2008; 78: 216-219