Skip to main content
    • Aa
    • Aa

Abnormal anterior cingulate cortical activity during emotional n-back task performance distinguishes bipolar from unipolar depressed females

  • M. A. Bertocci (a1), G. M. Bebko (a1), B. C. Mullin (a1), S. A. Langenecker (a2), C. D. Ladouceur (a1), J. R. C. Almeida (a1) and M. L. Phillips (a1) (a3)...

Depression in the context of bipolar disorder (BDd) is often misdiagnosed as unipolar disorder depression (UDd) leading to poor clinical outcomes for many bipolar sufferers. We examined neural circuitry supporting emotion regulation in females with either BDd or UDd as a first stage toward identifying biomarkers that may differentiate BDd from UDd.


Fifty-seven females aged 18–45 years participated in this study: 23 with UDd, 18 with bipolar disorder type I depression (BDId) and 16 healthy females. During 3-T functional magnetic resonance imaging (fMRI), the participants performed an emotional face n-back (EFNBACK) task, that is an n-back task with high (2-back) and low (0-back) memory load conditions flanked by two positive, negative or neutral face distracters. This paradigm examines executive control with emotional distracters–emotion regulation.


High memory load with neutral face distracters elicited greater bilateral and left dorsal anterior midcingulate cortex (dAMCC) activity in UDd than in healthy and BDId females respectively, and greater bilateral putamen activity in both depressed groups versus healthy females. High memory load with happy face distracters elicited greater left putamen activity in UDd than in healthy females. Psychotropic medication was associated with greater putamen activity to these contrasts in UDd females.


During high memory load with neutral face distracters, elevated dAMCC activity in UDd suggests abnormal recruitment of attentional control circuitry to maintain task performance, whereas elevated putamen activity unrelated to psychotropic medication in BDId females may suggest an attentional bias toward ambiguous neutral face distracters. Differential patterns of functional abnormalities in neural circuitry supporting attentional control during emotion regulation, especially in the dAMCC, is a promising neuroimaging measure to distinguish UDd from BDId in females.

Corresponding author
*Address for correspondence: M. A. Bertocci, Ph.D., Western Psychiatric Institute and Clinic, Loeffler Building, room 205, 121 Meyran Avenue, Pittsburgh, PA 15213, USA. (Email:
Hide All
Almeida JR, Versace A, Hassel S, Kupfer DJ, Phillips ML (2010). Elevated amygdala activity to sad facial expressions: a state marker of bipolar but not unipolar depression. Biological Psychiatry 67, 414421.
Anand A, Li Y, Wang Y, Gardner K, Lowe M (2007). Reciprocal effects of antidepressant treatment on activity and connectivity of the mood regulating circuit: an fMRI study. Journal of Neuropsychiatry Clinical Neuroscience 19, 274282.
Annett M (1970). A classification of hand preference by association analysis. British Journal of Psychology 61, 303321.
Blair K, Spreen O (1989). Predicting premorbid IQ: a revision of the National Adult Reading Test. Clinical Neuropsychologist 3, 129136.
Bush G, Shin LM (2006). The Multi-Source Interference Task: an fMRI task that reliably activates the cingulo-frontal-parietal cognitive/attention network. Nature Protocols 1, 308313.
Chen C, Lenox B, Jacob R, Calder A, Lupson V, Bisbrown-Chippendale R, Suckling J, Bullmore E (2006). Explicit and implicit facial affect recognition in manic and depressed states of bipolar disorder: a functional magnetic resonance imaging study. Biological Psychiatry 59, 3139.
Dannlowski U, Ohrmann P, Bauer J, Kugel H, Arolt V, heindel W, Kersting A, Baune B, Suslow T (2007). Amygdala reactivity to masked negative faces is associated with automatic judgmental bias in major depression: a 3T fMRI study. Journal of Psychiatry and Neuroscience 32, 423429.
Deckersbach T, Rauch S, Buhlman U, Ostacher M, Beucke J, Nierenberg A, Sachs G, Dougherty DD (2008). An fMRI investigation of working memory and sadness in females with bipolar disorder: a brief report. Bipolar Disorders 10, 928942.
Drevets WC (2003). Neuroimaging abnormalities in the amygdala in mood disorders. Annals of the New York Academy of Sciences 985, 420444.
Elliott R, Rubinsztein JS, Sahakian BJ, Dolan RJ (2002). The neural basis of mood-congruent processing biases in depression. Archives of General Psychiatry 59, 597604.
Epstein J, Pan H, Kocsis JH, Yang Y, Butler T, Chusid J, Hochberg H, Murrough J, Strohmayer E, Stern E, Silbersweig DA (2006). Lack of ventral striatal response to positive stimuli in depressed versus normal subjects. American Journal of Psychiatry 163, 17841790.
Fales C, Barch D, Rundle M, Mintun M, Snyder A, Cohen J, Mathews J, Sheline Y (2008). Altered emotional interference processing in affective and cognitive-control brain circuitry in major depression. Biological Psychiatry 63, 377384.
First M, Spitzer R, Gibbon M, Williams J (1995). Structured Clinical Interview for DSM-IV Axis I Disorders, Version 2.0. Biometric Research Department, New York State Psychiatric Institute: New York.
Folstein M, Folstein S, McHugh P (1975). ‘Mini-Mental State’. A practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research 12, 189198.
Fu CHY, Williams SCR, Cleare AJ, Brammer MJ, Walsh ND, Kim J, Andrew CM, Pich EM, Williams PM, Reed LJ, Mitterschiffthaler MT, Suckling J, Bullmore ET (2004). Attenuation of the neural response to sad faces in major depression by antidepressant treatment: a prospective, event-related functional magnetic resonance imaging study. Archives of General Psychiatry 61, 877889.
Grimm S, Beck J, Schuepbach D, Hell D, Boesinger P, Permpohl F, Niehaus l, Boeker H, Northoff G (2008). Imbalance between left and right dorsolateral prefrontal cortex in major depression is linked to negative emotional judgment: an fMRI study in severe major depressive disorder. Biological Psychiatry 63, 369376.
Gruber SA, Rogowska J, Yurgelun-Todd DA (2004). Decreased activation of the anterior cingulate in bipolar patients: an fMRI study. Journal of Affective Disorders 82, 191201.
Haber SN, Kim K-S, Mailly P, Calzavara R (2006). Reward-related cortical inputs define a large striatal region in primates that interface with associative cortical connections, providing a substrate for incentive-based learning. Journal of Neuroscience 26, 83688376.
Hamilton M (1960). A rating scale for depression. Journal of Neurology, Neurosurgery, and Psychiatry 23, 5662.
Hirschfeld RM, Lewis L, Vornik LA (2003). 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. Journal of Clinical Psychiatry 64, 161174.
Johnstone T, van Reekum C, Urry H, Kalin N, Davidson R (2007). Failure to regulate: counterproductive recruitment of top-down prefrontal-subcortical circuitry in major depression. Journal of Neuroscience 27, 88778884.
Koch K, Pauly K, Kellermann T, Seiferth NY, Reske M, Backes V, Stöcker T, Shah NJ, Amunts K, Kircher T, Schneider F, Habel U (2007). Gender differences in the cognitive control of emotion: an fMRI study. Neuropsychologia 45, 27442754.
Ladouceur CD, Silk JS, Dahl RE, Ostapenko L, Kronhaus DM, Phillips ML (2009). Fearful faces influence attentional control processes in anxious youth and adults. Emotion 9, 855864.
Langenecker S, Bieliauskas L, Rapport L, Zubieta J, Wilde E, Berent S (2005). Face emotion perception and executive functioning deficitis in depression. Journal of Clinical and Experimental Neuropsychology 27, 320333.
Langenecker SA, Kennedy S, Guidotti L, Briceno E, Own L, Hooven T, Young E, Akil H, Noll DC, Zubieta J (2007). Frontal and limbic activation during inhibitory control predicts treatment response in major depressive disorder. Biological Psychiatry 62, 12721280.
Langenecker SA, Saunders E, Kade A, Ransom M, McInnis M (2010). Intermediate cognitive phenotypes in bipolar disorder. Journal of Affective Disorders 122, 285293.
Lawrence NS, Williams AM, Surguladze S, Giampietro V, Brammer MJ, Andrew C, Frangou S, Ecker C, Phillips ML (2004). Subcortical and ventral prefrontal cortical neural responses to facial expressions distinguish patients with bipolar disorder and major depression. Biological Psychiatry 55, 578587.
Lorenzetti V, Allen NB, Fornito A, Yücel M (2009). Structural brain abnormalities in major depressive disorder: a selective review of recent MRI studies. Journal of Affective Disorders 117, 117.
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.
Malhi G, Lagopoulos J, Ward P, Kumari V, Mitchell P, Parker GB, Ivanovski B, Schdev P (2004). Cognitive generation of affect in bipolar depression: an fMRI study. European Journal of Neuroscience 19, 741754.
McRae K, Ochsner KN, Mauss IB, Gabrieli JJD, Gross JJ (2008). Gender differences in emotion regulation: an fMRI study of cognitive reappraisal. Group Processes and Intergroup Relations 11, 143162.
Mitterschiffthaler MT, Williams SCR, Walsh ND, Cleare AJ, Donaldson C, Scott J, Fu CHY (2008). Neural basis of the emotional Stroop interference effect in major depression. Psychological Medicine 38, 247256.
Ochsner KN, Gross JJ (2005). The cognitive control of emotion. Trends in Cognitive Sciences 9, 242249.
Pavuluri MN, Oconnor MM, Harral E, Sweeney JA (2007). Affective neural circuitry during facial emotion processing in pediatric bipolar disorder. Biological Psychiatry 62, 158167.
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 (2003). Understanding the neurobiology of emotion perception: implications for psychiatry. British Journal of Psychiatry 182, 190192.
Phillips ML, Drevets WC, Rauch SL, Lane R (2003). Neurobiology of emotion perception II: Implications for major psychiatric disorders. Biological Psychiatry 54, 515528.
Rich BA, Vinton DT, Roberson-Nay R, Hommer RE, Berghorst LH, McClure EB, Fromm SJ, Pine DS, Leibenluft E (2006). Limbic hyperactivation during processing of neutral facial expressions in children with bipolar disorder. Proceedings of the National Academy of Sciences USA 103, 89008905.
Schienle A, Schäfer A, Stark R, Walter B, Vaitl D (2005). Gender differences in the processing of disgust- and fear-inducing pictures: an fMRI study. Neuroreport 16, 277280.
Siegle GJ, Steinhauer SR, Thase ME, Stenger AV, Carter CS (2002). Can't shake that feeling: event-related fMRI assessment of sustained amygdala activity in response to emotional information in depressed individuals. Biological Psychiatry 51, 693707.
Siegle GJ, Thompson W, Carter CS, Steinhauer SR, Thase ME (2007). Increased amygdala and decreased dorsolateral prefrontal BOLD responses in unipolar depression: related and independent features. Biological Psychiatry 61, 198209.
Strakowski SM, Adler CM, DelBello MP (2002). Volumetric MRI studies of mood disorders: do they distinguish unipolar and bipolar disorder? Bipolar Disorders 4, 8088.
Surguladze S, Brammer MJ, Keedwell P, Giampietro V, Young AW, Travis MJ, Williams SCR, Phillips ML (2005). A differential pattern of neural response toward sad versus happy facial expressions in major depressive disorder. Biological Psychiatry 57, 201209.
Surguladze SA, Brammer MJ, Young AW, Andrew C, Travis MJ, Williams SCR, Phillips ML (2003). A preferential increase in the extrastriate response to signals of danger. NeuroImage 19, 13171328.
Tottenhan N, Tanaka J, Leon A, McCarry T, Nurse M, Hare T (2009). The NimStim set of facial expressions: judgments from untrained research participants. Psychiatry Research 168, 242249.
Ward B (2002). AlphaSim. National Institute of Mental Health: Bethesda, MD.
Weissman MM, Bland RC, Canino GJ, Faravelli C, Greenwald S, Hwu H-G, Joyce PR, Karam EG, Lee C-K, Lellouch J, Lépine J-P, Newman SC, Rubio-Stipec M, Wells JE, Wickramaratne PJ, Wittchen H-U, Yeh E-K (1996). Cross-national epidemiology of major depression and bipolar disorder. Journal of the American Medical Association 276, 293299.
Young AW, Rowland D, Calder AJ, Etcoff NL, Seth A, Perrett DI (1997). Facial expression megamix: tests of dimensional and category accounts of emotion recognition. Cognition 63, 271313.
Young R, Biggs J, Ziegler V, Meyer D (1978). A rating scale for mania: reliability, validity, and sensitivity. British Journal of Psychiatry 133, 429435.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Psychological Medicine
  • ISSN: 0033-2917
  • EISSN: 1469-8978
  • URL: /core/journals/psychological-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *


Type Description Title
Supplementary Materials

Bertocci Supplementary Materials
Bertocci Supplementary Materials

 Word (206 KB)
206 KB


Altmetric attention score

Full text views

Total number of HTML views: 9
Total number of PDF views: 76 *
Loading metrics...

Abstract views

Total abstract views: 316 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 22nd October 2017. This data will be updated every 24 hours.