Neural deficits at the interface of affect and cognition may improve with pharmacotherapy in pediatric bipolar disorder (PBD).
We examined lamotrigine treatment impact on the neural interface of working memory and affect in PBD.
Un-medicated, acutely ill, patients with mania and hypomania (n = 17), and healthy controls (HC; n = 13; mean age = 13.36 ± 2.55) performed an affective two-back functional magnetic resonance imaging task with blocks of angry vs neutral faces (i.e., angry face condition) or happy vs neutral faces (i.e., happy face condition) before treatment and at follow-up, after 8-week treatment with second-generation antipsychotics followed by 6 weeks of lamotrigine monotherapy.
At baseline, for the angry face condition, PBD, relative to HC, showed reduced activation in the left ventrolateral prefrontal cortex (VLPFC) and right caudate; for the happy face condition, PBD showed increased activation in bilateral PFC and right amygdala and middle temporal gyrus. Post-treatment, PBD showed greater activation in right amygdala relative to HC for both conditions. Patients, relative to HC, exhibited greater changes over time in the right VLPFC and amygdala, left subgenual anterior cingulate cortex and left caudate for the angry face condition, and in right middle temporal gyrus for the happy face condition.
Pharmacotherapy resulted in symptom improvement and normalization of higher cortical emotional and cognitive regions in patients relative to HC, suggesting that the VLPFC dysfunction may be state-specific in PBD. Amygdala was overactive in PBD, relative to HC, regardless of reduction in manic symptoms, and may be a trait marker of PBD.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
Aaron AR, Fletcher PC, Bullmore ET, Sahakian BJ, Robbins TW (2003) Stop-signal inhibition disrupted by damage to right inferior frontal gyrus in humans. Nat Neurosci 6:115–116
Adler C, Holland S, Schmithorse V, Wilke M, Weiss K, Pan H, Strakowski S (2004) Abnormal frontal white matter tracts in bipolar disorder: a diffusion tensor imaging study. Bipolar Disord 6:197–203
Alexander GE, DeLong MR, Strick PL (1986) Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci 9:357–338
American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders IV, 4th edn. American Psychiatric Association, Washington
Annett M (1970) A classification of hand preference by association analysis. Br J Psychol 61:303–321
Baddeley A (2003) Working memory: looking back and looking forward. Nat Rev 4:829–839
Badre D, Wagner AD (2007) Left ventrolateral prefrontal cortex and the cognitive control of memory. Neuropsychologia 45:2883–2901
Bauer MS, Mitchner L (2004) What is a “mood stabilizer”? An evidence-based response. Am J Psychiatry 161(1):3–18
Biederman J, Mick E, Faraone SV, Spencer T, Wilens TE, Wozniak J (2000) Pediatric mania: a developmental subtype of bipolar disorder? Biol Psychiatry 48:458–466
Blumberg HP, Leung HC, Skudlarski P, Lacadie C et al (2003) A functional magnetic resonance imaging study of bipolar disorder: state and trait-related dysfunction in ventral prefrontal cortices. Arch Gen Psychiatry 60:599–607
Bora E, Fornito A, Yücel M, Pantelis C (2010) Voxelwise meta-analysis of gray matter abnormalities in bipolar disorder. Biol Psychiatry 67(11):1097–1105
Botvinick M, Braver TS, Barch DM, Carter CS, Cohen JD (2001) Conflict monitoring and cognitive control. Psychol Rev 108(3):624–652
Braver TS, Bongiolatti SR (2002) The role of frontopolar cortex in subgoal processing during working memory. Neuroimage 15:523–536
Brotman MA, Rich BA, Guyer AE, Lunsfoird JR, Horsey SE, Reising MM, Thomas LA, Fromm SJ, Towbin K (2010) Amygdala activation during emotion processing of neutral faces in childre nwith severe mood dysregulation versus ADHD or bipolar disorder. Am J Psychiatry 167(1):61–69
Casey BJ, Cohen JD, Jezzard P, Turner R, Noll DC, Trainor RJ, Giedd J, Kaysen D, Hertz-Pannier L, Rapoport JL (1995) Activation of prefrontal cortex in children during a nonspatial working memory task with functional MRI. Neuroimage 2:221–229
Casey BJ, Giedd JN, Thomas KM (2000) Structural and functional brain development and its relation to cognitive development. Biol Psychol 54:241–257
Chang KD, Wagner C, Garrett A, Howe M, Reiss A (2008) A preliminary functional magnetic resonance imaging study of prefrontal-amygdalar activation changes in adolescents with bipolar depression treated with lamotrigine. Bipolar Disord 10:426–431
Cox RW, AFNI (1996) Software for analysis and visualization of functional magnetic resonance neuroimages. Comput Biomed Res 29:162–173
Dickstein DP, Rich BA, Roberson-Nay R, Berghorst L, Vinton D, Pine DS, Leibenluft E (2007) Neural activation during encoding of emotional faces in pediatric bipolar disorder. Bipolar Disord 9(7):679–692
Dolcos F, McCarthy G (2006) Brain systems mediating cognitive interference by emotional distraction. J Neurosci 26(7):2072–2079
Drevets WC, Savitz J, Trimble M (2008) The subgenual anterior cingulate cortex in mood disorders. CNS Spectr 13(8):663–681
Eddy WF, Fitzgerald M, Genovese CR, Mockus A, Noll DC (1996) Functional image analysis software - computational olio. In: Prat A (ed) Proceedings in computational statistics. Physica-Verlag, Heidelberg, pp 39–49
Foland LC, Altshuler LL, Bookheimer SY, Eisenberger N, Townsend J, Thompson PM (2008) Evidence for deficitent modulation of amygdale response by prefrontal cortex in bipolar mania. Psychiatry Res Neuroimaging 162:27–37
Frangou S, Haldane M, Roddy D, Kumari V (2005) Evidence for deficit in tasks of ventral, but not dorsal, prefrontal executive function as an endophenotypic marker for bipolar disorder. Biol Psychiatry 58(10):838–839
Geddes JR, Calabrese JR, Goodwin GM (2009) Lamotrigine for treatment of bipolar depression: independent meta-analysis and meta-regression of individual patient data from five randomised trials. Br J Psychiatry 194:4–9
Geller B, Warner K, Williams M, Zimerman B (1998) Prepubertal and young adolescent bipolarity versus ADHD: assessment and validity using the WASH-U-KSADS, CBCL, and TRF. J Affect Disord 51(2):93–100
Goodwin GM, Bowden CL, Calabrese JR, Grunze H, Kasper S, White R et al. (2004) A pooled analysis of 2 placebo-controlled 18-month trials of lamotrigine and lithium maintenance in bipolar I disorder. J Clin Psychiatry 65:432–441
Gruber O, Tost H, Henseler I, Schmael C, Scherk H, Ende G, Ruf M, Falkai P, Rietschel M (2009) Pathological amygdala activation during working memory performance: evidence for a pathophysiological trait marker in bipolar affective disorder. Hum Brain Mapp 31(1):115–125
Gur RC, Sara R, Hagendoorn M et al (2002) A method for obtaining 3-dimensional facial expressions and its standardization for use in neurocognitive studies. J Neurosci Meth 115:137–143
Hart SJ, Green SR, Casp M, Belger A (2010) Emotional priming during Stroop task performance. Neuroimage 49:2662–2670
Kaufman J, Birmaher B, Brent DA, Ryan ND, Rao U (2000) K-SADS-PL. J Am Acad Child Adolesc Psychiatry 39(10):1208
Konishi S, Nakajima K, Uchida I, Kikyo H, Kameyama M, Miyashita Y (1999) Common inhibitory mechanism in human inferior prefrontal cortex revealed by event-related functional MRI. Brain 122:981–991
Lawrence NS, Williams AM, Surguladze S, Giampietro V, Brammer MJ, Andrew C, Frangou S, Ecker C, Phillips M (2004) Subcortical and ventral prefrontal cortical neural responses to facial expressions distinguish patients with bipolar disorder and major depression. Biol Psychiatry 55:578–587
Leibenluft E, Rich BA, Vinton DT, Nelson EE, Fromm SJ, Berghorst LH, Joshi P, Robb A, Schachar RJ, Dickstein DP, McClure EB, Pine DS (2007) Neural circuitry engaged during unsuccessful motor inhibition in pediatric bipolar disorder. Am J Psychiatry 164(1):52–60
Levy R, Friedman HR, Davachi L, Goldman-Rakic PS (1997) Differential activation of the caudate nucleus in primates performing spatial and nonspatial working memory tasks. J Neurosci 17(10):3870–3882
Lewis SJG, Dove A, Robbins TW, Barker RA, Owen AM (2004) Striatal contributions to working memory: a functional magnetic resonance imaging study in humans. Eur J Neurosci 19:755–760
Li X, Teneback CC, Nahas Z, Kozel FA, Large C, Cohn J et al (2004) Interleaved transcranial magnetic stimulation/functional MRI confirms that lamotrigine inhibits cortical excitability in healthy young men. Neuropsychopharmacology 29:1395–1407
Owen AM, McMillan KM, Laird AR, Bullmore E (2005) N-back working memory paradigm: a meta-analysis of normative functional Neuroimaging studies. Hum Brain Mapp 25:46–59
Passarotti AM, Sweeney JA, Pavuluri MN (2009) Developmental differences between adolescents and adults during directed and incidental processing of emotional facial expressions. Social Cognitive and Affective Neuroscience 4:387–398
Passarotti AM, Sweeney JA, Pavuluri MN (2010a) Differential engagement of cognitive and affective neural systems in pediatric bipolar disorder and attention deficit hyperactivity disorder. J Int Neuropsychol Soc 16(1):106–117
Passarotti AM, Sweeney JA, Pavuluri MN (2010b) Neural correlates of response inhibition deficits in pediatric bipolar disorder and attention deficit hyperactivity disorder. Psychiatry Res Neuroimaging 181(1):36–43
Passarotti AM, Sweeney JA, Pavuluri MN (2010c) Emotion processing influences working memory circuits in pediatric bipolar disorder and attention deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 9(10):1064–1080
Pavuluri MN, O’Connor MM, Harral EM, Sweeney JA (2007) Affective neural circuitry during facial emotion processing in pediatric bipolar disorder. Biol Psychiatry 62(2):158–167
Pavuluri MN, O’ Connor MM, Harral EM, Sweeney JA (2008) An fMRI study of the interface between affective and cognitive neural circuitry in pediatric bipolar disorder. Psychiatry Res 162(3):244–245
Pavuluri M, Passarotti A, Harral E, Sweeney J (2009a) An fMRI study of the neural correlates of incidental versus directed emotion processing in pediatric bipolar disorder. J Am Acad Child Adolesc Psychiatry 48:308–319
Pavuluri M, West A, Hill S, Jindal K, Sweeney J (2009b) Neurocognitive function in pediatric bipolar disorder: 3-year follow-ups show cognitive development lagging behind health youth. J Am Acad Child Adolesc Psychiatry 48:235–236
Pavuluri MN, Henry DB, Moss M, Mohammed T, Carbray JA, Sweeney JA (2009c) Effectiveness of lamotrigine in maintaining symptom control in pediatric bipolar disorder. J Child Adolesc Psychopharmacol 19(1):75–82
Pavuluri MN, Passarotti AM, Harral EM, Sweeney JA (2010a) Enhanced prefrontal function with pharmacotherapy on a response inhibition task in adolescent bipolar disorder. J Clin Psychiatry 71:1–9
Pavuluri MN, Passarotti AM, Mohammed T, Carbray J, Sweeney JA (2010b) Enhanced working and verbal memory after lamotrigine treatment in pediatric bipolar disorder. Bipolar Disord 12(2):213–220
Pavuluri MN, Passarotti AM, Parnes SA, Fitzgerald JM, Sweeney JA (2010c) A Pharmacological fMRI study probing the interface of cognitive and emotional brain systems in pediatric bipolar disorder. J Child Adolesc Psychopharmacol 20(5):395–406
Petrides M (1994) Frontal lobes and behaviour. Curr Opin Neurobiol 4(2):207–211
Petrides M, Pandya D (2002) Comparative cytoarchitectonic analysis of the human and the macaque ventrolateral prefrontal cortex and corticocortical connection patterns in the monkey. Eur J Neurosci 16:291–310
Philips 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. Mol Psychiatry 13:833–857
Poznanski E, Grossman J, Buchsbaum Y, Banegas M, Freeman L, Gibbons R (1984) Preliminary studies of the reliability and validity of the children’s depression rating scale. J Am Acad Child Adolesc Psychiatry 23(2):191–197
Psychological Corporation (1999) Wechsler Abbreviated Scale of Intelligence (WASI). Harcourt Brace & Company, San Antonio
Rich BA, Vinton DT, Roberson-Nay R et al (2006) Limbic hyperactivation during processing of neutral facial expressions in children with bipolar disorder. Proc Natl Acad Sci USA 103(23):8900–8905
Roberson-Nay R, McClure EB, Monk CS, Nelson EE, Guyer AE, Fromm SJ, Charney DS, Leibenluft E, Blair J, Ernst M, Pine DS (2006) Increased amygdala activity during successful memory encoding in adolescent major depressive disorder: an FMRI study. Biol Psychiatry 60(9):966–973
Rosenthal R (1991) Meta-analytic procedures for social research. Sage, Newbury Park
Rubia K, Cubillo A, Smith AB, Woolley J, Heyman I, Brammer M (2010) Disorder-specific dysfunction in right inferior prefrontal cortex during two inhibition tasks in boys with attention-deficit hyperactivity disorder compared to boys with obsessive-compulsive disorder. Hum Brain Mapp 31:287–299
Smith EE, Jonides J (1998) Neuroimaging analyses of working memory. PNAS 95:12061–12068
Tergau F, Wischer S, Somal HS, Nitsche MA, Joe Mercer A, Paulus W et al (2003) Relationship between lamotrigine oral dose, serum level and its inhibitory effect on CNS: insights from transcranial magnetic stimulation. Epilepsy Res 56:67–77
Van der Schot A, Kahn R, Ramsey N, Nolen W, Vink M (2010) Trait and state dependent functional impairments in bipolar disorder. Psychiatry Res Neuroimaging 184:135–142
Versace A, Thompson WK, Zhou D, Almeida JRC, Hassel S, Klein CR, Kupfer DJ, Phillips ML (2010) Abnormal left and right amygdale-orbitofrintal cortical functional connectivity to emotional faces: state vs trait vulnerability markers of depression in bipolar disorder. Biol Psychiatry 67:422–431
Wang SJ, Sihra TS, Gean PW (2001) Lamotrigine inhibition of glutamate release from isolated cerebrocortical nerve terminals (synaptosomes) by suppression of voltage-activated calcium channel activity. NeuroReport 12:2255–2258
Wang F, Kalmar JH, He Y, Jackowski M, Chepenik LG, Edmiston EE, Tie K, Gong G, Shah MP, Jones M, Uderman J, Constable RT, Blumberg HP (2009) Functional and structural connectivity between the perigenual anterior cingulate and amygdala in bipolar disorder. Biol Psychiatry 66(5):516–521
Ward B (2000) ALPHASIM (Natl. Inst. Of Health, Bethesda). Available at: http://afni.nimh.nih.gov/pub/dist/doc/manual/AlphaSim.pdf.
White HS (1999) Comparative anticonvulsant and mechanistic profile of the established and newer antiepileptic drugs. Epilepsia 40(Suppl 5):S2–S10
Young LT (2004) What exactly is a mood stabilizer? J Psychiatry Neurosci 29(2):87–88
Young RC, Biggs JT, Ziegler VE, Meyer DA (1978) A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry 133:429–435
We wish to thank the children and families for their participation and for making this study possible. This work is supported by NIH K23 RR18638-01, the Dana Foundation, and NARSAD. The present study complies with the current laws of the USA.
Conflicts of interest
Dr. Passarotti has no financial relationships to disclose. Dr. Pavuluri’s work, unrelated to this manuscript, is supported by NARSAD Independent Investigator Award, NIMH, NICHD, DANA foundation, and American Foundation for Suicide Prevention. Dr. Sweeney, also unrelated to this work, has received support from NIH, Janssen and Eli Lilly.
About this article
Cite this article
Passarotti, A.M., Sweeney, J.A. & Pavuluri, M.N. Fronto-limbic dysfunction in mania pre-treatment and persistent amygdala over-activity post-treatment in pediatric bipolar disorder. Psychopharmacology 216, 485–499 (2011). https://doi.org/10.1007/s00213-011-2243-2
- Functional magnetic resonance imaging (fMRI)
- Working memory
- Face emotion
- Brain imaging