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Abnormalities in left inferior frontal gyral thickness and parahippocampal gyral volume in young people at high genetic risk for bipolar disorder

  • G. Roberts (a1) (a2), R. Lenroot (a1) (a3), A. Frankland (a1) (a2), P. K. Yeung (a3), N. Gale (a1) (a2), A. Wright (a1) (a2), P. Lau (a1) (a2), F. Levy (a1) (a4), W. Wen (a1) and P. B. Mitchell (a1) (a2) (a4)...



Fronto-limbic structural brain abnormalities have been reported in patients with bipolar disorder (BD), but findings in individuals at increased genetic risk of developing BD have been inconsistent. We conducted a study in adolescents and young adults (12–30 years) comparing measures of fronto-limbic cortical and subcortical brain structure between individuals at increased familial risk of BD (at risk; AR), subjects with BD and controls (CON). We separately examined cortical volume, thickness and surface area as these have distinct neurodevelopmental origins and thus may reflect differential effects of genetic risk.


We compared fronto-limbic measures of grey and white matter volume, cortical thickness and surface area in 72 unaffected-risk individuals with at least one first-degree relative with bipolar disorder (AR), 38 BD subjects and 72 participants with no family history of mental illness (CON).


The AR group had significantly reduced cortical thickness in the left pars orbitalis of the inferior frontal gyrus (IFG) compared with the CON group, and significantly increased left parahippocampal gyral volume compared with those with BD.


The finding of reduced cortical thickness of the left pars orbitalis in AR subjects is consistent with other evidence supporting the IFG as a key region associated with genetic liability for BD. The greater volume of the left parahippocampal gyrus in those at high risk is in line with some prior reports of regional increases in grey matter volume in at-risk subjects. Assessing multiple complementary morphometric measures may assist in the better understanding of abnormal developmental processes in BD.


Corresponding author

*Address for correspondence: P. B. Mitchell, School of Psychiatry, University of New South Wales, Sydney, Australia. (Email:


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Alemán-Gómez, Y, Janssen, J, Schnack, H, Balaban, E, Pina-Camacho, L, Alfaro-Almagro, F, Castro-Fornieles, J, Otero, S, Baeza, I, Moreno, D (2013). The human cerebral cortex flattens during adolescence. Journal of Neuroscience 33, 1500415010.
Ashburner, J, Csernansk, JG, Davatzikos, C, Fox, NC, Frisoni, GB, Thompson, PM (2003). Computer-assisted imaging to assess brain structure in healthy and diseased brains. Lancet Neurology 2, 7988.
Badre, D, Wagner, AD (2007). Left ventrolateral prefrontal cortex and the cognitive control of memory. Neuropsychologia 45, 28832901.
Benjamini, Y, Hochberg, Y (2000). On the adaptive control of the false discovery rate in multiple testing with independent statistics. Journal of Educational and Behavioral Statistics 25, 6083.
Birmaher, B, Axelson, D, Monk, K, Kalas, C, Goldstein, B, Hickey, MB, Obreja, M, Ehmann, M, Iyengar, S, Shamseddeen, W, Kupfer, D, Brent, D (2009). Lifetime psychiatric disorders in school-aged offspring of parents with bipolar disorder: the Pittsburgh Bipolar Offspring Study. Archives of General Psychiatry 66, 287296.
Brambilla, P, Harenski, K, Nicoletti, M, Sassi, RB, Mallinger, AG, Frank, E, Kupfer, DJ, Keshavan, MS, Soares, JC (2003). MRI investigation of temporal lobe structures in bipolar patients. Journal of Psychiatric Research 37, 287295.
Breakspear, M, Roberts, G, Green, MJ, Nguyen, VT, Frankland, A, Levy, F, Lenroot, R, Mitchell, PB (2015). Network dysfunction of emotional and cognitive processes in those at genetic risk of bipolar disorder. Brain 138, 34273439.
Brotman, MA, Deveney, CM, Thomas, LA, Hinton, KE, Yi, JY, Pine, DS, Leibenluft, E (2014). Parametric modulation of neural activity during face emotion processing in unaffected youth at familial risk for bipolar disorder. Bipolar Disorders 16, 756763.
Chang, K, Karchemskiy, A, Barnea-Goraly, N, Garrett, A, Simeonova, DI, Reiss, A (2005). Reduced amygdalar gray matter volume in familial pediatric bipolar disorder. Journal of the American Academy of Child and Adolescent Psychiatry 44, 565573.
Chen, BK, Sassi, R, Axelson, D, Hatch, JP, Sanches, M, Nicoletti, M, Brambilla, P, Keshavan, MS, Ryan, ND, Birmaher, B (2004). Cross-sectional study of abnormal amygdala development in adolescents and young adults with bipolar disorder. Biological Psychiatry 56, 399405.
Chen, CH, Suckling, J, Lennox, BR, Ooi, C, Bullmore, ET (2011). A quantitative meta-analysis of fMRI studies in bipolar disorder. Bipolar Disorders 13, 115.
Connor, SE, Ng, V, McDonald, C, Schulze, K, Morgan, K, Dazzan, P, Murray, RM (2004). A study of hippocampal shape anomaly in schizophrenia and in families multiply affected by schizophrenia or bipolar disorder. Neuroradiology 46, 523534.
Dale, AM, Fischl, B, Sereno, MI (1999). Cortical surface-based analysis: segmentation and surface reconstruction. NeuroImage 9, 179194.
Desikan, RS, Ségonne, F, Fischl, B, Quinn, BT, Dickerson, BC, Blacker, D, Buckner, RL, Dale, AM, Maguire, RP, Hyman, BT (2006). An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. NeuroImage 31, 968980.
Dickstein, DP, Milham, MP, Nugent, AC, Drevets, WC, Charney, DS, Pine, DS, Leibenluft, E (2005). Frontotemporal alterations in pediatric bipolar disorder: results of a voxel-based morphometry study. Archives of General Psychiatry 62, 734741.
Elvsåshagen, T, Westlye, LT, Bøen, E, Hol, PK, Andreassen, OA, Boye, B, Malt, UF (2013). Bipolar II disorder is associated with thinning of prefrontal and temporal cortices involved in affect regulation. Bipolar Disorders 15, 855864.
Fischl, B, Dale, AM (2000). Measuring the thickness of the human cerebral cortex from magnetic resonance images. Proceedings of the National Academy of Sciences 97, 1105011055.
Fischl, B, van der Kouwe, A, Destrieux, C, Halgren, E, Segonne, F, Salat, DH, Busa, E, Seidman, LJ, Goldstein, J, Kennedy, D, Caviness, V, Makris, N, Rosen, B, Dale, AM (2004). Automatically parcellating the human cerebral cortex. Cerebral Cortex 14, 1122.
Foland-Ross, LC, Thompson, PM, Sugar, CA, Madsen, SK, Shen, JK, Penfold, C, Ahlf, K, Rasser, PE, Fischer, J, Yang, Y (2011). Investigation of cortical thickness abnormalities in lithium-free adults with bipolar I disorder using cortical pattern matching. American Journal of Psychiatry 168, 530539.
Fornito, A, Malhi, GS, Lagopoulos, J, Ivanovski, B, Wood, SJ, Saling, MM, Pantelis, C, Yücel, M (2008). Anatomical abnormalities of the anterior cingulate and paracingulate cortex in patients with bipolar I disorder. Psychiatry Research: Neuroimaging 162, 123132.
Frazier, JA, Hodge, SM, Breeze, JL, Giuliano, AJ, Terry, JE, Moore, CM, Kennedy, DN, Lopez-Larson, MP, Caviness, VS, Seidman, LJ (2008). Diagnostic and sex effects on limbic volumes in early-onset bipolar disorder and schizophrenia. Schizophrenia Bulletin 34, 3746.
Geller, B, Harms, MP, Wang, L, Tillman, R, DelBello, MP, Bolhofner, K, Csernansky, JG (2009). Effects of age, sex, and independent life events on amygdala and nucleus accumbens volumes in child bipolar I disorder. Biological Psychiatry 65, 432437.
Gogtay, N, Ordonez, A, Herman, DH, Hayashi, KM, Greenstein, D, Vaituzis, C, Lenane, M, Clasen, L, Sharp, W, Giedd, JN, Jung, D, Nugent III, TF, Toga, AW, Leibenluft, E, Thompson, PM, Rapoport, JL (2007). Dynamic mapping of cortical development before and after the onset of pediatric bipolar illness. Journal of Child Psychology and Psychiatry 48, 852862.
Goodwin, FK, Jamison, KR (2007). Manic–Depressive Illness: Bipolar Disorders and Recurrent Depression. Oxford University Press: New York.
Greenlee, JD, Oya, H, Kawasaki, H, Volkov, IO, Kaufman, OP, Kovach, C, Howard, MA, Brugge, JF (2004). A functional connection between inferior frontal gyrus and orofacial motor cortex in human. Journal of Neurophysiology 92, 11531164.
Hajek, T, Carrey, N, Alda, M (2005). Neuroanatomical abnormalities as risk factors for bipolar disorder. Bipolar Disorders 7, 393403.
Hajek, T, Cooke, C, Kopecek, M, Novak, T, Hoschl, C, Alda, M (2015). Using structural MRI to identify individuals at genetic risk for bipolar disorders: a 2-cohort, machine learning study. Journal of Psychiatry and Neuroscience 40, 316324.
Hajek, T, Cullis, J, Novak, T, Kopecek, M, Blagdon, R, Propper, L, Stopkova, P, Duffy, A, Hoschl, C, Uher, R (2013). Brain structural signature of familial predisposition for bipolar disorder: replicable evidence for involvement of the right inferior frontal gyrus. Biological Psychiatry 73, 144152.
Hartberg, C, Sundet, K, Rimol, L, Haukvik, U, Lange, E, Nesvåg, R, Dale, A, Melle, I, Andreassen, O, Agartz, I (2011). Brain cortical thickness and surface area correlates of neurocognitive performance in patients with schizophrenia, bipolar disorder, and healthy adults. Journal of the International Neuropsychological Society 17, 10801093.
Hegarty, CE, Foland-Ross, LC, Narr, KL, Sugar, CA, McGough, JJ, Thompson, PM, Altshuler, LL (2012). ADHD comorbidity can matter when assessing cortical thickness abnormalities in patients with bipolar disorder. Bipolar Disorders 14, 843855.
Houenou, J, Frommberger, J, Carde, S, Glasbrenner, M, Diener, C, Leboyer, M, Wessa, M (2011). Neuroimaging-based markers of bipolar disorder: evidence from two meta-analyses. Journal of Affective Disorders 132, 344355.
Hulshoff Pol, HE, van Baal, GC, Schnack, HG, Brans, RG, van der Schot, AC, Brouwer, RM, van Haren, NE, Lepage, C, Collins, DL, Evans, AC, Boomsma, DI, Nolen, W, Kahn, RS (2012). Overlapping and segregating structural brain abnormalities in twins with schizophrenia or bipolar disorder. Archives of General Psychiatry 69, 349359.
Karchemskiy, A, Garrett, A, Howe, M, Adleman, N, Simeonova, DI, Alegria, D, Reiss, A, Chang, K (2011). Amygdalar, hippocampal, and thalamic volumes in youth at high risk for development of bipolar disorder. Psychiatry Research 194, 319325.
Kovacs, M (1992). Children's Depression Inventory (CDI) . Multi-Health Systems: New York.
Ladouceur, CD, Almeida, JR, Birmaher, B, Axelson, DA, Nau, S, Kalas, C, Monk, K, Kupfer, DJ, Phillips, ML (2008). Subcortical gray matter volume abnormalities in healthy bipolar offspring: potential neuroanatomical risk marker for bipolar disorder? Journal of the American Academy of Child and Adolescent Psychiatry 47, 532539.
Leckman, JF, Sholomskas, D, Thompson, WD, Belanger, A, Weissman, MM (1982). Best estimate of lifetime psychiatric diagnosis: a methodological study. Archives of General Psychiatry 39, 879883.
Lim, CS, Baldessarini, RJ, Vieta, E, Yucel, M, Bora, E, Sim, K (2013). Longitudinal neuroimaging and neuropsychological changes in bipolar disorder patients: review of the evidence. Neuroscience and Biobehavioral Reviews 37, 418435.
López-Larson, MP, DelBello, MP, Zimmerman, ME, Schwiers, ML, Strakowski, SM (2002). Regional prefrontal gray and white matter abnormalities in bipolar disorder. Biological Psychiatry 52, 93100.
Loranger, AW, Levine, PM (1978). Age at onset of bipolar affective illness. Archives of General Psychiatry 35, 13451348.
Lyoo, IK, Kim, MJ, Stoll, AL, Demopulos, CM, Parow, AM, Dager, SR, Friedman, SD, Dunner, DL, Renshaw, PF (2004). Frontal lobe gray matter density decreases in bipolar I disorder. Biological Psychiatry 55, 648651.
Lyoo, IK, Sung, YH, Dager, SR, Friedman, SD, Lee, JY, Kim, SJ, Kim, N, Dunner, DL, Renshaw, PF (2006). Regional cerebral cortical thinning in bipolar disorder. Bipolar Disorders 8, 6574.
Matsuo, K, Kopecek, M, Nicoletti, MA, Hatch, JP, Watanabe, Y, Nery, FG, Zunta-Soares, G, Soares, JC (2012). New structural brain imaging endophenotype in bipolar disorder. Molecular Psychiatry 17, 412420.
Maxwell, ME (1992). Family Interview for Genetic Studies: Clinical Neurogenetics Branch. Intramural Research Program, National Institute of Mental Health: Bethesda, MD.
McDonald, C, Bullmore, ET, Sham, PC, Chitnis, X, Wickham, H, Bramon, E, Murray, RM (2004 a). Association of genetic risks for schizophrenia and bipolar disorder with specific and generic brain structural endophenotypes. Archives of General Psychiatry 61, 974984.
McDonald, C, Zanelli, J, Rabe-Hesketh, S, Ellison-Wright, I, Sham, P, Kalidindi, S, Murray, RM, Kennedy, N (2004 b). Meta-analysis of magnetic resonance imaging brain morphometry studies in bipolar disorder. Biological Psychiatry 56, 411417.
McIntosh, AM, Job, DE, Moorhead, TWJ, Harrison, LK, Lawrie, SM, Johnstone, EC (2005). White matter density in patients with schizophrenia, bipolar disorder and their unaffected relatives. Biological Psychiatry 58, 254257.
Meda, SA, Pryweller, JR, Thornton-Wells, TA (2012). Regional brain differences in cortical thickness, surface area and subcortical volume in individuals with Williams syndrome. PLOS ONE 7, e31913.
Montgomery, SA, Åsberg, M (1979). A new depression scale designed to be sensitive to change. British Journal of Psychiatry 134, 382389.
Nery, FG, Monkul, ES, Lafer, B (2013). Gray matter abnormalities as brain structural vulnerability factors for bipolar disorder: a review of neuroimaging studies of individuals at high genetic risk for bipolar disorder. Australian and New Zealand Journal of Psychiatry 47, 11241135.
Noga, JT, Vladar, K, Torrey, EF (2001). A volumetric magnetic resonance imaging study of monozygotic twins discordant for bipolar disorder. Psychiatry Research 106, 2534.
Nurnberger, JI Jr., Blehar, MC, Kaufmann, CA, York-Cooler, C, Simpson, SG, Harkavy-Friedman, J, Severe, JB, Malaspina, D, Reich, T (1994). Diagnostic Interview for Genetic Studies: rationale, unique features, and training. Archives of General Psychiatry 51, 849859.
Nurnberger, JI Jr., McInnis, M, Reich, W, Kastelic, E, Wilcox, HC, Glowinski, A, Mitchell, P, Fisher, C, Erpe, M, Gershon, ES, Berrettini, W, Laite, G, Schweitzer, R, Rhoadarmer, K, Coleman, VV, Cai, X, Azzouz, F, Liu, H, Kamali, M, Brucksch, C, Monahan, PO (2011). A high-risk study of bipolar disorder: childhood clinical phenotypes as precursors of major mood disorders. Archives of General Psychiatry 68, 10121020.
Otten, M, Meeter, M (2015). Hippocampal structure and function in individuals with bipolar disorder: a systematic review. Journal of Affective Disorders 174, 113125.
Papmeyer, M, Giles, S, Sussmann, JE, Kielty, S, Stewart, T, Lawrie, SM, Whalley, HC, McIntosh, AM (2015). Cortical thickness in individuals at high familial risk of mood disorders as they develop major depressive disorder. Biological Psychiatry 78, 5866.
Perich, T, Lau, P, Hadzi-Pavlovic, D, Roberts, G, Frankland, A, Wright, A, Green, M, Breakspear, M, Corry, J, Radlinska, B, McCormack, C, Joslyn, C, Levy, F, Lenroot, R, Nurnberger, JI Jr., Mitchell, PB (2015). What clinical features precede the onset of bipolar disorder? Journal of Psychiatric Research 62, 7177.
Phillips, ML, Ladouceur, CD, Drevets, WC (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, Swartz, HA (2014). A critical appraisal of neuroimaging studies of bipolar disorder: toward a new conceptualization of underlying neural circuitry and a road map for future research. American Journal of Psychiatry 171, 829843.
Pontious, A, Kowalczyk, T, Englund, C, Hevner, RF (2007). Role of intermediate progenitor cells in cerebral cortex development. Developmental Neuroscience 30, 2432.
Rimol, LM, Nesvåg, R, Hagler, DJ Jr., Bergmann, Ø, Fennema-Notestine, C, Hartberg, CB, Haukvik, UK, Lange, E, Pung, CJ, Server, A (2012). Cortical volume, surface area, and thickness in schizophrenia and bipolar disorder. Biological Psychiatry 71, 552560.
Roberts, G, Green, MJ, Breakspear, M, McCormack, C, Frankland, A, Wright, A, Levy, F, Lenroot, R, Chan, HN, Mitchell, PB (2013). Reduced inferior frontal gyrus activation during response inhibition to emotional stimuli in youth at high risk of bipolar disorder. Biological Psychiatry 74, 5561.
Sarıçiçek, A, Yalın, N, Hıdıroğlu, C, Çavuşoğlu, B, Taş, C, Ceylan, D, Zorlu, N, Ada, E, Tunca, Z, Özerdem, A (2015). Neuroanatomical correlates of genetic risk for bipolar disorder: a voxel-based morphometry study in bipolar type I patients and healthy first degree relatives. Journal of Affective Disorders 186, 110118.
Selvaraj, S, Arnone, D, Job, D, Stanfield, A, Farrow, TF, Nugent, AC, Scherk, H, Gruber, O, Chen, X, Sachdev, PS (2012). Grey matter differences in bipolar disorder: a meta-analysis of voxel-based morphometry studies. Bipolar Disorders 14, 135145.
Singh, MK, Chang, KD (2013). Brain structural response in individuals at familial risk for bipolar disorder: a tale of two outcomes. Biological Psychiatry 73, 109110.
Strakowski, SM, Adler, CM, Almeida, J, Altshuler, LL, Blumberg, HP, Chang, KD, DelBello, MP, Frangou, S, McIntosh, A, Phillips, ML, Sussman, JE, Townsend, JD (2012). The functional neuroanatomy of bipolar disorder: a consensus model. Bipolar Disorders 14, 313325.
Tang, Y, Hojatkashani, C, Dinov, ID, Sun, B, Fan, L, Lin, X, Qi, H, Hua, X, Liu, S, Toga, AW (2010). The construction of a Chinese MRI brain atlas: a morphometric comparison study between Chinese and Caucasian cohorts. NeuroImage 51, 3341.
Vadakkumpadan, F, Tong, Y, Sun, Y (2006). Statistical analysis of morphological differences between brains. International Journal of Neuroscience 116, 407418.
van Erp, TG, Thompson, PM, Kieseppa, T, Bearden, CE, Marino, AC, Hoftman, GD, Haukka, J, Partonen, T, Huttunen, M, Kaprio, J, Lonnqvist, J, Poutanen, VP, Toga, AW, Cannon, TD (2012). Hippocampal morphology in lithium and non-lithium-treated bipolar I disorder patients, non-bipolar co-twins, and control twins. Human Brain Mapping 33, 501510.
Venkatasubramanian, G, Zutshi, A, Jindal, S, Srikanth, SG, Kovoor, JM, Kumar, JK, Janardhan Reddy, Y (2012). Comprehensive evaluation of cortical structure abnormalities in drug-naïve, adult patients with obsessive–compulsive disorder: a surface-based morphometry study. Journal of Psychiatric Research 46, 11611168.
Walterfang, M, Wood, AG, Barton, S, Velakoulis, D, Chen, J, Reutens, DC, Kempton, MJ, Haldane, M, Pantelis, C, Frangou, S (2009). Corpus callosum size and shape alterations in individuals with bipolar disorder and their first-degree relatives. Progress in Neuro-Psychopharmacology and Biological Psychiatry 33, 10501057.
Wechsler, D (1999). Wechsler Abbreviated Scale of Intelligence. The Psychological Corporation, Harcourt Brace & Company: New York.
Winkler, AM, Kochunov, P, Blangero, J, Almasy, L, Zilles, K, Fox, PT, Duggirala, R, Glahn, DC (2010). Cortical thickness or grey matter volume? The importance of selecting the phenotype for imaging genetics studies. NeuroImage 53, 11351146.
Young, R, Biggs, J, Ziegler, V, Meyer, D (1978). A rating scale for mania: reliability, validity and sensitivity. British Journal of Psychiatry 133, 429435.


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