Abstract
Neuroimaging studies suggest anterior-limbic structural brain abnormalities in patients with bipolar disorder (BD), but few studies have shown these abnormalities in unaffected but genetically liable family members. In this study, we report morphometric correlates of genetic risk for BD using voxel-based morphometry. In 35 BD type I (BD-I) patients, 20 unaffected first-degree relatives (UAR) of BD patients and 40 healthy control subjects underwent 3 T magnetic resonance scanner imaging. Preprocessing of images used DARTEL (diffeomorphic anatomical registration through exponentiated lie algebra) for voxel-based morphometry in SPM8 (Wellcome Department of Imaging Neuroscience, London, UK). The whole-brain analysis revealed that the gray matter (GM) volumes of the left anterior insula and right inferior frontal gyrus showed a significant main effect of diagnosis. Multiple comparison analysis showed that the BD-I patients and the UAR subjects had smaller left anterior insular GM volumes compared with the healthy subjects, the BD-I patients had smaller right inferior frontal gyrus compared with the healthy subjects. For white matter (WM) volumes, there was a significant main effect of diagnosis for medial frontal gyrus. The UAR subjects had smaller right medial frontal WM volumes compared with the healthy subjects. These findings suggest that morphometric brain abnormalities of the anterior-limbic neural substrate are associated with family history of BD, which may give insight into the pathophysiology of BD, and be a potential candidate as a morphological endophenotype of BD.
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References
Goodwin FK, Jamison KR . Manic-Depressive Illness. Bipolar Disorders and Recurrent Depression, 2nd edn. Oxford University Press: New York, 2007.
Bora E, Yucel M, Pantelis C . Cognitive endophenotypes of bipolar disorder: a meta-analysis of neuropsychological deficits in euthymic patients and their first-degree relatives. J Affect Disord 2009; 113: 1–20.
Arts B, Jabben N, Krabbendam L, van Os J . Meta-analyses of cognitive functioning in euthymic bipolar patients and their first-degree relatives. Psychol Med 2008; 38: 771–785.
Bora E, Vahip S, Akdeniz F, Ilerisoy H, Aldemir E, Alkan M . Executive and verbal working memory dysfunction in first-degree relatives of patients with bipolar disorder. Psychiatr Res 2008; 161: 318–324.
Soares JC, Mann JJ . The anatomy of mood disorders—review of structural neuroimaging studies. Biol Psychiatry 1997; 41: 86–106.
Adler CM, DelBello MP, Strakowski SM . Brain network dysfunction in bipolar disorder. CNS Spectr 2006; 11: 312–320.
Hajek T, Kozeny J, Kopecek M, Alda M, Hoschl C . Reduced subgenual cingulate volumes in mood disorders: a meta-analysis. J Psychiatry Neurosci 2008; 33: 91–99.
McDonald C, Zanelli J, Rabe-Hesketh S, Ellison-Wright I, Sham P, Kalidindi S et al. Meta-analysis of magnetic resonance imaging brain morphometry studies in bipolar disorder. Biol Psychiatry 2004; 56: 411–417.
Kempton MJ, Geddes JR, Ettinger U, Williams SC, Grasby PM . Meta-analysis, database, and meta-regression of 98 structural imaging studies in bipolar disorder. Arch Gen Psychiatry 2008; 65: 1017–1032.
Ellison-Wright I, Bullmore E . Anatomy of bipolar disorder and schizophrenia: a meta-analysis. Schizophr Res 2010; 117: 1–12.
McIntosh AM, Job DE, Moorhead TW, Harrison LK, Forrester K, Lawrie SM et al. Voxel-based morphometry of patients with schizophrenia or bipolar disorder and their unaffected relatives. Biol Psychiatry 2004; 56: 544–552.
McDonald C, Bullmore ET, Sham PC, Chitnis X, Wickham H, Bramon E et al. Association of genetic risks for schizophrenia and bipolar disorder with specific and generic brain structural endophenotypes. Arch Gen Psychiatry 2004; 61: 974–984.
Ladouceur CD, Almeida JR, Birmaher B, Axelson DA, Nau S, Kalas C et al. Subcortical gray matter volume abnormalities in healthy bipolar offspring: potential neuroanatomical risk marker for bipolar disorder? J Am Acad Child Adolesc Psychiatry 2008; 47: 532–539.
Kempton MJ, Haldane M, Jogia J, Grasby PM, Collier D, Frangou S . Dissociable brain structural changes associated with predisposition, resilience, and disease expression in bipolar disorder. J Neurosci 2009; 29: 10863–10868.
First MB, Spitzer RL, Gibbon M, Williams JBW . Structured Clinical Interview for DSM-IV Axis I Disorders, Research Version, Patient Edition. Biometrics Research Department, New York State Psychiatric Institute: New York, 1996.
First MB, Spitzer RL, Gibbon M, Janet W . Structured Clinical Interview for DSM-IV Axis I Disorders-Non-Patient Edition. Biometrics Research Department, New York State Psychiatric Institute: New York, 1996.
Oldfield RC . The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 1971; 9: 97–113.
Young RC, Biggs JT, Ziegler VE, Meyer DA . 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.
Montgomery SA, Asberg M . A new depression scale designed to be sensitive to change. Br J Psychiatry 1979; 134: 382–389.
Muller MJ, Szegedi A, Wetzel H, Benkert O . Moderate and severe depression. Gradations for the Montgomery-Asberg depression rating scale. J Affect Disord 2000; 60: 137–140.
Hamilton M . The assessment of anxiety states by rating. Br J Med Psychol 1959; 32: 50–55.
Barratt ES . Impulsiveness and aggression. In: Monahan J, Steadman HJ (eds). Violence and Mental Disorder: Developments in Risk Assessments. University of Chicago Press: Chicago, IL, 1994, pp 61–79.
Patton JH, Stanford MS, Barratt ES . Factor structure of the Barratt impulsiveness scale. J Clin Psychology 1995; 51: 768–774.
Stonnington CM, Tan G, Kloppel S, Chu C, Draganski B, Jack Jr CR et al. Interpreting scan data acquired from multiple scanners: a study with Alzheimer's disease. Neuroimage 2008; 39: 1180–1185.
Tzourio-Mazoyer N, Landeau B, Papathanassiou D, Crivello F, Etard O, Delcroix N et al. Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage 2002; 15: 273–289.
Maldjian JA, Laurienti PJ, Kraft RA, Burdette JH . An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. Neuroimage 2003; 19: 1233–1239.
Maldjian JA, Laurienti PJ, Burdette JH . Precentral gyrus discrepancy in electronic versions of the Talairach atlas. Neuroimage 2004; 21: 450–455.
Lancaster JL, Woldorff MG, Parsons LM, Liotti M, Freitas CS, Rainey L et al. Automated Talairach atlas labels for functional brain mapping. Hum Brain Mapp 2000; 10: 120–131.
Augustine JR . Circuitry and functional aspects of the insular lobe in primates including humans. Brain Res Brain Res Rev 1996; 22: 229–244.
Singer T, Critchley HD, Preuschoff K . A common role of insula in feelings, empathy and uncertainty. Trends Cogn Sci 2009; 13: 334–340.
Phan KL, Wager T, Taylor SF, Liberzon I . Functional neuroanatomy of emotion: a meta-analysis of emotion activation studies in PET and fMRI. Neuroimage 2002; 16: 331–348.
Fusar-Poli P, Placentino A, Carletti F, Landi P, Allen P, Surguladze S et al. Functional atlas of emotional faces processing: a voxel-based meta-analysis of 105 functional magnetic resonance imaging studies. J Psychiatry Neurosci 2009; 34: 418–432.
Mah L, Zarate Jr CA, Singh J, Duan YF, Luckenbaugh DA, Manji HK et al. Regional cerebral glucose metabolic abnormalities in bipolar II depression. Biol Psychiatry 2007; 61: 765–775.
Jang DP, Lee SH, Park CW, Lee SY, Kim YB, Cho ZH . Effects of fluoxetine on the rat brain in the forced swimming test: a [F-18] FDG micro-PET imaging study. Neurosci Lett 2009; 451: 60–64.
Pennington K, Dicker P, Hudson L, Cotter DR . Evidence for reduced neuronal somal size within the insular cortex in schizophrenia, but not in affective disorders. Schizophr Res 2008; 106: 164–171.
Lyoo IK, Kim MJ, Stoll AL, Demopulos CM, Parow AM, Dager SR et al. Frontal lobe gray matter density decreases in bipolar I disorder. Biol Psychiatry 2004; 55: 648–651.
Stanfield AC, Moorhead TW, Job DE, McKirdy J, Sussmann JE, Hall J et al. Structural abnormalities of ventrolateral and orbitofrontal cortex in patients with familial bipolar disorder. Bipolar Disord 2009; 11: 135–144.
Adler CM, DelBello MP, Jarvis K, Levine A, Adams J, Strakowski SM . Voxel-based study of structural changes in first-episode patients with bipolar disorder. Biol Psychiatry 2007; 61: 776–781.
Vita A, De Peri L, Sacchetti E . Gray matter, white matter, brain, and intracranial volumes in first-episode bipolar disorder: a meta-analysis of magnetic resonance imaging studies. Bipolar Disord 2009; 11: 807–814.
Adler CM, Levine AD, DelBello MP, Strakowski SM . Changes in gray matter volume in patients with bipolar disorder. Biol Psychiatry 2005; 58: 151–157.
Lopez-Larson MP, DelBello MP, Zimmerman ME, Schwiers ML, Strakowski SM . Regional prefrontal gray and white matter abnormalities in bipolar disorder. Biol Psychiatry 2002; 52: 93–100.
Aron AR, Fletcher PC, Bullmore ET, Sahakian BJ, Robbins TW . Stop-signal inhibition disrupted by damage to right inferior frontal gyrus in humans. Nat Neurosci 2003; 6: 115–116.
Menon V, Adleman NE, White CD, Glover GH, Reiss AL . Error-related brain activation during a Go/NoGo response inhibition task. Hum Brain Mapp 2001; 12: 131–143.
Rubia K, Smith AB, Brammer MJ, Taylor E . Right inferior prefrontal cortex mediates response inhibition while mesial prefrontal cortex is responsible for error detection. Neuroimage 2003; 20: 351–358.
Hampshire A, Chamberlain SR, Monti MM, Duncan J, Owen AM . The role of the right inferior frontal gyrus: inhibition and attentional control. Neuroimage 2010; 50: 1313–1319.
Najt P, Perez J, Sanches M, Peluso MA, Glahn D, Soares JC . Impulsivity and bipolar disorder. Eur Neuropsychopharmacol 2007; 17: 313–320.
Leibenluft E, Rich BA, Vinton DT, Nelson EE, Fromm SJ, Berghorst LH et al. Neural circuitry engaged during unsuccessful motor inhibition in pediatric bipolar disorder. Am J Psychiatry 2007; 164: 52–60.
Strakowski SM, Adler CM, Cerullo MA, Eliassen JC, Lamy M, Fleck DE et al. MRI brain activation in first-episode bipolar mania during a response inhibition task. Early Interv Psychiatry 2008; 2: 225–233.
Matsuo K, Nicoletti MA, Peluso MA, Hatch JP, Nemoto K, Watanabe Y et al. Anterior cingulate volumes associated with trait impulsivity in individuals with bipolar disorder. Bipolar Disord 2009; 11: 628–636.
Fletcher PC, Henson RN . Frontal lobes and human memory: insights from functional neuroimaging. Brain 2001; 124: 849–881.
Moore GJ, Bebchuk JM, Wilds IB, Chen G, Manji HK . Lithium-induced increase in human brain grey matter. Lancet 2000; 356: 1241–1242.
Braus DF, Ende G, Weber-Fahr W, Demirakca T, Henn FA . Favorable effect on neuronal viability in the anterior cingulate gyrus due to long-term treatment with atypical antipsychotics: an MRSI study. Pharmacopsychiatry 2001; 34: 251–253.
Monkul ES, Matsuo K, Nicoletti MA, Dierschke N, Hatch JP, Dalwani M et al. Prefrontal gray matter increases in healthy individuals after lithium treatment: a voxel-based morphometry study. Neurosci Lett 2007; 429: 7–11.
Phillips ML, Travis MJ, Fagiolini A, Kupfer DJ . Medication effects in neuroimaging studies of bipolar disorder. Am J Psychiatry 2008; 165: 313–320.
Brambilla P, Bellani M, Yeh PH, Soares JC . Myelination in bipolar patients and the effects of mood stabilizers on brain anatomy. Curr Pharm Des 2009; 15: 2632–2636.
Pantelis C, Velakoulis D, McGorry PD, Wood SJ, Suckling J, Phillips LJ et al. Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison. Lancet 2003; 361: 281–288.
Jovicich J, Czanner S, Greve D, Haley E, van der Kouwe A, Gollub R et al. Reliability in multi-site structural MRI studies: effects of gradient non-linearity correction on phantom and human data. Neuroimage 2006; 30: 436–443.
Paulus MP, Stein MB . An insular view of anxiety. Biol Psychiatry 2006; 60: 383–387.
Acknowledgements
This work is partly supported by NARSAD, MH 68766, MH 068662, RR 20571, UTHSCSA GCRC (M01-RR-01346), the Veterans Administration (Merit Review), the Krus Endowed Chair in Psychiatry (UTHSCSA) and KAKENHI-C 21591519.
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Matsuo, K., Kopecek, M., Nicoletti, M. et al. New structural brain imaging endophenotype in bipolar disorder. Mol Psychiatry 17, 412–420 (2012). https://doi.org/10.1038/mp.2011.3
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DOI: https://doi.org/10.1038/mp.2011.3
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