Skip to main content

Examination of the predictive value of structural magnetic resonance scans in bipolar disorder: a pattern classification approach

  • V. Rocha-Rego (a1) (a2), J. Jogia (a1), A. F. Marquand (a1), J. Mourao-Miranda (a1) (a3), A. Simmons (a1) (a2) (a4) and S. Frangou (a5)...

Bipolar disorder (BD) is one of the leading causes of disability worldwide. Patients are further disadvantaged by delays in accurate diagnosis ranging between 5 and 10 years. We applied Gaussian process classifiers (GPCs) to structural magnetic resonance imaging (sMRI) data to evaluate the feasibility of using pattern recognition techniques for the diagnostic classification of patients with BD.


GPCs were applied to gray (GM) and white matter (WM) sMRI data derived from two independent samples of patients with BD (cohort 1: n = 26; cohort 2: n = 14). Within each cohort patients were matched on age, sex and IQ to an equal number of healthy controls.


The diagnostic accuracy of the GPC for GM was 73% in cohort 1 and 72% in cohort 2; the sensitivity and specificity of the GM classification were respectively 69% and 77% in cohort 1 and 64% and 99% in cohort 2. The diagnostic accuracy of the GPC for WM was 69% in cohort 1 and 78% in cohort 2; the sensitivity and specificity of the WM classification were both 69% in cohort 1 and 71% and 86% respectively in cohort 2. In both samples, GM and WM clusters discriminating between patients and controls were localized within cortical and subcortical structures implicated in BD.


Our results demonstrate the predictive value of neuroanatomical data in discriminating patients with BD from healthy individuals. The overlap between discriminative networks and regions implicated in the pathophysiology of BD supports the biological plausibility of the classifiers.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Examination of the predictive value of structural magnetic resonance scans in bipolar disorder: a pattern classification approach
      Available formats
      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Examination of the predictive value of structural magnetic resonance scans in bipolar disorder: a pattern classification approach
      Available formats
      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Examination of the predictive value of structural magnetic resonance scans in bipolar disorder: a pattern classification approach
      Available formats
The online version of this article is published within an Open Access environment subject to the conditions of the Creative Commons Attribution-NonCommercial-ShareAlike licence . The written permission of Cambridge University Press must be obtained for commercial re-use.
Corresponding author
* Address for correspondence: Professor S. Frangou, Professor of Psychiatry, Chief, Psychosis Research Program, Icahn School of Medicine at Mount Sinai, Icahn Medical Institute, Box 1230, 1425 Madison Avenue, New York, NY 10029, USA. (Email:
Hide All
Angst, F, Stassen, HH, Clayton, PJ, Angst, J (2002). Mortality of patients with mood disorders: follow-up over 34–38 years. Journal of Affective Disorders 68, 167181.
APA (1994). Diagnostic and Statistical Manual of Mental Disorders: DSM-IV. American Psychiatric Association: Washington, DC.
Arnone, D, Cavanagh, J, Gerber, D, Lawrie, SM, Ebmeier, KP, McIntosh, AM (2009). Magnetic resonance imaging studies in bipolar disorder and schizophrenia: meta-analysis. British Journal of Psychiatry 195, 194201.
Ashburner, J, Friston, KJ (2005). Unified segmentation. NeuroImage 26, 839851.
Baldessarini, RJ, Tondo, L (2003). Suicide risk and treatments for patients with bipolar disorder. Journal of the American Medical Association 290, 15171519.
Bearden, CE, Thompson, PM, Dalwani, M, Hayashi, KM, Lee, AD, Nicoletti, M, Trakhtenbroit, M, Glahn, DC, Brambilla, P, Sassi, RB, Mallinger, AG, Frank, E (2007). Greater cortical gray matter density in lithium-treated patients with bipolar disorder. Biological Psychiatry 62, 716.
Bearden, CE, van Erp, TG, Dutton, RA, Boyle, C, Madsen, S, Luders, E, Kieseppa, T, Tuulio-Henriksson, A, Huttunen, M, Partonen, T, Kaprio, J, Lönnqvist, J, Thompson, PM, Cannon, TD (2011). Mapping corpus callosum morphology in twin pairs discordant for bipolar disorder. Cerebral Cortex 21, 24152424.
Bellani, M, Yeh, PH, Tansella, M, Balestrieri, M, Soares, JC, Brambilla, P (2009). DTI studies of corpus callosum in bipolar disorder. Biochemical Society Transactions 37, 10961098.
Berk, M, Dodd, S, Callaly, P, Berk, L, Fitzgerald, P, de Castella, AR, Filia, S, Filia, K, Tahtalian, S, Biffin, F, Kelin, K, Smith, M, Montgomery, W, Kulkarni, J (2007). History of illness prior to a diagnosis of bipolar disorder or schizoaffective disorder. Journal of Affective Disorders 103, 181186.
Berk, M, Malhi, GS, Hallam, K, Gama, CS, Dodd, S, Andreazza, AC, Frey, BN, Kapczinski, F (2009). Early intervention in bipolar disorders: clinical, biochemical and neuroimaging imperatives. Journal of Affective Disorders 114, 113.
Bishop, C (2006). Pattern Recognition and Machine Learning. Springer: New York.
Bora, E, Fornito, A, Yücel, M, Pantelis, C (2010). Voxelwise meta-analysis of gray matter abnormalities in bipolar disorder. Biological Psychiatry 67, 10971105.
Davatzikos, C (2004). Why voxel-based morphometric analysis should be used with great caution when characterizing group differences. NeuroImage 23, 1720.
Ecker, C, Rocha-Rego, V, Johnston, P, Mourao-Miranda, J, Marquand, A, Daly, EM, Brammer, MJ, Murphy, C, Murphy, DG; MRC AIMS Consortium (2010). Investigating the predictive value of whole-brain structural MR scans in autism: a pattern classification approach. NeuroImage 49, 4456.
Ellison-Wright, I, Bullmore, E (2010). Anatomy of bipolar disorder and schizophrenia: a meta-analysis. Schizophrenia Research 117, 112.
Fennig, S, Craig, T, Lavelle, J, Kovasznay, B, Bromet, EJ (1994). Best-estimate versus structured interview-based diagnosis in first-admission psychosis. Comprehensive Psychiatry 35, 341348.
First, MB, Spitzer, RL, Gibbon, M, Williams, JBW (2002 a). Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Non-Patient Edition (SCID-I/NP). Biometrics Research, New York State Psychiatric Institute: New York.
First, MB, Spitzer, RL, Gibbon, M, Williams, JBW (2002 b). Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition (SCID-I/P). Biometrics Research, New York State Psychiatric Institute: New York.
Frangou, S (2005). The Maudsley Bipolar Disorder Project. Epilepsia 46, 1925.
Frangou, S (2009). Risk and resilience in bipolar disorder: rationale and design of the Vulnerability to Bipolar Disorders Study (VIBES). Biochemical Society Transactions 37, 10851089.
Frangou, S, Donaldson, S, Hadjulis, M, Landau, S, Goldstein, LH (2005). The Maudsley Bipolar Disorder Project: executive dysfunction in bipolar disorder I and its clinical correlates. Biological Psychiatry 58, 859864.
Fu, CH, Mourao-Miranda, J, Costafreda, SG, Khanna, A, Marquand, AF, Williams, SC, Brammer, MJ (2008). Pattern classification of sad facial processing: toward the development of neurobiological markers in depression. Biological Psychiatry 63, 656662.
Germana, C, Kempton, MJ, Sarnicola, A, Christodoulou, T, Haldane, M, Hadjulis, M, Girardi, P, Tatarelli, R, Frangou, S (2010). The effects of lithium and anticonvulsants on brain structure in bipolar disorder. Acta Psychiatrica Scandinavica 122, 481487.
Guyon, I, Weston, J, Barnhill, S, Vapnik, V (2002). Gene selection for cancer classification using support vector machines. Machine Learning 46, 389422.
Hallahan, B, Newell, J, Soares, JC, Brambilla, P, Strakowski, SM, Fleck, DE, Kieseppä, T, Altshuler, LL, Fornito, A, Malhi, GS, McIntosh, AM, Yurgelun-Todd, DA, Labar, KS, Sharma, V, MacQueen, GM, Murray, RM, McDonald, C (2011). Structural magnetic resonance imaging in bipolar disorder: an international collaborative mega-analysis of individual adult patient data. Biological Psychiatry 69, 326335.
Hamilton, M (1960). A rating scale for depression. Journal of Neurology, Neurosurgery and Psychiatry 23, 5662.
Hirschfeld, RM (2010). The mood disorder questionnaire: its impact on the field. Depression and Anxiety 27, 627630.
Hirschfeld, RM, Calabrese, JR, Weissman, MM, Reed, M, Davies, MA, Frye, MA, Keck, PE Jr., Lewis, L, McElroy, SL, McNulty, JP, Wagner, KD (2003). Screening for bipolar disorder in the community. Journal of Clinical Psychiatry 64, 5359.
Hirschfeld, RM, Williams, JB, Spitzer, RL, Calabrese, JR, Flynn, L, Keck, PE Jr., Lewis, L, McElroy, SL, Post, RM, Rapport, DJ, Russell, JM, Sachs, GS, Zajecka, J (2000). Development and validation of a screening instrument for bipolar spectrum disorder: the Mood Disorder Questionnaire. American Journal Psychiatry 157, 18731875.
Judd, LL, Akiskal, HS, Schettler, PJ, Endicott, J, Maser, J, Solomon, DA, Coryell, W, Maser, JD, Keller, MB (2002). The long-term natural history of the weekly symptomatic status of bipolar I disorder. Archives of General Psychiatry 59, 530537.
Kapczinski, F, Dias, VV, Kauer-Sant'Anna, M, Brietzke, E, Vazquez, GH, Vieta, E, Berk, M (2009). The potential use of biomarkers as an adjunctive tool for staging bipolar disorder. Progress in Neuro-Psychopharmacology and Biological Psychiatry 33, 13661371.
Kempton, MJ, Geddes, JR, Ettinger, U, Williams, SC, Grasby, PM (2008). Meta-analysis, database, and meta-regression of 98 structural imaging studies in bipolar disorder. Archives of General Psychiatry 65, 10171032.
Kempton, MJ, Haldane, M, Jogia, J, Grasby, PM, Collier, D, Frangou, S (2009). Dissociable brain structural changes associated with predisposition, resilience, and disease expression in bipolar disorder. Journal of Neuroscience 29, 10 86310 868.
Kempton, MJ, Salvador, Z, Munafò, MR, Geddes, JR, Simmons, A, Frangou, S, Williams, SC (2011). Structural neuroimaging studies in major depressive disorder: meta-analysis and comparison with bipolar disorder. Archives of General Psychiatry 68, 675690.
Ketter, TA, Houston, JP, Adams, DH, Risser, RC, Meyers, AL, Williamson, DJ, Tohen, M (2006). Differential efficacy of olanzapine and lithium in preventing manic or mixed recurrence in patients with bipolar I disorder based on number of previous manic or mixed episodes. Journal of Clinical Psychiatry 67, 95101.
Klöppel, S, Abdulkadir, A, Jack, CR Jr., Koutsouleris, N, Mourão-Miranda, J, Vemuri, P (2012). Diagnostic neuroimaging across diseases. NeuroImage 61, 457463.
Klöppel, S, Stonnington, CM, Chu, C, Draganski, B, Scahill, RI, Rohrer, JD, Fox, NC, Jack, CR Jr., Ashburner, J, Frackowiak, RS (2008). Automatic classification of MR scans in Alzheimer's disease. Brain 131, 681689.
Koutsouleris, N, Meisenzahl, EM, Davatzikos, C, Bottlender, R, Frodl, T, Scheuerecker, J, Schmitt, G, Zetzsche, T, Decker, P, Reiser, M, Möller, HJ, Gaser, C (2009). Use of neuroanatomical pattern classification to identify subjects in at-risk mental states of psychosis and predict disease transition. Archives of General Psychiatry 66, 700712.
Lish, JD, Dime-Meenan, S, Whybrow, PC, Price, RA, Hirschfeld, RM (1994). The National Depressive and Manic-depressive Association (DMDA) survey of bipolar members. Journal of Affective Disorders 31, 281294.
Marquand, A, Howard, M, Brammer, M, Chu, C, Coen, S, Mourao-Miranda, J (2010). Quantitative prediction of subjective pain intensity from whole-brain fMRI data using Gaussian processes. NeuroImage 49, 21782189.
Marquand, AF, De Simoni, S, O'Daly, OG, Williams, SC, Mourao-Miranda, J, Mehta, MA (2011). Pattern classification of working memory networks reveals differential effects of methylphenidate, atomoxetine, and placebo in healthy volunteers. Neuropsychopharmacology 36, 12371247.
Marquand, AF, Mourao-Miranda, J, Brammer, MJ, Cleare, AJ, Fu, CH (2008). Neuroanatomy of verbal working memory as a diagnostic biomarker for depression. Neuroreport 19, 15071511.
Maxwell, E (1992). The Family Interview for Genetic Studies Manual. National Institute of Mental Health: Washington DC.
McElroy, SL, Altshuler, LL, Suppes, T, Keck, PE Jr., Frye, MA, Denicoff, KD, Nolen, WA, Kupka, RW, Leverich, GS, Rochussen, JR, Rush, AJ, Post, RM (2001). Axis I psychiatric comorbidity and its relationship to historical illness variables in 288 patients with bipolar disorder. American Journal of Psychiatry 158, 420426.
McIntosh, AM, Job, DE, Moorhead, TW, Harrison, LK, Lawrie, SM, Johnstone, EC (2005). White matter density in patients with schizophrenia, bipolar disorder and their unaffected relatives. Biological Psychiatry 58, 254257.
Menzin, J, Sussman, M, Tafesse, E, Duczakowski, C, Neumann, P, Friedman, M (2009). A model of the economic impact of a bipolar disorder screening program in primary care. Journal of Clinical Psychiatry 70, 12301236.
Merikangas, KR, Jin, R, He, JP, Kessler, RC, Lee, S, Sampson, NA, Viana, MC, Andrade, LH, Hu, C, Karam, EG, Ladea, M, Medina-Mora, ME, Ono, Y, Posada-Villa, J, Sagar, R, Wells, JE, Zarkov, Z (2011). Prevalence and correlates of bipolar spectrum disorder in the World Mental Health Survey Initiative. Archives of General Psychiatry 68, 241251.
Mourao-Miranda, J, Reinders, AA, Rocha-Rego, V, Lappin, J, Rondina, J, Morgan, C, Morgan, KD, Fearon, P, Jones, PB, Doody, GA, Murray, RM, Kapur, S, Dazzan, P (2012). Individualized prediction of illness course at the first psychotic episode: a support vector machine MRI study. Psychological Medicine 42, 10371047.
Nelson, HE, Wilson, JR (1992). The National Adult Reading Test (NART). Test Manual. NFER-Nelson: Windsor.
Perugi, G, Micheli, C, Akiskal, HS, Madaro, D, Socci, C, Quilici, C, Musetti, L (2000). Polarity of the first episode, clinical characteristics, and course of manic depressive illness: a systematic retrospective investigation of 320 bipolar I patients. Comprehensive Psychiatry 41, 1318.
Phillips, ML, Travis, MJ, Fagiolini, A, Kupfer, DJ (2008). Medication effects in neuroimaging studies of bipolar disorder. American Journal of Psychiatry 165, 313320.
Post, RM, Leverich, GS, Altshuler, LL, Frye, MA, Suppes, TM, Keck, PE Jr., McElroy, SL, Kupka, R, Nolen, WA, Grunze, H, Walden, J (2003). An overview of recent findings of the Stanley Foundation Bipolar Network (Part I). Bipolar Disorder 5, 310319.
Rasmussen, CE, Williams, CKI (2006). Gaussian Processes for Machine Learning. The MIT Press: Cambridge, MA.
Scherk, H, Kemmer, C, Usher, J, Reith, W, Falkai, P, Gruber, O (2008). No change to grey and white matter volumes in bipolar I disorder patients. European Archives of Psychiatry and Clinical 258, 345349.
Schimmelmann, BG, Conus, P, Edwards, J, McGorry, PD, Lambert, M (2005). Diagnostic stability 18 months after treatment initiation for first-episode psychosis. Journal of Clinical Psychiatry 66, 12391246.
Segal, DL, Hersen, M, Van Hasselt, VB (1994). Reliability of the Structured Clinical Interview for DSM-III-R: an evaluative review. Comprehensive Psychiatry 35, 316327.
Selvaraj, S, Arnone, D, Job, D, Stanfield, A, Farrow, TF, Nugent, AC, Scherk, H, Gruber, O, Chen, X, Sachdev, PS, Dickstein, DP, Malhi, GS, Ha, TH, Ha, K, Phillips, ML, McIntosh, AM (2012). Grey matter differences in bipolar disorder: a meta-analysis of voxel-based morphometry studies. Bipolar Disorders 14, 135145.
Simmons, A, Arridge, SR, Barker, GJ, Williams, SC (1996). Simulation of MRI cluster plots and application to neurological segmentation. Magnetic Resonance Imaging 14, 7392.
Simmons, A, Westman, E, Muehlboeck, S, Mecocci, P, Vellas, B, Tsolaki, M, Kłoszewska, I, Wahlund, LO, Soininen, H, Lovestone, S, Evans, A, Spenger, C (2011). The AddNeuroMed framework for multi-centre MRI assessment of Alzheimer's disease: experience from the first 24 months. International Journal of Geriatric Psychiatry 26, 7582.
Spitzer, RL, Endicott, J (1978). A diagnostic interview: the schedule for affective disorders and schizophrenia. Archives of General Psychiatry 35, 873–843.
Stanfield, AC, Moorhead, TW, Job, DE, McKirdy, J, Sussmann, J, Hall, J, Giles, S, Johnstone, EC, Lawrie, SM, McIntosh, AM (2009). Structural abnormalities of ventrolateral and orbitofrontal cortex in patients with familial bipolar disorder. Bipolar Disorder 11, 135144.
Stensland, MD, Schultz, JF, Frytak, JR (2008). Diagnosis of unipolar depression following initial identification of bipolar disorder: a common and costly misdiagnosis. Journal of Clinical Psychiatry 69, 749758.
van Erp, TG, Thompson, PM, Kieseppa, T, Bearden, CE, Marino, AC, Hoftman, GD, Haukka, J, Partonen, T, Huttunen, M, Kaprio, J, Lönnqvist, 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.
Vederine, FE, Wessa, M, Leboyer, M, Houenou, J (2011). Meta-analysis of whole-brain diffusion tensor imaging studies in bipolar disorder. Progress in Neuro-Psychopharmacology and Biological Psychiatry 35, 18201826.
Vemuri, P, Gunter, JL, Senjem, ML, Whitwell, JL, Kantarci, K, Knopman, DS, Boeve, BF, Petersen, RC, Jack, CR Jr. (2008). Alzheimer's disease diagnosis in individual subjects using structural MR images: validation studies. NeuroImage 39, 11861197.
Vita, A, De Peri, L, Sacchetti, E (2009). Gray matter, white matter, brain, and intracranial volumes in first-episode bipolar disorder: a meta-analysis of magnetic resonance imaging studies. Bipolar Disorder 8, 807814.
Walterfang, M, Malhi, GS, Wood, AG, Reutens, DC, Chen, J, Barton, S, Yücel, M, Velakoulis, D, Pantelis, C (2009 a). Corpus callosum size and shape in established bipolar affective disorder. Australian and New Zealand Journal of Psychiatry 43, 838845.
Walterfang, M, Wood, AG, Barton, S, Velakoulis, D, Chen, J, Reutens, DC, Kempton, MJ, Haldane, M, Pantelis, C, Frangou, S (2009 b). 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.
WHO (2004). The Global Burden of Disease. World Health Organization: Geneva.
Williams, JB, Gibbon, M, First, MB, Spitzer, RL, Davies, M, Borus, J, Howes, MJ, Kane, J, Pope, HG Jr., Rounsaville, B, Wittchen, H (1992). The Structured Clinical Interview for DSM-III-R (SCID). II. Multisite test-retest reliability. Archives of General Psychiatry 49, 630636.
Wilson, SM, Ogar, JM, Laluz, V, Growdon, M, Jang, J, Glenn, S, Miller, BL, Weiner, MW, Gorno-Tempini, ML (2009). Automated MRI-based classification of primary progressive aphasia variants. NeuroImage 47, 15581567.
Yu, K, Cheung, C, Leung, M, Li, Q, Chua, S, McAlonan, G (2010). Are bipolar disorder and schizophrenia neuroanatomically distinct? An anatomical likelihood meta-analysis. Frontiers in Human Neuroscience 4, 189.
Zimmerman, M, Galione, JN, Chelminski, I, Young, D, Dalrymple, K (2011). Psychiatric diagnoses in patients who screen positive on the Mood Disorder Questionnaire: implications for using the scale as a case-finding instrument for bipolar disorder. Psychiatry Research 185, 444449.
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

Rocha-Rego Supplementary Material

 Word (122 KB)
122 KB
Supplementary materials

Rocha-Rego Supplementary Material

 PDF (346 KB)
346 KB


Altmetric attention score

Full text views

Total number of HTML views: 40
Total number of PDF views: 215 *
Loading metrics...

Abstract views

Total abstract views: 688 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 22nd March 2018. This data will be updated every 24 hours.