Skip to main content Accessibility help

Brain functional changes in first-degree relatives of patients with bipolar disorder: evidence for default mode network dysfunction

  • S. Alonso-Lana (a1) (a2) (a3), M. Valentí (a4), A. Romaguera (a1), C. Sarri (a5), S. Sarró (a1) (a2), A. Rodríguez-Martínez (a6), J. M. Goikolea (a4), B. L. Amann (a1) (a2), T. Maristany (a7), R. Salvador (a1) (a2), E. Vieta (a2) (a4), P. J. McKenna (a1) (a2) and E. Pomarol-Clotet (a1) (a2)...



Relatively few studies have investigated whether relatives of patients with bipolar disorder show brain functional changes, and these have focused on activation changes. Failure of de-activation during cognitive task performance is also seen in the disorder and may have trait-like characteristics since it has been found in euthymia.


A total of 20 euthymic patients with bipolar disorder, 20 of their unaffected siblings and 40 healthy controls underwent functional magnetic resonance imaging during performance of the n-back working memory task. An analysis of variance (ANOVA) was fitted to individual whole-brain maps from each set of patient–relative–matched pair of controls. Clusters of significant difference among the groups were used as regions of interest to compare mean activations/de-activations between them.


A single cluster of significant difference among the three groups was found in the whole-brain ANOVA. This was located in the medial prefrontal cortex, a region of task-related de-activation in the healthy controls. Both the patients and their siblings showed significantly reduced de-activation compared with the healthy controls in this region, but the failure was less marked in the relatives.


Failure to de-activate the medial prefrontal cortex in both euthymic bipolar patients and their unaffected siblings adds to evidence for default mode network dysfunction in the disorder, and suggests that it may act as a trait marker.


Corresponding author

*Address for correspondence: S. Alonso-Lana, FIDMAG Germanes Hospitalàries Research Foundation, C/Dr Antoni Pujades, 38, E-08830 Sant Boi de Llobregat, Barcelona, Spain. (Email:


Hide All
Allin, MP, Marshall, N, Schulze, K, Walshe, M, Hall, MH, Picchioni, M, Murray, RM, McDonald, C (2010). A functional MRI study of verbal fluency in adults with bipolar disorder and their unaffected relatives. Psychological Medicine 40, 20252035.
Bellack, AS, Green, MF, Cook, JA, Fenton, W, Harvey, PD, Heaton, RK, Laughren, T, Leon, AC, Mayo, DJ, Patrick, DL, Patterson, TL, Rose, A, Stover, E, Wykes, T (2007). Assessment of community functioning in people with schizophrenia and other severe mental illnesses: a white paper based on an NIMH-sponsored workshop. Schizophrenia Bulletin 33, 805822.
Broyd, SJ, Demanuele, C, Debener, S, Helps, SK, James, CJ, Sonuga-Barke, EJ (2009). Default-mode brain dysfunction in mental disorders: a systematic review. Neuroscience and Biobehavioral Reviews 33, 279296.
Buckner, RL, Andrews-Hanna, JR, Schacter, DL (2008). The brain's default network: anatomy, function, and relevance to disease. Annals of the New York Academy of Sciences 1124, 138.
Calhoun, VD, Maciejewski, PK, Pearlson, GD, Kiehl, KA (2008). Temporal lobe and “default” hemodynamic brain modes discriminate between schizophrenia and bipolar disorder. Human Brain Mapping 29, 12651275.
Chen, CH, Suckling, J, Lennox, BR, Ooi, C, Bullmore, ET (2011). A quantitative meta-analysis of fMRI studies in bipolar disorder. Bipolar Disorder 13, 115.
Costafreda, SG, Fu, CH, Picchioni, M, Toulopoulou, T, McDonald, C, Kravariti, E, Walshe, M, Prata, D, Murray, RM, McGuire, PK (2011). Pattern of neural responses to verbal fluency shows diagnostic specificity for schizophrenia and bipolar disorder. BMC Psychiatry 11, 18.
Craddock, N, Sklar, P (2013). Genetics of bipolar disorder. Lancet 381, 16541662.
Cremaschi, L, Penzo, B, Palazzo, M, Dobrea, C, Cristoffanini, M, Dell'Osso, B, Altamura, AC (2013). Assessing working memory via N-back task in euthymic bipolar I disorder patients: a review of functional magnetic resonance imaging studies. Neuropsychobiology 68, 6370.
Del Ser, T, Gonzalez-Montalvo, JI, Martinez-Espinosa, S, Delgado-Villapalos, C, Bermejo, F (1997). Estimation of premorbid intelligence in Spanish people with the Word Accentuation Test and its application to the diagnosis of dementia. Brain and Cognition 33, 343356.
Drapier, D, Surguladze, S, Marshall, N, Schulze, K, Fern, A, Hall, MH, Walshe, M, Murray, RM, McDonald, C (2008). Genetic liability for bipolar disorder is characterized by excess frontal activation in response to a working memory task. Biological Psychiatry 64, 513520.
Fernandez-Corcuera, P, Salvador, R, Monte, GC, Salvador Sarro, S, Goikolea, JM, Amann, B, Moro, N, Sans-Sansa, B, Ortiz-Gil, J, Vieta, E, Maristany, T, McKenna, PJ, Pomarol-Clotet, E (2013). Bipolar depressed patients show both failure to activate and failure to de-activate during performance of a working memory task. Journal of Affective Disorders 148, 170178.
Frodl, T, Scheuerecker, J, Albrecht, J, Kleemann, AM, Muller-Schunk, S, Koutsouleris, N, Moller, HJ, Bruckmann, H, Wiesmann, M, Meisenzahl, E (2009). Neuronal correlates of emotional processing in patients with major depression. World Journal of Biological Psychiatry 10, 202208.
Gevins, A, Cutillo, B (1993). Spatiotemporal dynamics of component processes in human working memory. Electroencephalography and Clinical Neurophysiology 87, 128143.
Gomar, JJ, Ortiz-Gil, J, McKenna, PJ, Salvador, R, Sans-Sansa, B, Sarro, S, Guerrero, A, Pomarol-Clotet, E (2011). Validation of the Word Accentuation Test (TAP) as a means of estimating premorbid IQ in Spanish speakers. Schizophrenia Research 128, 175176.
Green, DM, Swets, JA (1966). Signal Detection Theory and Psychophysics. Krieger: New York.
Grimm, S, Boesiger, P, Beck, J, Schuepbach, D, Bermpohl, F, Walter, M, Ernst, J, Hell, D, Boeker, H, Northoff, G (2009). Altered negative BOLD responses in the default-mode network during emotion processing in depressed subjects. Neuropsychopharmacology 34, 932943.
Gusnard, DA, Raichle, ME (2001). Searching for a baseline: functional imaging and the resting human brain. Nature Reviews Neuroscience 2, 685694.
Hafeman, DM, Chang, KD, Garrett, AS, Sanders, EM, Phillips, ML (2012). Effects of medication on neuroimaging findings in bipolar disorder: an updated review. Bipolar Disorder 14, 375410.
Hamilton, M (1960). A rating scale for depression. Journal of Neurology, Neurosurgery and Psychiatry 23, 5662.
Jastak, S, Wilkinson, GS (1984). The Wide Range Achievement Test–Revised Administration Manual. Jastak Associates: Wilmington, DE.
Kanske, P, Heissler, J, Schonfelder, S, Forneck, J, Wessa, M (2013). Neural correlates of emotional distractibility in bipolar disorder patients, unaffected relatives, and individuals with hypomanic personality. American Journal of Psychiatry 170, 14871496.
Kupferschmidt, DA, Zakzanis, KK (2011). Toward a functional neuroanatomical signature of bipolar disorder: quantitative evidence from the neuroimaging literature. Psychiatry Research 193, 7179.
Linke, J, King, AV, Rietschel, M, Strohmaier, J, Hennerici, M, Gass, A, Meyer-Lindenberg, A, Wessa, M (2012). Increased medial orbitofrontal and amygdala activation: evidence for a systems-level endophenotype of bipolar I disorder. American Journal of Psychiatry 169, 316325.
McGuffin, P, Rijsdijk, F, Andrew, M, Sham, P, Katz, R, Cardno, A (2003). The heritability of bipolar affective disorder and the genetic relationship to unipolar depression. Archives of General Psychiatry 60, 497502.
Nelson, HE, Willison, JR (1991). The Revised National Adult Reading Test. NFER-Nelson: Windsor.
Poldrack, RA (2007). Region of interest analysis for fMRI. Social Cognitive and Affective Neuroscience 2, 6770.
Pomarol-Clotet, E, Alonso-Lana, S, Moro, N, Sarro, S, Bonnin, MC, Goikolea, JM, Fernandez-Corcuera, P, Amann, BL, Romaguera, A, Vieta, E, Blanch, J, McKenna, PJ, Salvador, R (2015). Brain functional changes across the different phases of bipolar disorder. British Journal of Psychiatry 206, 136144.
Pomarol-Clotet, E, Salvador, R, Sarro, S, Gomar, J, Vila, F, Martinez, A, Guerrero, A, Ortiz-Gil, J, Sans-Sansa, B, Capdevila, A, Cebamanos, JM, McKenna, PJ (2008). Failure to deactivate in the prefrontal cortex in schizophrenia: dysfunction of the default mode network? Psychological Medicine 38, 11851193.
Pompei, F, Jogia, J, Tatarelli, R, Girardi, P, Rubia, K, Kumari, V, Frangou, S (2011). Familial and disease specific abnormalities in the neural correlates of the Stroop Task in bipolar disorder. NeuroImage 56, 16771684.
Price, JL, Drevets, WC (2012). Neural circuits underlying the pathophysiology of mood disorders. Trends in Cognitive Sciences 16, 6171.
Raichle, ME, MacLeod, AM, Snyder, AZ, Powers, WJ, Gusnard, DA, Shulman, GL (2001). A default mode of brain function. Proceedings of the National Academy of Sciences of the USA 98, 676682.
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.
Robins, LN, Cottler, LB, Bucholz, KK, Compton, WM, North, CS, Rourke, K (2000). Computerized Diagnostic Interview Schedule for the DSM-IV (C DIS-IV). NIMH/University of Florida: Gainesville, FL.
Savitz, J, Drevets, WC (2009). Bipolar and major depressive disorder: neuroimaging the developmental-degenerative divide. Neuroscience and Biobehavioral Reviews 33, 699771.
Sepede, G, De Berardis, D, Campanella, D, Perrucci, MG, Ferretti, A, Serroni, N, Moschetta, FS, Del Gratta, C, Salerno, RM, Ferro, FM, Di Giannantonio, M, Onofrj, M, Romani, GL, Gambi, F (2012). Impaired sustained attention in euthymic bipolar disorder patients and non-affected relatives: an fMRI study. Bipolar Disorder 14, 764779.
Sheline, YI, Barch, DM, Price, JL, Rundle, MM, Vaishnavi, SN, Snyder, AZ, Mintun, MA, Wang, S, Coalson, RS, Raichle, ME (2009). The default mode network and self-referential processes in depression. Proceedings of the National Academy of Sciences of the USA 106, 19421947.
Smith, SM, Jenkinson, M, Woolrich, MW, Beckmann, CF, Behrens, TE, Johansen-Berg, H, Bannister, PR, De Luca, M, Drobnjak, I, Flitney, DE, Niazy, RK, Saunders, J, Vickers, J, Zhang, Y, De Stefano, N, Brady, JM, Matthews, PM (2004). Advances in functional and structural MR image analysis and implementation as FSL. NeuroImage 23 (Suppl. 1), S208S219.
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 Disorder 14, 313325.
Strakowski, SM, Delbello, MP, Adler, CM (2005). The functional neuroanatomy of bipolar disorder: a review of neuroimaging findings. Molecular Psychiatry 10, 105116.
Surguladze, SA, Marshall, N, Schulze, K, Hall, MH, Walshe, M, Bramon, E, Phillips, ML, Murray, RM, McDonald, C (2010). Exaggerated neural response to emotional faces in patients with bipolar disorder and their first-degree relatives. NeuroImage 53, 5864.
Thermenos, HW, Goldstein, JM, Milanovic, SM, Whitfield-Gabrieli, S, Makris, N, Laviolette, P, Koch, JK, Faraone, SV, Tsuang, MT, Buka, SL, Seidman, LJ (2010). An fMRI study of working memory in persons with bipolar disorder or at genetic risk for bipolar disorder. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 153B, 120131.
Townsend, J, Bookheimer, SY, Foland-Ross, LC, Sugar, CA, Altshuler, LL (2010). fMRI abnormalities in dorsolateral prefrontal cortex during a working memory task in manic, euthymic and depressed bipolar subjects. Psychiatry Research 182, 2229.
Whalley, HC, Sussmann, JE, Chakirova, G, Mukerjee, P, Peel, A, McKirdy, J, Hall, J, Johnstone, EC, Lawrie, SM, McIntosh, AM (2011). The neural basis of familial risk and temperamental variation in individuals at high risk of bipolar disorder. Biological Psychiatry 70, 343349.
Whitfield-Gabrieli, S, Moran, JM, Nieto-Castanon, A, Triantafyllou, C, Saxe, R, Gabrieli, JD (2011). Associations and dissociations between default and self-reference networks in the human brain. NeuroImage 55, 225232.
Young, RC, Biggs, JT, Ziegler, VE, Meyer, DA (1978). A rating scale for mania: reliability, validity and sensitivity. British Journal of Psychiatry 133, 429435.


Brain functional changes in first-degree relatives of patients with bipolar disorder: evidence for default mode network dysfunction

  • S. Alonso-Lana (a1) (a2) (a3), M. Valentí (a4), A. Romaguera (a1), C. Sarri (a5), S. Sarró (a1) (a2), A. Rodríguez-Martínez (a6), J. M. Goikolea (a4), B. L. Amann (a1) (a2), T. Maristany (a7), R. Salvador (a1) (a2), E. Vieta (a2) (a4), P. J. McKenna (a1) (a2) and E. Pomarol-Clotet (a1) (a2)...


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed