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Tracing the psychopathology of bipolar disorder to the functional architecture of intrinsic brain activity and its neurotransmitter modulation: a three-dimensional model


Bipolar disorder (BD) shows complex alterations in psychomotor, affective, and thought dimensions, as described by Kraepelin in his fundamental model of manic-depressive illness. In turn, the expression of behavioral/phenomenological dimensions is traceable to intrinsic brain activity. We reported a data overview on intrinsic brain functioning and its changes in BD. Accordingly, we proposed a three-dimensional model of the relationship between brain functioning and behavioral/phenomenological patterns, along with its application to BD. In this model, intrinsic brain activity is organized in distinct units in accordance to connectivity patterns and related setting of input/output processing, underlying the different behavioral/phenomenological dimensions. An external unit (mainly involving the sensorimotor network) is connected with the external environment and sets the exteroceptive input/somatomotor output processing, underlying the psychomotor dimension. An internal unit (mainly involving the salience network) is connected to the internal/body environment and sets the interoceptive input/visceromotor output processing, underlying the affective dimension. Finally, an associative unit (mainly involving the default-mode network) is not connected with the environment and sets the processing of associative inputs/outputs, underlying the thought dimension. In each unit, neurotransmitter signaling couples the subcortical-cortical loop, which modulates the network activity levels, in turn setting input/output processing and related expression levels of the behavioral/phenomenological dimension. Different combinations in neurotransmitter signaling favor network balancing into distinct functional brain states, which manifest in different combinations of excitation or inhibition in psychomotricity, affectivity, and thought, resulting in the manic, depressive, and mixed states of BD. Our working model might provide a coherent framework for tracing the complex BD psychopathology to core functional brain alterations.

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Fig. 1: Three-dimensional model: functional units of intrinsic brain activity and behavioral/phenomenological dimensions.
Fig. 2a: Three-dimensional model: functional brain states and behavioral/phenomenological states.
Fig. 2b: Psychopathological states of bipolar disorder.


  1. 1.

    A.P.A. Diagnostic and statistical manual for mental disorders. 5th ed. (DSM-5). Washington: American Psychiatric Association; 2013.

    Google Scholar 

  2. 2.

    Kraepelin E. Clinical psychiatry. New York: Macmillan. 1902.

  3. 3.

    Kraepelin E. Manic-depressive insanity and paranoia. Reprint of the 1921 ed. Pub. by E&S, Livingstone, Edinburgh; 1921.

  4. 4.

    Swann AC, Lafer B, Perugi G, Frye MA, Bauer M, Bahk WM, et al. Bipolar mixed states: an international society for bipolar disorders task force report of symptom structure, course of illness, and diagnosis. Am J Psychiatry. 2013;170:31–42.

    PubMed  Article  Google Scholar 

  5. 5.

    Biswal B, Yetkin FZ, Haughton VM, Hyde JS. Functional connectivity in the motor cortex of resting human brain using echo-planar MRI. Magn Reson Med. 1995;34:537–41.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Raichle ME, MacLeod AM, Snyder AZ, Powers WJ, Gusnard DA, Shulman GL. A default mode of brain function. Proc Natl Acad Sci USA. 2001;98:676–82.

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Fox MD, Raichle ME. Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging. Nat Rev Neurosci. 2007;8:700–11.

    CAS  Article  Google Scholar 

  8. 8.

    Yeo BT, Krienen FM, Sepulcre J, Sabuncu MR, Lashkari D, Hollinshead M, et al. The organization of the human cerebral cortex estimated by intrinsic functional connectivity. J Neurophysiol. 2011;106:1125–65.

    Article  PubMed  Google Scholar 

  9. 9.

    Yuan R, Di X, Taylor PA, Gohel S, Tsai YH, Biswal BB. Functional topography of the thalamocortical system in human. Brain Struct Funct. 2016;221:1971–84.

    PubMed  Article  Google Scholar 

  10. 10.

    Choi EY, Yeo BT, Buckner RL. The organization of the human striatum estimated by intrinsic functional connectivity. J Neurophysiol. 2012;108:2242–63.

    PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Conio B, Martino M, Magioncalda P, Escelsior A, Inglese M, Amore M, et al. Opposite effects of dopamine and serotonin on resting-state networks: review and implications for psychiatric disorders. Mol Psychiatry. 2020;25:82–93.

    PubMed  Article  Google Scholar 

  12. 12.

    Rocchi G, Sterlini B, Tardito S, Inglese M, Corradi A, Filaci G, et al. Opioidergic system and functional architecture of intrinsic brain activity: implications for psychiatric disorders. Neuroscientist. 2020;26:343–58.

    PubMed  Article  Google Scholar 

  13. 13.

    Buckner RL, Andrews-Hanna JR, Schacter DL. The brain’s default network: anatomy, function, and relevance to disease. Ann NY Acad Sci. 2008;1124:1–38.

    PubMed  Article  Google Scholar 

  14. 14.

    Bressler SL, Menon V. Large-scale brain networks in cognition: emerging methods and principles. Trends Cogn Sci. 2010;14:277–90.

    PubMed  Article  Google Scholar 

  15. 15.

    Menon V. Large-scale brain networks and psychopathology: a unifying triple network model. Trends Cogn Sci. 2011;15:483–506.

    Article  PubMed  Google Scholar 

  16. 16.

    Ongur D, Lundy M, Greenhouse I, Shinn AK, Menon V, Cohen BM, et al. Default mode network abnormalities in bipolar disorder and schizophrenia. Psychiatry Res. 2010;183:59–68.

    PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Martino M, Magioncalda P, Huang Z, Conio B, Piaggio N, Duncan NW, et al. Contrasting variability patterns in the default mode and sensorimotor networks balance in bipolar depression and mania. Proc Natl Acad Sci USA. 2016;113:4824–9.

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Anticevic A, Cole MW, Repovs G, Murray JD, Brumbaugh MS, Winkler AM, et al. Characterizing thalamo-cortical disturbances in schizophrenia and bipolar illness. Cereb Cortex. 2014;24:3116–30.

    PubMed  Article  Google Scholar 

  19. 19.

    Martino M, Magioncalda P, Conio B, Capobianco L, Russo D, Adavastro G, et al. Abnormal functional relationship of sensorimotor network with neurotransmitter-related nuclei via subcortical-cortical loops in manic and depressive phases of bipolar disorder. Schizophr Bull. 2020;46:163–74.

    PubMed  Article  Google Scholar 

  20. 20.

    Nikolaus S, Antke C, Muller HW. In vivo imaging of synaptic function in the central nervous system: II. Mental and affective disorders. Behav Brain Res. 2009;204:32–66.

    PubMed  Article  Google Scholar 

  21. 21.

    Northoff G, Hirjak D, Wolf RC, Magioncalda P, Martino M. All roads lead to the motor cortex: psychomotor mechanisms and their biochemical modulation in psychiatric disorders. Mol Psychiatry. 2020; [Online ahead of print].

  22. 22.

    Buzsaki G. Rhythms of the brain. New York: Oxford University Press; 2006.

    Book  Google Scholar 

  23. 23.

    Buzsaki G, Draguhn A. Neuronal oscillations in cortical networks. Science. 2004;304:1926–9.

    CAS  Article  Google Scholar 

  24. 24.

    Amaral D. The functional organization of perception and movement. In: Kandel E, Schwartz J, Jessell T, Siegelbaum S, Hudspeth A. Principles of Neural Science - 5th ed. New York: Mc Graw Hill; 2013.

  25. 25.

    Raichle ME. The brain’s default mode network. Annu Rev Neurosci. 2015;38:433–47.

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Wang P, Kong R, Kong X, Liegeois R, Orban C, Deco G, et al. Inversion of a large-scale circuit model reveals a cortical hierarchy in the dynamic resting human brain. Sci Adv. 2019;5:eaat7854.

    PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Seeley WW, Menon V, Schatzberg AF, Keller J, Glover GH, Kenna H, et al. Dissociable intrinsic connectivity networks for salience processing and executive control. J Neurosci. 2007;27:2349–56.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Craig AD. How do you feel? Interoception: the sense of the physiological condition of the body. Nat Rev Neurosci. 2002;3:655–66.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Damasio A. Self comes to mind: constructing the conscious brain. New York: Pantheon; 2010.

  30. 30.

    Drevets WC, Savitz J, Trimble M. The subgenual anterior cingulate cortex in mood disorders. CNS Spectr. 2008;13:663–81.

    PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Ongur D, Ferry AT, Price JL. Architectonic subdivision of the human orbital and medial prefrontal cortex. J Comp Neurol. 2003;460:425–49.

    PubMed  Article  Google Scholar 

  32. 32.

    Ranganath C, Heller A, Cohen MX, Brozinsky CJ, Rissman J. Functional connectivity with the hippocampus during successful memory formation. Hippocampus. 2005;15:997–1005.

    PubMed  Article  Google Scholar 

  33. 33.

    Kandel ER, Kupfermann I, Iversen S. Learning and memory. In: Kandel E, Schwartz J, Jessell T, Siegelbaum S, Hudspeth A. Principles of neural science - 5th ed. New York: Mc Graw Hill; 2013.

  34. 34.

    Engel AK, Fries P, Singer W. Dynamic predictions: oscillations and synchrony in top-down processing. Nat Rev Neurosci. 2001;2:704–16.

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Garrett DD, Samanez-Larkin GR, MacDonald SW, Lindenberger U, McIntosh AR, Grady CL. Moment-to-moment brain signal variability: a next frontier in human brain mapping? Neurosci Biobehav Rev. 2013;37:610–24.

    PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Margulies DS, Ghosh SS, Goulas A, Falkiewicz M, Huntenburg JM, Langs G, et al. Situating the default-mode network along a principal gradient of macroscale cortical organization. Proc Natl Acad Sci USA. 2016;113:12574–9.

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Huang S, Li Y, Zhang W, Zhang B, Liu X, Mo L, et al. Multisensory competition is modulated by sensory pathway interactions with fronto-sensorimotor and default-mode network regions. J Neurosci: Off J Soc Neurosci. 2015;35:9064–77.

    CAS  Article  Google Scholar 

  38. 38.

    Fox MD, Snyder AZ, Vincent JL, Corbetta M, Van Essen DC, Raichle ME. The human brain is intrinsically organized into dynamic, anticorrelated functional networks. Proc Natl Acad Sci USA. 2005;102:9673–8.

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Zuo XN, Di Martino A, Kelly C, Shehzad ZE, Gee DG, Klein DF, et al. The oscillating brain: complex and reliable. Neuroimage. 2010;49:1432–45.

    PubMed  Article  PubMed Central  Google Scholar 

  40. 40.

    Aru J, Priesemann V, Wibral M, Lana L, Pipa G, Singer W, et al. Untangling cross-frequency coupling in neuroscience. Curr Opin Neurobiol. 2015;31:51–61.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Schmitt LI, Wimmer RD, Nakajima M, Happ M, Mofakham S, Halassa MM. Thalamic amplification of cortical connectivity sustains attentional control. Nature. 2017;545:219–23.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42.

    Wichmann T, DeLong M. Basal Ganglia. In: Kandel E, Schwartz J, Jessell T, Siegelbaum S, Hudspeth A. Principles of neural science - 5h ed. New York: Mc Graw Hill; 2013.

  43. 43.

    Vargas C, Lopez-Jaramillo C, Vieta E. A systematic literature review of resting state network-functional MRI in bipolar disorder. J Affect Disord. 2013;150:727–35.

    PubMed  Article  Google Scholar 

  44. 44.

    Anand A, Li Y, Wang Y, Lowe MJ, Dzemidzic M. Resting state corticolimbic connectivity abnormalities in unmedicated bipolar disorder and unipolar depression. Psychiatry Res. 2009;171:189–98.

    PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Russo D, Martino M, Magioncalda P, Inglese M, Amore M, Northoff G. Opposing changes in the functional architecture of large-scale networks in bipolar mania and depression. Schizophr Bull. 2020;46:971–80.

    PubMed  Article  Google Scholar 

  46. 46.

    Magioncalda P, Martino M, Conio B, Escelsior A, Piaggio N, Presta A, et al. Functional connectivity and neuronal variability of resting state activity in bipolar disorder-reduction and decoupling in anterior cortical midline structures. Hum Brain Mapp. 2015;36:666–82.

    PubMed  Article  Google Scholar 

  47. 47.

    Zhang J, Magioncalda P, Huang Z, Tan Z, Hu X, Hu Z, et al. Altered global signal topography and its different regional localization in motor cortex and hippocampus in mania and depression. Schizophr Bull. 2019;45:902–10.

    PubMed  Article  Google Scholar 

  48. 48.

    Martino M, Magioncalda P, Saiote C, Conio B, Escelsior A, Rocchi G, et al. Abnormal functional-structural cingulum connectivity in mania: combined functional magnetic resonance imaging-diffusion tensor imaging investigation in different phases of bipolar disorder. Acta Psychiatr Scand. 2016;134:339–49.

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Brady RO Jr, Tandon N, Masters GA, Margolis A, Cohen BM, Keshavan M, et al. Differential brain network activity across mood states in bipolar disorder. J Affect Disord. 2017;207:367–76.

    PubMed  Article  Google Scholar 

  50. 50.

    Lee I, Nielsen K, Nawaz U, Hall MH, Ongur D, Keshavan M, et al. Diverse pathophysiological processes converge on network disruption in mania. J Affect Disord. 2019;244:115–23.

    PubMed  Article  Google Scholar 

  51. 51.

    Liu CH, Ma X, Li F, Wang YJ, Tie CL, Li SF, et al. Regional homogeneity within the default mode network in bipolar depression: a resting-state functional magnetic resonance imaging study. PloS One. 2012;7:e48181.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52.

    Liu CH, Li F, Li SF, Wang YJ, Tie CL, Wu HY, et al. Abnormal baseline brain activity in bipolar depression: a resting state functional magnetic resonance imaging study. Psychiatry Res. 2012;203:175–9.

    PubMed  Article  Google Scholar 

  53. 53.

    Altinay MI, Hulvershorn LA, Karne H, Beall EB, Anand A. Differential resting-state functional connectivity of striatal subregions in bipolar depression and hypomania. Brain Connect. 2016;6:255–65.

    PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Brady RO Jr, Masters GA, Mathew IT, Margolis A, Cohen BM, Ongur D, et al. State dependent cortico-amygdala circuit dysfunction in bipolar disorder. J Affect Disord. 2016;201:79–87.

    PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Brady RO Jr, Margolis A, Masters GA, Keshavan M, Ongur D. Bipolar mood state reflected in cortico-amygdala resting state connectivity: a cohort and longitudinal study. J Affect Disord. 2017;217:205–9.

    PubMed  PubMed Central  Article  Google Scholar 

  56. 56.

    Syan SK, Smith M, Frey BN, Remtulla R, Kapczinski F, Hall GBC, et al. Resting-state functional connectivity in individuals with bipolar disorder during clinical remission: a systematic review. J Psychiatry Neurosci. 2018;43:298–316.

    PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Shiah IS, Yatham LN. Serotonin in mania and in the mechanism of action of mood stabilizers: a review of clinical studies. Bipolar Disord. 2000;2:77–92.

    CAS  PubMed  Article  Google Scholar 

  58. 58.

    Mosienko V, Beis D, Pasqualetti M, Waider J, Matthes S, Qadri F, et al. Life without brain serotonin: reevaluation of serotonin function with mice deficient in brain serotonin synthesis. Behav Brain Res. 2015;277:78–88.

    CAS  PubMed  Article  Google Scholar 

  59. 59.

    Dalley JW, Roiser JP. Dopamine, serotonin and impulsivity. Neuroscience. 2012;215:42–58.

    CAS  PubMed  Article  Google Scholar 

  60. 60.

    Winter C, von Rumohr A, Mundt A, Petrus D, Klein J, Lee T, et al. Lesions of dopaminergic neurons in the substantia nigra pars compacta and in the ventral tegmental area enhance depressive-like behavior in rats. Behav Brain Res. 2007;184:133–41.

    CAS  PubMed  Article  Google Scholar 

  61. 61.

    van Enkhuizen J, Geyer MA, Minassian A, Perry W, Henry BL, Young JW. Investigating the underlying mechanisms of aberrant behaviors in bipolar disorder from patients to models: rodent and human studies. Neurosci Biobehav Rev. 2015;58:4–18.

    PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    Cosgrove VE, Kelsoe JR, Suppes T. Toward a valid animal model of bipolar disorder: how the research domain criteria help bridge the clinical-basic science divide. Biol Psychiatry. 2016;79:62–70.

    PubMed  Article  Google Scholar 

  63. 63.

    Jaspers K. General psychopathology. Heidelberg, New York: Springer Publisher. 1963.

    Google Scholar 

  64. 64.

    Zuo XN, Xu T, Milham MP. Harnessing reliability for neuroscience research. Nat Hum Behav. 2019;3:768–71.

    PubMed  Article  Google Scholar 

  65. 65.

    Dong HM, Castellanos FX, Yang N, Zhang Z, Zhou Q, He Y, et al. Charting brain growth in tandem with brain templates at school age. Sci Bull. 2020;65:1924–34.

    Article  Google Scholar 

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Correspondence to Matteo Martino or Paola Magioncalda.

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Martino, M., Magioncalda, P. Tracing the psychopathology of bipolar disorder to the functional architecture of intrinsic brain activity and its neurotransmitter modulation: a three-dimensional model. Mol Psychiatry (2021).

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