Boosting the ToM network: Specific psychotherapy increases neural correlates of affective theory of mind in euthymic bipolar disorder

Published:September 07, 2022DOI:



      In BD, impaired affective theory of mind (aToM) performance and aberrant neural activation in the ToM brain network partly explain social functioning impairments. However, it is not yet known whether psychotherapy of BD influences neuroimaging markers of aToM.


      In the present study conducted within the multicentric randomized controlled trial of the BipoLife consortium, euthymic BD patients underwent two group interventions over 6 months (M = 28.45 weeks): a specific, cognitive-behavioral intervention (SEKT, n = 31) targeting impulse regulation, ToM, and social skills versus an emotion-focused intervention (FEST, n = 28). To compare the effect of SEKT and FEST on neural correlates of aToM, patients performed an aToM task during functional magnetic resonance imaging before and after interventions (final fMRI sample of pre- and post-completers, SEKT: n = 16; FEST: n = 17). Healthy controls (n = 32) were scanned twice with the same time interval. Since ToM was trained in SEKT, we expected an increased ToM network activation in SEKT relative to FEST post-intervention.


      Both treatments effectively stabilized patients’ euthymic state in terms of affective symptoms, life satisfaction, and global functioning. Confirming our expectations, SEKT patients showed increased neural activation within regions of the ToM network, the bilateral temporoparietal junction (TPJ), the posterior cingulate cortex (PCC), and the precuneus, whereas FEST patients did not.


      The stabilizing effect of SEKT on clinical outcomes went along with increased neural activation of the ToM network, while FEST possibly exerted its positive effect by other, yet unexplored routes.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


        • Sanchez-Moreno J.
        • Martinez-Aran A.
        • Tabarés-Seisdedos R.
        • Torrent C.
        • Vieta E.
        • Ayuso-Mateos J.
        Functioning and disability in bipolar disorder: an extensive review.
        Psychotherapy and psychosomatics. 2009; 78: 285-297
        • Elgie R.
        • Morselli P.L.
        Social functioning in bipolar patients: the perception and perspective of patients, relatives and advocacy organizations ? a review.
        Bipolar Disorders. 2007; 9: 144-157
        • Vlad M.
        • Raucher-Chéné D.
        • Henry A.
        • Kaladjian A.
        Functional outcome and social cognition in bipolar disorder: Is there a connection?.
        European Psychiatry. 2018; 52: 116-125
        • Popolo R.
        • Borsella I.
        • Meschini L.
        • Pianella U.
        • Zampaglione G.
        • Vinci G.
        • et al.
        Cognitive theory of mind in bipolar disorder: Comparisons with healthy controls and associations with function.
        Psychiatry Research. 2020; 290113030
        • Happé F.
        • Cook J.L.
        • Bird G.
        The Structure of Social Cognition: In(ter)dependence of Sociocognitive Processes.
        Annu Rev Psychol. 2017; 68: 243-267
        • Singer T.
        The neuronal basis and ontogeny of empathy and mind reading: review of literature and implications for future research.
        Neuroscience & Biobehavioral Reviews. 2006; 30: 855-863
        • Walter H.
        Social Cognitive Neuroscience of Empathy: Concepts, Circuits, and Genes.
        Emotion Review. 2012; 4: 9-17
        • Schurz M.
        • Radua J.
        • Tholen M.G.
        • Maliske L.
        • Margulies D.S.
        • Mars R.B.
        • et al.
        Toward a hierarchical model of social cognition: A neuroimaging meta-analysis and integrative review of empathy and theory of mind.
        Psychol Bull. 2021; 147: 293-327
        • Malhi G.S.
        • Lagopoulos J.
        • Das P.
        • Moss K.
        • Berk M.
        • Coulston C.M.
        A functional MRI study of Theory of Mind in euthymic bipolar disorder patients.
        Bipolar disorders. 2008; 10: 943-956
        • Kim E.
        • Jung Y.-C.
        • Ku J.
        • Kim J.-J.
        • Lee H.
        • Kim S.Y.
        • et al.
        Reduced activation in the mirror neuron system during a virtual social cognition task in euthymic bipolar disorder.
        Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2009; 33: 1409-1416
        • Willert A.
        • Mohnke S.
        • Erk S.
        • Schnell K.
        • Romanczuk-Seiferth N.
        • Quinlivan E.
        • et al.
        Alterations in neural Theory of Mind processing in euthymic patients with bipolar disorder and unaffected relatives.
        Bipolar Disord. 2015; 17: 880-891
        • Van Overwalle F.
        • Baetens K.
        Understanding others' actions and goals by mirror and mentalizing systems: a meta-analysis.
        Neuroimage. 2009; 48: 564-584
        • Bora E.
        • Bartholomeusz C.
        • Pantelis C.
        Meta-analysis of Theory of Mind (ToM) impairment in bipolar disorder.
        Psychol Med. 2016; 46: 253-264
        • Feyerabend J.
        • Luttke S.
        • Grosse-Wentrup F.
        • Wolter S.
        • Hautzinger M.
        • Wolkenstein L.
        Theory of mind in remitted bipolar disorder: Younger patients struggle in tasks of higher ecological validity.
        J Affect Disord. 2018; 231: 32-40
      1. Budak E (2011): Theory of mind and its relationship with clinical features and social functioning in remitted bipolar patients: Thesis. Istanbul. Bakırkoy Research and Training Hospital.

        • Espinós U.
        • Fernández-Abascal E.G.
        • Ovejero M.
        Theory of mind in remitted bipolar disorder: Interpersonal accuracy in recognition of dynamic nonverbal signals.
        Plos one. 2019; 14e0222112
        • Inder M.L.
        • Crowe M.T.
        • Luty S.E.
        • Carter J.D.
        • Moor S.
        • Frampton C.M.
        • et al.
        Randomized, controlled trial of Interpersonal and Social Rhythm Therapy for young people with bipolar disorder.
        Bipolar disorders. 2015; 17: 128-138
        • Ott C.V.
        • Macoveanu J.
        • Bowie C.R.
        • Fisher P.M.
        • Knudsen G.M.
        • Kessing L.V.
        • et al.
        Change in prefrontal activity and executive functions after action-based cognitive remediation in bipolar disorder: a randomized controlled trial.
        Neuropsychopharmacology. 2020; : 1-9
        • Linden D.E.J.
        How psychotherapy changes the brain–the contribution of functional neuroimaging.
        Molecular psychiatry. 2006; 11: 528-538
        • Mwangi B.
        • Wu M.-J.
        • Cao B.
        • Passos I.C.
        • Lavagnino L.
        • Keser Z.
        • et al.
        Individualized prediction and clinical staging of bipolar disorders using neuroanatomical biomarkers.
        Biological psychiatry: cognitive neuroscience and neuroimaging. 2016; 1: 186-194
        • Njau S.
        • Townsend J.
        • Wade B.
        • Hellemann G.
        • Bookheimer S.
        • Narr K.
        • et al.
        Neural Subtypes of Euthymic Bipolar I Disorder Characterized by Emotion Regulation Circuitry.
        Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. 2020; 5: 591-600
        • Ritter P.S.
        • Bermpohl F.
        • Gruber O.
        • Hautzinger M.
        • Jansen A.
        • Juckel G.
        • et al.
        Aims and structure of the German Research Consortium BipoLife for the study of bipolar disorder.
        International journal of bipolar disorders. 2016; 4: 1-9
        • Stamm T.J.
        • Zwick J.C.
        • O’Malley G.
        • Sondergeld L.-M.
        • Hautzinger M.
        Adjuvant psychotherapy in early-stage bipolar disorder: study protocol for a randomized controlled trial.
        Trials. 2020; 21: 1-11
        • Schnell K.
        • Bluschke S.
        • Konradt B.
        • Walter H.
        Functional relations of empathy and mentalizing: an fMRI study on the neural basis of cognitive empathy.
        Neuroimage. 2011; 54: 1743-1754
        • Walter H.
        • Schnell K.
        • Erk S.
        • Arnold C.
        • Kirsch P.
        • Esslinger C.
        • et al.
        Effects of a genome-wide supported psychosis risk variant on neural activation during a theory-of-mind task.
        Mol Psychiatry. 2011; 16: 462-470
        • Mitchell R.L.
        • Phillips L.H.
        The overlapping relationship between emotion perception and theory of mind.
        Neuropsychologia. 2015; 70: 1-10
        • Samamé C.
        Social cognition throughout the three phases of bipolar disorder: a state-of-the-art overview.
        Psychiatry research. 2013; 210: 1275-1286
        • Luperdi S.C.
        • Correa-Ghisays P.
        • Vila-Francés J.
        • Selva-Vera G.
        • Salazar-Fraile J.
        • Cardoner N.
        • et al.
        Is processing speed a valid neurocognitive endophenotype in bipolar disorder? Evidence from a longitudinal, family study.
        Journal of Psychiatric Research. 2021; 141: 241-247
        • Rogers C.R.
        Client-centered therapy.
        Curr Psychother. 2013; : 95-150
        • Frank E.
        • Kupfer D.J.
        • Thase M.E.
        • Mallinger A.G.
        • Swartz H.A.
        • Fagiolini A.M.
        • et al.
        Two-year outcomes for interpersonal and social rhythm therapy in individuals with bipolar I disorder.
        Archives of general psychiatry. 2005; 62: 996-1004
        • Haffner P.
        • Quinlivan E.
        • Fiebig J.
        • Sondergeld L.M.
        • Strasser E.S.
        • Adli M.
        • et al.
        Improving functional outcome in bipolar disorder: a pilot study on metacognitive training.
        Clinical psychology & psychotherapy. 2018; 25: 50-58
      2. Wells A (2011): Metacognitive therapy for anxiety and depression. Guilford press.

      3. Deckersbach T, Hansen N, Holzel B (2014): Mindfulness-based cognitive therapy for bipolar disorder. Mindfulness-Based Treatment Approaches: Elsevier, pp 77-94.

      4. Shannon CE, Weaver W (1949): A mathematical model of communication. Urbana, IL: University of Illinois Press.

        • Keller M.B.
        • Lavori P.W.
        • Friedman B.
        • Nielsen E.
        • Endicott J.
        • McDonald-Scott P.
        • et al.
        The longitudinal interval follow-up evaluation: A comprehensive method for assessing outcome in prospective longitudinal studies.
        Archives of general psychiatry. 1987; 44: 540-548
        • Vogelbacher C.
        • Sommer J.
        • Schuster V.
        • Bopp M.H.
        • Falkenberg I.
        • Ritter P.S.
        • et al.
        The German research consortium for the study of bipolar disorder (BipoLife): a magnetic resonance imaging study protocol.
        International journal of bipolar disorders. 2021; 9: 1-15
        • Little R.J.
        A test of missing completely at random for multivariate data with missing values.
        Journal of the American statistical Association. 1988; 83: 1198-1202
      5. Team RC (2020): R: the R project for statistical computing. 2019. URL: https://www r-project org/[accessed 2020-03-30].

      6. Ashburner J, Barnes G, Chen C-C, Daunizeau J, Flandin G, Friston K, et al. (2014): SPM12 manual. Wellcome Trust Centre for Neuroimaging, London, UK. 2464.

        • Ashburner J.
        A fast diffeomorphic image registration algorithm.
        Neuroimage. 2007; 38: 95-113
        • Mohnke S.
        • Erk S.
        • Schnell K.
        • Romanczuk-Seiferth N.
        • Schmierer P.
        • Romund L.
        • et al.
        Theory of mind network activity is altered in subjects with familial liability for schizophrenia.
        Soc Cogn Affect Neurosci. 2016; 11: 299-307
        • Mohnke S.
        • Erk S.
        • Schnell K.
        • Schutz C.
        • Romanczuk-Seiferth N.
        • Grimm O.
        • et al.
        Further evidence for the impact of a genome-wide-supported psychosis risk variant in ZNF804A on the Theory of Mind Network.
        Neuropsychopharmacology. 2014; 39: 1196-1205
        • Schurz M.
        • Radua J.
        • Aichhorn M.
        • Richlan F.
        • Perner J.
        Fractionating theory of mind: a meta-analysis of functional brain imaging studies.
        Neurosci Biobehav Rev. 2014; 42: 9-34
        • Adenauer H.
        • Catani C.
        • Gola H.
        • Keil J.
        • Ruf M.
        • Schauer M.
        • et al.
        Narrative exposure therapy for PTSD increases top-down processing of aversive stimuli-evidence from a randomized controlled treatment trial.
        BMC neuroscience. 2011; 12: 1-13
        • Pally R.
        The predicting brain: Unconscious repetition, conscious reflection and therapeutic change.
        The International Journal of Psychoanalysis. 2007; 88: 861-881
        • Kleim B.
        • Grey N.
        • Wild J.
        • Nussbeck F.W.
        • Stott R.
        • Hackmann A.
        • et al.
        Cognitive change predicts symptom reduction with cognitive therapy for posttraumatic stress disorder.
        J Consult Clin Psychol. 2013; 81: 383-393
        • Bölte S.
        • Ciaramidaro A.
        • Schlitt S.
        • Hainz D.
        • Kliemann D.
        • Beyer A.
        • et al.
        Training-induced plasticity of the social brain in autism spectrum disorder.
        The British Journal of Psychiatry. 2015; 207: 149-157
        • Habel U.
        • Koch K.
        • Kellermann T.
        • Reske M.
        • Frommann N.
        • Wölwer W.
        • et al.
        Training of affect recognition in schizophrenia: neurobiological correlates.
        Social neuroscience. 2010; 5: 92-104
        • Rosenblau G.
        • O'Connell G.
        • Heekeren H.R.
        • Dziobek I.
        Neurobiological mechanisms of social cognition treatment in high-functioning adults with autism spectrum disorder.
        Psychological medicine. 2020; 50: 2374-2384
        • Kanske P.
        • Böckler A.
        • Trautwein F.-M.
        • Singer T.
        Dissecting the social brain: Introducing the EmpaToM to reveal distinct neural networks and brain–behavior relations for empathy and Theory of Mind.
        NeuroImage. 2015; 122: 6-19
        • Mühlbacher M.
        • Egger C.
        • Kaplan P.
        • Simhandl C.
        • Grunze H.
        • Geretsegger C.
        • et al.
        Reliability and concordance validity of a German version of the Young Mania Rating Scale (YMRS-D).
        Neuropsychiatrie: Klinik, Diagnostik, Therapie und Rehabilitation: Organ der Gesellschaft Osterreichischer Nervenarzte und Psychiater. 2011; 25: 16-25
      7. Krüger S, Bräunig P, Shugar G (1997): Manie-Selbstbeurteilungsskala: MSS; deutsche Bearbeitung des Self-Report manic inventory (SRMI). Beltz.

        • Roniger A.
        • Späth C.
        • Schweiger U.
        • Klein J.
        A psychometric evaluation of the German version of the quick inventory of depressive symptomatology (QIDS-SR16) in outpatients with depression.
        Fortschritte der Neurologie· Psychiatrie. 2015; 83: e17-e22
      8. Ackenheil M, Stotz G, Dietz-Bauer R (1999): Mini International Neuropsychiatric Interview. German Version 5.0.0, DSM-IV. München: Psychiatrische Universitätsklinik München.