Altered Neurobiological Processing of Unintentional Social Norm Violations: A Multiplex, Multigenerational Functional Magnetic Resonance Imaging Study on Social Anxiety Endophenotypes

Published:March 15, 2019DOI:



      Patients with social anxiety disorder (SAD) fear negative evaluation in social situations. Specifically, previous work indicated that social anxiety is associated with increased medial prefrontal cortex activation in response to unintentional social norm (SN) transgressions, accompanied by increased embarrassment ratings for such SN violations. Here, we used data from the multiplex, multigenerational LFLSAD (Leiden Family Lab study on Social Anxiety Disorder), which involved two generations of families genetically enriched for SAD, and investigated whether these neurobiological and behavioral correlates of unintentional SN processing are SAD endophenotypes. Of four endophenotype criteria, we examined two: first, the cosegregation of these characteristics with social anxiety (SA) within families of SAD probands (criterion 4), and second, the heritability of the candidate endophenotypes (criterion 3).


      Participants (n = 110, age range 9.0–61.5 years, eight families) performed the revised Social Norm Processing Task; functional magnetic resonance imaging data and behavioral ratings related to this paradigm were used to examine whether brain activation in response to processing unintentional SN violations and ratings of embarrassment were associated with SA levels. Next, heritability of these measurements was estimated.


      As expected, voxelwise functional magnetic resonance imaging analyses revealed positive associations between SA levels and brain activation in the medial prefrontal cortex and medial temporal gyrus, superior temporal gyrus, and superior temporal sulcus, and these brain activation levels displayed moderate to moderately high heritability. Furthermore, although SA levels correlated positively with behavioral ratings of embarrassment for SN transgressions, these behavioral characteristics were not heritable.


      These results show, for the first time, that brain responses in the medial prefrontal cortex and medial temporal gyrus, superior temporal gyrus, and superior temporal sulcus, related to processing unintentional SN violations, provide a neurobiological candidate endophenotype of SAD.


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        • Kessler R.C.
        • Petukhova M.
        • Sampson N.A.
        • Zaslavsky A.M.
        • Wittchen H.-U.
        Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States.
        Int J Methods Psychiatr Res. 2012; 21: 169-184
        • Blanco C.
        • Xu Y.
        • Schneier F.R.
        • Okuda M.
        • Liu S.-M.
        • Heimberg R.G.
        Predictors of persistence of social anxiety disorder: A national study.
        J Psychiatr Res. 2011; 45: 1557-1563
        • Beesdo-Baum K.
        • Knappe S.
        • Asselmann E.
        • Zimmermann P.
        • Brückl T.
        • Höfler M.
        • et al.
        The “Early Developmental Stages of Psychopathology (EDSP) study”: A 20-year review of methods and findings.
        Soc Psychiatry Psychiatr Epidemiol. 2015; 50: 851-866
        • Haller S.P.W.
        • Cohen Kadosh K.
        • Scerif G.
        • Lau J.Y.F.
        Social anxiety disorder in adolescence: How developmental cognitive neuroscience findings may shape understanding and interventions for psychopathology.
        Dev Cogn Neurosci. 2015; 13: 11-20
        • Stein D.J.
        • Lim C.C.W.
        • Roest A.M.
        • de Jonge P.
        • Aguilar-Gaxiola S.
        • Al-Hamzawi A.
        • et al.
        The cross-national epidemiology of social anxiety disorder: Data from the World Mental Health Survey Initiative.
        BMC Med. 2017; 15: 143
        • Merikangas K.R.
        • He J.-P.
        • Burstein M.
        • Swanson S.A.
        • Avenevoli S.
        • Cui L.
        • et al.
        Lifetime prevalence of mental disorders in U.S. adolescents: Results from the National Comorbidity Survey Replication--Adolescent Supplement (NCS-A).
        J Am Acad Child Adolesc Psychiatry. 2010; 49: 980-989
        • Weisberg R.B.
        • Beard C.
        • Moitra E.
        • Dyck I.
        • Keller M.B.
        Adequacy of treatment received by primary care patients with anxiety disorders.
        Depress Anxiety. 2014; 31: 443-450
        • Wittchen H.U.
        • Fuetsch M.
        • Sonntag H.
        • Müller N.
        • Liebowitz M.
        Disability and quality of life in pure and comorbid social phobia: Findings from a controlled study.
        Eur Psychiatry. 2000; 15: 46-58
        • McKnight P.E.
        • Monfort S.S.
        • Kashdan T.B.
        • Blalock D.V.
        • Calton J.M.
        Anxiety symptoms and functional impairment: A systematic review of the correlation between the two measures.
        Clin Psychol Rev. 2016; 45: 115-130
        • Baxter A.J.
        • Vos T.
        • Scott K.M.
        • Ferrari A.J.
        • Whiteford H.A.
        The global burden of anxiety disorders in 2010.
        Psychol Med. 2014; 44: 1-12
        • Marín O.
        Developmental timing and critical windows for the treatment of psychiatric disorders.
        Nat Med. 2016; 22: 1229-1238
        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).
        American Psychiatric Association Publishing, Washington, DC2013
        • Moscovitch D.A.
        What is the core fear in social phobia? A new model to facilitate individualized case conceptualization and treatment.
        Cogn Behav Pract. 2009; 16: 123-134
        • Heimberg R.G.
        • Hofmann S.G.
        • Liebowitz M.R.
        • Schneier F.R.
        • Smits J.A.J.
        • Stein M.B.
        • et al.
        Social anxiety disorder in DSM-5.
        Depress Anxiety. 2014; 31: 472-479
        • Berthoz S.
        • Armony J.L.
        • Blair R.J.R.
        • Dolan R.J.
        An fMRI study of intentional and unintentional (embarrassing) violations of social norms.
        Brain. 2002; 125: 1696-1708
        • Blair K.S.
        • Geraci M.
        • Hollon N.
        • Otero M.
        • DeVido J.
        • Majestic C.
        • et al.
        Social norm processing in adult social phobia: Atypically increased ventromedial frontal cortex responsiveness to unintentional (embarrassing) transgressions.
        Am J Psychiatry. 2010; 167: 1526-1532
        • Bas-Hoogendam J.M.
        • van Steenbergen H.
        • van der Wee N.J.A.
        • Westenberg P.M.
        Not intended, still embarrassed: Social anxiety is related to increased levels of embarrassment in response to unintentional social norm violations.
        Eur Psychiatry. 2018; 52: 15-21
        • Bas-Hoogendam J.M.
        • van Steenbergen H.
        • Kreuk T.
        • van der Wee N.J.A.
        • Westenberg P.M.
        How embarrassing! The behavioral and neural correlates of processing social norm violations.
        PLoS One. 2017; 12: e0176326
        • Wong Q.J.J.
        • Rapee R.M.
        The aetiology and maintenance of social anxiety disorder: A synthesis of complimentary theoretical models and formulation of a new integrated model.
        J Affect Disord. 2016; 203: 84-100
        • Stein D.J.
        Social anxiety disorder and the psychobiology of self-consciousness.
        Front Hum Neurosci. 2015; 9: 489
        • Gottesman II,
        • Gould T.D.
        The endophenotype concept in psychiatry: Etymology and strategic intentions.
        Am J Psychiatry. 2003; 160: 636-645
        • Lenzenweger M.F.
        Endophenotype, intermediate phenotype, biomarker: Definitions, concept comparisons, clarifications.
        Depress Anxiety. 2013; 30: 185-189
        • Bas-Hoogendam J.M.
        • Blackford J.U.
        • Brühl A.B.
        • Blair K.S.
        • van der Wee N.J.A.
        • Westenberg P.M.
        Neurobiological candidate endophenotypes of social anxiety disorder.
        Neurosci Biobehav Rev. 2016; 71: 362-378
        • Miller G.A.
        • Rockstroh B.
        Endophenotypes in psychopathology research: Where do we stand?.
        Annu Rev Clin Psychol. 2013; 9: 177-213
        • Puls I.
        • Gallinat J.
        The concept of endophenotypes in psychiatric diseases meeting the expectations?.
        Pharmacopsychiatry. 2008; 41: S37-S43
        • Glahn D.C.
        • Thompson P.M.
        • Blangero J.
        Neuroimaging endophenotypes: Strategies for finding genes influencing brain structure and function.
        Hum Brain Mapp. 2007; 28: 488-501
        • Bandelow B.
        • Baldwin D.
        • Abelli M.
        • Altamura C.
        • Dell’Osso B.
        • Domschke K.
        • et al.
        Biological markers for anxiety disorders, OCD and PTSD—a consensus statement. Part I: Neuroimaging and genetics.
        World J Biol Psychiatry. 2016; 17: 321-365
        • Isomura K.
        • Boman M.
        • Rück C.
        • Serlachius E.
        • Larsson H.
        • Lichtenstein P.
        • Mataix-Cols D.
        Population-based, multi-generational family clustering study of social anxiety disorder and avoidant personality disorder.
        Psychol Med. 2015; 45: 1581-1589
        • Scaini S.
        • Belotti R.
        • Ogliari A.
        Genetic and environmental contributions to social anxiety across different ages: A meta-analytic approach to twin data.
        J Anxiety Disord. 2014; 28: 650-656
        • Stein M.B.
        • Chartier M.J.
        • Hazen A.L.
        • Kozak M.V.
        • Tancer M.E.
        • Lander S.
        • et al.
        A direct-interview family study of generalized social phobia.
        Am J Psychiatry. 1998; 155: 90-97
        • Merikangas K.R.
        • Lieb R.
        • Wittchen H.-U.
        • Avenevoli S.
        Family and high-risk studies of social anxiety disorder.
        Acta Psychiatr Scand. 2003; Suppl: 28-37
        • Bas-Hoogendam J.M.
        • Harrewijn A.
        • van der Molen M.J.W.
        • van Steenbergen H.
        • van Vliet I.
        • Houwing-Duistermaat J.
        • et al.
        Preregistration: Hypothesized endophenotype: Prefrontal cortex (MRI), part of “Profiling Endophenotypes in Social Anxiety Disorder: A neurocognitive approach.”.
        Database Open Sci Framew. 2014;
        • Bas-Hoogendam J.M.
        • Harrewijn A.
        • Tissier R.L.M.
        • van der Molen M.J.W.
        • van Steenbergen H.
        • van Vliet I.M.
        • et al.
        The Leiden Family Lab study on Social Anxiety Disorder: A multiplex, multigenerational family study on neurocognitive endophenotypes.
        Int J Methods Psychiatr Res. 2018; 27: e1616
        • Blokland G.A.M.
        • de Zubicaray G.I.
        • McMahon K.L.
        • Wright M.J.
        Genetic and environmental influences on neuroimaging phenotypes: A meta-analytical perspective on twin imaging studies.
        Twin Res Hum Genet. 2012; 15: 351-371
        • Mattay V.S.
        • Goldberg T.E.
        Imaging genetic influences in human brain function.
        Curr Opin Neurobiol. 2004; 14: 239-247
        • Shan Z.Y.
        • Vinkhuyzen A.A.E.
        • Thompson P.M.
        • McMahon K.L.
        • Blokland G.A.M.
        • de Zubicaray G.I.
        • et al.
        Genes influence the amplitude and timing of brain hemodynamic responses.
        Neuroimage. 2016; 124: 663-671
        • Sallis H.
        • Davey Smith G.
        • Munafò M.R.
        Genetics of biologically based psychological differences.
        Philos Trans R Soc B Biol Sci. 2018; 373 (pii:20170162)
        • Nivard M.G.
        • Dolan C.V.
        • Kendler K.S.
        • Kan K.-J.
        • Willemsen G.
        • van Beijsterveldt C.E.M.
        • et al.
        Stability in symptoms of anxiety and depression as a function of genotype and environment: A longitudinal twin study from ages 3 to 63 years.
        Psychol Med. 2015; 45: 1039-1049
        • Stein M.B.
        • Jang K.L.
        • Livesley W.J.
        Heritability of social anxiety-related concerns and personality characteristics: A twin study.
        J Nerv Ment Dis. 2002; 190: 219-224
        • Bas-Hoogendam J.M.
        • Harrewijn A.
        • van der Molen M.J.W.
        • van Steenbergen H.
        • van Vliet I.
        • Houwing-Duistermaat J.
        • et al.
        Preregistration: Methods: Study design and sample: Part of “Profiling Endophenotypes in Social Anxiety Disorder: A neurocognitive approach.”.
        Database Open Sci Framew. 2014;
        • Sheehan D.V.
        • Lecrubier Y.
        • Sheehan K.H.
        • Amorim P.
        • Janavs J.
        • Weiller E.
        • et al.
        The Mini-International Neuropsychiatric Interview (M.I.N.I.): The development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10.
        J Clin Psychiatry. 1998; 59: 22-33
        • van Vliet I.M.
        • de Beurs E.
        [The MINI-International Neuropsychiatric Interview: A brief structured diagnostic psychiatric interview for DSM-IV and ICD-10 psychiatric disorders].
        Tijdschr Psychiatr. 2007; 49: 393-397
        • Bauhuis O.
        • Jonker K.
        • Verdellen C.
        • Reynders J.
        • Verbraak M.
        De introductie van een Nederlandstalig instrument om DSM-IV-Tr-diagnoses bij kinderen te stellen (Introducing an instrument in Dutch to determine DSM-IV_TR diagnoses in children).
        Kind Adolesc Prakt. 2013; 12: 20-26
        • Sheehan D.V.
        • Sheehan K.H.
        • Shytle R.D.
        • Janavs J.
        • Bannon Y.
        • Rogers J.E.
        • et al.
        Reliability and validity of the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID).
        J Clin Psychiatry. 2010; 71: 313-326
        • Fresco D.M.
        • Coles M.E.
        • Heimberg R.G.
        • Liebowitz M.R.
        • Hami S.
        • Stein M.B.
        • Goetz D.
        The Liebowitz Social Anxiety Scale: A comparison of the psychometric properties of self-report and clinician-administered formats.
        Psychol Med. 2001; 31: 1025-1035
        • La Greca A.M.
        • Lopez N.
        Social anxiety among adolescents: Linkages with peer relations and friendships.
        J Abnorm Child Psychol. 1998; 26: 83-94
        • Galván A.
        Neural plasticity of development and learning.
        Hum Brain Mapp. 2010; 31: 879-890
        • Bas-Hoogendam J.M.
        • van Steenbergen H.
        • Tissier R.L.M.
        • Houwing-Duistermaat J.J.
        • Westenberg P.M.
        • van der Wee N.J.A.
        Subcortical brain volumes, cortical thickness and cortical surface area in families genetically enriched for social anxiety disorder: A multiplex multigenerational neuroimaging study.
        EBioMedicine. 2018; 36: 410-428
        • Bas-Hoogendam J.M.
        • van Steenbergen H.
        • Kreuk T.
        • van der Wee N.
        • Westenberg P.M.
        Revised Social Norm Processing Task (SNPT-R).
        Database Open Sci Framew. 2017;
        • R Core Team
        R: A language and environment for statistical computing.
        (Available at:) (Accessed August 16, 2018)
        • Jenkinson M.
        • Beckmann C.F.
        • Behrens T.E.J.
        • Woolrich M.W.
        • Smith S.M.
        Neuroimage. 2012; 62: 782-790
        • Worsley K.J.
        Statistical analysis of activation images.
        in: Jezzard P. Matthews P.M. Smith S.M. Functional MRI: An Introduction to Methods. Oxford University Press, Oxford, UK2001: 1-23
        • Tissier R.
        • Tsonaka R.
        • Mooijaart S.P.
        • Slagboom E.
        • Houwing-Duistermaat J.J.
        Secondary phenotype analysis in ascertained family designs: Application to the Leiden longevity study.
        Stat Med. 2017; 36: 2288-2301
        • Bas-Hoogendam J.M.
        • Harrewijn A.
        • van der Molen M.J.W.
        • van Steenbergen H.
        • van Vliet I.
        • Houwing-Duistermaat J.
        • et al.
        Preregistration: General Background and Key Question of Project, part of “Profiling Endophenotypes in Social Anxiety Disorder: a neurocognitive approach.”.
        Database Open Sci Framew. 2014;
        • Jenkins A.C.
        • Mitchell J.P.
        Medial prefrontal cortex subserves diverse forms of self-reflection.
        Soc Neurosci. 2011; 6: 211-218
        • Amodio D.M.
        • Frith C.D.
        Meeting of minds: The medial frontal cortex and social cognition.
        Nat Rev Neurosci. 2006; 7: 268-277
        • Blair K.S.
        • Blair R.J.R.
        A cognitive neuroscience approach to generalized anxiety disorder and social phobia.
        Emot Rev. 2012; 4: 133-138
        • Blair K.
        • Geraci M.
        • Devido J.
        • McCaffrey D.
        • Chen G.
        • Vythilingam M.
        • et al.
        Neural response to self- and other referential praise and criticism in generalized social phobia.
        Arch Gen Psychiatry. 2008; 65: 1176-1184
        • Blair K.S.
        • Geraci M.
        • Otero M.
        • Majestic C.
        • Odenheimer S.
        • Jacobs M.
        • et al.
        Atypical modulation of medial prefrontal cortex to self-referential comments in generalized social phobia.
        Psychiatry Res. 2011; 193: 38-45
        • Heitmann C.Y.
        • Peterburs J.
        • Mothes-Lasch M.
        • Hallfarth M.C.
        • Böhme S.
        • Miltner W.H.R.
        • Straube T.
        Neural correlates of anticipation and processing of performance feedback in social anxiety.
        Hum Brain Mapp. 2014; 35: 6023-6031
        • Miskovic V.
        • Schmidt L.A.
        Social fearfulness in the human brain.
        Neurosci Biobehav Rev. 2012; 36: 459-478
        • Brühl A.B.
        • Delsignore A.
        • Komossa K.
        • Weidt S.
        Neuroimaging in social anxiety disorder: A meta-analytic review resulting in a new neurofunctional model.
        Neurosci Biobehav Rev. 2014; 47: 260-280
        • Beauchamp M.S.
        The social mysteries of the superior temporal sulcus.
        Trends Cogn Sci. 2015; 19: 489-490
        • Schirmer A.
        • Meck W.H.
        • Penney T.B.
        The socio-temporal brain: Connecting people in time.
        Trends Cogn Sci. 2016; 20: 760-772
        • Deen B.
        • Koldewyn K.
        • Kanwisher N.
        • Saxe R.
        Functional organization of social perception and cognition in the superior temporal sulcus.
        Cereb Cortex. 2015; 25: 4596-4609
        • Frith C.D.
        • Frith U.
        Social cognition in humans.
        Curr Biol. 2007; 17: R724-R732
        • Saxe R.
        • Xiao D.-K.
        • Kovacs G.
        • Perrett D.I.
        • Kanwisher N.
        A region of right posterior superior temporal sulcus responds to observed intentional actions.
        Neuropsychologia. 2004; 42: 1435-1446
        • Pelphrey K.A.
        • Morris J.P.
        • McCarthy G.
        Grasping the intentions of others: The perceived intentionality of an action influences activity in the superior temporal sulcus during social perception.
        J Cogn Neurosci. 2004; 16: 1706-1716
        • Paulus F.M.
        • Müller-Pinzler L.
        • Jansen A.
        • Gazzola V.
        • Krach S.
        Mentalizing and the role of the posterior superior temporal sulcus in sharing others’ embarrassment.
        Cereb Cortex. 2015; 25: 2065-2075
        • Gentili C.
        • Gobbini M.I.
        • Ricciardi E.
        • Vanello N.
        • Pietrini P.
        • Haxby J.V.
        • Guazzelli M.
        Differential modulation of neural activity throughout the distributed neural system for face perception in patients with social phobia and healthy subjects.
        Brain Res Bull. 2008; 77: 286-292
        • Straube T.
        • Kolassa I.-T.
        • Glauer M.
        • Mentzel H.-J.
        • Miltner W.H.R.
        Effect of task conditions on brain responses to threatening faces in social phobics: An event-related functional magnetic resonance imaging study.
        Biol Psychiatry. 2004; 56: 921-930
        • Gorka A.X.
        • Torrisi S.
        • Shackman A.J.
        • Grillon C.
        • Ernst M.
        Intrinsic functional connectivity of the central nucleus of the amygdala and bed nucleus of the stria terminalis.
        Neuroimage. 2018; 168: 392-402
        • Pitcher D.
        • Japee S.
        • Rauth L.
        • Ungerleider L.G.
        The superior temporal sulcus is causally connected to the amygdala: A combined TBS-fMRI study.
        J Neurosci. 2017; 37: 1156-1161
        • Ganis G.
        • Thompson W.L.
        • Kosslyn S.M.
        Brain areas underlying visual mental imagery and visual perception: An fMRI study.
        Cogn Brain Res. 2004; 20: 226-241
        • Simon D.
        • Kaufmann C.
        • Müsch K.
        • Kischkel E.
        • Kathmann N.
        Fronto-striato-limbic hyperactivation in obsessive-compulsive disorder during individually tailored symptom provocation.
        Psychophysiology. 2010; 47: 728-738
        • Bas-Hoogendam J.M.
        • van Steenbergen H.
        • Pannekoek J.N.
        • Fouche J.-P.
        • Lochner C.
        • Hattingh C.J.
        • et al.
        Voxel-based morphometry multi-center mega-analysis of brain structure in social anxiety disorder.
        Neuroimage Clin. 2017; 16: 678-688
        • Lerch J.P.
        • van der Kouwe A.J.W.
        • Raznahan A.
        • Paus T.
        • Johansen-Berg H.
        • Miller K.L.
        • et al.
        Studying neuroanatomy using MRI.
        Nat Neurosci. 2017; 20: 314-326
        • Bas-Hoogendam J.M.
        Commentary: Gray matter structural alterations in social anxiety disorder: A voxel-based meta-analysis.
        Front Psychiatry. 2019; 10: 1
        • Steiger V.R.
        • Brühl A.B.
        • Weidt S.
        • Delsignore A.
        • Rufer M.
        • Jäncke L.
        • et al.
        Pattern of structural brain changes in social anxiety disorder after cognitive behavioral group therapy: A longitudinal multimodal MRI study.
        Mol Psychiatry. 2017; 22: 1164-1171