Advertisement

Reduced Amygdala–Prefrontal Functional Connectivity in Children With Autism Spectrum Disorder and Co-occurring Disruptive Behavior

Published:February 04, 2019DOI:https://doi.org/10.1016/j.bpsc.2019.01.009

      Abstract

      Background

      Disruptive behaviors are prevalent in children with autism spectrum disorder (ASD) and often cause substantial impairments. However, the underlying neural mechanisms of disruptive behaviors remain poorly understood in ASD. In children without ASD, disruptive behavior is associated with amygdala hyperactivity and reduced connectivity with the ventrolateral prefrontal cortex (vlPFC). This study examined amygdala reactivity and connectivity in children with ASD with and without co-occurring disruptive behavior disorders. We also investigated differential contributions of externalizing behaviors and callous-unemotional traits to variance in amygdala connectivity and reactivity.

      Methods

      This cross-sectional study involved behavioral assessments and neuroimaging in three groups of children 8 to 16 years of age: 18 children had ASD and disruptive behavior, 20 children had ASD without disruptive behavior, and 19 children were typically developing control participants matched for age, gender, and IQ. During functional magnetic resonance imaging, participants completed an emotion perception task of fearful versus calm faces. Task-specific changes in amygdala reactivity and connectivity were examined using whole-brain, psychophysiological interaction, and multiple regression analyses.

      Results

      Children with ASD and disruptive behavior showed reduced amygdala–vlPFC connectivity compared with children with ASD without disruptive behavior. Externalizing behaviors and callous-unemotional traits were associated with amygdala reactivity to fearful faces in children with ASD after controlling for suppressor effects.

      Conclusions

      Reduced amygdala–vlPFC connectivity during fear processing may differentiate children with ASD and disruptive behavior from children with ASD without disruptive behavior. The presence of callous-unemotional traits may have implications for identifying differential patterns of amygdala activity associated with increased risk of aggression in ASD. These findings suggest a neural mechanism of emotion dysregulation associated with disruptive behavior in children with ASD.

      Keywords

      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'

      References

        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders.
        5th ed. American Psychiatric Association, Washington, DC2013
        • Kanne S.M.
        • Mazurek M.O.
        Aggression in children and adolescents with ASD: Prevalence and risk factors.
        J Autism Dev Disord. 2011; 41: 926-937
        • Simonoff E.
        • Pickles A.
        • Charman T.
        • Chandler S.
        • Loucas T.
        • Baird G.
        Psychiatric disorders in children with autism spectrum disorders: Prevalence, comorbidity, and associated factors in a population-derived sample.
        J Am Acad Child Adolesc Psychiatry. 2008; 47: 921-929
        • Mazurek M.O.
        • Kanne S.M.
        • Wodka E.L.
        Physical aggression in children and adolescents with autism spectrum disorders.
        Res Autism Spectr Disord. 2013; 7: 455-465
        • Arnold L.E.
        • Vitiello B.
        • McDougle C.
        • Scahill L.
        • Shah B.
        • Gonzalez N.M.
        • et al.
        Parent-defined target symptoms respond to risperidone in RUPP autism study: Customer approach to clinical trials.
        J Am Acad Child Adolesc Psychiatry. 2003; 42: 1443-1450
        • Noordermeer S.D.
        • Luman M.
        • Oosterlaan J.
        A systematic review and meta-analysis of neuroimaging in oppositional defiant disorder (ODD) and conduct disorder (CD) taking attention-deficit hyperactivity disorder (ADHD) into account.
        Neuropsychol Rev. 2016; 26: 44-72
        • Alegria A.A.
        • Radua J.
        • Rubia K.
        Meta-analysis of fMRI studies of disruptive behavior disorders.
        Am J Psychiatry. 2016; 173: 1119-1130
        • Herpertz S.C.
        • Huebner T.
        • Marx I.
        • Vloet T.D.
        • Fink G.R.
        • Stoecker T.
        • et al.
        Emotional processing in male adolescents with childhood-onset conduct disorder.
        J Child Psychol Psychiatry. 2008; 49: 781-791
        • Passamonti L.
        • Fairchild G.
        • Goodyer I.M.
        • Hurford G.
        • Hagan C.C.
        • Rowe J.B.
        • et al.
        Neural abnormalities in early-onset and adolescence-onset conduct disorder.
        Arch Gen Psychiatry. 2010; 67: 729-738
        • Viding E.
        • Sebastian C.L.
        • Dadds M.R.
        • Lockwood P.L.
        • Cecil C.A.
        • De Brito S.A.
        • et al.
        Amygdala response to preattentive masked fear in children with conduct problems: The role of callous-unemotional traits.
        Am J Psychiatry. 2012; 169: 1109-1116
        • Marsh A.A.
        • Finger E.C.
        • Mitchell D.G.
        • Reid M.E.
        • Sims C.
        • Kosson D.S.
        • et al.
        Reduced amygdala response to fearful expressions in children and adolescents with callous-unemotional traits and disruptive behavior disorders.
        Am J Psychiatry. 2008; 165: 712-720
        • Decety J.
        • Michalska K.J.
        • Akitsuki Y.
        • Lahey B.B.
        Atypical empathic responses in adolescents with aggressive conduct disorder: A functional MRI investigation.
        Biol Psychol. 2009; 80: 203-211
        • Coccaro E.F.
        • McCloskey M.S.
        • Fitzgerald D.A.
        • Phan K.L.
        Amygdala and orbitofrontal reactivity to social threat in individuals with impulsive aggression.
        Biol Psychiatry. 2007; 62: 168-178
        • Aghajani M.
        • Klapwijk E.T.
        • van der Wee N.J.
        • Veer I.M.
        • Rombouts S.A.
        • Boon A.E.
        • et al.
        Disorganized amygdala networks in conduct-disordered juvenile offenders with callous-unemotional traits.
        Biol Psychiatry. 2017; 82: 283-293
        • Silvers J.A.
        • Insel C.
        • Powers A.
        • Franz P.
        • Helion C.
        • Martin R.E.
        • et al.
        VlPFC–vmPFC–amygdala interactions underlie age-related differences in cognitive regulation of emotion.
        Cereb Cortex. 2016; 27: 3502-3514
        • Ochsner K.N.
        • Bunge S.A.
        • Gross J.J.
        • Gabrieli J.D.
        Rethinking feelings: An FMRI study of the cognitive regulation of emotion.
        J Cogn Neurosci. 2002; 14: 1215-1229
        • Davidson R.J.
        • Putnam K.M.
        • Larson C.L.
        Dysfunction in the neural circuitry of emotion regulation—a possible prelude to violence.
        Science. 2000; 289: 591-594
        • Coccaro E.F.
        • Sripada C.S.
        • Yanowitch R.N.
        • Phan K.L.
        Corticolimbic function in impulsive aggressive behavior.
        Biol Psychiatry. 2011; 69: 1153-1159
        • Samson A.C.
        • Hardan A.Y.
        • Lee I.A.
        • Phillips J.M.
        • Gross J.J.
        Maladaptive behavior in autism spectrum disorder: The role of emotion experience and emotion regulation.
        J Autism Dev Disord. 2015; 45: 3424-3432
        • Samson A.C.
        • Hardan A.Y.
        • Podell R.W.
        • Phillips J.M.
        • Gross J.J.
        Emotion regulation in children and adolescents with autism spectrum disorder.
        Autism Res. 2015; 8: 9-18
        • Pitskel N.B.
        • Bolling D.Z.
        • Kaiser M.D.
        • Pelphrey K.A.
        • Crowley M.J.
        Neural systems for cognitive reappraisal in children and adolescents with autism spectrum disorder.
        Dev Cogn Neurosci. 2014; 10: 117-128
        • Swartz J.R.
        • Wiggins J.L.
        • Carrasco M.
        • Lord C.
        • Monk C.S.
        Amygdala habituation and prefrontal functional connectivity in youth with autism spectrum disorders.
        J Am Acad Child Adolesc Psychiatry. 2013; 52: 84-93
        • Rowe R.
        • Maughan B.
        • Moran P.
        • Ford T.
        • Briskman J.
        • Goodman R.
        The role of callous and unemotional traits in the diagnosis of conduct disorder.
        J Child Psychol Psychiatry. 2010; 51: 688-695
        • O'Nions E.
        • Sebastian C.L.
        • McCrory E.
        • Chantiluke K.
        • Happe F.
        • Viding E.
        Neural bases of Theory of Mind in children with autism spectrum disorders and children with conduct problems and callous-unemotional traits.
        Dev Sci. 2014; 17: 786-796
        • Klapwijk E.T.
        • Aghajani M.
        • Colins O.F.
        • Marijnissen G.M.
        • Popma A.
        • van Lang N.D.
        • et al.
        Different brain responses during empathy in autism spectrum disorders versus conduct disorder and callous-unemotional traits.
        J Child Psychol Psychiatry. 2016; 57: 737-747
        • Bours C.
        • Bakker-Huvenaars M.
        • Tramper J.
        • Bielczyk N.
        • Scheepers F.
        • Nijhof K.
        • et al.
        Emotional face recognition in male adolescents with autism spectrum disorder or disruptive behavior disorder: An eye-tracking study.
        Eur Child Adolesc Psychiatry. 2018; 27: 1143-1157
        • Tye C.
        • Bedford R.
        • Asherson P.
        • Ashwood K.
        • Azadi B.
        • Bolton P.
        • et al.
        Callous-unemotional traits moderate executive function in children with ASD and ADHD: A pilot event-related potential study.
        Dev Cogn Neurosci. 2017; 26: 84-90
        • Carter Leno V.
        • Charman T.
        • Pickles A.
        • Jones C.R.
        • Baird G.
        • Happe F.
        • et al.
        Callous-unemotional traits in adolescents with autism spectrum disorder.
        Br J Psychiatry. 2015; 207: 392-399
        • Rogers J.
        • Viding E.
        • Blair R.J.
        • Frith U.
        • Happe F.
        Autism spectrum disorder and psychopathy: Shared cognitive underpinnings or double hit?.
        Psychol Med. 2006; 36: 1789-1798
        • White S.F.
        • Marsh A.A.
        • Fowler K.A.
        • Schechter J.C.
        • Adalio C.
        • Pope K.
        • et al.
        Reduced amygdala response in youths with disruptive behavior disorders and psychopathic traits: Decreased emotional response versus increased top-down attention to nonemotional features.
        Am J Psychiatry. 2012; 169: 750-758
        • Jones A.P.
        • Laurens K.R.
        • Herba C.M.
        • Barker G.J.
        • Viding E.
        Amygdala hypoactivity to fearful faces in boys with conduct problems and callous-unemotional traits.
        Am J Psychiatry. 2009; 166: 95-102
        • Cardinale E.M.
        • Breeden A.L.
        • Robertson E.L.
        • Lozier L.M.
        • Vanmeter J.W.
        • Marsh A.A.
        Externalizing behavior severity in youths with callous–unemotional traits corresponds to patterns of amygdala activity and connectivity during judgments of causing fear.
        Dev Psychopathol. 2018; 30: 191-201
        • Wang Dapretto M.
        • Hariri A.R.
        • Sigman M.
        • Bookheimer S.Y.
        Neural correlates of facial affect processing in children and adolescents with autism spectrum disorder.
        J Am Acad Child Adolesc Psychiatry. 2004; 43: 481-490
        • Pelphrey K.A.
        • Morris J.P.
        • McCarthy G.
        • Labar K.S.
        Perception of dynamic changes in facial affect and identity in autism.
        Soc Cogn Affect Neurosci. 2007; 2: 140-149
        • Nomi J.S.
        • Uddin L.Q.
        Face processing in autism spectrum disorders: From brain regions to brain networks.
        Neuropsychologia. 2015; 71: 201-216
        • Perlman S.B.
        • Hudac C.M.
        • Pegors T.
        • Minshew N.J.
        • Pelphrey K.A.
        Experimental manipulation of face-evoked activity in the fusiform gyrus of individuals with autism.
        Soc Neurosci. 2011; 6: 22-30
        • Kleinhans N.M.
        • Richards T.
        • Johnson L.C.
        • Weaver K.E.
        • Greenson J.
        • Dawson G.
        • et al.
        FMRI evidence of neural abnormalities in the subcortical face processing system in ASD.
        Neuroimage. 2011; 54: 697-704
        • Kleinhans N.M.
        • Richards T.
        • Weaver K.
        • Johnson L.C.
        • Greenson J.
        • Dawson G.
        • et al.
        Association between amygdala response to emotional faces and social anxiety in autism spectrum disorders.
        Neuropsychologia. 2010; 48: 3665-3670
        • Monk C.S.
        • Weng S.-J.
        • Wiggins J.L.
        • Kurapati N.
        • Louro H.M.
        • Carrasco M.
        • et al.
        Neural circuitry of emotional face processing in autism spectrum disorders.
        J Psychiatry Neurosci. 2010; 35: 105-114
        • Tottenham N.
        • Hertzig M.E.
        • Gillespie-Lynch K.
        • Gilhooly T.
        • Millner A.J.
        • Casey B.
        Elevated amygdala response to faces and gaze aversion in autism spectrum disorder.
        Soc Cogn Affect Neurosci. 2013; 9: 106-117
        • Kliemann D.
        • Dziobek I.
        • Hatri A.
        • Baudewig J.
        • Heekeren H.R.
        The role of the amygdala in atypical gaze on emotional faces in autism spectrum disorders.
        J Neurosci. 2012; 32: 9469-9476
        • Sebastian C.L.
        • McCrory E.J.
        • Cecil C.A.
        • Lockwood P.L.
        • De Brito S.A.
        • Fontaine N.M.
        • et al.
        Neural responses to affective and cognitive theory of mind in children with conduct problems and varying levels of callous-unemotional traits.
        Arch Gen Psychiatry. 2012; 69: 814-822
        • Lozier L.M.
        • Cardinale E.M.
        • VanMeter J.W.
        • Marsh A.A.
        Mediation of the relationship between callous-unemotional traits and proactive aggression by amygdala response to fear among children with conduct problems.
        JAMA Psychiatry. 2014; 71: 627-636
        • Cohen J.
        • Cohen P.
        • West S.G.
        • Aiken L.S.
        Applied Multiple Correlation/Regression Analysis for the Behavioral Sciences.
        Routledge, New York, NY2003
        • Hicks B.M.
        • Patrick C.J.
        Psychopathy and negative emotionality: Analyses of suppressor effects reveal distinct relations with emotional distress, fearfulness, and anger-hostility.
        J Abnorm Psychol. 2006; 115: 276-287
        • Fusar-Poli P.
        • Placentino A.
        • Carletti F.
        • Landi P.
        • Allen P.
        • Surguladze S.
        • et al.
        Functional atlas of emotional faces processing: A voxel-based meta-analysis of 105 functional magnetic resonance imaging studies.
        J Psychiatry Neurosci. 2009; 34: 418-432
        • Achenbach T.M.
        • Rescorla L.A.
        Manual for the ASEBA School-Age Forms & Profiles.
        University of Vermont, Research Center for Children, Youth, and Families, Burlington, VT2001
        • Frick P.J.
        The Inventory of Callous-Unemotional Traits.
        University of New Orleans, New Orleans, LA2003
        • Le Couteur A.
        • Lord C.
        • Rutter M.
        The Autism Diagnostic Interview-Revised (ADI-R).
        Western Psychological Services, Los Angeles, CA2003
        • Lord C.
        • Rutter M.
        • DiLavore P.C.
        • Risi S.
        Autism Diagnostic Observation Schedule.
        2nd ed. Western Psychological Services, Los Angeles, CA2012
        • Linke A.C.
        • Olson L.
        • Gao Y.
        • Fishman I.
        • Müller R.-A.
        Psychotropic medication use in autism spectrum disorders may affect functional brain connectivity.
        Biol Psychiatry Cogn Neurosci Neuroimaging. 2017; 2: 518-527
        • Kaufman J.
        • Birmaher B.
        • Axelson D.
        • Perepletchikova F.
        • Brent D.
        • Ryan N.
        Schedule for Affective Disorders and Schizophrenia for School Aged Children: Present and Lifetime Version for DSM-5 (K-SADS-PL DSM-5).
        (Available at:) (Accessed July 8, 2018)
        • Tottenham N.
        • Tanaka J.W.
        • Leon A.C.
        • McCarry T.
        • Nurse M.
        • Hare T.A.
        • et al.
        The NimStim set of facial expressions: Judgments from untrained research participants.
        Psychiatry Res. 2009; 168: 242-249
        • Sukhodolsky D.G.
        • Vander Wyk B.C.
        • Eilbott J.A.
        • McCauley S.A.
        • Ibrahim K.
        • Crowley M.J.
        • et al.
        Neural mechanisms of cognitive-behavioral therapy for aggression in children and adolescents: Design of a randomized controlled trial within the National Institute for Mental Health Research domain criteria construct of frustrative non-reward.
        J Child Adolesc Psychopharmacol. 2016; 26: 38-48
        • Friston K.
        • Buechel C.
        • Fink G.
        • Morris J.
        • Rolls E.
        • Dolan R.
        Psychophysiological and modulatory interactions in neuroimaging.
        Neuroimage. 1997; 6: 218-229
        • Markon K.E.
        • Chmielewski M.
        • Miller C.J.
        The reliability and validity of discrete and continuous measures of psychopathology: A quantitative review.
        Psychol Bull. 2011; 137: 856-879
        • von dem Hagen E.A.
        • Stoyanova R.S.
        • Rowe J.B.
        • Baron-Cohen S.
        • Calder A.J.
        Direct gaze elicits atypical activation of the theory-of-mind network in autism spectrum conditions.
        Cereb Cortex. 2014; 24: 1485-1492
        • Green S.A.
        • Hernandez L.
        • Tottenham N.
        • Krasileva K.
        • Bookheimer S.Y.
        • Dapretto M.
        Neurobiology of sensory overresponsivity in youth with autism spectrum disorders.
        JAMA Psychiatry. 2015; 72: 778-786
        • Banks S.J.
        • Eddy K.T.
        • Angstadt M.
        • Nathan P.J.
        • Phan K.L.
        Amygdala–frontal connectivity during emotion regulation.
        Soc Cogn Affect Neurosci. 2007; 2: 303-312
        • Buhle J.T.
        • Silvers J.A.
        • Wager T.D.
        • Lopez R.
        • Onyemekwu C.
        • Kober H.
        • et al.
        Cognitive reappraisal of emotion: A meta-analysis of human neuroimaging studies.
        Cereb Cortex. 2014; 24: 2981-2990
        • Diekhof E.K.
        • Geier K.
        • Falkai P.
        • Gruber O.
        Fear is only as deep as the mind allows: A coordinate-based meta-analysis of neuroimaging studies on the regulation of negative affect.
        Neuroimage. 2011; 58: 275-285
        • McRae K.
        • Gross J.J.
        • Weber J.
        • Robertson E.R.
        • Sokol-Hessner P.
        • Ray R.D.
        • et al.
        The development of emotion regulation: An fMRI study of cognitive reappraisal in children, adolescents and young adults.
        Soc Cogn Affect Neurosci. 2012; 7: 11-22
        • Mazefsky C.A.
        • Herrington J.
        • Siegel M.
        • Scarpa A.
        • Maddox B.B.
        • Scahill L.
        • et al.
        The role of emotion regulation in autism spectrum disorder.
        J Am Acad Child Adolesc Psychiatry. 2013; 52: 679-688
        • White S.F.
        • Williams W.C.
        • Brislin S.J.
        • Sinclair S.
        • Blair K.S.
        • Fowler K.A.
        • et al.
        Reduced activity within the dorsal endogenous orienting of attention network to fearful expressions in youth with disruptive behavior disorders and psychopathic traits.
        Dev Psychopathol. 2012; 24: 1105-1116
        • Di Martino A.
        • Ross K.
        • Uddin L.Q.
        • Sklar A.B.
        • Castellanos F.X.
        • Milham M.P.
        Functional brain correlates of social and nonsocial processes in autism spectrum disorders: An activation likelihood estimation meta-analysis.
        Biol Psychiatry. 2009; 65: 63-74
        • Rudie J.D.
        • Shehzad Z.
        • Hernandez L.M.
        • Colich N.L.
        • Bookheimer S.Y.
        • Iacoboni M.
        • et al.
        Reduced functional integration and segregation of distributed neural systems underlying social and emotional information processing in autism spectrum disorders.
        Cereb Cortex. 2011; 22: 1025-1037
        • Ibrahim K.
        • Sukhodolsky D.G.
        RDoC and autism.
        in: Volkmar F.R. Encyclopedia of Autism Spectrum Disorders. Springer, New York, NY2018
        • Ewbank M.P.
        • Passamonti L.
        • Hagan C.C.
        • Goodyer I.M.
        • Calder A.J.
        • Fairchild G.
        Psychopathic traits influence amygdala–anterior cingulate cortex connectivity during facial emotion processing.
        Soc Cogn Affect Neurosci. 2018; 13: 525-534
        • Lecavalier L.
        • McCracken C.E.
        • Aman M.G.
        • McDougle C.J.
        • McCracken J.T.
        • Tierney E.
        • et al.
        An exploration of concomitant psychiatric disorders in children with autism spectrum disorder.
        Compr Psychiatry. 2019; 88: 57-64
        • Ball T.M.
        • Ramsawh H.J.
        • Campbell-Sills L.
        • Paulus M.P.
        • Stein M.B.
        Prefrontal dysfunction during emotion regulation in generalized anxiety and panic disorders.
        Psychol Med. 2012; 43: 1475-1486
        • Kim M.J.
        • Gee D.G.
        • Loucks R.A.
        • Davis F.C.
        • Whalen P.J.
        Anxiety dissociates dorsal and ventral medial prefrontal cortex functional connectivity with the amygdala at rest.
        Cereb Cortex. 2010; 21: 1667-1673
        • Makovac E.
        • Meeten F.
        • Watson D.R.
        • Herman A.
        • Garfinkel S.N.
        • Critchley H.D.
        • et al.
        Alterations in amygdala-prefrontal functional connectivity account for excessive worry and autonomic dysregulation in generalized anxiety disorder.
        Biol Psychiatry. 2016; 80: 786-795
        • Yang Y.D.
        • Sukhodolsky D.G.
        • Lei J.
        • Dayan E.
        • Pelphrey K.A.
        • Ventola P.
        Distinct neural bases of disruptive behavior and autism symptom severity in boys with autism spectrum disorder.
        J Neurodev Disord. 2017; 9: 1
        • Zurcher N.R.
        • Rogier O.
        • Boshyan J.
        • Hippolyte L.
        • Russo B.
        • Gillberg N.
        • et al.
        Perception of social cues of danger in autism spectrum disorders.
        PLoS One. 2013; 8: e81206
        • Aoki Y.
        • Cortese S.
        • Tansella M.
        Neural bases of atypical emotional face processing in autism: A meta-analysis of fMRI studies.
        World J Biol Psychiatry. 2015; 16: 291-300

      Linked Article

      • Developmental Considerations of Comorbidity in Autism Spectrum Disorder: The Need for Science Across Multiple Units of Analysis
        Biological Psychiatry: Cognitive Neuroscience and NeuroimagingVol. 4Issue 12
        • Preview
          In the last 2 decades, we have seen heightened interest in comorbidity in autism spectrum disorder (ASD). Research in this area has spanned clinical studies, intervention trials, and neurobiological models. Difficulty with emotion regulation (ER) and cognitive control are pervasive problems in individuals with ASD. It is possible that some of the core diagnostic features of ASD may underlie these issues. Examining the circuitry primarily involved in the regulation of emotional behavior in the context of functional connectivity models of autism is indeed a new direction.
        • Full-Text
        • PDF