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Dynamic Alterations in Neural Networks Supporting Aversive Learning in Children Exposed to Trauma: Neural Mechanisms Underlying Psychopathology

Published:September 24, 2021DOI:https://doi.org/10.1016/j.biopsych.2021.09.013

      Abstract

      Background

      Altered aversive learning represents a potential mechanism through which childhood trauma (CT) might influence risk for psychopathology. This study examines the temporal dynamics of neural activation and patterns of functional connectivity during aversive learning in children with and without exposure to CT involving interpersonal violence and evaluates whether these neural patterns mediate the association of CT with psychopathology in a longitudinal design.

      Methods

      A total of 147 children (aged 8–16 years, 77 with CT) completed a fear conditioning procedure during a functional magnetic resonance imaging scan. Dynamic patterns of neural activation were examined, and functional connectivity was assessed with generalized psychophysiological interaction analyses. We evaluated whether the associations between CT and psychopathology symptoms at baseline and 2-year follow-up were mediated by neural activation and connectivity during aversive learning.

      Results

      Children exposed to trauma displayed blunted patterns of neural activation over time to the conditioned threat versus safety stimuli (CS+>CS−) in the right amygdala. In addition, trauma was associated with reduced functional connectivity of right amygdala with the hippocampus, posterior parahippocampal gyrus, and posterior cingulate cortex and with elevated connectivity with the anterior cingulate cortex to CS+>CS−. The longitudinal association between CT and later externalizing symptoms was mediated by blunted activation in the right amygdala. Reduced amygdala-hippocampal connectivity mediated the association of CT with transdiagnostic anxiety symptoms, and elevated amygdala–anterior cingulate cortex connectivity mediated the association of CT with generalized anxiety symptoms.

      Conclusions

      CT is associated with poor threat-safety discrimination and altered functional coupling between salience and default mode network regions during aversive learning. These altered dynamics may be key mechanisms linking CT with distinct forms of psychopathology.

      Keywords

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      References

        • McLaughlin K.A.
        • Koenen K.C.
        • Hill E.D.
        • Petukhova M.
        • Sampson N.A.
        • Zaslavsky A.M.
        • Kessler R.C.
        Trauma exposure and posttraumatic stress disorder in a national sample of adolescents.
        J Am Acad Child Adolesc Psychiatry. 2013; 52: 815-830.e14
        • Finkelhor D.
        • Ormrod R.
        • Turner H.
        • Hamby S.L.
        The victimization of children and youth: A comprehensive, national survey.
        Child Maltreat. 2005; 10: 5-25
        • Green J.G.
        • McLaughlin K.A.
        • Berglund P.A.
        • Gruber M.J.
        • Sampson N.A.
        • Zaslavsky A.M.
        • Kessler R.C.
        Childhood adversities and adult psychiatric disorders in the national comorbidity survey replication I: Associations with first onset of DSM-IV disorders.
        Arch Gen Psychiatry. 2010; 67: 113-123
        • McLaughlin K.A.
        • Green J.G.
        • Gruber M.J.
        • Sampson N.A.
        • Zaslavsky A.M.
        • Kessler R.C.
        Childhood adversities and adult psychiatric disorders in the national comorbidity survey replication II: Associations with persistence of DSM-IV disorders.
        Arch Gen Psychiatry. 2010; 67: 124-132
        • McLaughlin K.A.
        • Greif Green J.G.
        • Gruber M.J.
        • Sampson N.A.
        • Zaslavsky A.M.
        • Kessler R.C.
        Childhood adversities and first onset of psychiatric disorders in a national sample of US adolescents.
        Arch Gen Psychiatry. 2012; 69: 1151-1160
        • McLaughlin K.A.
        • Sheridan M.A.
        • Lambert H.K.
        Childhood adversity and neural development: Deprivation and threat as distinct dimensions of early experience.
        Neurosci Biobehav Rev. 2014; 47: 578-591
        • Jovanovic T.
        • Ressler K.J.
        How the neurocircuitry and genetics of fear inhibition may inform our understanding of PTSD.
        Am J Psychiatry. 2010; 167: 648-662
        • Lissek S.
        • van Meurs B.
        Learning models of PTSD: Theoretical accounts and psychobiological evidence.
        Int J Psychophysiol. 2015; 98: 594-605
        • McLaughlin K.A.
        • DeCross S.N.
        • Jovanovic T.
        • Tottenham N.
        Mechanisms linking childhood adversity with psychopathology: Learning as an intervention target.
        Behav Res Ther. 2019; 118: 101-109
        • Johansen J.P.
        • Cain C.K.
        • Ostroff L.E.
        • LeDoux J.E.
        Molecular mechanisms of fear learning and memory.
        Cell. 2011; 147: 509-524
        • Lau J.Y.
        • Britton J.C.
        • Nelson E.E.
        • Angold A.
        • Ernst M.
        • Goldwin M.
        • et al.
        Distinct neural signatures of threat learning in adolescents and adults.
        Proc Natl Acad Sci U S A. 2011; 108: 4500-4505
        • LeDoux J.
        The emotional brain, fear, and the amygdala.
        Cell Mol Neurobiol. 2003; 23: 727-738
        • Phelps E.A.
        • LeDoux J.E.
        Contributions of the amygdala to emotion processing: From animal models to human behavior.
        Neuron. 2005; 48: 175-187
        • Fullana M.A.
        • Harrison B.J.
        • Soriano-Mas C.
        • Vervliet B.
        • Cardoner N.
        • Àvila-Parcet A.
        • Radua J.
        Neural signatures of human fear conditioning: An updated and extended meta-analysis of fMRI studies.
        Mol Psychiatry. 2016; 21: 500-508
        • Pattwell S.S.
        • Bath K.G.
        Emotional learning, stress, and development: An ever-changing landscape shaped by early-life experience.
        Neurobiol Learn Mem. 2017; 143: 36-48
        • McLaughlin K.A.
        • Sheridan M.A.
        • Gold A.L.
        • Duys A.
        • Lambert H.K.
        • Peverill M.
        • et al.
        Maltreatment exposure, brain structure, and fear conditioning in children and adolescents.
        Neuropsychopharmacology. 2016; 41: 1956-1964
        • Lissek S.
        • Powers A.S.
        • McClure E.B.
        • Phelps E.A.
        • Woldehawariat G.
        • Grillon C.
        • Pine D.S.
        Classical fear conditioning in the anxiety disorders: A meta-analysis.
        Behav Res Ther. 2005; 43: 1391-1424
        • Craske M.G.
        • Waters A.M.
        • Lindsey Bergman R.
        • Naliboff B.
        • Lipp O.V.
        • Negoro H.
        • Ornitz E.M.
        Is aversive learning a marker of risk for anxiety disorders in children?.
        Behav Res Ther. 2008; 46: 954-967
        • Waters A.M.
        • Henry J.
        • Neumann D.L.
        Aversive Pavlovian conditioning in childhood anxiety disorders: Impaired response inhibition and resistance to extinction.
        J Abnorm Psychol. 2009; 118: 311-321
        • Fairchild G.
        • Van Goozen S.H.
        • Stollery S.J.
        • Goodyer I.M.
        Fear conditioning and affective modulation of the startle reflex in male adolescents with early-onset or adolescence-onset conduct disorder and healthy control subjects.
        Biol Psychiatry. 2008; 63: 279-285
        • Bifulco A.
        • Brown G.W.
        • Harris T.O.
        Childhood experience of care and abuse (CECA): A retrospective interview measure.
        J Child Psychol Psychiatry. 1994; 35: 1419-1435
        • Steinberg A.M.
        • Brymer M.J.
        • Kim S.
        • Briggs E.C.
        • Ippen C.G.
        • Ostrowski S.A.
        • et al.
        Psychometric properties of the UCLA PTSD Reaction Index: Part I.
        J Trauma Stress. 2013; 26: 1-9
        • Bernstein D.P.
        • Ahluvalia T.
        • Pogge D.
        • Handelsman L.
        Validity of the Childhood Trauma Questionnaire in an adolescent psychiatric population.
        J Am Acad Child Adolesc Psychiatry. 1997; 36: 340-348
        • Finkelhor D.
        • Hamby S.L.
        • Ormrod R.
        • Turner H.
        The Juvenile Victimization Questionnaire: Reliability, validity, and national norms.
        Child Abuse Negl. 2005; 29: 383-412
        • Raviv A.
        • Erel O.
        • Fox N.A.
        • Leavitt L.A.
        • Raviv A.
        • Dar I.
        • et al.
        Individual measurement of exposure to everyday violence among elementary schoolchildren across various settings.
        J Community Psychol. 2001; 29: 117-140
        • Kovacs M.
        Children’s Depression Inventory Manual. Multi-Health Systems, North Tonawanda, NY1992
        • Kovacs M.
        Children’s Depression Inventory (CDI and CDI 2).
        The Encyclopedia of Clinical Psychology. John Wiley & Sons, Inc, 2015: 1-5
        • Birmaher B.
        • Khetarpal S.
        • Brent D.
        • Cully M.
        • Balach L.
        • Kaufman J.
        • Neer S.M.
        The screen for child anxiety related emotional disorders (SCARED): Scale construction and psychometric characteristics.
        J Am Acad Child Adolesc Psychiatry. 1997; 36: 545-553
        • Steinberg A.M.
        • Brymer M.J.
        • Decker K.B.
        • Pynoos R.S.
        The University of California at los Angeles post-traumatic stress disorder reaction index.
        Curr Psychiatry Rep. 2004; 6: 96-100
        • Achenbach T.M.
        Integrative Guide for the 1991 CBCL/4–18, YSR, and TRF Profiles.
        Department of Psychiatry, University of Vermont, 1991
        • Silvers J.A.
        • Lumian D.S.
        • Gabard-Durnam L.
        • Gee D.G.
        • Goff B.
        • Fareri D.S.
        • et al.
        Previous institutionalization is followed by broader amygdala–hippocampal–PFC network connectivity during aversive learning in human development.
        J Neurosci. 2016; 36: 6420-6430
        • Baker K.B.
        • Kim J.J.
        Amygdalar lateralization in fear conditioning: Evidence for greater involvement of the right amygdala.
        Behav Neurosci. 2004; 118: 15-23
        • LaBar K.S.
        • Gatenby J.C.
        • Gore J.C.
        • LeDoux J.E.
        • Phelps E.A.
        Human amygdala activation during conditioned fear acquisition and extinction: A mixed-trial fMRI study.
        Neuron. 1998; 20: 937-945
        • Marschner A.
        • Kalisch R.
        • Vervliet B.
        • Vansteenwegen D.
        • Büchel C.
        Dissociable Roles for the hippocampus and the amygdala in Human Cued versus Context Fear Conditioning.
        J Neurosci. 2008; 28: 9030-9036
        • Phelps E.A.
        • O’Connor K.J.
        • Gatenby J.C.
        • Gore J.C.
        • Grillon C.
        • Davis M.
        Activation of the left amygdala to a cognitive representation of fear.
        Nat Neurosci. 2001; 4: 437-441
        • Akaike H.
        Information theory as an extension of the maximum likelihood principle. Á.
        in: Petrov B.N. Csaki F. Second International Symposium on Information Theory. Akadémiai Kiadó, Budapest1973: 276-281
        • McLaren D.G.
        • Ries M.L.
        • Xu G.
        • Johnson S.C.
        A generalized form of context-dependent psychophysiological interactions (gPPI): A comparison to standard approaches.
        NeuroImage. 2012; 61: 1277-1286
        • Hayes A.F.
        Beyond baron and Kenny: Statistical mediation analysis in the new millennium.
        Commun Monogr. 2009; 76: 408-420
        • Shrout P.E.
        • Bolger N.
        Mediation in experimental and non-experimental studies: New procedures and recommendations.
        Psychol Methods. 2002; 7: 422-445
        • Hayes A.F.
        Introduction to Mediation, Moderation, and Conditional Process Analysis: A Regression-Based Approach.
        2nd ed. Guilford Publications, New York2017
        • Benjamini Y.
        • Hochberg Y.
        Controlling the false discovery rate: A practical and powerful approach to multiple testing.
        J R Stat Soc B. 1995; 57: 289-300
        • Modecki K.L.
        • Murphy L.K.
        • Waters A.M.
        Exposure to violence and neglect images differentially influences fear learning and extinction.
        Biol Psychol. 2020; 151: 107832
        • Lambert H.K.
        • Sheridan M.A.
        • Sambrook K.A.
        • Rosen M.L.
        • Askren M.K.
        • McLaughlin K.A.
        Hippocampal Contribution to Context Encoding across Development is Disrupted following early-life Adversity.
        J Neurosci. 2017; 37: 1925-1934
        • Pollak S.D.
        • Tolley-Schell S.A.
        Selective attention to facial emotion in physically abused children.
        J Abnorm Psychol. 2003; 112: 323-338
        • McLaughlin K.A.
        • Sheridan M.A.
        • Humphreys K.L.
        • Belsky J.
        • Ellis B.J.
        The value of dimensional models of early experience: Thinking clearly about concepts and categories.
        Perspect Psychol Sci. 2021; (1745691621992346)
        • Machlin L.
        • Miller A.B.
        • Snyder J.
        • McLaughlin K.A.
        • Sheridan M.A.
        Differential associations of deprivation and threat with cognitive control and fear conditioning in early childhood.
        Front Behav Neurosci. 2019; 13: 80
        • Maren S.
        • Phan K.L.
        • Liberzon I.
        The contextual brain: Implications for fear conditioning, extinction and psychopathology [No. 6].
        Nat Rev Neurosci. 2013; 14: 417-428
        • Aminoff E.M.
        • Kveraga K.
        • Bar M.
        The role of the parahippocampal cortex in cognition.
        Trends Cogn Sci. 2013; 17: 379-390
        • Liberzon I.
        • Abelson J.L.
        Context processing and the neurobiology of post-traumatic stress disorder.
        Neuron. 2016; 92: 14-30
        • Sierra-Mercado D.
        • Padilla-Coreano N.
        • Quirk G.J.
        Dissociable Roles of prelimbic and infralimbic cortices, Ventral hippocampus, and basolateral amygdala in the Expression and Extinction of Conditioned Fear [No. 2].
        Neuropsychopharmacology. 2011; 36: 529-538
        • Shenhav A.
        • Botvinick M.M.
        • Cohen J.D.
        The expected value of control: An integrative theory of anterior cingulate cortex function.
        Neuron. 2013; 79: 217-240
        • Jalnapurkar I.
        • Allen M.
        • Pigott T.
        Sex differences in anxiety disorders: A review.
        PDA. 2018; 4: 1-9
        • Craske M.G.
        • Treanor M.
        • Conway C.C.
        • Zbozinek T.
        • Vervliet B.
        Maximizing exposure therapy: An inhibitory learning approach.
        Behav Res Ther. 2014; 58: 10-23
        • Neumann D.L.
        • Waters A.M.
        • Westbury H.R.
        The use of an unpleasant sound as the unconditional stimulus in aversive Pavlovian conditioning experiments that involve children and adolescent participants.
        Behav Res Methods. 2008; 40: 622-625