Resting-State Functional Connectivity in Generalized Anxiety Disorder and Social Anxiety Disorder: Evidence for a Dimensional Approach

Generalized anxiety disorder (GAD) and social anxiety disorder (SAD) are currently considered distinct diagnostic categories. Accumulating data suggest the study of anxiety disorders may benefit from the use of dimensional conceptualizations. One such dimension of shared dysfunction is emotion regulation (ER). The current study evaluated dimensional (ER) and categorical (diagnosis) neurocorrelates of resting-state functional connectivity (rsFC) in participants with GAD and SAD and healthy controls (HC). Functional magnetic resonance imaging (fMRI) rsFC was estimated between all regions of the default mode network (DMN), salience network (SN), and bilateral amygdala (N = 37: HC-19; GAD-10; SAD-8). Thereafter, rsFC was predicted by both ER, (using the Difficulties in Emotion Regulation Scale [DERS]), and diagnosis (DSM-5) within a single unified analysis of covariance (ANCOVA). For the ER dimension, there was a significant association between impaired ER abilities and anticorrelated rsFC of amygdala and DMN (L.amygdala-ACC: p = 0.011, beta = -0.345), as well as amygdala and SN (L.amygdala-posterior cingulate cortex [PCC]: p = 0.032, beta = -0.409). Diagnostic status was significantly associated with rsFC differences between the SAD and HC groups, both within the DMN (PCC-MPFC: p = 0.009) and between the DMN and SN (R.LP-ACC: p = 0.010). Although preliminary, our results exemplify the potential contribution of the dimensional approach to the study of GAD and SAD and support a combined categorical and dimensional model of rsFC of anxiety disorders.

[1]  M. Fox,et al.  Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging , 2007, Nature Reviews Neuroscience.

[2]  Costin Tanase,et al.  Altered cerebral blood flow patterns associated with pathologic worry in the elderly , 2011, Depression and anxiety.

[3]  Nicola Vanello,et al.  Proneness to social anxiety modulates neural complexity in the absence of exposure: A resting state fMRI study using Hurst exponent , 2015, Psychiatry Research: Neuroimaging.

[4]  B. Olatunji,et al.  Emotion Regulation and the Anxiety Disorders: An Integrative Review , 2010, Journal of psychopathology and behavioral assessment.

[5]  J. Gross,et al.  The cognitive control of emotion , 2005, Trends in Cognitive Sciences.

[6]  Cynthia L. Turk,et al.  Preliminary evidence for an emotion dysregulation model of generalized anxiety disorder. , 2005, Behaviour research and therapy.

[7]  G L Shulman,et al.  INAUGURAL ARTICLE by a Recently Elected Academy Member:A default mode of brain function , 2001 .

[8]  M. Mintun,et al.  The default mode network and self-referential processes in depression , 2009, Proceedings of the National Academy of Sciences.

[9]  J. Fudge,et al.  Intrinsic functional connectivity of amygdala-based networks in adolescent generalized anxiety disorder. , 2013, Journal of the American Academy of Child and Adolescent Psychiatry.

[10]  S. Hofmann,et al.  Negative self-focused cognitions mediate the effect of trait social anxiety on state anxiety. , 2008, Behaviour research and therapy.

[11]  Qian Cui,et al.  Disrupted cortical hubs in functional brain networks in social anxiety disorder , 2015, Clinical Neurophysiology.

[12]  Stephen M. Smith,et al.  Investigations into resting-state connectivity using independent component analysis , 2005, Philosophical Transactions of the Royal Society B: Biological Sciences.

[13]  Thomas T. Liu,et al.  A component based noise correction method (CompCor) for BOLD and perfusion based fMRI , 2007, NeuroImage.

[14]  Benjamin J. Shannon,et al.  Parietal lobe contributions to episodic memory retrieval , 2005, Trends in Cognitive Sciences.

[15]  T. Insel,et al.  Toward the future of psychiatric diagnosis: the seven pillars of RDoC , 2013, BMC Medicine.

[16]  R. Kalisch The functional neuroanatomy of reappraisal: Time matters , 2009, Neuroscience & Biobehavioral Reviews.

[17]  Xi-Nian Zuo,et al.  Reliable intrinsic connectivity networks: Test–retest evaluation using ICA and dual regression approach , 2010, NeuroImage.

[18]  Katherine E. Prater,et al.  Failure of anterior cingulate activation and connectivity with the amygdala during implicit regulation of emotional processing in generalized anxiety disorder. , 2010, The American journal of psychiatry.

[19]  Huafu Chen,et al.  Regional homogeneity changes in social anxiety disorder: A resting-state fMRI study , 2011, Psychiatry Research: Neuroimaging.

[20]  M. Paulus,et al.  Interoception in anxiety and depression , 2010, Brain Structure and Function.

[21]  J. Gross,et al.  Emotion reactivity and regulation in late-life generalized anxiety disorder: functional connectivity at baseline and post-treatment. , 2015, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[22]  D. Pine,et al.  Social Anxiety and Emotion Regulation: A Model for Developmental Psychopathology Perspectives on Anxiety Disorders , 2015 .

[23]  C. Andreescu,et al.  The ages of anxiety—differences across the lifespan in the default mode network functional connectivity in generalized anxiety disorder , 2014, International journal of geriatric psychiatry.

[24]  Georg Northoff,et al.  How is our self related to midline regions and the default-mode network? , 2011, NeuroImage.

[25]  E. Kandel,et al.  Resolving Emotional Conflict: A Role for the Rostral Anterior Cingulate Cortex in Modulating Activit , 2006 .

[26]  Brian Patenaude,et al.  Neurobiological Signatures of Anxiety and Depression in Resting-State Functional Magnetic Resonance Imaging , 2015, Biological Psychiatry.

[27]  Huafu Chen,et al.  Multivariate classification of social anxiety disorder using whole brain functional connectivity , 2013, Brain Structure and Function.

[28]  J. Haxby,et al.  Neural systems for recognition of familiar faces , 2007, Neuropsychologia.

[29]  C. Grillon,et al.  The dorsal medial prefrontal (anterior cingulate) cortex–amygdala aversive amplification circuit in unmedicated generalised and social anxiety disorders: an observational study , 2014 .

[30]  A. Song,et al.  The involvement of the dopaminergic midbrain and cortico-striatal-thalamic circuits in the integration of reward prospect and attentional task demands. , 2012, Cerebral cortex.

[31]  R. Rapee,et al.  A cognitive-behavioral model of anxiety in social phobia. , 1997, Behaviour research and therapy.

[32]  D. Sheehan,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. , 1998, The Journal of clinical psychiatry.

[33]  T. Insel,et al.  Wesleyan University From the SelectedWorks of Charles A . Sanislow , Ph . D . 2010 Research Domain Criteria ( RDoC ) : Toward a New Classification Framework for Research on Mental Disorders , 2018 .

[34]  A. Wells A cognitive model of social phobia , 1995 .

[35]  Mauricio R. Delgado,et al.  Overlapping neural systems mediating extinction, reversal and regulation of fear , 2010, Trends in Cognitive Sciences.

[36]  Cheryl L. Grady,et al.  Distributed self in episodic memory: neural correlates of successful retrieval of self-encoded positive and negative personality traits , 2004, NeuroImage.

[37]  Aaron C. Koralek,et al.  Two Takes on the Social Brain: A Comparison of Theory of Mind Tasks , 2007, Journal of Cognitive Neuroscience.

[38]  S. Rauch,et al.  What is an anxiety disorder? , 2009, Depression and anxiety.

[39]  E. Kandel,et al.  Resolving Emotional Conflict: A Role for the Rostral Anterior Cingulate Cortex in Modulating Activity in the Amygdala , 2006, Neuron.

[40]  John D E Gabrieli,et al.  Emotion regulation ability varies in relation to intrinsic functional brain architecture. , 2015, Social cognitive and affective neuroscience.

[41]  H. Walter,et al.  Behavioural and neural correlates of self-focused emotion regulation in social anxiety disorder. , 2014, Journal of psychiatry & neuroscience : JPN.

[42]  Jennifer A. Silvers,et al.  Functional imaging studies of emotion regulation: a synthetic review and evolving model of the cognitive control of emotion , 2012, Annals of the New York Academy of Sciences.

[43]  Do P. M. Tromp,et al.  Reduced structural connectivity of a major frontolimbic pathway in generalized anxiety disorder. , 2012, Archives of general psychiatry.

[44]  Heide Klumpp,et al.  ABERRANT AMYGDALA–FRONTAL CORTEX CONNECTIVITY DURING PERCEPTION OF FEARFUL FACES AND AT REST IN GENERALIZED SOCIAL ANXIETY DISORDER , 2013, Depression and anxiety.

[45]  S. Strakowski,et al.  NEUROCIRCUITRY OF GENERALIZED ANXIETY DISORDER IN ADOLESCENTS: A PILOT FUNCTIONAL NEUROIMAGING AND FUNCTIONAL CONNECTIVITY STUDY , 2012, Depression and anxiety.

[46]  Siegfried Kasper,et al.  Reduced resting-state functional connectivity between amygdala and orbitofrontal cortex in social anxiety disorder , 2011, NeuroImage.

[47]  D. Kupfer,et al.  Neuroscience, clinical evidence, and the future of psychiatric classification in DSM-5. , 2011, The American journal of psychiatry.

[48]  T. Lincoln,et al.  Emotion regulation difficulties in social anxiety disorder and their specific contributions to anxious responding. , 2015, Journal of clinical psychology.

[49]  E. Leibenluft,et al.  Mothers' neural activation in response to pictures of their children and other children , 2004, Biological Psychiatry.

[50]  D. Mennin,et al.  Evidence of Broad Deficits in Emotion Regulation Associated with Chronic Worry and Generalized Anxiety Disorder , 2006, Cognitive Therapy and Research.

[51]  Wei Zhang,et al.  Selective aberrant functional connectivity of resting state networks in social anxiety disorder , 2010, NeuroImage.

[52]  Jennifer Urbano Blackford,et al.  Amygdala–cingulate intrinsic connectivity is associated with degree of social inhibition , 2014, Biological Psychology.

[53]  Amanda V. Utevsky,et al.  Precuneus Is a Functional Core of the Default-Mode Network , 2014, The Journal of Neuroscience.

[54]  Katherine E. Prater,et al.  Disrupted amygdalar subregion functional connectivity and evidence of a compensatory network in generalized anxiety disorder. , 2009, Archives of general psychiatry.

[55]  Jennifer S. Beer,et al.  Prefrontal involvement in the regulation of emotion: convergence of rat and human studies , 2006, Current Opinion in Neurobiology.

[56]  Kerry J Ressler,et al.  The neurobiology of anxiety disorders: brain imaging, genetics, and psychoneuroendocrinology. , 2010, Clinics in laboratory medicine.

[57]  G. Glover,et al.  Dissociable Intrinsic Connectivity Networks for Salience Processing and Executive Control , 2007, The Journal of Neuroscience.

[58]  Xin Wang,et al.  Neural Dysregulation in Posttraumatic Stress Disorder: Evidence for Disrupted Equilibrium Between Salience and Default Mode Brain Networks , 2012, Psychosomatic medicine.

[59]  Pradeep J Nathan,et al.  Modulation of Resting-State Amygdala-Frontal Functional Connectivity by Oxytocin in Generalized Social Anxiety Disorder , 2014, Neuropsychopharmacology.

[60]  C. Olson,et al.  Functional heterogeneity in cingulate cortex: the anterior executive and posterior evaluative regions. , 1992, Cerebral cortex.

[61]  V. Menon,et al.  Saliency, switching, attention and control: a network model of insula function , 2010, Brain Structure and Function.

[62]  M. Paulus,et al.  Prefrontal dysfunction during emotion regulation in generalized anxiety and panic disorders , 2012, Psychological Medicine.

[63]  K. L. Gratz,et al.  Multidimensional Assessment of Emotion Regulation and Dysregulation: Development, Factor Structure, and Initial Validation of the Difficulties in Emotion Regulation Scale , 2004 .

[64]  N. Woodward,et al.  Resting-State Functional Connectivity in Psychiatric Disorders. , 2015, JAMA psychiatry.

[65]  A. Anderson,et al.  Six degrees of separation: the amygdala regulates social behavior and perception , 2009, Nature Neuroscience.

[66]  Bruce W. Smith,et al.  Reduced Dorsal Anterior Cingulate Cortical Activity During Emotional Regulation and Top-Down Attentional Control in Generalized Social Phobia, Generalized Anxiety Disorder, and Comorbid Generalized Social Phobia/Generalized Anxiety Disorder , 2012, Biological Psychiatry.

[67]  Pia Baldinger,et al.  Disrupted Effective Connectivity Between the Amygdala and Orbitofrontal Cortex in Social Anxiety Disorder During Emotion Discrimination Revealed by Dynamic Causal Modeling for fMRI , 2013, Cerebral cortex.

[68]  C. N. Macrae,et al.  Finding the Self? An Event-Related fMRI Study , 2002, Journal of Cognitive Neuroscience.

[69]  M. Hamilton A RATING SCALE FOR DEPRESSION , 1960, Journal of neurology, neurosurgery, and psychiatry.

[70]  C. Kilts,et al.  Differential functional connectivity within an emotion regulation neural network among individuals resilient and susceptible to the depressogenic effects of early life stress , 2012, Psychological Medicine.

[71]  Daniel S Pine,et al.  Anxiety and anxiety disorders in children and adolescents: developmental issues and implications for DSM-V. , 2009, The Psychiatric clinics of North America.

[72]  R. Lanius,et al.  Resting-State Neuroimaging Studies: A New Way of Identifying Differences and Similarities among the Anxiety Disorders? , 2014, Canadian journal of psychiatry. Revue canadienne de psychiatrie.

[73]  Karl J. Friston,et al.  Functional Connectivity: The Principal-Component Analysis of Large (PET) Data Sets , 1993, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[74]  Maurizio Corbetta,et al.  The human brain is intrinsically organized into dynamic, anticorrelated functional networks. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[75]  J. Haxby,et al.  Neural response to the visual familiarity of faces , 2006, Brain Research Bulletin.

[76]  M. Tull,et al.  An examination of recent non-clinical panic attacks, panic disorder, anxiety sensitivity, and emotion regulation difficulties in the prediction of generalized anxiety disorder in an analogue sample. , 2009, Journal of anxiety disorders.

[77]  Jason P. Mitchell Mentalizing and Marr: An information processing approach to the study of social cognition , 2006, Brain Research.

[78]  J. Haxby,et al.  Beyond amygdala: Default Mode Network activity differs between patients with Social Phobia and healthy controls , 2009, Brain Research Bulletin.

[79]  H. Heinze,et al.  The resting brain and our self: Self-relatedness modulates resting state neural activity in cortical midline structures , 2008, Neuroscience.

[80]  G. Shulman,et al.  Medial prefrontal cortex and self-referential mental activity: Relation to a default mode of brain function , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[81]  D. Mennin,et al.  Mindfulness and emotion regulation difficulties in generalized anxiety disorder: preliminary evidence for independent and overlapping contributions. , 2009, Behavior therapy.

[82]  D. Schacter,et al.  The Brain's Default Network , 2008, Annals of the New York Academy of Sciences.

[83]  J. Gross,et al.  Neural bases of social anxiety disorder: emotional reactivity and cognitive regulation during social and physical threat. , 2009, Archives of general psychiatry.

[84]  Matthew D. Lieberman,et al.  Altered emotion regulation capacity in social phobia as a function of comorbidity. , 2015, Social cognitive and affective neuroscience.

[85]  S. Rombouts,et al.  Resting-state functional connectivity abnormalities in limbic and salience networks in social anxiety disorder without comorbidity , 2013, European Neuropsychopharmacology.