Altered Effective Connectivity Network of the Amygdala in Social Anxiety Disorder: A Resting-State fMRI Study

The amygdala is often found to be abnormally recruited in social anxiety disorder (SAD) patients. The question whether amygdala activation is primarily abnormal and affects other brain systems or whether it responds “normally” to an abnormal pattern of information conveyed by other brain structures remained unanswered. To address this question, we investigated a network of effective connectivity associated with the amygdala using Granger causality analysis on resting-state functional MRI data of 22 SAD patients and 21 healthy controls (HC). Implications of abnormal effective connectivity and clinical severity were investigated using the Liebowitz Social Anxiety Scale (LSAS). Decreased influence from inferior temporal gyrus (ITG) to amygdala was found in SAD, while bidirectional influences between amygdala and visual cortices were increased compared to HCs. Clinical relevance of decreased effective connectivity from ITG to amygdala was suggested by a negative correlation of LSAS avoidance scores and the value of Granger causality. Our study is the first to reveal a network of abnormal effective connectivity of core structures in SAD. This is in support of a disregulation in predescribed modules involved in affect control. The amygdala is placed in a central position of dysfunction characterized both by decreased regulatory influence of orbitofrontal cortex and increased crosstalk with visual cortex. The model which is proposed based on our results lends neurobiological support towards cognitive models considering disinhibition and an attentional bias towards negative stimuli as a core feature of the disorder.

[1]  R. Davidson,et al.  The functional neuroanatomy of emotion and affective style , 1999, Trends in Cognitive Sciences.

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

[3]  Stephen M. Smith,et al.  Advances and Pitfalls in the Analysis and Interpretation of Resting-State FMRI Data , 2010, Front. Syst. Neurosci..

[4]  Xiaoping Hu,et al.  Effect of hemodynamic variability on Granger causality analysis of fMRI , 2010, NeuroImage.

[5]  Marc Joliot,et al.  The resting state questionnaire: An introspective questionnaire for evaluation of inner experience during the conscious resting state , 2010, Brain Research Bulletin.

[6]  Qin Yang,et al.  Evaluation of the effective connectivity of supplementary motor areas during motor imagery using Granger causality mapping , 2009, NeuroImage.

[7]  Olivier David,et al.  fMRI connectivity, meaning and empiricism Comments on: Roebroeck et al. The identification of interacting networks in the brain using fMRI: Model selection, causality and deconvolution , 2011, NeuroImage.

[8]  S. Rombouts,et al.  Consistent resting-state networks across healthy subjects , 2006, Proceedings of the National Academy of Sciences.

[9]  E. Gilboa-Schechtman,et al.  Memory bias in generalized social phobia: remembering negative emotional expressions. , 2000, Journal of anxiety disorders.

[10]  T. Furmark,et al.  Cerebral blood flow during anticipation of public speaking in social phobia: a PET study , 2002, Biological Psychiatry.

[11]  V. Menon,et al.  A critical role for the right fronto-insular cortex in switching between central-executive and default-mode networks , 2008, Proceedings of the National Academy of Sciences.

[12]  G. Quirk,et al.  Neurons in medial prefrontal cortex signal memory for fear extinction , 2002, Nature.

[13]  B. Biswal,et al.  Functional connectivity of default mode network components: Correlation, anticorrelation, and causality , 2009, Human brain mapping.

[14]  M. Corbetta,et al.  Control of goal-directed and stimulus-driven attention in the brain , 2002, Nature Reviews Neuroscience.

[15]  Dan J Stein,et al.  Social Anxiety Disorder , 1999, CNS Spectrums.

[16]  Thomas Straube,et al.  Effect of task conditions on brain responses to threatening faces in social phobics: An event-related functional magnetic resonance imaging study , 2004, Biological Psychiatry.

[17]  A. Nardi,et al.  Social anxiety disorder women easily recognize fearfull, sad and happy faces: the influence of gender. , 2010, Journal of psychiatric research.

[18]  Nicola Vanello,et al.  Differential modulation of neural activity throughout the distributed neural system for face perception in patients with Social Phobia and healthy subjects , 2008, Brain Research Bulletin.

[19]  C. Granger.  Investigating causal relations by econometric models and cross-spectral methods , 1969 .

[20]  F. Volkmar,et al.  Abnormal ventral temporal cortical activity during face discrimination among individuals with autism and Asperger syndrome. , 2000, Archives of general psychiatry.

[21]  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.

[22]  B. Harrison,et al.  Influence of the fusiform gyrus on amygdala response to emotional faces in the non-clinical range of social anxiety , 2009, Psychological Medicine.

[23]  C. Segebarth,et al.  Identifying Neural Drivers with Functional MRI: An Electrophysiological Validation , 2008, PLoS biology.

[24]  Fanny Eugène,et al.  Amygdala activation in the processing of neutral faces in social anxiety disorder: Is neutral really neutral? , 2006, Psychiatry Research: Neuroimaging.

[25]  Thomas E. Nichols,et al.  Thresholding of Statistical Maps in Functional Neuroimaging Using the False Discovery Rate , 2002, NeuroImage.

[26]  L. Abbott,et al.  Responses of neurons in primary and inferior temporal visual cortices to natural scenes , 1997, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[27]  Yihong Yang,et al.  Evaluating the effective connectivity of resting state networks using conditional Granger causality , 2010, Biological Cybernetics.

[28]  Wei Liao,et al.  Nonlinear connectivity by Granger causality , 2011, NeuroImage.

[29]  Stephen M. Smith,et al.  fMRI resting state networks define distinct modes of long-distance interactions in the human brain , 2006, NeuroImage.

[30]  Gregory G. Brown,et al.  Increased amygdala activation to angry and contemptuous faces in generalized social phobia. , 2002, Archives of general psychiatry.

[31]  Rainer Goebel,et al.  The identification of interacting networks in the brain using fMRI: Model selection, causality and deconvolution , 2011, NeuroImage.

[32]  Rainer Goebel,et al.  Investigating directed cortical interactions in time-resolved fMRI data using vector autoregressive modeling and Granger causality mapping. , 2003, Magnetic resonance imaging.

[33]  N. Sadato,et al.  Neural Interaction of the Amygdala with the Prefrontal and Temporal Cortices in the Processing of Facial Expressions as Revealed by fMRI , 2001, Journal of Cognitive Neuroscience.

[34]  Wei Liao,et al.  Kernel Granger Causality Mapping Effective Connectivity on fMRI Data , 2009, IEEE Transactions on Medical Imaging.

[35]  L. Brothers,et al.  Response of neurons in the macaque amygdala to complex social stimuli , 1990, Behavioural Brain Research.

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

[37]  Wolfgang Grodd,et al.  Subcortical correlates of differential classical conditioning of aversive emotional reactions in social phobia , 1999, Biological Psychiatry.

[38]  M. Maroun,et al.  The Role of the Medial Prefrontal Cortex-Amygdala Circuit in Stress Effects on the Extinction of Fear , 2007, Neural plasticity.

[39]  Justin L. Vincent,et al.  Intrinsic Fluctuations within Cortical Systems Account for Intertrial Variability in Human Behavior , 2007, Neuron.

[40]  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.

[41]  Karl J. Friston.  Causal Modelling and Brain Connectivity in Functional Magnetic Resonance Imaging , 2009, PLoS biology.

[42]  M. Kenward,et al.  An Introduction to the Bootstrap , 2007 .

[43]  M. Ding,et al.  Granger causal influence predicts BOLD activity levels in the default mode network , 2011, Human brain mapping.

[44]  Jeffrey L. Geller,et al.  Social Phobia: Diagnosis, Assessment, and Treatment , 1997 .

[45]  Maurice M Ohayon,et al.  Social phobia and depression: prevalence and comorbidity. , 2010, Journal of psychosomatic research.

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

[47]  Yong He,et al.  Disrupted small-world networks in schizophrenia. , 2008, Brain : a journal of neurology.

[48]  Abraham Z. Snyder,et al.  A default mode of brain function: A brief history of an evolving idea , 2007, NeuroImage.

[49]  Claus C. Hilgetag,et al.  Sequence of information processing for emotions based on the anatomic dialogue between prefrontal cortex and amygdala , 2007, NeuroImage.

[50]  Rainer Goebel,et al.  Mapping directed influence over the brain using Granger causality and fMRI , 2005, NeuroImage.

[51]  S. Baron-Cohen,et al.  Recognition of Mental State Terms , 1994, British Journal of Psychiatry.

[52]  Qiyong Gong,et al.  Evaluation of the effective connectivity of the dominant primary motor cortex during bimanual movement using Granger causality , 2008, Neuroscience Letters.

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

[54]  Martin P Paulus,et al.  Anxiety vulnerability is associated with altered anterior cingulate response to an affective appraisal task , 2008, Neuroreport.

[55]  R. Dolan,et al.  The human amygdala and orbital prefrontal cortex in behavioural regulation , 2007, Philosophical Transactions of the Royal Society B: Biological Sciences.

[56]  K. Mogg,et al.  Time course of attentional bias for threat information in non-clinical anxiety. , 1997, Behaviour research and therapy.

[57]  H Fischer,et al.  Cerebral blood flow in subjects with social phobia during stressful speaking tasks: a PET study. , 2001, The American journal of psychiatry.

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

[59]  J. Angst,et al.  Social phobia. , 1995, European archives of psychiatry and clinical neuroscience.

[60]  P. McGuire,et al.  Structural magnetic resonance imaging in anxiety disorders: an update of research findings. , 2008, Revista brasileira de psiquiatria.

[61]  A. Etkin,et al.  Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. , 2007, The American journal of psychiatry.

[62]  M. Franklin.  Social phobia : diagnosis, assessment, and treatment , 1996 .

[63]  K. Phan,et al.  Anterior cingulate neurochemistry in social anxiety disorder: 1H-MRS at 4 Tesla , 2005, Neuroreport.

[64]  Karl J. Friston.  Dynamic causal modeling and Granger causality Comments on: The identification of interacting networks in the brain using fMRI: Model selection, causality and deconvolution , 2011, NeuroImage.

[65]  J. Lorberbaum,et al.  Neural correlates of speech anticipatory anxiety in generalized social phobia , 2004, Neuroreport.

[66]  Justin L. Vincent,et al.  Spontaneous neuronal activity distinguishes human dorsal and ventral attention systems. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[67]  D. Skuse.  Genetic influences on the neural basis of social cognition , 2006, Philosophical Transactions of the Royal Society B: Biological Sciences.

[68]  S. Bögels,et al.  Attention processes in the maintenance and treatment of social phobia: hypervigilance, avoidance and self-focused attention. , 2004, Clinical psychology review.

[69]  Erin B. McClure-Tone,et al.  Amygdala and ventrolateral prefrontal cortex function during anticipated peer evaluation in pediatric social anxiety. , 2008, Archives of general psychiatry.

[70]  V. Calhoun,et al.  Changes in the interaction of resting‐state neural networks from adolescence to adulthood , 2009, Human brain mapping.

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

[72]  Clarissa Trzesniak,et al.  Neuroimaging in social anxiety disorder: A systematic review of the literature , 2010, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[73]  M. Raichle,et al.  Disease and the brain's dark energy , 2010, Nature Reviews Neurology.

[74]  R. Heimberg,et al.  Recognition bias for critical faces in social phobia: a replication and extension. , 2005, Behaviour research and therapy.

[75]  David H. Skuse,et al.  Dopaminergic-neuropeptide interactions in the social brain , 2009, Trends in Cognitive Sciences.

[76]  Christoph Mulert,et al.  Neuroimaging in anxiety disorders , 2011, Dialogues in clinical neuroscience.

[77]  Lars-Göran Öst,et al.  Recognition bias for critical faces in social phobics. , 1996, Behaviour research and therapy.

[78]  Sonia J. Bishop,et al.  Neurocognitive mechanisms of anxiety: an integrative account , 2007, Trends in Cognitive Sciences.

[79]  Daniel A. Fitzgerald,et al.  Association between Amygdala Hyperactivity to Harsh Faces and Severity of Social Anxiety in Generalized Social Phobia , 2006, Biological Psychiatry.

[80]  Maurizio Corbetta,et al.  Large-scale brain networks account for sustained and transient activity during target detection , 2009, NeuroImage.

[81]  J. P. Hamilton,et al.  Investigating neural primacy in Major Depressive Disorder: Multivariate granger causality analysis of resting-state fMRI time-series data , 2010, Molecular Psychiatry.

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

[83]  U Klose,et al.  fMRI reveals amygdala activation to human faces in social phobics , 1998, Neuroreport.

[84]  D. J. Stein,et al.  Resting brain perfusion in social anxiety disorder: A voxel-wise whole brain comparison with healthy control subjects , 2008, Progress in Neuro-Psychopharmacology and Biological Psychiatry.