Decreased frontal regulation during pain anticipation in unmedicated subjects with major depressive disorder

Major depressive disorder (MDD) is characterized by impaired processing of negative information, possibly due to dysfunction in both, the bottom-up emotional network and top-down modulatory network. By acquiring functional magnetic resonance imaging (fMRI) on a pain-anticipation task, we tested the hypothesis that individuals with MDD would show increased negative biasing that may be associated with reduced frontal connectivity. Thirty-one (15 females) unmedicated young adults with current MDD and 22 (11 females) healthy subjects with no history of MDD were recruited. Groups did not differ significantly in age, race, level of education, marital status or gender distribution. fMRI data were collected during an event-related pain-anticipation paradigm, during which subjects were cued to anticipate painful heat stimuli of high or low intensity. All temperature stimuli were applied to each subject’s left forearm. We found that relative to healthy comparison subjects, participants with MDD showed significantly stronger responses to high versus low pain anticipation within right ventral anterior insula (AI), but overlapping response within right dorsal AI, which correlated positively with the depression symptoms severity in the MDD group. Functional connectivity analyses showed increased functional connectivity between dorsal insula and posterior thalamus and decreased functional connectivity between dorsal insula and the right inferior frontal gyrus in the MDD compared with the non-MDD group. Our results demonstrate that unmedicated individuals with current MDD compared with healthy never-depressed subjects show both differential and overlapping response within AI during anticipation of pain. Furthermore, the overlapping insular response is less regulated by frontal brain systems and is more subservient to affective processing regions in the posterior thalamus in MDD. These results support and provide functional validation of the co-occurring enhanced ‘bottom-up’ and attenuated ‘top-down’ processing of salient, unpleasant emotional information in MDD.

[1]  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.

[2]  C. Keysers,et al.  Probabilistic tractography recovers a rostrocaudal trajectory of connectivity variability in the human insular cortex , 2011, Human brain mapping.

[3]  H. Burton,et al.  The posterior thalamic region and its cortical projection in new world and old world monkeys , 1976, The Journal of comparative neurology.

[4]  Edward E. Smith,et al.  Placebo-Induced Changes in fMRI in the Anticipation and Experience of Pain , 2004, Science.

[5]  K. Mogg,et al.  Attentional bias in anxiety and depression: the role of awareness. , 1995, The British journal of clinical psychology.

[6]  B. Abler,et al.  Anticipation of aversive stimuli activates extended amygdala in unipolar depression. , 2007, Journal of psychiatric research.

[7]  Naomi B. Pitskel,et al.  Three Systems of Insular Functional Connectivity Identified with Cluster Analysis , 2010, Cerebral cortex.

[8]  D L Rosene,et al.  Cingulate cortex of the rhesus monkey: I. Cytoarchitecture and thalamic afferents , 1987, The Journal of comparative neurology.

[9]  T. Johnstone,et al.  Perceived Controllability Modulates the Neural Response to Pain , 2004, The Journal of Neuroscience.

[10]  M. Olfson,et al.  Major depressive disorder, somatic pain, and health care costs in an urban primary care practice. , 2006, The Journal of clinical psychiatry.

[11]  N. Christenfeld Memory for pain and the delayed effects of distraction. , 1997, Health psychology : official journal of the Division of Health Psychology, American Psychological Association.

[12]  Philippe R Goldin,et al.  Neural mechanisms underlying 5-HTTLPR-related sensitivity to acute stress. , 2012, The American journal of psychiatry.

[13]  A. Craig,et al.  Pain mechanisms: labeled lines versus convergence in central processing. , 2003, Annual review of neuroscience.

[14]  Nikolaus Weiskopf,et al.  Anterolateral Prefrontal Cortex Mediates the Analgesic Effect of Expected and Perceived Control over Pain , 2006, The Journal of Neuroscience.

[15]  Anthony R. McIntosh,et al.  Limbic–frontal circuitry in major depression: a path modeling metanalysis , 2004, NeuroImage.

[16]  J L Lancaster,et al.  Automated Talairach Atlas labels for functional brain mapping , 2000, Human brain mapping.

[17]  M. Thase,et al.  Can’t shake that feeling: event-related fMRI assessment of sustained amygdala activity in response to emotional information in depressed individuals , 2002, Biological Psychiatry.

[18]  Abraham Z. Snyder,et al.  Altered Emotional Interference Processing in Affective and Cognitive-Control Brain Circuitry in Major Depression , 2008, Biological Psychiatry.

[19]  David A. Seminowicz,et al.  A re-examination of pain–cognition interactions: Implications for neuroimaging , 2007, PAIN.

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

[21]  David A. Williams,et al.  The relationship between depression, clinical pain, and experimental pain in a chronic pain cohort. , 2005, Arthritis and rheumatism.

[22]  Katrin Amunts,et al.  Cytoarchitecture and probabilistic maps of the human posterior insular cortex. , 2010, Cerebral cortex.

[23]  A. Craig How do you feel? Interoception: the sense of the physiological condition of the body , 2002, Nature Reviews Neuroscience.

[24]  A. Beck,et al.  Comparison of Beck Depression Inventories -IA and -II in psychiatric outpatients. , 1996, Journal of personality assessment.

[25]  M. Thase,et al.  Increased Amygdala and Decreased Dorsolateral Prefrontal BOLD Responses in Unipolar Depression: Related and Independent Features , 2007, Biological Psychiatry.

[26]  R W Cox,et al.  AFNI: software for analysis and visualization of functional magnetic resonance neuroimages. , 1996, Computers and biomedical research, an international journal.

[27]  S. Lyubomirsky,et al.  Effects of ruminative and distracting responses to depressed mood on retrieval of autobiographical memories. , 1998, Journal of personality and social psychology.

[28]  Elena Peltz,et al.  Functional connectivity of the human insular cortex during noxious and innocuous thermal stimulation , 2011, NeuroImage.

[29]  A. Simmons,et al.  Neural Correlates of Altered Pain Response in Women with Posttraumatic Stress Disorder from Intimate Partner Violence , 2010, Biological Psychiatry.

[30]  Brian Knutson,et al.  Neural Responses to Monetary Incentives in Major Depression , 2008, Biological Psychiatry.

[31]  A. Schwartzman,et al.  Stress and selective attention: the interplay of mood, cortisol levels, and emotional information processing. , 2002, Psychophysiology.

[32]  A. Simmons,et al.  Anxiety positive subjects show altered processing in the anterior insula during anticipation of negative stimuli , 2011, Human brain mapping.

[33]  A. Craig,et al.  How do you feel — now? The anterior insula and human awareness , 2009, Nature Reviews Neuroscience.

[34]  H. Mayberg Limbic-cortical dysregulation: a proposed model of depression. , 1997, The Journal of neuropsychiatry and clinical neurosciences.

[35]  Jonathan D. Cohen,et al.  Improved Assessment of Significant Activation in Functional Magnetic Resonance Imaging (fMRI): Use of a Cluster‐Size Threshold , 1995, Magnetic resonance in medicine.

[36]  W. Katon,et al.  Depression and pain comorbidity: a literature review. , 2003, Archives of internal medicine.

[37]  Karl-Jürgen Bär,et al.  Increased Prefrontal Activation During Pain Perception in Major Depression , 2007, Biological Psychiatry.

[38]  Peter Herscovitch,et al.  Neural and behavioral responses to tryptophan depletion in unmedicated patients with remitted major depressive disorder and controls. , 2004, Archives of general psychiatry.

[39]  Raffael Kalisch,et al.  A meta-analysis of instructed fear studies: Implications for conscious appraisal of threat , 2010, NeuroImage.

[40]  John E. Roberts,et al.  Rumination, negative cognition, and their interactive effects on depressed mood. , 2007, Emotion.

[41]  Joseph E LeDoux The Emotional Brain: The Mysterious Underpinnings of Emotional Life , 1996 .

[42]  S. Paradiso The Emotional Brain: The Mysterious Underpinnings of Emotional Life , 1998 .

[43]  A. Beck Depression : clinical, experimental, and theoretical aspects , 1967 .

[44]  D. German,et al.  Elevated neuron number in the limbic thalamus in major depression. , 2004, The American journal of psychiatry.

[45]  M. Torrens Co-Planar Stereotaxic Atlas of the Human Brain—3-Dimensional Proportional System: An Approach to Cerebral Imaging, J. Talairach, P. Tournoux. Georg Thieme Verlag, New York (1988), 122 pp., 130 figs. DM 268 , 1990 .

[46]  M. Yașargil,et al.  Topographic anatomy of the insular region. , 1999, Journal of neurosurgery.

[47]  A. Schulze-Bonhage,et al.  Functional organization of the human anterior insular cortex , 2009, Neuroscience Letters.

[48]  Katiuscia Sacco,et al.  Functional connectivity of the insula in the resting brain , 2011, NeuroImage.

[49]  T. Egner,et al.  Emotional processing in anterior cingulate and medial prefrontal cortex , 2011, Trends in Cognitive Sciences.

[50]  R. Wenzlaff,et al.  Unmasking a cognitive vulnerability to depression: how lapses in mental control reveal depressive thinking. , 1998, Journal of personality and social psychology.

[51]  Tonio Ball,et al.  Pain and emotion in the insular cortex: evidence for functional reorganization in major depression , 2012, Neuroscience Letters.

[52]  A. Craig,et al.  Interoception and Emotion : a Neuroanatomical Perspective , 2007 .

[53]  S. Minoshima,et al.  Keeping pain out of mind: the role of the dorsolateral prefrontal cortex in pain modulation. , 2003, Brain : a journal of neurology.

[54]  Robert A Koeppe,et al.  Dysregulation of endogenous opioid emotion regulation circuitry in major depression in women. , 2006, Archives of general psychiatry.

[55]  A. Simmons,et al.  Altered insula activation during pain anticipation in individuals recovered from anorexia nervosa: evidence of interoceptive dysregulation. , 2013, The International journal of eating disorders.

[56]  Luke J. Chang,et al.  Decoding the role of the insula in human cognition: functional parcellation and large-scale reverse inference. , 2013, Cerebral cortex.

[57]  C. Saper,et al.  Organization of visceral and limbic connections in the insular cortex of the rat , 1991, The Journal of comparative neurology.

[58]  Heather L. Urry,et al.  Failure to Regulate: Counterproductive Recruitment of Top-Down Prefrontal-Subcortical Circuitry in Major Depression , 2007, The Journal of Neuroscience.

[59]  Martin P Paulus,et al.  Association of major depressive disorder with altered functional brain response during anticipation and processing of heat pain. , 2008, Archives of general psychiatry.

[60]  B Beuthien-Baumann,et al.  Changes in brain metabolism associated with remission in unipolar major depression , 2004, Acta psychiatrica Scandinavica.

[61]  Daniella J. Furman,et al.  Functional neuroimaging of major depressive disorder: a meta-analysis and new integration of base line activation and neural response data. , 2012, The American journal of psychiatry.

[62]  A. Simmons,et al.  Right Anterior Insula Hypoactivity During Anticipation of Homeostatic Shifts in Major Depressive Disorder , 2010, Psychosomatic medicine.

[63]  T. Baumgartner,et al.  Neural correlates of ‘pessimistic’ attitude in depression , 2009, Psychological Medicine.

[64]  Dawn R. Collins,et al.  Amygdala oscillations and the consolidation of emotional memories , 2002, Trends in Cognitive Sciences.

[65]  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.

[66]  L. F. Barrett,et al.  Handbook of emotions, 2nd ed. , 2000 .

[67]  Karl J. Friston,et al.  Psychophysiological and Modulatory Interactions in Neuroimaging , 1997, NeuroImage.

[68]  E. Reiman,et al.  Thermosensory activation of insular cortex , 2000, Nature Neuroscience.

[69]  V. Arolt,et al.  Human Fear Conditioning and Extinction in Neuroimaging: A Systematic Review , 2009, PloS one.

[70]  Z. Segal,et al.  Cognitive reactivity and vulnerability: empirical evaluation of construct activation and cognitive diatheses in unipolar depression. , 2005, Clinical psychology review.

[71]  M. Baulac,et al.  Functional anatomy of the insula: new insights from imaging , 2003, Surgical and Radiologic Anatomy.

[72]  Daniel K Sodickson,et al.  Thalamic resting-state functional networks: disruption in patients with mild traumatic brain injury. , 2011, Radiology.

[73]  K. Zilles,et al.  A link between the systems: functional differentiation and integration within the human insula revealed by meta-analysis , 2010, Brain Structure and Function.

[74]  E. G. Jones,et al.  A projection from the medial pulvinar to the amygdala in primates , 1976, Brain Research.

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

[76]  N. Garmezy On some risks in risk research , 1977, Psychological Medicine.

[77]  Bradford C. Dickerson,et al.  Dissociable large-scale networks anchored in the right anterior insula subserve affective experience and attention , 2012, NeuroImage.

[78]  Samuel R. Friedman,et al.  Depression: Clinical, Experimental, and Theoretical Aspects , 1968 .

[79]  S. Petersen,et al.  Role of the anterior insula in task-level control and focal attention , 2010, Brain Structure and Function.