Intrinsic functional connectivity of the periaqueductal gray, a resting fMRI study

The periaqueductal gray (PAG) is known to play a crucial role in pain modulation and has shown a strong interaction with anterior cingulate cortex in previous functional imaging studies. We investigated the intrinsic functional connectivity of PAG using resting fMRI data from 100 subjects. The results showed that PAG is functionally connected to ACC (rostral and pregenual ACC) and also rostral ventromedial medulla (RVM), forming a core ACC-PAG-RVM network for pain modulation even no pain stimulus is applied. The comparison between genders showed that for the contrast of female minus male, significant difference was observed at mid-cingulate cortex; for the contrast of male minus female, significant differences were observed at left medial orbital prefrontal cortex, and uncus; right insula/operculum and prefrontal cortex. We believe eluciation of this intrinsic PAG network during the resting state will enhance our physiological and pathological understandings of the development and maintenance of chronic pain states.

[1]  Stafford L. Lightman,et al.  The HPA axis in major depression: classical theories and new developments , 2008, Trends in Neurosciences.

[2]  Darin D Dougherty,et al.  Regional cerebral blood flow in the amygdala and medial prefrontal cortex during traumatic imagery in male and female Vietnam veterans with PTSD. , 2004, Archives of general psychiatry.

[3]  Y. Hosobuchi,et al.  Pain relief by electrical stimulation of the central gray matter in humans and its reversal by naloxone. , 1977, Science.

[4]  S. Rauch,et al.  A functional magnetic resonance imaging study of amygdala and medial prefrontal cortex responses to overtly presented fearful faces in posttraumatic stress disorder. , 2005, Archives of general psychiatry.

[5]  Justin L. Vincent,et al.  Evidence for a frontoparietal control system revealed by intrinsic functional connectivity. , 2008, Journal of neurophysiology.

[6]  C. Büchel,et al.  Mechanisms of placebo analgesia: rACC recruitment of a subcortical antinociceptive network , 2006, Pain.

[7]  C. Büchel,et al.  Activation of the Opioidergic Descending Pain Control System Underlies Placebo Analgesia , 2009, Neuron.

[8]  D. Hassabis,et al.  When Fear Is Near: Threat Imminence Elicits Prefrontal-Periaqueductal Gray Shifts in Humans , 2007, Science.

[9]  D. Chialvo,et al.  Beyond Feeling: Chronic Pain Hurts the Brain, Disrupting the Default-Mode Network Dynamics , 2008, The Journal of Neuroscience.

[10]  Y. Hosobuchi,et al.  Autopsy analysis of the safety, efficacy and cartography of electrical stimulation of the central gray in humans , 1986, Brain Research.

[11]  Kevin Murphy,et al.  The impact of global signal regression on resting state correlations: Are anti-correlated networks introduced? , 2009, NeuroImage.

[12]  Vinod Menon,et al.  Functional connectivity in the resting brain: A network analysis of the default mode hypothesis , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[13]  Irene Tracey,et al.  The Cerebral Signature for Pain Perception and Its Modulation , 2007, Neuron.

[14]  Keith A. Johnson,et al.  Cortical Hubs Revealed by Intrinsic Functional Connectivity: Mapping, Assessment of Stability, and Relation to Alzheimer's Disease , 2009, The Journal of Neuroscience.

[15]  Justin L. Vincent,et al.  Distinct brain networks for adaptive and stable task control in humans , 2007, Proceedings of the National Academy of Sciences.

[16]  B. Rosen,et al.  A Functional Magnetic Resonance Imaging Study on the Neural Mechanisms of Hyperalgesic Nocebo Effect , 2008, The Journal of Neuroscience.

[17]  G. Gebhart,et al.  Chronic pain and medullary descending facilitation , 2002, Trends in Neurosciences.

[18]  Archana Venkataraman,et al.  Intrinsic functional connectivity as a tool for human connectomics: theory, properties, and optimization. , 2010, Journal of neurophysiology.

[19]  Justin L. Vincent,et al.  Distinct cortical anatomy linked to subregions of the medial temporal lobe revealed by intrinsic functional connectivity. , 2008, Journal of neurophysiology.

[20]  P. Mason Deconstructing Endogenous Pain Modulation , 2005 .

[21]  H. Johansen-Berg,et al.  Distinct and overlapping functional zones in the cerebellum defined by resting state functional connectivity. , 2010, Cerebral cortex.

[22]  M. Fox,et al.  Noninvasive functional and structural connectivity mapping of the human thalamocortical system. , 2010, Cerebral cortex.

[23]  Randy L. Gollub,et al.  Exploring the brain in pain: Activations, deactivations and their relation , 2010, PAIN.

[24]  Irene Tracey,et al.  Imaging pain in patients: is it meaningful? , 2006, Current opinion in neurology.

[25]  P. Rainville Brain mechanisms of pain affect and pain modulation , 2002, Current Opinion in Neurobiology.

[26]  Katiuscia Sacco,et al.  Altered Resting State in Diabetic Neuropathic Pain , 2009, PloS one.

[27]  Thomas E. Nichols,et al.  Placebo Effects Mediated by Endogenous Opioid Activity on μ-Opioid Receptors , 2005, The Journal of Neuroscience.

[28]  J. Brooks,et al.  REVIEW: From nociception to pain perception: imaging the spinal and supraspinal pathways , 2005, Journal of anatomy.

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

[30]  H. Fields State-dependent opioid control of pain , 2004, Nature Reviews Neuroscience.

[31]  P. Petrovic,et al.  Placebo and Opioid Analgesia-- Imaging a Shared Neuronal Network , 2002, Science.

[32]  F. Graeff,et al.  Panic Disorder: Is the PAG Involved? , 2009, Neural plasticity.

[33]  Andreas Schulze-Bonhage,et al.  The reliability of fMRI activations in the medial temporal lobes in a verbal episodic memory task , 2005, NeuroImage.

[34]  K. Sacco,et al.  Altered resting state attentional networks in diabetic neuropathic pain , 2009, Journal of Neurology, Neurosurgery & Psychiatry.

[35]  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.

[36]  F. Migliorati,et al.  Low-frequency BOLD fluctuations demonstrate altered thalamocortical connectivity in diabetic neuropathic pain , 2009, BMC Neuroscience.

[37]  Irene Tracey,et al.  The influence of negative emotions on pain: Behavioral effects and neural mechanisms , 2009, NeuroImage.

[38]  M. Mintun,et al.  Brain work and brain imaging. , 2006, Annual review of neuroscience.

[39]  D. Hassabis,et al.  From Threat to Fear: The Neural Organization of Defensive Fear Systems in Humans , 2009, The Journal of Neuroscience.

[40]  J. Price,et al.  Free will versus survival: Brain systems that underlie intrinsic constraints on behavior , 2005, The Journal of comparative neurology.

[41]  Daniel S. Margulies,et al.  Mapping the functional connectivity of anterior cingulate cortex , 2007, NeuroImage.

[42]  R. Buckner,et al.  Task-free presurgical mapping using functional magnetic resonance imaging intrinsic activity. , 2009, Journal of neurosurgery.

[43]  M. Baliki,et al.  Towards a theory of chronic pain , 2009, Progress in Neurobiology.

[44]  K. Davis,et al.  Two systems of resting state connectivity between the insula and cingulate cortex , 2009, Human brain mapping.

[45]  B Carder,et al.  Analgesia from Electrical Stimulation in the Brainstem of the Rat , 1971, Science.

[46]  F. Graeff,et al.  Neurobiology of panic disorder: From animal models to brain neuroimaging , 2008, Neuroscience & Biobehavioral Reviews.

[47]  Steven C. R. Williams,et al.  Evidence of dysfunctional pain inhibition in Fibromyalgia reflected in rACC during provoked pain , 2009, PAIN®.

[48]  I. Antonijevic HPA axis and sleep: Identifying subtypes of major depression , 2008, Stress.

[49]  Randy L Buckner,et al.  Reduced functional connectivity in a right-hemisphere network for volitional ocular motor control in schizophrenia. , 2010, Brain : a journal of neurology.

[50]  R. Buckner,et al.  Segregated Cerebellar-Cortical Circuits Revealed by Intrinsic Functional Connectivity , 2009, NeuroImage.

[51]  M. Heinricher,et al.  Descending control of nociception: Specificity, recruitment and plasticity , 2009, Brain Research Reviews.

[52]  Benjamin J. Shannon,et al.  Coherent spontaneous activity identifies a hippocampal-parietal memory network. , 2006, Journal of neurophysiology.

[53]  W. Drevets Neuroimaging studies of mood disorders , 2000, Biological Psychiatry.

[54]  B. Biswal,et al.  Functional connectivity in the motor cortex of resting human brain using echo‐planar mri , 1995, Magnetic resonance in medicine.

[55]  H. Critchley The human cortex responds to an interoceptive challenge. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[56]  David A Lewis,et al.  Neural and behavioral substrates of mood and mood regulation , 2002, Biological Psychiatry.

[57]  M. T. Shipley,et al.  Columnar organization in the midbrain periaqueductal gray: modules for emotional expression? , 1994, Trends in Neurosciences.

[58]  Katja Wiech,et al.  Prestimulus functional connectivity determines pain perception in humans , 2009, Proceedings of the National Academy of Sciences.

[59]  A. Murphy,et al.  The Role of the Periaqueductal Gray in the Modulation of Pain in Males and Females: Are the Anatomy and Physiology Really that Different? , 2009, Neural plasticity.

[60]  B. Vogt Pain and emotion interactions in subregions of the cingulate gyrus , 2005, Nature Reviews Neuroscience.

[61]  D. V. Reynolds,et al.  Surgery in the Rat during Electrical Analgesia Induced by Focal Brain Stimulation , 1969, Science.