Sex differences in brain activation to anticipated and experienced pain in the medial prefrontal cortex

Previous studies on sex differences in neural responses to noxious stimuli yielded mixed results. Both increased and decreased brain activation in several brain areas in women as compared to men has been reported. The current event‐related functional magnetic resonance imaging study used a parametric design with different levels of the intensity of electrical stimulation in order to investigate sex differences in brain activation during pain processing. Four intensity levels, which were determined individually according to subjective ratings, ranging from stimulation below the stimulus detection threshold to moderately painful stimuli, were applied. Females experienced mild and moderate pain at lower stimulus intensity than males. Pronounced sex differences in brain activation were found in response to stimulation below the detection threshold and for the most intense pain stimuli in the medial prefrontal cortex (MPFC). Under both the conditions, women showed stronger activation in a region of the pregenual MPFC, which has been implicated in introspective, self‐focused informationprocessing. The results suggest that women, as compared to men, show increased self‐related attention during anticipation of pain and in response to intense pain. Hum Brain Mapp, 2009. © 2008 Wiley‐Liss, Inc.

[1]  G. Pagnoni,et al.  Does Anticipation of Pain Affect Cortical Nociceptive Systems? , 2002, The Journal of Neuroscience.

[2]  M. Sullivan,et al.  Gender Differences in Pain and Pain Behavior: The Role of Catastrophizing , 2000, Cognitive Therapy and Research.

[3]  G. Affleck,et al.  The relationship of gender to pain, pain behavior, and disability in osteoarthritis patients: the role of catastrophizing , 2000, Pain.

[4]  R. Treede,et al.  Human brain mechanisms of pain perception and regulation in health and disease , 2005, European journal of pain.

[5]  R. Fillingim,et al.  Sex differences in opioid analgesia: clinical and experimental findings , 2004, European journal of pain.

[6]  L. Chang,et al.  Sex specific alterations in autonomic function among patients with irritable bowel syndrome , 2005, Gut.

[7]  R. Kessler,et al.  Regional cerebral activation in irritable bowel syndrome and control subjects with painful and nonpainful rectal distention. , 2000, Gastroenterology.

[8]  Thomas Straube,et al.  Neural Mechanisms of Automatic and Direct Processing of Phobogenic Stimuli in Specific Phobia , 2006, Biological Psychiatry.

[9]  D. Chialvo,et al.  Chronic Pain and the Emotional Brain: Specific Brain Activity Associated with Spontaneous Fluctuations of Intensity of Chronic Back Pain , 2006, The Journal of Neuroscience.

[10]  M. Raichle,et al.  Emotion-induced changes in human medial prefrontal cortex: II. During anticipatory anxiety. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[11]  E. Keogh,et al.  Gender, coping and the perception of pain , 2002, Pain.

[12]  Kevin N. Ochsner,et al.  The neural correlates of direct and reflected self-knowledge , 2005, NeuroImage.

[13]  C Büchel,et al.  Painful stimuli evoke different stimulus-response functions in the amygdala, prefrontal, insula and somatosensory cortex: a single-trial fMRI study. , 2002, Brain : a journal of neurology.

[14]  David Silbersweig,et al.  Fear-related activity in subgenual anterior cingulate differs between men and women , 2005, Neuroreport.

[15]  Roger B. Fillingim,et al.  Gender differences in the responses to noxious stimuli , 1995 .

[16]  L. Lenchik Functional imaging , 2007, Annals of Biomedical Engineering.

[17]  Kevin N. Ochsner,et al.  Neural correlates of individual differences in pain-related fear and anxiety , 2006, Pain.

[18]  R. Peyron,et al.  Functional imaging of brain responses to pain. A review and meta-analysis (2000) , 2000, Neurophysiologie Clinique/Clinical Neurophysiology.

[19]  Thomas Weiss,et al.  Acupuncture Decreases Somatosensory Evoked Potential Amplitudes to Noxious Stimuli in Anesthetized Volunteers , 2004, Anesthesia and analgesia.

[20]  M. Bushnell,et al.  Pain affect encoded in human anterior cingulate but not somatosensory cortex. , 1997, Science.

[21]  Lin Chang,et al.  Sex-related differences in IBS patients: central processing of visceral stimuli. , 2003, Gastroenterology.

[22]  C. Frith,et al.  Meeting of minds: the medial frontal cortex and social cognition , 2006, Nature Reviews Neuroscience.

[23]  R. Dolan,et al.  A Functional Anatomy of Anticipatory Anxiety , 1999, NeuroImage.

[24]  T. Dao,et al.  Gender Differences in Pain , 1995 .

[25]  O. Robin,et al.  Influence of sex and anxiety on pain threshold and tolerance. , 1987, Functional neurology.

[26]  Thomas Straube,et al.  Effects of cognitive-behavioral therapy on brain activation in specific phobia , 2006, NeuroImage.

[27]  Pierre Rainville,et al.  Memory Traces of Pain in Human Cortex , 2007, The Journal of Neuroscience.

[28]  Ravi S. Menon,et al.  Dissociating pain from its anticipation in the human brain. , 1999, Science.

[29]  Ranjan Maitra,et al.  Sex differences in the cerebral BOLD signal response to painful heat stimuli. , 2006, American journal of physiology. Regulatory, integrative and comparative physiology.

[30]  Satoshi Minoshima,et al.  Gender differences in pain perception and patterns of cerebral activation during noxious heat stimulation in humans , 1998, Pain.

[31]  L. Arendt-Nielsen,et al.  Dispositional anxiety and the experience of pain: gender‐specific effects , 2003, European journal of pain.

[32]  A. Aloisi Gonadal Hormones and Sex Differences in Pain Reactivity , 2003, The Clinical journal of pain.

[33]  Y. Tousignant-Laflamme,et al.  Sex differences in cardiac and autonomic response to clinical and experimental pain in LBP patients , 2006, European journal of pain.

[34]  K J Berkley Sex differences in pain , 1997, Behavioral and Brain Sciences.

[35]  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 .

[36]  I. Tracey Nociceptive processing in the human brain , 2005, Current Opinion in Neurobiology.

[37]  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.

[38]  Raymond J. Dolan,et al.  Levels of appraisal: A medial prefrontal role in high-level appraisal of emotional material , 2006, NeuroImage.

[39]  E. Keogh,et al.  Investigating the effect of anxiety sensitivity, gender and negative interpretative bias on the perception of chest pain , 2004, Pain.

[40]  R. Fillingim,et al.  Catastrophizing as a mediator of sex differences in pain: differential effects for daily pain versus laboratory-induced pain , 2004, Pain.

[41]  B. Bromm,et al.  The intracutaneous stimulus: a new pain model for algesimetric studies. , 1984, Methods and findings in experimental and clinical pharmacology.

[42]  Thomas Straube,et al.  Waiting for spiders: Brain activation during anticipatory anxiety in spider phobics , 2007, NeuroImage.

[43]  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.

[44]  J. Streltzer Textbook of Pain, 4th ed , 2001 .

[45]  M. Catherine Bushnell,et al.  Sex differences in pain perception and anxiety. A psychophysical study with topical capsaicin , 2004, Pain.

[46]  C. Büchel,et al.  Dissociable Neural Responses Related to Pain Intensity, Stimulus Intensity, and Stimulus Awareness within the Anterior Cingulate Cortex: A Parametric Single-Trial Laser Functional Magnetic Resonance Imaging Study , 2002, The Journal of Neuroscience.

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

[48]  A. Unruh Gender variations in clinical pain experience , 1996, Pain.

[49]  Thomas Weiss,et al.  Time course of amygdala activation during aversive conditioning depends on attention , 2007, NeuroImage.

[50]  V. Helgeson,et al.  Sex Differences in Coping Behavior: A Meta-Analytic Review and an Examination of Relative Coping , 2002 .

[51]  M. Mandelkern,et al.  Gender differences in regional brain response to visceral pressure in IBS patients , 2000, European journal of pain.

[52]  R. Fillingim,et al.  Sex differences in the perception of noxious experimental stimuli: a meta-analysis , 1998, Pain.

[53]  G. Rollman,et al.  Does past pain influence current pain: biological and psychosocial models of sex differences , 2004, European journal of pain.

[54]  C. Braun,et al.  Somatosensory event-related potentials to painful and non-painful stimuli: effects of attention , 1989, Pain.

[55]  Patrizia Baraldi,et al.  Functional activity mapping of the mesial hemispheric wall during anticipation of pain , 2003, NeuroImage.

[56]  A. Aloisi,et al.  Sex differences in pain and analgesia: the role of gonadal hormones , 2004, European journal of pain.

[57]  B. Naliboff,et al.  Heart rate mediation of sex differences in pain tolerance in children , 2005, Pain.

[58]  K. Berkley,et al.  Chapter 39 – Sex and gender differences in pain , 2003 .

[59]  R. Fillingim Sex, Gender, and Pain , 2000 .

[60]  A. Aloisi,et al.  Gender-related effects of chronic non-malignant pain and opioid therapy on plasma levels of macrophage migration inhibitory factor (MIF) , 2005, Pain.

[61]  K. Luan Phan,et al.  Functional Neuroanatomy of Emotion: A Meta-Analysis of Emotion Activation Studies in PET and fMRI , 2002, NeuroImage.

[62]  Rainer Goebel,et al.  Analysis of functional image analysis contest (FIAC) data with brainvoyager QX: From single‐subject to cortically aligned group general linear model analysis and self‐organizing group independent component analysis , 2006, Human brain mapping.

[63]  T. Dao,et al.  Gender Differences in Pain , 2000 .

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

[65]  Tatsuo Yamamoto,et al.  [Sex and/or gender differences in pain]. , 2009, Masui. The Japanese journal of anesthesiology.

[66]  Thomas E. Nichols,et al.  Gender differences in patterns of cerebral activation during equal experience of painful laser stimulation. , 2002, The journal of pain : official journal of the American Pain Society.