title: The anxiolytic effects of midazolam during anticipation to pain revealed using fMRI.
abstract: OBJECTIVE
  Functional neuroimaging can distinguish components of the pain experience associated with anticipation to pain from those associated with the experience of pain itself. Anticipation to pain is thought to increase the suffering of chronic pain patients. Inappropriate anxiety, of which anticipation is a component, is also a cause of disability. We present a pharmacological functional magnetic resonance imaging (fMRI) study in which we investigate the selective modulation by midazolam of brain activity associated with anticipation to pain compared to pain itself.
  
  
  METHODS
  Eight right-handed male volunteers underwent fMRI combined with a thermal pain conditioning paradigm and midazolam (30 mug/kg) or saline administration on different occasions, with order randomized across volunteers. Volunteers learned to associate a colored light with either painful, hot stimulation or nonpainful, warm stimulation to the back of the left hand.
  
  
  RESULTS
  Comparison of the period during thermal stimulation (pain-warm) revealed a network of brain activity commonly associated with noxious stimulation, including activities in the anterior cingulate cortex (ACC), the bilateral insular cortices (anterior and posterior), the thalamus, S1, the motor cortex, the brainstem, the prefrontal cortex and the cerebellum. Comparison of the periods preceding thermal stimulation (anticipation to pain-anticipation to warm) revealed activity principally in the ACC, the contralateral anterior insular cortex and the ipsilateral S2/posterior insula. Detected by a region-of-interest analysis, midazolam reduced the activity associated specifically with anticipation to pain while controlling for anticipation to warm. This was most significant in the contralateral anterior insula (P<.05). There were no significant drug effects on the activity associated with pain itself.
  
  
  CONCLUSIONS
  In identifying a pharmacological effect on activity preceding but not during pain, we have successfully demonstrated an fMRI assay that can be used to study the action of anxiolytic agents in a relatively small cohort of humans.
authors.affiliation: Department of Clinical Neurology, Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB), University of Oxford, John Radcliffe Hospital, OX3 9DU Oxford, UK. wiserg@cardiff.ac.uk
authors.forename: Richard G
authors.initials: RG
authors.lastname: Wise
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Lujan
authors.forename: Petra
authors.initials: P
authors.lastname: Schweinhardt
authors.forename: Guy D
authors.initials: GD
authors.lastname: Peskett
authors.forename: Richard
authors.initials: R
authors.lastname: Rogers
authors.forename: Irene
authors.initials: I
authors.lastname: Tracey
mesh_terms: D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001519:Behavior; D001921:Brain / Q000473:pathology; D001931:Brain Mapping / Q000379:methods; D015331:Cohort Studies; D003116:Color; D003975:Diazepam / Q000494:pharmacology; D006801:Humans; D008027:Light; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008874:Midazolam / Q000494:pharmacology*; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D014151:Anti-Anxiety Agents; D003975:Diazepam; D008874:Midazolam