title: Fatigue sensation induced by the sounds associated with mental fatigue and its related neural activities: revealed by magnetoencephalography.
abstract: BACKGROUND
  It has been proposed that an inappropriately conditioned fatigue sensation could be one cause of chronic fatigue. Although classical conditioning of the fatigue sensation has been reported in rats, there have been no reports in humans. Our aim was to examine whether classical conditioning of the mental fatigue sensation can take place in humans and to clarify the neural mechanisms of fatigue sensation using magnetoencephalography (MEG).
  
  
  METHODS
  Ten and 9 healthy volunteers participated in a conditioning and a control experiment, respectively. In the conditioning experiment, we used metronome sounds as conditioned stimuli and two-back task trials as unconditioned stimuli to cause fatigue sensation. Participants underwent MEG measurement while listening to the metronome sounds for 6 min. Thereafter, fatigue-inducing mental task trials (two-back task trials), which are demanding working-memory task trials, were performed for 60 min; metronome sounds were started 30 min after the start of the task trials (conditioning session). The next day, neural activities while listening to the metronome for 6 min were measured. Levels of fatigue sensation were also assessed using a visual analogue scale. In the control experiment, participants listened to the metronome on the first and second days, but they did not perform conditioning session. MEG was not recorded in the control experiment.
  
  
  RESULTS
  The level of fatigue sensation caused by listening to the metronome on the second day was significantly higher relative to that on the first day only when participants performed the conditioning session on the first day. Equivalent current dipoles (ECDs) in the insular cortex, with mean latencies of approximately 190 ms, were observed in six of eight participants after the conditioning session, although ECDs were not identified in any participant before the conditioning session.
  
  
  CONCLUSIONS
  We demonstrated that the metronome sounds can cause mental fatigue sensation as a result of repeated pairings of the sounds with mental fatigue and that the insular cortex is involved in the neural substrates of this phenomenon.
authors.affiliation: Department of Physiology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan. a.ishii@med.osaka-cu.ac.jp
authors.forename: Akira
authors.initials: A
authors.lastname: Ishii
authors.forename: Masaaki
authors.initials: M
authors.lastname: Tanaka
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Iwamae
authors.forename: Chongsoo
authors.initials: C
authors.lastname: Kim
authors.forename: Emi
authors.initials: E
authors.lastname: Yamano
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Watanabe
mesh_terms: D000328:Adult; D001921:Brain / Q000503:physiopathology*; D005221:Fatigue / Q000503:physiopathology*; D015673:Fatigue Syndrome, Chronic / Q000503:physiopathology; D005260:Female; D006801:Humans; D015225:Magnetoencephalography; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology*; D005222:Mental Fatigue / Q000503:physiopathology*; D009483:Neuropsychological Tests