title: Probing thalamic integrity in schizophrenia using concurrent transcranial magnetic stimulation and functional magnetic resonance imaging.
abstract: BACKGROUND
  Schizophrenia is a devastating illness with an indeterminate pathophysiology. Several lines of evidence implicate dysfunction in the thalamus, a key node in the distributed neural networks underlying perception, emotion, and cognition. Existing evidence of aberrant thalamic function is based on indirect measures of thalamic activity, but dysfunction has not yet been demonstrated with a causal method.
  
  
  OBJECTIVE
  To test the hypothesis that direct physiological stimulation of the cortex will produce an abnormal thalamic response in individuals with schizophrenia.
  
  
  METHODS
  We stimulated the precentral gyrus with single-pulse transcranial magnetic stimulation (spTMS) and measured the response to this pulse in synaptically connected regions (thalamus, medial superior frontal cortex, insula) using concurrent functional magnetic resonance imaging. The mean hemodynamic response from these regions was fit with the sum of 2 gamma functions, and response parameters were compared across groups.
  
  
  METHODS
  Academic research laboratory.
  
  
  METHODS
  Patients with schizophrenia and sex- and age-matched psychiatrically healthy subjects were recruited from the community.
  
  
  METHODS
  Peak amplitude of the thalamic hemodynamic response to spTMS of the precentral gyrus.
  
  
  RESULTS
  The spTMS-evoked responses did not differ between groups at the cortical stimulation site. Compared with healthy subjects, patients with schizophrenia showed a reduced response to spTMS in the thalamus (P=1.86 × 10(-9)) and medial superior frontal cortex (P=.02). Similar results were observed in the insula. Sham TMS indicated that these results could not be attributed to indirect effects of TMS coil discharge. Functional connectivity analyses revealed weaker thalamus-medial superior frontal cortex and thalamus-insula connectivity in patients with schizophrenia compared with control subjects.
  
  
  CONCLUSIONS
  Individuals with schizophrenia showed reduced thalamic activation in response to direct perturbation delivered to the cortex. These results extend prior work implicating the thalamus in the pathophysiology of schizophrenia and suggest that the thalamus contributes to the patterns of aberrant connectivity characteristic of this disease.
authors.affiliation: Department of Psychiatry, University of Wisconsin–Madison, 53706, USA. guller@wisc.edu
authors.forename: Yelena
authors.initials: Y
authors.lastname: Guller
authors.forename: Fabio
authors.initials: F
authors.lastname: Ferrarelli
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Shackman
authors.forename: Simone
authors.initials: S
authors.lastname: Sarasso
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Peterson
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Langheim
authors.forename: Mary E
authors.initials: ME
authors.lastname: Meyerand
authors.forename: Giulio
authors.initials: G
authors.lastname: Tononi
authors.forename: Bradley R
authors.initials: BR
authors.lastname: Postle
mesh_terms: D000328:Adult; D001931:Brain Mapping; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008875:Middle Aged; D012559:Schizophrenia / Q000503:physiopathology*; D012720:Severity of Illness Index; D013788:Thalamus / Q000503:physiopathology*; D050781:Transcranial Magnetic Stimulation / Q000379:methods*