title: Repetitive Transcranial Magnetic Stimulation Educes Frequency-Specific Causal Relationships in the Motor Network.
abstract: Repetitive transcranial magnetic stimulation (rTMS) has the potential to treat brain disorders by modulating the activity of disease-specific brain networks, yet the rTMS frequencies used are delivered in a binary fashion - excitatory (>1 Hz) and inhibitory (≤1 Hz).
  
  
  
  To assess the effective connectivity of the motor network at different rTMS stimulation rates during positron-emission tomography (PET) and confirm that not all excitatory rTMS frequencies act on the motor network in the same manner.
  
  
  
  We delivered image-guided, supra-threshold rTMS at 3 Hz, 5 Hz, 10 Hz, 15 Hz and rest (in separate randomized sessions) to the primary motor cortex (M1) of the lightly anesthetized baboon during PET imaging. Each rTMS/PET session was analyzed using normalized cerebral blood flow (CBF) measurements. Path analysis - using structural equation modeling (SEM) - was employed to determine the effective connectivity of the motor network at all rTMS frequencies. Once determined, the final model of the motor network was used to assess any differences in effective connectivity at each rTMS frequency.
  
  
  
  The exploratory SEM produced a very well fitting final network model (χ(2) = 18.04, df = 21, RMSEA = 0.000, p = 0.647, TLI = 1.12) using seven nodes of the motor network. 5 Hz rTMS produced the strongest path coefficients in four of the seven connections, suggesting that this frequency is the optimal rTMS frequency for stimulation the motor network (as a whole); however, the premotor cerebellum connection was optimally stimulated at 10 Hz rTMS and the supplementary motor area caudate connection was optimally driven at 15 Hz rTMS.
  
  
  
  We have demonstrated that 1) 5 Hz rTMS revealed the strongest path coefficients (i.e. causal influence) on the nodes of the motor network, 2) stimulation at "excitatory" rTMS frequencies did not produce increased CBF in all nodes of the motor network, 3) specific rTMS frequencies may be used to target specific none-to-node interactions in the stimulated brain network, and 4) more research needs to be performed to determine the optimum frequency for each brain circuit and/or node.
authors.affiliation: Research Imaging Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States. Electronic address: salinasf@uthscsa.edu.
authors.forename: Felipe S
authors.initials: FS
authors.lastname: Salinas
authors.affiliation: Research Imaging Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.
authors.forename: Crystal
authors.initials: C
authors.lastname: Franklin
authors.affiliation: Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, United States.
authors.forename: Shalini
authors.initials: S
authors.lastname: Narayana
authors.affiliation: Department of Neurology, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.
authors.forename: C Ákos
authors.initials: CÁ
authors.lastname: Szabó
authors.affiliation: Research Imaging Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Fox
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000502:physiology; D002560:Cerebrovascular Circulation / Q000502:physiology; D019054:Evoked Potentials, Motor / Q000502:physiology*; D005260:Female; D008297:Male; D009044:Motor Cortex / Q000502:physiology*; D009415:Nerve Net / Q000502:physiology*; D010215:Papio; D049268:Positron-Emission Tomography / Q000379:methods; D011897:Random Allocation; D050781:Transcranial Magnetic Stimulation / Q000379:methods*
keywords: Effective connectivity; Motor cortex; Network; PET; Rate; TMS