Cortical excitability in a nonhuman primate model of TMS

Forty years ago in a Letter to the Editor, Merton & Morton [[1]Merton P.A. Morton H.B. Stimulation of the cerebral cortex in the intact human subject.Nature. 1980 May; 285: 227Crossref PubMed Scopus (773) Google Scholar] demonstrated that it was possible to induce a motor-evoked potential (MEP) in a human via non-invasive transcranial electrical stimulation. Shortly thereafter, Barker demonstrated this was possible via transcranial magnetic stimulation (TMS) [[2]Barker A.T. Jalinous R. Freeston I.L. Non-invasive magnetic stimulation of human motor cortex.Lancet. 1985 May 11; 325: 1106-1107Abstract Scopus (3008) Google Scholar]. Now, 35 years later, single-pulse TMS is often used to evaluate the effect of psychoactive medications or electromagnetic therapeutics on cortical excitability [[3]Ziemann U. Reis J. Schwenkreis P. Rosanova M. Strafella A. Badawy R. Müller-Dahlhaus F. TMS and drugs revisited 2014.Clin Neurophysiol. 2015 Oct 1; 126: 1847-1868Crossref PubMed Scopus (380) Google Scholar]. It has also been used to investigate cortical plasticity in healthy individuals and those recovering from neurologic injury [[4]Hallett M. Transcranial magnetic stimulation and the human brain.Nature. 2000 Jul; 406: 147-150Crossref PubMed Scopus (1105) Google Scholar]. Most of this discovery research is being done in humans, which can be slow and associated with risks and confounds that could be avoided if a robust animal model were available. Nonhuman primates (NHPs) are particularly well-suited for translational TMS research given the similarities in cerebral and spinal anatomy. In NHPs and humans, descending corticospinal tract fibers synapse in the ventral horn of the spinal cord or directly on motor neurons. These monosynaptic connections are the anatomical infrastructure behind the MEP– one of the most common dependent measures in neuromodulation research. In rodents, however, these monosynaptic cortico-motor projections are absent (reviews [[5]Lemon R.N. Griffiths J. Comparing the function of the corticospinal system in different species: organizational differences for motor specialization?.Muscle Nerve: Off J Am Assoc Electrodiagn Med. 2005 Sep; 32: 261-279Crossref Scopus (317) Google Scholar,[6]Courtine G. Bunge M.B. Fawcett J.W. Grossman R.G. Kaas J.H. Lemon R. Maier I. Martin J. Nudo R.J. Ramon-Cueto A. Rouiller E.M. Can experiments in nonhuman primates expedite the translation of treatments for spinal cord injury in humans?.Nat Med. 2007 May; 13: 561-566Crossref PubMed Scopus (297) Google Scholar]). NHPs also have a cerebral organization that is similar to humans and a relatively large cortex/total brain volume ratio. To address the gap in our current capabilities, we have been developing an NHP model for TMS studies of cortical excitability. Through MRI-guided positioning and online MEP monitoring it is possible to collect 1) a motor threshold and 2) motor cortical recruitment curves with high test-retest reliability from both the arm and the leg using a figure-of-eight coil, often used in human laboratory research (Fig. 1). An overview of the methods and results is listed below (for details see Supplemental Material). We welcome feedback on this work-in-progress and are happy to share our protocols with others. Our hope is that this Letter becomes a catalyst for a greater conversation about the utility NHP models could bring to the brain stimulation field. Several other groups have been investigating TMS-evoked MEPS from NHPs for many years [7Baker S.N. Olivier E. Lemon R.N. Recording an identified pyramidal volley evoked by transcranial magnetic stimulation in a conscious macaque monkey.Exp Brain Res. 1994 Jan 1; 99: 529-532Crossref PubMed Scopus (55) Google Scholar, 8Lisanby S.H. Wassermann E.M. Ziemann U. Luber B. Finck D. Osman M. Dichter G. Sackeim H.A. Motor evoked potentials to paired transcranial magnetic stimulation (TMS) in the alert and sedated rhesus monkey.Electroencephalogr Clin Neurophysiol. 1997; 1: 151Crossref Google Scholar, 9Amaya F. Paulus W. Treue S. Liebetanz D. Transcranial magnetic stimulation and PAS-induced cortical neuroplasticity in the awake rhesus monkey.Clin Neurophysiol. 2010 Dec 1; 121: 2143-2151Crossref PubMed Scopus (15) Google Scholar, 10Mueller J.K. Grigsby E.M. Prevosto V. Petraglia III, F.W. Rao H. Deng Z.D. Peterchev A.V. Sommer M.A. Egner T. Platt M.L. Grill W.M. Simultaneous transcranial magnetic stimulation and single-neuron recording in alert non-human primates.Nat Neurosci. 2014 Aug; 17: 1130Crossref PubMed Scopus (77) Google Scholar], yet this field is still very small. This is the first proof-of-principle demonstration of feasibility and reliability in obtaining stimulus-response curves from the arm and foot of NHPs. The strength of this model comes in part from the utilization of MRI scans, the use of female rhesus who have less temporalis muscle than males, and dynamic neuronavigation to maintain coil position during MEP recording. All procedures were approved by the Institutional Animal Care and Use Committee of Wake Forest University. Five female rhesus macaques (14 ± 1.2 years) participated in 2 experiments, 4–5 weeks apart. Coregistration and neuronavigation: A T1-weighted MRI scan from each animal was imported into the neuronavigation system (Brainsight 2.4, Rogue Research Inc., Canada), wherein head models and markers were created before the experiment. Scalp targets were first estimated based on the location most likely to induce the largest electrical field at the cortical targets (see Fig. 1 for induced electrical field maps, SIMNIBS 3.1). EMG: Once the animal was in place (supine with head and chest elevated approximately 45°), the forearm and lower leg were shaved, and disposable surface electrodes (24mm Covidien) were placed over the right flexor digitorum and left tibialis anterior. The EMG signal was recorded at 3kHzwith a 16-470Hz bandpass filter (MEP Unit, Rogue Research Inc., Canada). The MEP base line was confirmed to be free of noise. TMS: First, we identified the scalp position associated with the most reliable MEP in the forearm using online visual feedback from the MEP unit. Monophasic TMS pulses were applied using a figure-of-eight coil (C–B60 coil, Magpro X100 Magoption stimulator, Magventure Inc., Denmark). This position was marked as a target on the scalp and in the neuronavigation software. The motor threshold was determined through parameter estimation by sequential testing. A TMS-evoked recruitment curve was then collected (50 pulses at 75–130% RMT). This was repeated for the tibialis anterior. The procedure was repeated during Experiment 2. Analysis: The peak-to-peak amplitude of the unrectified EMG signal was computed in the 50ms response window beginning 10ms after the TMS pulse. Data analysis included curve estimation for each animal for each experiment and cross correlation of the data for experiments 1 and 2 within each animal for each limb (SPSS 26.0, IBM Statistics). The animals had an average resting MT of 76.7% ± 5.1% maximum machine output (MO; Arm) & 75.5% ± 4.2% MO (Leg). Curve estimation analysis revealed that the recruitment curve was best modeled by an exponential function (Arm: R2 = 0.73–0.97; Leg: 0.83–0.98) with significant test-retest reliability within each animal (Arm: R2 = 0.69–0.94; Leg: 0.89–0.94; p < 0.001 2-tailed). To improve the translational relevance of this model, the next step in this neuronavigation-assisted research program is to apply TMS to awake NHPs (which has been done in the past) [8Lisanby S.H. Wassermann E.M. Ziemann U. Luber B. Finck D. Osman M. Dichter G. Sackeim H.A. Motor evoked potentials to paired transcranial magnetic stimulation (TMS) in the alert and sedated rhesus monkey.Electroencephalogr Clin Neurophysiol. 1997; 1: 151Crossref Google Scholar, 9Amaya F. Paulus W. Treue S. Liebetanz D. Transcranial magnetic stimulation and PAS-induced cortical neuroplasticity in the awake rhesus monkey.Clin Neurophysiol. 2010 Dec 1; 121: 2143-2151Crossref PubMed Scopus (15) Google Scholar, 10Mueller J.K. Grigsby E.M. Prevosto V. Petraglia III, F.W. Rao H. Deng Z.D. Peterchev A.V. Sommer M.A. Egner T. Platt M.L. Grill W.M. Simultaneous transcranial magnetic stimulation and single-neuron recording in alert non-human primates.Nat Neurosci. 2014 Aug; 17: 1130Crossref PubMed Scopus (77) Google Scholar]. In addition to the use of sedated animals, another limitation is the relatively wide electric field induction on the cortical surface. Although the C–B60 coil was intentionally chosen after pilot-testing other coils (See Supplementary Material), the induced electric fields are much less focused than they would be on a human brain with the same coil and intensity. Hence, the C–B60 coil in a female rhesus macaque may not be an optimal model for studies that require precise somatotopic localizations (e.g. motor mapping after stroke). For such studies, inovel coil designs or alternative bioenergetic approaches (e.g. focused ultrasound) may be needed. Another fruitful future research area would be the integration of NHP head modeling into common software packages (e.g. SIMNIBS). Developing an automated pipeline for animal-specific dosing would refine the translational utility of this model. Finally, while human recruitment curves are best fit with a Boltzman Equation, we were unable to find a saturation dose in these animals (due to the relatively high motor thresholds). The consistency of the data, however, demonstrates that stable relationships exist which lend themselves to experimental inquiry. Inasmuch as the field and funding agencies view these NHP models as useful translational tools, NHP TMS could be a fruitful opportunity for therapeutic discovery. Colleen A. Hanlon: Conceptualization, Methodology, Investigation, Formal analysis, Writing, Visualization, Resources, Project administration. Paul W. Czoty: Conceptualization, Methodology, Investigation, Formal analysis, Writing – reviewing & editing, Resources. Hilary R. Smith: Conceptualization, Methodology, Investigation, Writing. Phillip M. Epperly: Conceptualization, Methodology, Investigation, Animal Care. Lindsey K. Galbo: Conceptualization, Methodology, Investigation, Animal Care. Dr. Hanlon has served as a consultant to the Roswell Park Cancer Institute and Brainsway, Inc. Neither of these entities were involved in this research project. She has received research support from the National Institute of Health (NIH) . Dr. Czoty has received research support from the NIH . Other authors declare no potential conflict of interest. This research as supported by the National Institute on Alcohol and Alcoholism ( P50AA026117 , T32AA007565 ). We would like to thank Alexander Opitz Ph.D.& Ivan Alekseichuk Ph.D. at University of Minnesota for providing us with a head model of the NHP template brain that is compatible with SIMNIBS. The following is the Supplementary data to this article: Download .docx (.22 MB) Help with docx files Multimedia component 1

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