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Simultaneous transcranial magnetic stimulation and single-neuron recording in alert non-human primates


Transcranial magnetic stimulation (TMS) is a widely used, noninvasive method for stimulating nervous tissue, yet its mechanisms of effect are poorly understood. Here we report new methods for studying the influence of TMS on single neurons in the brain of alert non-human primates. We designed a TMS coil that focuses its effect near the tip of a recording electrode and recording electronics that enable direct acquisition of neuronal signals at the site of peak stimulus strength minimally perturbed by stimulation artifact in awake monkeys (Macaca mulatta). We recorded action potentials within 1 ms after 0.4-ms TMS pulses and observed changes in activity that differed significantly for active stimulation as compared with sham stimulation. This methodology is compatible with standard equipment in primate laboratories, allowing easy implementation. Application of these tools will facilitate the refinement of next generation TMS devices, experiments and treatment protocols.

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Figure 1: Models and measurements of the chamber-centric coil compared with the Magstim 70-mm butterfly coil at 100% stimulator output (Magstim Rapid2 base unit).
Figure 2: Voltage artifact reduction strategies.
Figure 3: Examination of mechanical artifacts resulting from 100% intensity TMS.
Figure 4: Recordings of neuronal spikes activated by single pulse TMS.
Figure 5: Population responses to TMS.


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We thank C. Kozyrkov for her assistance with preliminary data collection. This work was supported by a Research Incubator Award from the Duke Institute for Brain Sciences to T.E., M.L.P., M.A.S., and W.M.G. and by NIH grant R21 NS078687 to M.A.S.

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Authors and Affiliations



T.E., M.L.P., M.A.S. and W.M.G. designed the experiments. J.K.M., Z.-D.D., A.V.P. and W.M.G. developed and constructed the TMS coil and associated electronics. Z.-D.D., J.K.M., A.V.P. and W.M.G. conducted the modeling. V.P., F.W.P., J.K.M., E.M.G., H.R. and M.A.S. used the TMS technology in combination with neurophysiological techniques to collect and analyze the single-neuron recording data in monkeys. J.K.M., M.A.S. and W.M.G. wrote the manuscript with editorial input from all of the other authors.

Corresponding author

Correspondence to Warren M Grill.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Novel chamber-centric TMS coil.

(a) Model of monkey skull with cylinder head holder at top, recording chamber placed over M1 at right, and green clay representing dental acrylic. (b) Chamber-centric stimulation coil in position for stimulation; it slides around the recording chamber. (c) Top-down, (d) face-on, and (e) inverted view of the chamber-centric coil.

Supplementary Figure 2 Structural model of final coil design.

(a) Boundary conditions of model. Red outlines the border of the radial force exerted by the stimulation coil while the blue, vertical midline to the right is the axis of symmetry of the coil constrained to zero displacement in the horizontal direction. (b) Estimate of the internal stresses resultant from the peak force of the coil windings during stimulation. Units in Pa.

Supplementary Figure 3 Measurements of heating, current flow and electric field waveform for the chamber-centric coil compared with a Magstim double 70-mm coil at 100% stimulator intensity (Magstim Rapid2 base unit).

(a) Changes in coil temperature as a function of TMS pulses delivered. (b) Coil currents as a function of time. (c) Electric field waveforms measured in saline, 1.2 cm from coil centers, as a function of time.

Supplementary Figure 4 Analysis of current artifacts resulting from TMS in the recording electronics.

(a) Schematic of the headstage front-end highlighting the induction loop around the recording leads. Also shown at the bottom of the schematic is the capacitive coupling of the animal tissue to the TMS coil and other noise sources. (b) Schematic of the headstage frontend with additional preamps connected to measure the induced currents in the recording leads with a 100 Ω series sense resistor (Rshunt). The connection of the test leads, however, creates additional induction loops, generating further currents in the recording leads. (c) Schematic of the headstage front-end highlighting induction loops through the ground lead. Currents through the ground lead can be larger than the recording electrode current due to the large area of the inductive loops, the possibility of multiple loops through the ground lead, and the low impedance of ground loops. The contact area of the grounding electrode is large, however, resulting in negligible injected current density. (d) Illustration of TMS coil and the locations of the recording leads connected to the recording electrode and guide tube. Note that the majority of the induction loop area of the recording leads is relatively distant from the TMS coil. The 15.2 V estimate of the voltage generated in the loop in equation (1) of the Online Methods is therefore a worst-case calculation.

Supplementary Figure 5 Measurements of TMS-induced currents.

(a) The headstage and recording electronics were modified to avoid saturation and voltage clamping due to TMS, to determine the voltage across the front-end dc bias resistor. (b) Currents measured in panel a for 10% to 100% stimulator output. At 100% output, about 4 nA of current due to TMS was observed. (c) 100 Ω sense resistor (Rshunt) used to measure current in headstage front-end, as an alternate method to verify the small currents generated in the recording leads during TMS. (d) Currents measured in shunt resistor of panel c for 25% and 50% stimulator output. Note the capacitive spikes at the beginning, middle and end of the TMS waveform at 50% stimulator output due to direct capacitive coupling between the TMS coil and saline (Vtms and Ctms in the schematic). The capacitive spikes saturate the measurement amplifiers (SR560 in the schematic) at higher stimulation intensities. Due to the linear scaling of stimulation intensity, though, doubling the peak (non capacitive spike) current for 50% stimulator output yields a good estimate of the peak current at 100% stimulator output, which is less than 1 μA.

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Mueller, J., Grigsby, E., Prevosto, V. et al. Simultaneous transcranial magnetic stimulation and single-neuron recording in alert non-human primates. Nat Neurosci 17, 1130–1136 (2014).

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