Characterizing off-target corticospinal responses to double-cone transcranial magnetic stimulation

Abstract

Introduction

The double-cone coil (D-CONE) is frequently used in transcranial magnetic stimulation (TMS) experiments that target the motor cortex (M1) lower-limb representation. Anecdotal evidence and modeling studies have shed light on the off-target effects of D-CONE TMS but the physiological extent remains undetermined.

Purpose

To characterize the off-target effects of D-CONE TMS based on bilateral corticospinal responses in the legs and hands.

Methods

Thirty (N = 30) participants (9 women, age: 26 ± 5yrs) completed a stimulus–response curve procedure with D-CONE TMS applied to the dominant vastus lateralis (cVL) and motor-evoked potentials (MEPs) recorded in each active VL and resting first dorsal interosseous (FDI). As a positive control (CON), the dominant FDI was directly targeted with a figure-of-eight coil and MEPs were similarly recorded in each active FDI and resting VL. MEPMAX, V50 and MEP latencies were compared with repeated-measures ANOVAs or mixed-effects analysis and Bonferroni-corrected pairwise comparisons.

Results

Off-target responses were evident in all muscles, with similar MEPMAX in the target (cVL) and off-target (iVL) leg (p = 0.99) and cFDI compared with CON (p = 0.99). cFDI and CON MEPMAX were greater than iFDI (p < 0.01). A main effect of target (p < 0.001) indicated that latencies were shorter with CON but similar in all muscles with D-CONE.

Discussion

Concurrent MEP recordings in bilateral upper- and lower-extremity muscles confirm that lower-limb D-CONE TMS produces substantial distance-dependent off-target effects. In addition to monitoring corticospinal responses in off-target muscles to improve targeting accuracy in real-time, future studies may incorporate off-target information into statistical models post-hoc.

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Data availability

The raw data and material supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher.

References

  1. Barker AT, Jalinous R, Freeston IL (1985) Non-invasive magnetic stimulation of human motor cortex. Lancet 1:1106–1107. https://doi.org/10.1016/s0140-6736(85)92413-4

    CAS  Article  PubMed  Google Scholar 

  2. Brasil-Neto JP, McShane LM, Fuhr P, Hallett M, Cohen LG (1992) Topographic mapping of the human motor cortex with magnetic stimulation: factors affecting accuracy and reproducibility. Electroencephalogr Clin Neurophysiol 85:9–16. https://doi.org/10.1016/0168-5597(92)90095-s

    CAS  Article  PubMed  Google Scholar 

  3. Brownstein CG, Ansdell P, Škarabot J et al (2018a) Motor cortical and corticospinal function differ during an isometric squat compared with isometric knee extension. Exp Physiol 103:1251–1263. https://doi.org/10.1113/ep086982

    Article  PubMed  Google Scholar 

  4. Brownstein CG, Ansdell P, Škarabot J, Howatson G, Goodall S, Thomas K (2018b) An optimal protocol for measurement of corticospinal excitability, short intracortical inhibition and intracortical facilitation in the rectus femoris. J Neurol Sci 394:45–56. https://doi.org/10.1016/j.jns.2018.09.001

    Article  PubMed  Google Scholar 

  5. Bungert A, Antunes A, Espenhahn S, Thielscher A (2016) Where does TMS stimulate the motor cortex? Combining electrophysiological measurements and realistic field estimates to reveal the affected cortex position. Cereb Cortex 27:5083–5094. https://doi.org/10.1093/cercor/bhw292

    Article  Google Scholar 

  6. Ciampi de Andrade D, Galhardoni R, Pinto LF, Lancelotti R, Rosi J Jr, Marcolin MA, Teixeira MJ (2012) Into the island: a new technique of non-invasive cortical stimulation of the insula. Neurophysiol Clin 42:363–368. https://doi.org/10.1016/j.neucli.2012.08.003

    CAS  Article  PubMed  Google Scholar 

  7. Danner N, Julkunen P, Kononen M, Saisanen L, Nurkkala J, Karhu J (2008) Navigated transcranial magnetic stimulation and computed electric field strength reduce stimulator-dependent differences in the motor threshold. J Neurosci Methods 174:116–122. https://doi.org/10.1016/j.jneumeth.2008.06.032

    Article  PubMed  Google Scholar 

  8. Davies JL (2020) Using transcranial magnetic stimulation to map the cortical representation of lower-limb muscles. Clin Neurophysiol Pract 5:87–99. https://doi.org/10.1016/j.cnp.2020.04.001

    Article  PubMed  PubMed Central  Google Scholar 

  9. de Goede AA, ter Braack EM, van Putten MJAM (2018) Accurate coil positioning is important for single and paired pulse tms on the subject level. Brain Topogr 31:917–930. https://doi.org/10.1007/s10548-018-0655-6

    Article  PubMed  PubMed Central  Google Scholar 

  10. De Ridder D, Vanneste S, Kovacs S, Sunaert S, Dom G (2011) Transient alcohol craving suppression by rTMS of dorsal anterior cingulate: an fMRI and LORETA EEG study. Neurosci Lett 496:5–10. https://doi.org/10.1016/j.neulet.2011.03.074

    CAS  Article  PubMed  Google Scholar 

  11. Deng Z-D, Lisanby SH, Peterchev AV (2013) Electric field depth–focality tradeoff in transcranial magnetic stimulation: simulation comparison of 50 coil designs. Brain Stimul 6:1–13. https://doi.org/10.1016/j.brs.2012.02.005

    Article  PubMed  Google Scholar 

  12. Deng Z-D, Lisanby SH, Peterchev AV (2014) Coil design considerations for deep transcranial magnetic stimulation. Clin Neurophysiol 125:1202–1212. https://doi.org/10.1016/j.clinph.2013.11.038

    Article  PubMed  Google Scholar 

  13. Devanne H, Lavoie BA, Capaday C (1997) Input-output properties and gain changes in the human corticospinal pathway. Exp Brain Res 114:329–338. https://doi.org/10.1007/pl00005641

    CAS  Article  PubMed  Google Scholar 

  14. Dharmadasa T, Matamala JM, Howells J, Simon NG, Vucic S, Kiernan MC (2019) The effect of coil type and limb dominance in the assessment of lower-limb motor cortex excitability using TMS. Neurosci Lett 699:84–90. https://doi.org/10.1016/j.neulet.2019.01.050

    CAS  Article  PubMed  Google Scholar 

  15. Di Lazzaro V, Restuccia D, Oliviero A et al (1998) Effects of voluntary contraction on descending volleys evoked by transcranial stimulation in conscious humans. J Physiol 508(Pt 2):625–633. https://doi.org/10.1111/j.1469-7793.1998.625bq.x

    Article  PubMed  PubMed Central  Google Scholar 

  16. Di Lazzaro V, Oliviero A, Pilato F et al (2004a) The physiological basis of transcranial motor cortex stimulation in conscious humans. Clin Neurophysiol 115:255–266. https://doi.org/10.1016/j.clinph.2003.10.009

    Article  PubMed  Google Scholar 

  17. Di Lazzaro V, Oliviero A, Pilato F et al (2004b) Direct recording of the output of the motor cortex produced by transcranial magnetic stimulation in a patient with cerebral cortex atrophy. Clin Neurophysiol 115:112–115. https://doi.org/10.1016/S1388-2457(03)00320-1

    Article  PubMed  Google Scholar 

  18. Dum RP, Strick PL (1996) Spinal cord terminations of the medial wall motor areas in macaque monkeys. J Neurosci 16:6513–6525. https://doi.org/10.1523/JNEUROSCI.16-20-06513.1996

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. Elias LJ, Bryden MP, Bulman-Fleming MB (1998) Footedness is a better predictor than is handedness of emotional lateralization. Neuropsychologia 36:37–43. https://doi.org/10.1016/s0028-3932(97)00107-3

    CAS  Article  PubMed  Google Scholar 

  20. Federico P, Perez MA (2016) Distinct corticocortical contributions to human precision and power grip. Cereb Cortex 27:5070–5082. https://doi.org/10.1093/cercor/bhw291

    Article  PubMed Central  Google Scholar 

  21. Groppa S, Oliviero A, Eisen A et al (2012) A practical guide to diagnostic transcranial magnetic stimulation: report of an IFCN committee. Clin Neurophysiol 123:858–882. https://doi.org/10.1016/j.clinph.2012.01.010

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. Hayashi T, Ko JH, Strafella AP, Dagher A (2013) Dorsolateral prefrontal and orbitofrontal cortex interactions during self-control of cigarette craving. Proc Natl Acad Sci USA 110:4422–4427. https://doi.org/10.1073/pnas.1212185110

    Article  PubMed  Google Scholar 

  23. Hayward G, Mehta MA, Harmer C, Spinks TJ, Grasby PM, Goodwin GM (2007) Exploring the physiological effects of double-cone coil TMS over the medial frontal cortex on the anterior cingulate cortex: an H2(15)O PET study. Eur J Neurosci 25:2224–2233. https://doi.org/10.1111/j.1460-9568.2007.05430.x

    Article  PubMed  Google Scholar 

  24. Hermens HJ, Freriks B, Disselhorst-Klug C, Rau G (2000) Development of recommendations for SEMG sensors and sensor placement procedures. J Electromyogr Kinesiol 10:361–374

    CAS  Article  Google Scholar 

  25. Huang Y-Z, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC (2005) Theta burst stimulation of the human motor cortex. Neuron 45:201–206. https://doi.org/10.1016/j.neuron.2004.12.033

    CAS  Article  PubMed  Google Scholar 

  26. Hupfeld KE, Swanson CW, Fling BW, Seidler RD (2020) TMS-induced silent periods: a review of methods and call for consistency. J Neurosci Methods 346:108950. https://doi.org/10.1016/j.jneumeth.2020.108950

    CAS  Article  PubMed  Google Scholar 

  27. Jayaram G, Stinear JW (2008) Contralesional paired associative stimulation increases paretic lower limb motor excitability post-stroke. Exp Brain Res 185:563–570. https://doi.org/10.1007/s00221-007-1183-x

    Article  PubMed  Google Scholar 

  28. Jo HJ, Perez MA (2019) Changes in motor-evoked potential latency during grasping after tetraplegia. J Neurophysiol 122:1675–1684. https://doi.org/10.1152/jn.00671.2018

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. Julkunen P, Saisanen L, Danner N, Niskanen E, Hukkanen T, Mervaala E, Kononen M (2009) Comparison of navigated and non-navigated transcranial magnetic stimulation for motor cortex mapping, motor threshold and motor evoked potentials. Neuroimage 44:790–795. https://doi.org/10.1016/j.neuroimage.2008.09.040

    Article  PubMed  Google Scholar 

  30. Jung J, Bungert A, Bowtell R, Jackson SR (2016) Vertex stimulation as a control site for transcranial magnetic stimulation: a concurrent TMS/fMRI study. Brain Stimul 9:58–64. https://doi.org/10.1016/j.brs.2015.09.008

    Article  PubMed  PubMed Central  Google Scholar 

  31. Jung J, Bungert A, Bowtell R, Jackson SR (2020) Modulating brain networks with transcranial magnetic stimulation over the primary motor cortex: a concurrent TMS/fMRI study. Front Hum Neurosci 14:31–31. https://doi.org/10.3389/fnhum.2020.00031

    Article  PubMed  PubMed Central  Google Scholar 

  32. Kesar TM, Stinear JW, Wolf SL (2018) The use of transcranial magnetic stimulation to evaluate cortical excitability of lower limb musculature: challenges and opportunities. Restor Neurol Neurosci 36:333–348. https://doi.org/10.3233/RNN-170801

    Article  PubMed  PubMed Central  Google Scholar 

  33. Komssi S, Aronen HJ, Huttunen J et al (2002) Ipsi- and contralateral EEG reactions to transcranial magnetic stimulation. Clin Neurophysiol 113:175–184. https://doi.org/10.1016/S1388-2457(01)00721-0

    Article  PubMed  Google Scholar 

  34. Kreuzer PM, Lehner A, Schlee W et al (2015) Combined rTMS treatment targeting the anterior cingulate and the temporal cortex for the treatment of chronic tinnitus. Sci Rep 5:18028. https://doi.org/10.1038/srep18028

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. Kreuzer PM, Downar J, de Ridder D, Schwarzbach J, Schecklmann M, Langguth B (2019) A comprehensive review of dorsomedial prefrontal cortex rTMS utilizing a double cone coil. Neuromodulation 22:851–866. https://doi.org/10.1111/ner.12874

    Article  PubMed  Google Scholar 

  36. Kukke SN, Paine RW, Chao CC, de Campos AC, Hallett M (2014) Efficient and reliable characterization of the corticospinal system using transcranial magnetic stimulation. J Clin Neurophysiol 31:246–252. https://doi.org/10.1097/wnp.0000000000000057

    Article  PubMed  PubMed Central  Google Scholar 

  37. Kuypers HGJM, Brinkman J (1970) Precentral projections to different parts of the spinal intermediate zone in the rhesus monkey. Brain Res 24:29–48. https://doi.org/10.1016/0006-8993(70)90272-6

    CAS  Article  PubMed  Google Scholar 

  38. Laakso I, Murakami T, Hirata A, Ugawa Y (2018) Where and what TMS activates: experiments and modeling. Brain Stimul 11:166–174. https://doi.org/10.1016/j.brs.2017.09.011

    Article  PubMed  Google Scholar 

  39. Lefaucheur JP, Aleman A, Baeken C et al (2020) Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): an update (2014–2018). Clin Neurophysiol 131:474–528. https://doi.org/10.1016/j.clinph.2019.11.002

    Article  PubMed  Google Scholar 

  40. Lenoir C, Algoet M, Mouraux A (2018) Deep continuous theta burst stimulation of the operculo-insular cortex selectively affects Aδ-fibre heat pain. J Physiol 596:4767–4787. https://doi.org/10.1113/jp276359

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. Lu M, Ueno S (2017) Comparison of the induced fields using different coil configurations during deep transcranial magnetic stimulation. PLoS ONE 12:e0178422. https://doi.org/10.1371/journal.pone.0178422

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. Modirrousta M, Meek BP, Sareen J, Enns MW (2015) Impaired trial-by-trial adjustment of cognitive control in obsessive compulsive disorder improves after deep repetitive transcranial magnetic stimulation. BMC Neurosci 16:63–63. https://doi.org/10.1186/s12868-015-0205-z

    Article  PubMed  PubMed Central  Google Scholar 

  43. Oldfield RC (1971) The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 9:97–113

    CAS  Article  Google Scholar 

  44. Orth M, Rothwell JC (2004) The cortical silent period: intrinsic variability and relation to the waveform of the transcranial magnetic stimulation pulse. Clin Neurophysiol 115:1076–1082. https://doi.org/10.1016/j.clinph.2003.12.025

    CAS  Article  PubMed  Google Scholar 

  45. Perich MG, Rajan K (2020) Rethinking brain-wide interactions through multi-region ‘network of networks’ models. Curr Opin Neurobiol 65:146–151. https://doi.org/10.1016/j.conb.2020.11.003

    CAS  Article  PubMed  Google Scholar 

  46. R Studio Team (2020) RStudio: integrated development for R. RStudio, PBC, Boston, MA URL http://www.rstudio.com/

  47. Reijonen J, Saisanen L, Kononen M, Mohammadi A, Julkunen P (2020) The effect of coil placement and orientation on the assessment of focal excitability in motor mapping with navigated transcranial magnetic stimulation. J Neurosci Methods 331:108521. https://doi.org/10.1016/j.jneumeth.2019.108521

    Article  PubMed  Google Scholar 

  48. Reithler J, Peters JC, Sack AT (2011) Multimodal transcranial magnetic stimulation: using concurrent neuroimaging to reveal the neural network dynamics of noninvasive brain stimulation. Prog Neurobiol 94:149–165. https://doi.org/10.1016/j.pneurobio.2011.04.004

    CAS  Article  PubMed  Google Scholar 

  49. Rossini PM, Burke D, Chen R, Cohen LG, Daskalakis Z, Iorio R (2015) Non-invasive electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves: basic principles and procedures for routine clinical and research application. An updated report from an I.F.C.N. Committee. Clin Neurophysiol. https://doi.org/10.1016/j.clinph.2015.02.001

    Article  PubMed  PubMed Central  Google Scholar 

  50. Roth Y, Pell GS, Chistyakov AV, Sinai A, Zangen A, Zaaroor M (2014) Motor cortex activation by H-coil and figure-8 coil at different depths. Combined motor threshold and electric field distribution study. Clin Neurophysiol 125:336–343. https://doi.org/10.1016/j.clinph.2013.07.013

    Article  PubMed  Google Scholar 

  51. Schecklmann M, Schmausser M, Klinger F, Kreuzer PM, Krenkel L, Langguth B (2020) Resting motor threshold and magnetic field output of the figure-of-8 and the double-cone coil. Sci Rep 10:1644. https://doi.org/10.1038/s41598-020-58034-2

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. Senefeld J, Magill SB, Harkins A, Harmer AR, Hunter SK (2018) Mechanisms for the increased fatigability of the lower limb in people with type 2 diabetes. J Appl Physiol 125:553–566. https://doi.org/10.1152/japplphysiol.00160.2018

    CAS  Article  PubMed  Google Scholar 

  53. Shimizu T, Hosomi K, Maruo T et al (2017) Efficacy of deep rTMS for neuropathic pain in the lower limb: a randomized, double-blind crossover trial of an H-coil and figure-8 coil. J Neurosurg 127:1172–1180. https://doi.org/10.3171/2016.9.Jns16815

    Article  PubMed  Google Scholar 

  54. Siebner HR, Hartwigsen G, Kassuba T, Rothwell JC (2009) How does transcranial magnetic stimulation modify neuronal activity in the brain? Implications for studies of cognition. Cortex 45:1035–1042. https://doi.org/10.1016/j.cortex.2009.02.007

    Article  PubMed  PubMed Central  Google Scholar 

  55. Swanson CW, Fling BW (2020) Associations between turning characteristics and corticospinal inhibition in young and older adults. Neuroscience 425:59–67. https://doi.org/10.1016/j.neuroscience.2019.10.051

    CAS  Article  PubMed  Google Scholar 

  56. Tastevin M, Baumstarck K, Groppi F, Cermolacce M, Lagrange G, Lançon C, Richieri R (2020) Double cone coil rTMS efficacy for treatment-resistant depression: a prospective randomized controlled trial. Brain Stimul 13:256–258. https://doi.org/10.1016/j.brs.2019.09.009

    Article  PubMed  Google Scholar 

  57. Tremblay F, Tremblay LE (2002) Cortico-motor excitability of the lower limb motor representation: a comparative study in Parkinson’s disease and healthy controls. Clin Neurophysiol 113:2006–2012. https://doi.org/10.1016/s1388-2457(02)00301-2

    Article  PubMed  Google Scholar 

  58. van den Bos MAJ, Geevasinga N, Menon P, Burke D, Kiernan MC, Vucic S (2017) Physiological processes influencing motor-evoked potential duration with voluntary contraction. J Neurophysiol 117:1156–1162. https://doi.org/10.1152/jn.00832.2016

    Article  PubMed  Google Scholar 

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Funding

Funding for this study was provided by the Department of Defense (Award number: W81XWH-16-PHTBIRP-CR3A).

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SDF, BCN, AG, CC: funding acquisition; FP, MCC, MEB, AMS, SRE, ADL, WRC, SAJ, SDF: data collection; FP, SDF, MCC: data analysis; FP, MCC, SDF: data interpretation; FP, SDF: manuscript draft; all authors contributed to the manuscript editing.

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Correspondence to S. D. Flanagan.

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Proessl, F., Canino, M.C., Beckner, M.E. et al. Characterizing off-target corticospinal responses to double-cone transcranial magnetic stimulation. Exp Brain Res (2021). https://doi.org/10.1007/s00221-021-06044-5

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Keywords

  • Transcranial magnetic stimulation
  • Motor cortex
  • Corticospinal excitability
  • Motor-evoked potentials
  • Lower limbs