Transcranial electrical stimulation motor threshold can estimate individualized tDCS dosage from reverse-calculation electric-field modeling

Kevin A Caulfield, Bashar W Badran, William H DeVries, Philipp M Summers, Emma Kofmehl, Xingbao Li, Jeffrey J Borckardt, Marom Bikson, Mark S George, Kevin A Caulfield, Bashar W Badran, William H DeVries, Philipp M Summers, Emma Kofmehl, Xingbao Li, Jeffrey J Borckardt, Marom Bikson, Mark S George

Abstract

Background: Unique amongst brain stimulation tools, transcranial direct current stimulation (tDCS) currently lacks an easy or widely implemented method for individualizing dosage.

Objective: We developed a method of reverse-calculating electric-field (E-field) models based on Magnetic Resonance Imaging (MRI) scans that can estimate individualized tDCS dose. We also evaluated an MRI-free method of individualizing tDCS dose by measuring transcranial magnetic stimulation (TMS) motor threshold (MT) and single pulse, suprathreshold transcranial electrical stimulation (TES) MT and regressing it against E-field modeling. Key assumptions of reverse-calculation E-field modeling, including the size of region of interest (ROI) analysis and the linearity of multiple E-field models were also tested.

Methods: In 29 healthy adults, we acquired TMS MT, TES MT, and anatomical T1-weighted MPRAGE MRI scans with a fiducial marking the motor hotspot. We then computed a "reverse-calculated tDCS dose" of tDCS applied at the scalp needed to cause a 1.00 V/m E-field at the cortex. Finally, we examined whether the predicted E-field values correlated with each participant's measured TMS MT or TES MT.

Results: We were able to determine a reverse-calculated tDCS dose for each participant using a 5 × 5 x 5 voxel grid region of interest (ROI) approach (average = 6.03 mA, SD = 1.44 mA, range = 3.75-9.74 mA). The Transcranial Electrical Stimulation MT, but not the Transcranial Magnetic Stimulation MT, significantly correlated with the ROI-based reverse-calculated tDCS dose determined by E-field modeling (R2 = 0.45, p < 0.001).

Conclusions: Reverse-calculation E-field modeling, alone or regressed against TES MT, shows promise as a method to individualize tDCS dose. The large range of the reverse-calculated tDCS doses between subjects underscores the likely need to individualize tDCS dose. Future research should further examine the use of TES MT to individually dose tDCS as an MRI-free method of dosing tDCS.

Keywords: Electric field modeling; Individualized dosing; Transcranial direct current stimulation; Transcranial electrical stimulation; Transcranial magnetic stimulation; tDCS; tDCS dosing.

Conflict of interest statement

Declaration of competing interest Marom Bikson has equity in Soterix Medical. The City University of New York has patents on brain stimulation with Marom Bikson as consultant. Marom Bikson consults for Halo Neuroscience, Boston Scientific, and GSK. We confirm that there are no additional known conflicts of interest associated with this publication and there was no financial support for this work that could have influenced its outcome.

Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

Figures

Fig. 1.. TES MT Materials and Methods.
Fig. 1.. TES MT Materials and Methods.
1A: Experimental set-up with labeled devices and electrodes. 1B: Image of the constant current stimulator (Digitimer DS7A) and settings that were used to acquire TES MTs. 1C: Modified PEST program window showing an example in which 5 pulses of TES determined a TES MT of 50 mA.
Fig. 2.. ROAST E-Field Modeling Pipeline Overview.
Fig. 2.. ROAST E-Field Modeling Pipeline Overview.
2A: MRI segmentation in SPM12 run by ROAST. 2B: Anatomical MRI Scan with an arrow pointing at the fiducial on the scalp indicating the motor hotspot coordinates (visualized in MRICroGL). 2C: Using ROAST, an anodal electrode was placed at the left motor hotspot and the cathode was placed on the left neck to approximate the TES electrode montage. 2D: ROAST E-field model output after the FEM was solved. 2E: Our 5 × 5 x 5 voxel grid ROI analysis measured the E-field average in a cuboidal volume that was immediately underneath the center of the anodal electrode in each participant. See Fig. 3 for detailed description.
Fig. 3.. Detailed Visual Representation of the…
Fig. 3.. Detailed Visual Representation of the 5 × 5 × 5 Voxel Grid ROI Analysis.
In order to standardize the exact location for the 5 × 5 x 5 voxel grid ROI analysis across participants, we centered the ROI at the cortex on the same XY plane as the center of the anodal electrode on the scalp. We then lowered the Z plane value until we reached the first coordinate with a grey matter voxel. This location served as the center of the 5 × 5 voxel grid in the XY plane. We created the 5 × 5 voxel grid by moving 2 voxels left, 2 voxels right, 2 voxels anterior, and 2 voxels posterior of this center voxel. We recorded the E-field values of each grey matter voxel in this grid and did not count any voxel without grey matter tissue. We repeated this method a total of 5 times, moving down one axial plane at a time by keeping the same X and Y coordinates and subtracting 1 from the Z plane for each level. In this example, the X and Y coordinates stay at 58 and 96 respectively, while the Z value changes with each grey matter tissue level from 206 through 202. After measuring all the grey matter voxels with E-field values, we computed the average and used this to calculate the reverse-calculation dose for a 1.00 V/m E-field at the cortex (Fig. 4).
Fig. 4.. Reverse-Calculation Modeling Formula.
Fig. 4.. Reverse-Calculation Modeling Formula.
4A: Since E-field modeling relies only upon the proper segmentation of tissue and different tissue conductivities, a single E-field model can be used to estimate the tDCS dose at the scalp that would be required to produce any threshold of E-field at the cortex(33). 4B: Example of how one E-field model produced by a 3 mA input can be used to reverse-calculate the required dose to produce a 1.00 V/m E-field. In this example, a 3 mA dose produced an ROI average E-field of 0.5542 V/m and the reverse-calculation dose was 5.43 mA.
Fig. 5.
Fig. 5.
A–C: Descriptive data for TMS MT, TES MT, and reverse-calculation doses for 1.00 V/m.
Fig. 6.
Fig. 6.
TMS MT Does Not Correlate with Reverse-Calculated tDCS Dose, F(1,27) = F(1,27) = 0.045, R2 = 0.002, p = 0.834.
Fig. 7.
Fig. 7.
TES MT Significantly Correlates with Reverse-Calculated tDCS Dose, F(1,27) = 21.88, R2 = 0.45, p < 0.001.

References

    1. Meron D, Hedger N, Garner M, Baldwin DS. Transcranial direct current stimulation (tDCS) in the treatment of depression: systematic review and metaanalysis of efficacy and tolerability. Neurosci Biobehav Rev 2015;57:46–62.
    1. Fröhlich F, Burrello TN, Mellin JM, Cordle AL, Lustenberger CM, Gilmore JH, et al. Exploratory study of once-daily transcranial direct current stimulation (tDCS) as a treatment for auditory hallucinations in schizophrenia. Eur Psychiatr 2016;33:54–60.
    1. Yuan T, Yadollahpour A, Salgado-Ramírez J, Robles-Camarillo D, Ortega-Palacios R. Transcranial direct current stimulation for the treatment of tinnitus: a review of clinical trials and mechanisms of action. BMC Neurosci 2018;19(1):66.
    1. Nitsche MA, Boggio PS, Fregni F, Pascual-Leone A. Treatment of depression with transcranial direct current stimulation (tDCS): a review. Exp Neurol 2009;219(1):14–9.
    1. Zaghi S, Heine N, Fregni F. Brain stimulation for the treatment of pain: a review of costs, clinical effects, and mechanisms of treatment for three different central neuromodulatory approaches. J Pain Manag 2009;2(3):339–52.
    1. Sauvaget A, Tostivint A, Etcheverrigaray F, Pichot A, Dert C, Schirr-Bonnais S, et al. Hospital production cost of transcranial direct current stimulation (tDCS) in the treatment of depression. Neurophysiol Clin Clin Neurophysiol 2019;49(1):11–8.
    1. Bikson M, Grossman P, Thomas C, Zannou AL, Jiang J, Adnan T, et al. Safety of transcranial direct current stimulation: evidence based update 2016. Brain Stimul 2016;9(5):641–61.
    1. Dobbs B, Pawlak N, Biagioni M, Agarwal S, Shaw M, Pilloni G, et al. Generalizing remotely supervised transcranial direct current stimulation (tDCS): feasibility and benefit in Parkinson’s disease. J NeuroEng Rehabil 2018;15(1):114.
    1. Kasschau M, Reisner J, Sherman K, Bikson M, Datta A, Charvet LE. Transcranial direct current stimulation is feasible for remotely supervised home delivery in multiple sclerosis. Neuromodulation : J Int Neuromodulation Soc 2016;19(8):824–31.
    1. Riggs A, Patel V, Paneri B, Portenoy RK, Bikson M, Knotkova H. At-home transcranial direct current stimulation (tDCS) with telehealth support for symptom control in chronically-ill patients with multiple symptoms. Front Behav Neurosci 2018;12:93.
    1. Nitsche MA, Paulus W. Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. J Physiol 2000;527(3):633–9.
    1. Horvath JC, Forte JD, Carter O. Evidence that transcranial direct current stimulation (tDCS) generates little-to-no reliable neurophysiologic effect beyond MEP amplitude modulation in healthy human subjects: a systematic review. Neuropsychologia 2015;66:213–36.
    1. Horvath JC, Forte JD, Carter O. Quantitative review finds No evidence of cognitive effects in healthy populations from single-session transcranial direct current stimulation (tDCS). Brain Stimul 2015;8(3):535–50.
    1. Horvath JC, Carter O, Forte JD. No significant effect of transcranial direct current stimulation (tDCS) found on simple motor reaction time comparing 15 different simulation protocols. Neuropsychologia 2016;91:544–52.
    1. Horvath JC, Vogrin SJ, Carter O, Cook MJ, Forte JD. Effects of a common transcranial direct current stimulation (tDCS) protocol on motor evoked potentials found to be highly variable within individuals over 9 testing sessions. Exp Brain Res 2016;234(9):2629–42.
    1. Héroux ME, Loo CK, Taylor JL, Gandevia SC. Questionable science and reproducibility in electrical brain stimulation research. PloS One 2017;12(4):e0175635.
    1. Vannorsdall TD, van Steenburgh JJ, Schretlen DJ, Jayatillake R, Skolasky RL, Gordon B. Reproducibility of tDCS results in a randomized trial: failure to replicate findings of tDCS-induced enhancement of verbal fluency. Cognit Behav Neurol Off J Soc Behav Cognit Neurol 2016;29(1):11–7.
    1. Koenigs M, Ukueberuwa D, Campion P, Grafman J, Wassermann E. Bilateral frontal transcranial direct current stimulation: failure to replicate classic findings in healthy subjects. Clin Neurophysiol 2009;120(1):80–4.
    1. López-Alonso V, Cheeran B, Río-Rodríguez D, Fernández-del-Olmo M. Inter-individual variability in response to non-invasive brain stimulation paradigms. Brain Stimul 2014;7(3):372–80.
    1. López-Alonso V, Fernández-del-Olmo M, Costantini A, Gonzalez-Henriquez JJ, Cheeran B. Intra-individual variability in the response to anodal transcranial direct current stimulation. Clin Neurophysiol 2015;126(12):2342–7.
    1. Wiethoff S, Hamada M, Rothwell JC. Variability in response to transcranial direct current stimulation of the motor cortex. Brain Stimul 2014;7(3):468–75.
    1. Chew T, Ho K-A, Loo CK. Inter-and intra-individual variability in response to transcranial direct current stimulation (tDCS) at varying current intensities. Brain Stimul 2015;8(6):1130–7.
    1. Falcone M, Bernardo L, Wileyto EP, Allenby C, Burke AM, Hamilton R, et al. Lack of effect of transcranial direct current stimulation (tDCS) on short-term smoking cessation: results of a randomized, sham-controlled clinical trial. Drug Alcohol Depend 2019;194:244–51.
    1. Loo CK, Sachdev P, Martin D, Pigot M, Alonzo A, Malhi GS, et al. A double-blind, sham-controlled trial of transcranial direct current stimulation for the treatment of depression. Int J Neuropsychopharmacol 2010;13(1):61–9.
    1. Loo CK, Husain MM, McDonald WM, Aaronson S, O’Reardon JP, Alonzo A, et al. International randomized-controlled trial of transcranial Direct Current Stimulation in depression. Brain Stimul 2018;11(1):125–33.
    1. Blumberger DM, Tran LC, Fitzgerald PB, Hoy KE, Daskalakis ZJ. A randomized double-blind sham-controlled study of transcranial direct current stimulation for treatment-resistant major depression. Front Psychiatr 2012;3:74.
    1. Rassovsky Y, Dunn W, Wynn JK, Wu AD, Iacoboni M, Hellemann G, et al. Single transcranial direct current stimulation in schizophrenia: randomized, cross-over study of neurocognition, social cognition, ERPs, and side effects. PloS One 2018;13(5):e0197023.
    1. Saleem GT, Ewen JB, Crasta JE, Slomine BS, Cantarero GL, Suskauer SJ. Single-arm, open-label, dose escalation phase I study to evaluate the safety and feasibility of transcranial direct current stimulation with electroencephalography biomarkers in paediatric disorders of consciousness: a study protocol. BMJ open 2019;9(8):e029967.
    1. Dmochowski JP, Datta A, Huang Y, Richardson JD, Bikson M, Fridriksson J, et al. Targeted transcranial direct current stimulation for rehabilitation after stroke. Neuroimage 2013;75:12–9.
    1. Dmochowski JP, Koessler L, Norcia AM, Bikson M, Parra LC. Optimal use of EEG recordings to target active brain areas with transcranial electrical stimulation. Neuroimage 2017;157:69–80.
    1. Cancelli A, Cottone C, Tecchio F, Truong DQ, Dmochowski J, Bikson M. A simple method for EEG guided transcranial electrical stimulation without models. J Neural Eng 2016;13(3):036022.
    1. Gebodh N, Esmaeilpour Z, Adair D, Chelette K, Dmochowski J, Woods AJ, et al. Inherent physiological artifacts in EEG during tDCS. Neuroimage 2019;185:408–24.
    1. Evans C, Bachmann C, Lee JS, Gregoriou E, Ward N, Bestmann S. Dose-controlled tDCS reduces electric field intensity variability at a cortical target site. Brain Stimul 2020;13(1):125–36.
    1. Dmochowski JP, Datta A, Bikson M, Su Y, Parra LC. Optimized multi-electrode stimulation increases focality and intensity at target. J Neural Eng 2011;8(4):046011.
    1. Datta A, Truong D, Minhas P, Parra LC, Bikson M. Inter-individual variation during transcranial direct current stimulation and normalization of dose using MRI-derived computational models. Front Psychiatr 2012;3:91.
    1. Bikson M, Rahman A, Datta A. Computational models of transcranial direct current stimulation. Clin EEG Neurosci 2012;43(3):176–83.
    1. Bikson M, Rahman A, Datta A, Fregni F, Merabet L. High-resolution modeling assisted design of customized and individualized transcranial direct current stimulation protocols. Neuromodulation 2012;15(4):306–15.
    1. Labruna L, Jamil A, Fresnoza S, Batsikadze G, Kuo MF, Vanderschelden B, et al. Efficacy of anodal transcranial direct current stimulation is related to sensitivity to transcranial magnetic stimulation. Brain Stimul 2016;9(1):8–15.
    1. Mikkonen M, Laakso I, Sumiya M, Koyama S, Hirata A, Tanaka S. TMS motor thresholds correlate with TDCS electric field strengths in hand motor area. Front Neurosci 2018;12(426).
    1. Badran BW, Ly M, DeVries WH, Glusman CE, Willis A, Pridmore S, et al. Are EMG and visual observation comparable in determining resting motor threshold? A reexamination after twenty years. Brain Stimul Basic Trans Clin Res Neuromodulation 2019;12(2):364–6.
    1. Badran BW, Caulfield KA, Lopez JW, Cox C, Stomberg-Firestein S, DeVries WH, et al. Personalized TMS helmets for quick and reliable TMS administration outside of a laboratory setting. Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation; 2020.
    1. Mishory A, Molnar C, Koola J, Li X, Kozel FA, Myrick H, et al. The maximum-likelihood strategy for determining transcranial magnetic stimulation motor threshold, using parameter estimation by sequential testing is faster than conventional methods with similar precision. J ECT 2004;20(3):160–5.
    1. Merton PA, Hill DK, Morton HB, Marsden CD. Scope of a technique for electrical stimulation of human brain, spinal cord, and muscle. Lancet 1982;2(8298):597–600.
    1. Merton PA, Morton HB. Stimulation of the cerebral cortex in the intact human subject. Nature 1980;285:227.
    1. Radman T, Ramos RL, Brumberg JC, Bikson M. Role of cortical cell type and morphology in subthreshold and suprathreshold uniform electric field stimulation in vitro. Brain Stimul 2009;2(4):215–28. e2283.
    1. Seo H, Jun SC. Relation between the electric field and activation of cortical neurons in transcranial electrical stimulation. Brain Stimul 2019;12(2):275–89.
    1. Reato D, Rahman A, Bikson M, Parra LC. Low-intensity electrical stimulation affects network dynamics by modulating population rate and spike timing. J Neurosci 2010;30(45):15067–79.
    1. Chakraborty D, Truong DQ, Bikson M, Kaphzan H. Neuromodulation of axon terminals. Cerebr Cortex 2018;28(8):2786–94.
    1. Monai H, Hirase H. Astrocytes as a target of transcranial direct current stimulation (tDCS) to treat depression. Neurosci Res 2018;126:15–21.
    1. Cancel LM, Arias K, Bikson M, Tarbell JM. Direct current stimulation of endothelial monolayers induces a transient and reversible increase in transport due to the electroosmotic effect. Sci Rep 2018;8(1):9265.
    1. Krause MR, Vieira PG, Csorba BA, Pilly PK, Pack CC. Transcranial alternating current stimulation entrains single-neuron activity in the primate brain. Proc Natl Acad Sci U S A 2019;116(12):5747–55.
    1. Datta A, Krause MR, Pilly PK, Choe J, Zanos TP, Thomas C, et al. On comparing in vivo intracranial recordings in non-human primates to predictions of optimized transcranial electrical stimulation. Conf Proc IEEE Eng Med Biol Soc 2016;2016:1774–7.
    1. Mishima T, Nagai T, Yahagi K, Akther S, Oe Y, Monai H, et al. Transcranial direct current stimulation (tDCS) induces adrenergic receptor-dependent microglial morphological changes in mice. eNeuro 2019;6(5).
    1. Yu TH, Wu YJ, Chien ME, Hsu KS. Transcranial direct current stimulation induces hippocampal metaplasticity mediated by brain-derived neurotrophic factor. Neuropharmacology 2019;144:358–67.
    1. Liu A, Voroslakos M, Kronberg G, Henin S, Krause MR, Huang Y, et al. Immediate neurophysiological effects of transcranial electrical stimulation. Nat Commun 2018;9(1):5092.
    1. Francis JT, Gluckman BJ, Schiff SJ. Sensitivity of neurons to weak electric fields. J Neurosci 2003;23(19):7255–61.
    1. Vöröslakos M, Takeuchi Y, Brinyiczki K, Zombori T, Oliva A, Fernández-Ruiz A, et al. Direct effects of transcranial electric stimulation on brain circuits in rats and humans. Nat Commun 2018;9(1):483.
    1. Esmaeilpour Z, Marangolo P, Hampstead BM, Bestmann S, Galletta E, Knotkova H, et al. Incomplete evidence that increasing current intensity of tDCS boosts outcomes. Brain Stimul 2018;11(2):310–21.
    1. Jamil A, Batsikadze G, Kuo HI, Labruna L, Hasan A, Paulus W, et al. Systematic evaluation of the impact of stimulation intensity on neuroplastic after-effects induced by transcranial direct current stimulation. J Physiol 2017;595(4):1273–88.
    1. Kidgell DJ, Daly RM, Young K, Lum J, Tooley G, Jaberzadeh S, et al. Different current intensities of anodal transcranial direct current stimulation do not differentially modulate motor cortex plasticity. Neural Plast 2013;2013.
    1. Batsikadze G, Moliadze V, Paulus W, Kuo MF, Nitsche M. Partially non-linear stimulation intensity-dependent effects of direct current stimulation on motor cortex excitability in humans. J Physiol 2013;591(7):1987–2000.
    1. Fresnoza S, Paulus W, Nitsche MA, Kuo MF. Nonlinear dose-dependent impact of D1 receptor activation on motor cortex plasticity in humans. J Neurosci 2014;34(7):2744–53.
    1. Shekhawat GS, Vanneste S. Optimization of transcranial direct current stimulation of dorsolateral prefrontal cortex for tinnitus: a non-linear dose-response effect. Sci Rep 2018;8(1):8311.
    1. Shekhawat GS, Stinear CM, Searchfield GD. Transcranial direct current stimulation intensity and duration effects on tinnitus suppression. Neurorehabilitation Neural Repair 2013;27(2):164–72.
    1. Hoy KE, Emonson MR, Arnold SL, Thomson RH, Daskalakis ZJ, Fitzgerald PB. Testing the limits: investigating the effect of tDCS dose on working memory enhancement in healthy controls. Neuropsychologia 2013;51(9):1777–84.
    1. Folmli B, Turman B, Johnson P, Abbott A. Dose response of somatosensory cortex repeated anodal transcranial direct current stimulation on vibrotactile detection: a randomized sham-controlled trial. J Neurophysiol 2018;120(2):610–6.
    1. Alonzo A, Brassil J, Taylor JL, Martin D, Loo CK. Daily transcranial direct current stimulation (tDCS) leads to greater increases in cortical excitability than second daily transcranial direct current stimulation. Brain Stimul 2012;5(3):208–13.
    1. Chhatbar PY, Ramakrishnan V, Kautz S, George MS, Adams RJ, Feng W. Transcranial direct current stimulation post-stroke upper extremity motor recovery studies exhibit a dose-response relationship. Brain Stimul 2016;9(1):16–26.
    1. Nikolin S, Martin D, Loo CK, Boonstra TW. Effects of TDCS dosage on working memory in healthy participants. Brain Stimul 2018;11(3):518–27.
    1. Hoy KE, Arnold SL, Emonson MR, Daskalakis ZJ, Fitzgerald PB. An investigation into the effects of tDCS dose on cognitive performance over time in patients with schizophrenia. Schizophr Res 2014;155(1–3):96–100.
    1. Jamil A, Batsikadze G, Kuo HI, Meesen R, Dechent P, Paulus W, et al. Current intensity- and polarity-specific online and aftereffects of transcranial direct current stimulation: an fMRI study. Hum Brain Mapp 2019;41(6):1644–66.
    1. Cuypers K, Leenus DJF, van den Berg FE, Nitsche MA, Thijs H, Wenderoth N, et al. Is motor learning mediated by tDCS intensity? PloS One 2013;8(6). e67344–e.
    1. Boggio PS, Ferrucci R, Rigonatti SP, Covre P, Nitsche M, Pascual-Leone A, et al. Effects of transcranial direct current stimulation on working memory in patients with Parkinson’s disease. J Neurol Sci 2006;249(1):31–8.
    1. Huang Y, Liu AA, Lafon B, Friedman D, Dayan M, Wang X, et al. Measurements and models of electric fields in the in vivo human brain during transcranial electric stimulation. eLife 2017;6.
    1. Huang Y, Datta A, Bikson M, Parra LC. ROAST: an open-source, fully-automated, realistic volumetric-approach-based simulator for TES. Conf Proc IEEE Eng Med Biol Soc 2018;2018:3072–5.
    1. Puonti O, Saturnino GB, Madsen KH, Thielscher A. Value and limitations of intracranial recordings for validating electric field modeling for transcranial brain stimulation. Neuroimage 2019;208:116431.
    1. Huang Y, Dmochowski JP, Su Y, Datta A, Rorden C, Parra LC. Automated MRI segmentation for individualized modeling of current flow in the human head. J Neural Eng 2013;10(6):066004.
    1. Huang Y, Datta A, Bikson M, Parra LC. Realistic volumetric-approach to simulate transcranial electric stimulation—ROAST—a fully automated open-source pipeline. J Neural Eng 2019;16(5):056006.
    1. Tetrahedral mesh generation from volumetric binary and grayscale images. In: Fang Q, Boas DA, editors. 2009 IEEE international symposium on biomedical imaging: from nano to macro. Ieee; 2009.
    1. Dular P, Geuzaine C, Henrotte F, Legros W. A general environment for the treatment of discrete problems and its application to the finite element method. IEEE Trans Magn 1998;34(5):3395–8.

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