Neuronal tuning: Selective targeting of neuronal populations via manipulation of pulse width and directionality

  • I. Halawa
    Corresponding author. Department of Clinical Neurophysiology, University Medical Centre Göttingen, Robert Koch Str. 40, 37075, Göttingen, Germany
    Department of Clinical Neurophysiology, University Medical Centre Göttingen, Robert Koch Str. 40, 37075, Göttingen, Germany

    Medical Research Center of Excellence, National Research Center, Cairo, Egypt
    Search for articles by this author
  • Y. Shirota
    Department of Clinical Neurophysiology, University Medical Centre Göttingen, Robert Koch Str. 40, 37075, Göttingen, Germany

    Department of Neurology, The University of Tokyo Hospital, Tokyo, Japan
    Search for articles by this author
  • A. Neef
    Center for Biostructural Imaging of Neurodegeneration (BIN), Göttingen, Germany

    Campus Institute for the Dynamics of Biological Networks, Göttingen, Germany
    Search for articles by this author
  • M. Sommer
    Department of Clinical Neurophysiology, University Medical Centre Göttingen, Robert Koch Str. 40, 37075, Göttingen, Germany
    Search for articles by this author
  • W. Paulus
    Department of Clinical Neurophysiology, University Medical Centre Göttingen, Robert Koch Str. 40, 37075, Göttingen, Germany
    Search for articles by this author
Published:April 29, 2019DOI:


      • Controlling and varying the pulse width when applying rTMS generates opposing plastic aftereffects.
      • The “classic” 1 Hz anteroposterior inhibitory paradigm switches towards facilitation with longer pulses.
      • Asymmetric anterior-posterior directed stimuli had stronger effects of as compared to symmetric pulse shapes.
      • Gradual switch from asymmetrical to symmetric pulse shapes went in line with gradual changes in aftereffects.
      • Bidirectional pulses of different intensity and length allow to target different direction specific neuronal components.



      Motor evoked potentials (MEP) in response to anteroposterior transcranial (AP) magnetic stimulation (TMS) are sensitive to the TMS pulse shape. We are now able to isolate distinct pulse properties, such as pulse width and directionality and evaluate them individually. Different pulse shapes induce different effects, likely by stimulating different populations of neurons. This implies that not all neurons respond in the same manner to stimulation, possibly, because individual segments of neurons differ in their membrane properties.


      To investigate the effect of different pulse widths and directionalities of TMS on MEP latencies, motor thresholds and plastic aftereffects of rTMS.


      Using a controllable pulse stimulator TMS (cTMS), we stimulated fifteen subjects with quasi-unidirectional TMS pulses of different pulse durations (40 μs, 80 μs and 120 μs) and determined thresholds and MEP AP latencies. We then compared the effects of 80 μs quasi-unidirectional pulses to those of 80 μs pulses with different pulse directionality characteristics (0.6 and 1.0 M ratios). We applied 900 pulses of the selected pulse shapes at 1 Hz.


      The aftereffects of 1 Hz rTMS depended on pulse shape and duration. 40 and 80 μs wide unidirectional pulses induced inhibition, 120 μs wide pulses caused excitation. Bidirectional pulses induced inhibition during the stimulation but had facilitatory aftereffects. Narrower pulse shapes caused longer latencies and higher resting motor thresholds (RMT) as compared to wider pulse shapes.


      We can tune the aftereffects of rTMS by manipulating pulse width and directionality; this may be due to the different membrane properties of the various neuronal segments such as dendrites.


      To date, rTMS frequency has been the main determinant of the plastic aftereffects. However, we showed that pulse width also plays a major role, probably by recruiting novel neuronal targets.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


        • Lefaucheur J.-P.
        • André-Obadia N.
        • Antal A.
        • Ayache S.S.
        • Baeken C.
        • Benninger D.H.
        • et al.
        Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS).
        Clin Neurophysiol. 2014; 125: 2150-2206
        • Strigaro G.
        • Hamada M.
        • Cantello R.
        • Rothwell J.C.
        59. Variability in response to 1Hz repetitive TMS.
        Clin Neurophysiol. 2016 Apr 1; 127: e146
        • Ridding M.C.
        • Rothwell J.C.
        Is there a future for therapeutic use of transcranial magnetic stimulation?.
        Nat Rev Neurosci. 2007; 8: 559
        • Fregni F.
        • Pascual-Leone A.
        Technology Insight: noninvasive brain stimulation in neurology—perspectives on the therapeutic potential of rTMS and tDCS.
        Nat Clin Pract Neurol. 2007 Jul; 3: 383-393
        • Fung P.K.
        • Robinson P.A.
        Neural field theory of calcium dependent plasticity with applications to transcranial magnetic stimulation.
        J Theor Biol. 2013 May; 324: 72-83
        • Soundara Rajan T.
        • Ghilardi M.F.M.
        • Wang H.-Y.
        • Mazzon E.
        • Bramanti P.
        • Restivo D.
        • et al.
        Mechanism of action for rTMS: a working hypothesis based on animal studies.
        Front Physiol. 2017 Jun 30; ([Internet]) ([cited 2018 Nov 27];8. Available from:)
        • Bey A.
        • Leue S.
        • Wienbruch C.
        A neuronal network model for simulating the effects of repetitive transcranial magnetic stimulation on local field potential power spectra. Langguth B, editor.
        PLoS One. 2012 Nov 7; 7e49097
        • Di Lazzaro V.
        • Ziemann U.
        The contribution of transcranial magnetic stimulation in the functional evaluation of microcircuits in human motor cortex.
        Front Neural Circuits. 2013; ([Internet]) ([cited 2016 Oct 27];7. Available from:)
        • Laakso I.
        • Murakami T.
        • Hirata A.
        • Ugawa Y.
        Where and what TMS activates: experiments and modeling.
        Brain Stimulat. 2018 Jan; 11: 166-174
        • Rusu C.V.
        • Murakami M.
        • Ziemann U.
        • Triesch J.
        A model of TMS-induced I-waves in motor cortex.
        Brain Stimulat. 2014 May; 7: 401-414
        • Chervyakov A.V.
        • Chernyavsky A.Y.
        • Sinitsyn D.O.
        • Piradov M.A.
        Possible mechanisms underlying the therapeutic effects of transcranial magnetic stimulation.
        Front Hum Neurosci. 2015 Jun 16; ([Internet]) ([cited 2018 Mar 21];9. Available from:)
        • Rossi S.
        • Hallett M.
        • Rossini P.M.
        • Pascual-Leone A.
        Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research.
        Clin Neurophysiol. 2009 Dec; 120: 2008-2039
        • Peterchev A.V.
        • Murphy D.L.
        • Lisanby S.H.
        Repetitive transcranial magnetic stimulator with controllable pulse parameters.
        J Neural Eng. 2011 Jun 1; 8036016
        • Delvendahl I.
        • Gattinger N.
        • Berger T.
        • Gleich B.
        • Siebner H.R.
        • Mall V.
        The role of pulse shape in motor cortex transcranial magnetic stimulation using full-sine stimuli.
        PLoS One. 2014; 9e115247
        • Peterchev A.V.
        • DʼOstilio K.
        • Rothwell J.C.
        • Murphy D.L.
        Controllable pulse parameter transcranial magnetic stimulator with enhanced circuit topology and pulse shaping.
        J Neural Eng. 2014 Oct 1; 11056023
        • Goetz S.M.
        • Truong C.N.
        • Gerhofer M.G.
        • Peterchev A.V.
        • Herzog H.-G.
        • Weyh T.
        Analysis and optimization of pulse dynamics for magnetic stimulation. Coles JA.
        PLoS One. 2013 Mar 1; 8e55771
        • Hamada M.
        • Murase N.
        • Hasan A.
        • Balaratnam M.
        • Rothwell J.C.
        The role of interneuron networks in driving human motor cortical plasticity.
        Cerebr Cortex. 2013 Jul 1; 23: 1593-1605
        • Huang G.
        • Mouraux A.
        MEP latencies predict the neuromodulatory effect of cTBS delivered to the ipsilateral and contralateral sensorimotor cortex.
        in: Tremblay F. PLoS One. vol. 10. 2015 Aug 11e0133893 (8)
        • Davidson T.W.
        • Bolic M.
        • Tremblay F.
        Predicting modulation in corticomotor excitability and in transcallosal inhibition in response to anodal transcranial direct current stimulation.
        Front Hum Neurosci. 2016 Feb 15; ([Internet]) ([cited 2018 May 24];10. Available from:)
        • Wiethoff S.
        • Hamada M.
        • Rothwell J.C.
        Variability in response to transcranial direct current stimulation of the motor cortex.
        Brain Stimulat. 2014 May; 7: 468-475
        • Ni Z.
        • Charab S.
        • Gunraj C.
        • Nelson A.J.
        • Udupa K.
        • Yeh I.-J.
        • et al.
        Transcranial magnetic stimulation in different current directions activates separate cortical circuits.
        J Neurophysiol. 2011 Feb 1; 105: 749-756
        • Rothkegel H.
        • Sommer M.
        • Paulus W.
        Breaks during 5Hz rTMS are essential for facilitatory after effects.
        Clin Neurophysiol. 2010 Mar; 121: 426-430
        • Sommer M.
        • Norden C.
        • Schmack L.
        • Rothkegel H.
        • Lang N.
        • Paulus W.
        Opposite optimal current flow directions for induction of neuroplasticity and excitation threshold in the human motor cortex.
        Brain Stimulat. 2013 May; 6: 363-370
        • Lazzaro V.D.
        • Oliviero A.
        • Saturno E.
        • Pilato F.
        • Insola A.
        • Mazzone P.
        • et al.
        The effect on corticospinal volleys of reversing the direction of current induced in the motor cortex by transcranial magnetic stimulation.
        Exp Brain Res. 2001 May 16; 138: 268-273
        • D'Ostilio K.
        • Goetz S.M.
        • Hannah R.
        • Ciocca M.
        • Chieffo R.
        • Chen J.-C.A.
        • et al.
        Effect of coil orientation on strength–duration time constant and I-wave activation with controllable pulse parameter transcranial magnetic stimulation.
        Clin Neurophysiol. 2016 Jan; 127: 675-683
        • Hannah R.
        • Rothwell J.C.
        Pulse duration as well as current direction determines the specificity of transcranial magnetic stimulation of motor cortex during contraction.
        (Brain Stimulat [Internet])2016 Oct ([cited 2016 Oct 27]; Available from:)
        • Chen M.
        • Deng H.
        • Schmidt R.L.
        • Kimberley T.J.
        Low-frequency repetitive transcranial magnetic stimulation targeted to premotor cortex followed by primary motor cortex modulates excitability differently than premotor cortex or primary motor cortex stimulation alone: rTMS to PMC + M1.
        Neuromodul Technol Neural Interface. 2015 Dec; 18: 678-685
        • Chen R.
        • Classen J.
        • Gerloff C.
        • Celnik P.
        • Wassermann E.M.
        • Hallett M.
        • et al.
        Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation.
        Neurology. 1997; 48: 1398-1403
        • Goetz S.M.
        • Luber B.
        • Lisanby S.H.
        • Murphy D.L.K.
        • Kozyrkov I.C.
        • Grill W.M.
        • et al.
        Enhancement of neuromodulation with novel pulse shapes generated by controllable pulse parameter transcranial magnetic stimulation.
        Brain Stimulat. 2016 Jan; 9: 39-47
        • Maeda F.
        • Keenan J.P.
        • Tormos J.M.
        • Topka H.
        • Pascual-Leone A.
        Modulation of corticospinal excitability by repetitive transcranial magnetic stimulation.
        Clin Neurophysiol. 2000 May; 111: 800-805
        • Sommer M.
        • Ciocca M.
        • Chieffo R.
        • Hammond P.
        • Neef A.
        • Paulus W.
        • et al.
        TMS of primary motor cortex with a biphasic pulse activates two independent sets of excitable neurones.
        (Brain Stimulat [Internet])2018 Jan ([cited 2018 Jan 10]; Available from:)
        • Grill W.M.
        Model-based analysis and design of waveforms for efficient neural stimulation.
        ([Internet])in: Progress in brain research. Elsevier, 2015 ([cited 2017 Oct 19]. pp. 147–62. Available from:)
        • Peterchev A.V.
        • Goetz S.M.
        • Westin G.G.
        • Luber B.
        • Lisanby S.H.
        Pulse width dependence of motor threshold and input–output curve characterized with controllable pulse parameter transcranial magnetic stimulation.
        Clin Neurophysiol. 2013 Jul; 124: 1364-1372
        • Fitzgerald P.B.
        • Brown T.L.
        • Daskalakis Z.J.
        • Chen R.
        • Kulkarni J.
        Intensity-dependent effects of 1 Hz rTMS on human corticospinal excitability.
        Clin Neurophysiol. 2002; 113: 1136-1141
        • Lang N.
        • Harms J.
        • Weyh T.
        • Lemon R.N.
        • Paulus W.
        • Rothwell J.C.
        • et al.
        Stimulus intensity and coil characteristics influence the efficacy of rTMS to suppress cortical excitability.
        Clin Neurophysiol. 2006 Oct; 117: 2292-2301
        • Nojima K.
        • Iramina K.
        Prediction of cortical excitability induced by 1 Hz rTMS: PREDICTION OF CORTICAL EXCITABILITY.
        IEEJ Trans Electr Electron Eng. 2017 Jul; 12: 601-607
        • Bi G.
        • Poo M.
        Synaptic modifications in cultured hippocampal neurons: dependence on spike timing, synaptic strength, and postsynaptic cell type.
        J Neurosci. 1998 Dec 15; 18: 10464-10472
        • Miyawaki Y.
        • Okada M.
        Mechanisms of spike inhibition in a cortical network induced by transcranial magnetic stimulation.
        Neurocomputing. 2005 Jun; 65–66: 463-468
        • Rahman A.
        • Reato D.
        • Arlotti M.
        • Gasca F.
        • Datta A.
        • Parra L.C.
        • et al.
        Cellular effects of acute direct current stimulation: somatic and synaptic terminal effects: somatic and terminal origin of DCS effects.
        J Physiol. 2013 May; 591: 2563-2578
        • Letzkus J.J.
        • Kampa B.M.
        • Stuart G.J.
        Learning rules for spike timing-dependent plasticity depend on dendritic synapse location.
        J Neurosci. 2006 Oct 11; 26: 10420-10429
        • Lee S.W.
        • Fried S.I.
        Enhanced control of cortical pyramidal neurons with micromagnetic stimulation.
        IEEE Trans Neural Syst Rehabil Eng. 2017 Sep; 25: 1375-1386
        • Stern S.
        • Agudelo-Toro A.
        • Rotem A.
        • Moses E.
        • Neef A.
        Chronaxie measurements in patterned neuronal cultures from rat Hippocampus.
        PLoS One. 2015 Jul 17; 10e0132577
        • Aberra A.S.
        • Peterchev A.V.
        • Grill W.M.
        Biophysically realistic neuron models for simulation of cortical stimulation.
        2018 Aug 20 ([cited 2018 Nov 9]; Available from:)
        • Salvador R.
        • Silva S.
        • Basser P.J.
        • Miranda P.C.
        Determining which mechanisms lead to activation in the motor cortex: a modeling study of transcranial magnetic stimulation using realistic stimulus waveforms and sulcal geometry.
        Clin Neurophysiol. 2011 Apr; 122: 748-758
        • Di Lazzaro V.
        • Rothwell J.
        • Capogna M.
        Noninvasive stimulation of the human brain: activation of multiple cortical circuits.
        Neuroscientist. 2018 Jun; 24: 246-260
        • Pröschel C.
        • Hansen J.N.
        • Ali A.
        • Tuttle E.
        • Lacagnina M.
        • Buscaglia G.
        • et al.
        Epilepsy-causing sequence variations in SIK1 disrupt synaptic activity response gene expression and affect neuronal morphology.
        Eur J Hum Genet. 2017 Feb; 25: 216-221
        • Rattay F.
        • Paredes L.P.
        • Leao R.N.
        Strength–duration relationship for intra- versus extracellular stimulation with microelectrodes.
        Neuroscience. 2012 Jul; 214: 1-13
        • Rothkegel H.
        • Sommer M.
        • Paulus W.
        • Lang N.
        Impact of pulse duration in single pulse TMS.
        Clin Neurophysiol. 2010 Nov; 121: 1915-1921
        • Murphy S.C.
        • Palmer L.M.
        • Nyffeler T.
        • Müri R.M.
        • Larkum M.E.
        Transcranial magnetic stimulation (TMS) inhibits cortical dendrites.
        Elife. 2016; 5e13598