Abstract
Crossover designs are used by a high proportion of studies investigating the effects of transcranial direct current stimulation (tDCS) on motor learning. These designs necessitate attention to aspects of data collection and analysis to take account of design-related confounds including order, carryover, and period effects. In this systematic review, we appraised the method sections of crossover-designed tDCS studies of motor learning and discussed the strategies adopted to address these factors. A systematic search of 10 databases was performed and 19 research papers, including 21 experimental studies, were identified. Potential risks of bias were addressed in all of the studies, however, not in a rigorous and structured manner. In the data collection phase, unclear methods of randomization, various lengths of washout period, and inconsistency in the counteracting period effect can be observed. In the analytical procedures, the stratification by sequence group was often ignored, and data were treated as if it belongs to a simple repeated-measures design. An inappropriate use of crossover design can seriously affect the findings and therefore the conclusions drawn from tDCS studies on motor learning. The results indicate a pressing need for the development of detailed guidelines for this type of studies to benefit from the advantages of a crossover design.
References
Amadi, U., Allman, C., Johansen-Berg, H., and Stagg, C.J. (2015). The homeostatic interaction between anodal transcranial direct current stimulation and motor learning in humans is related to GABA(A) activity. Brain Stimul. 8, 898–905.10.1016/j.brs.2015.04.010Search in Google Scholar PubMed PubMed Central
Ambrus, G.G., Chaieb, L., Stilling, R., Rothkegel, H., Antal, A., and Paulus, W. (2016). Monitoring transcranial direct current stimulation induced changes in cortical excitability during the serial reaction time task. Neurosci. Lett. 616, 98–104.10.1016/j.neulet.2016.01.039Search in Google Scholar PubMed
Avila, E., van der Geest, J.N., Kengne Kamga, S., Verhage, M.C., Donchin, O., and Frens, M.A. (2015). Cerebellar transcranial direct current stimulation effects on saccade adaptation. Neural Plast. 2015, 968970.10.1155/2015/968970Search in Google Scholar PubMed PubMed Central
Brunoni, A.R. and Fregni, F. (2011). Clinical trial design in non-invasive brain stimulation psychiatric research. Int. J. Methods Psychiatr. Res. 20, e19–e30.10.1002/mpr.338Search in Google Scholar PubMed PubMed Central
Brunoni, A.R. and Vanderhasselt, M.-A. (2014). Working memory improvement with non-invasive brain stimulation of the dorsolateral prefrontal cortex: a systematic review and meta-analysis. Brain Cognit. 86, 1–9.10.1016/j.bandc.2014.01.008Search in Google Scholar PubMed
Buch, E.R., Santarnecchi, E., Antal, A., Born, J., Celnik, P.A., Classen, J., Gerloff, C., Hallett, M., Hummel, F.C., and Nitsche, M.A. (2017). Effects of tDCS on motor learning and memory formation: a consensus and critical position paper. Clin. Neurophysiol. 128, 589–603.10.1016/j.clinph.2017.01.004Search in Google Scholar PubMed
Campbell, D.T. and Stanley, J.C. (1963). Experimental and Quasi-Experimental Designs for Research (Boston, MA: Houghton Mifflin).Search in Google Scholar
Chen, X., Zhao, P.L., and Zhang, J. (2002). A note on ANOVA assumptions and robust analysis for a cross-over study. Stat. Med. 21, 1377–1386.10.1002/sim.1103Search in Google Scholar PubMed
Chew, T., Ho, K.-A., and Loo, C.K. (2015). Inter-and intra-individual variability in response to transcranial direct current stimulation (tDCS) at varying current intensities. Brain Stimul. 8, 1130–1137.10.1016/j.brs.2015.07.031Search in Google Scholar PubMed
Cleophas, T.J. and Zwinderman, A.H. (2012). Statistics Applied to Clinical Studies (Springer Science & Business Media).10.1007/978-94-007-2863-9Search in Google Scholar
Conley, A.C., Marquez, J., Parsons, M.W., Fulham, W.R., Heathcote, A., and Karayanidis, F. (2015). Anodal tDCS over the motor cortex on prepared and unprepared responses in young adults. PLoS One 10, e0124509.10.1371/journal.pone.0124509Search in Google Scholar PubMed PubMed Central
Cuypers, K., Leenus, D.J., van den Berg, F.E., Nitsche, M.A., Thijs, H., Wenderoth, N., and Meesen, R.L. (2013). Is motor learning mediated by tDCS intensity? PLoS One 8, e67344.10.1371/journal.pone.0067344Search in Google Scholar PubMed PubMed Central
Dayan, E. and Cohen, L.G. (2011). Neuroplasticity subserving motor skill learning. Neuron 72, 443–454.10.1016/j.neuron.2011.10.008Search in Google Scholar PubMed PubMed Central
Dayan, E., Censor, N., Buch, E.R., Sandrini, M., and Cohen, L.G. (2013). Noninvasive brain stimulation: from physiology to network dynamics and back. Nat. Neurosci. 16, 838–844.10.1038/nn.3422Search in Google Scholar PubMed PubMed Central
DePuy, V. and Berger, V.W. (2005). Counterbalancing. Wiley StatsRef: Statistics Reference Online.Search in Google Scholar
Díaz-Uriarte, R. (2002). Incorrect analysis of crossover trials in animal behaviour research. Anim. Behav. 63, 815–822.10.1006/anbe.2001.1950Search in Google Scholar
Foerster, Á., Rocha, S., Araújo, M.D.G.R., Lemos, A., and Monte-Silva, K. (2015). Effects of transcranial direct current stimulation on motor learning in healthy individuals: a systematic review. Fisioter. Mov. 28, 159–167.10.1590/0103-5150.028.001.AR01Search in Google Scholar
Fregni, F., Boggio, P.S., Nitsche, M., Bermpohl, F., Antal, A., Feredoes, E., Marcolin, M.A., Rigonatti, S.P., Silva, M.T., and Paulus, W. (2005). Anodal transcranial direct current stimulation of prefrontal cortex enhances working memory. Exp. Brain Res. 166, 23–30.10.1007/s00221-005-2334-6Search in Google Scholar PubMed
Galea, J.M. and Celnik, P. (2009). Brain polarization enhances the formation and retention of motor memories. J. Neurophysiol. 102, 294–301.10.1152/jn.00184.2009Search in Google Scholar PubMed PubMed Central
Hashemirad, F., Zoghi, M., Fitzgerald, P.B., and Jaberzadeh, S. (2016). The effect of anodal transcranial direct current stimulation on motor sequence learning in healthy individuals: a systematic review and meta-analysis. Brain Cognit. 102, 1–12.10.1016/j.bandc.2015.11.005Search in Google Scholar PubMed
Hulst, T., John, L., Küper, M., van der Geest, J.N., Göricke, S.L., Donchin, O., and Timmann, D. (2017). Cerebellar patients do not benefit from cerebellar or M1 transcranial direct current stimulation during force-field reaching adaptation. J. Neurophysiol. 118, 732–748.10.1152/jn.00808.2016Search in Google Scholar PubMed PubMed Central
Hunter, T., Sacco, P., Nitsche, M.A., and Turner, D.L. (2009). Modulation of internal model formation during force field-induced motor learning by anodal transcranial direct current stimulation of primary motor cortex. J. Physiol. 587, 2949–2961.10.1113/jphysiol.2009.169284Search in Google Scholar PubMed PubMed Central
Jaberzadeh, S. and Zoghi, M. (2013). Non-invasive brain stimulation for enhancement of corticospinal excitability and motor performance. Basic Clin. Neurosci. 4, 257.Search in Google Scholar
Jaberzadeh, S., Bastani, A., and Kidgell, D. (2012). Does the longer application of anodal-transcranial direct current stimulaton increase corticomotor excitability further? A pilot study. Basic Clin. Neurosci. 3, 28–35.Search in Google Scholar
Kantak, S.S., Mummidisetty, C.K., and Stinear, J.W. (2012). Primary motor and premotor cortex in implicit sequence learning – evidence for competition between implicit and explicit human motor memory systems. Eur. J. Neurosci. 36, 2710–2715.10.1111/j.1460-9568.2012.08175.xSearch in Google Scholar PubMed
Karok, S. and Witney, A.G. (2013). Enhanced motor learning following task-concurrent dual transcranial direct current stimulation. PLoS One 8, e85693.10.1371/journal.pone.0085693Search in Google Scholar PubMed PubMed Central
López-Alonso, V., Fernández-del-Olmo, M., Costantini, A., Gonzalez-Henriquez, J.J., and Cheeran, B. (2015). Intra-individual variability in the response to anodal transcranial direct current stimulation. Clin. Neurophysiol. 126, 2342–2347.10.1016/j.clinph.2015.03.022Search in Google Scholar PubMed
Minarik, T., Sauseng, P., Dunne, L., Berger, B., and Sterr, A. (2015). Effects of anodal transcranial direct current stimulation on visually guided learning of grip force control. Biology (Basel) 4, 173–186.10.3390/biology4010173Search in Google Scholar PubMed PubMed Central
Nitsche, M.A. and Paulus, W. (2001). Sustained excitability elevations induced by transcranial DC motor cortex stimulation in humans. Neurology 57, 1899–1901.10.1212/WNL.57.10.1899Search in Google Scholar
Nitsche, M.A., Schauenburg, A., Lang, N., Liebetanz, D., Exner, C., Paulus, W., and Tergau, F. (2003). Facilitation of implicit motor learning by weak transcranial direct current stimulation of the primary motor cortex in the human. J. Cognit. Neurosci. 15, 619–626.10.1162/089892903321662994Search in Google Scholar PubMed
Nitsche, M.A., Jakoubkova, M., Thirugnanasambandam, N., Schmalfuss, L., Hullemann, S., Sonka, K., Paulus, W., Trenkwalder, C., and Happe, S. (2010). Contribution of the premotor cortex to consolidation of motor sequence learning in humans during sleep. J. Neurophysiol. 104, 2603–2614.10.1152/jn.00611.2010Search in Google Scholar PubMed
Palm, U., Reisinger, E., Keeser, D., Kuo, M.-F., Pogarell, O., Leicht, G., Mulert, C., Nitsche, M.A., and Padberg, F. (2013). Evaluation of sham transcranial direct current stimulation for randomized, placebo-controlled clinical trials. Brain Stimul. 6, 690–695.10.1016/j.brs.2013.01.005Search in Google Scholar PubMed
Pavlova, E., Kuo, M.F., Nitsche, M.A., and Borg, J. (2014). Transcranial direct current stimulation of the premotor cortex: effects on hand dexterity. Brain Res. 1576, 52–62.10.1016/j.brainres.2014.06.023Search in Google Scholar PubMed
Polanía, R., Nitsche, M.A., and Paulus, W. (2011). Modulating functional connectivity patterns and topological functional organization of the human brain with transcranial direct current stimulation. Hum. Brain Mapp. 32, 1236–1249.10.1002/hbm.21104Search in Google Scholar PubMed PubMed Central
Portney, L.G. and Watkins, M.P. (2000). Foundations of Clinical Research: Applications to Practice (Upper Saddle River, NJ, USA: Prentice Hall).Search in Google Scholar
Reed, J.F. (2004). Analysis of two-treatment, two-period crossover trials in emergency medicine. Ann. Emerg. Med. 43, 54–58.10.1016/S0196-0644(03)00661-9Search in Google Scholar
Reinhart, R.M. and Woodman, G.F. (2015). The surprising temporal specificity of direct-current stimulation. Trends Neurosci. 38, 459–461.10.1016/j.tins.2015.05.009Search in Google Scholar PubMed PubMed Central
Reinhart, R.M., Cosman, J.D., Fukuda, K., and Woodman, G.F. (2017). Using transcranial direct-current stimulation (tDCS) to understand cognitive processing. Atten. Percept. Psychophys. 79, 3–23.10.3758/s13414-016-1224-2Search in Google Scholar PubMed PubMed Central
Reis, J., Schambra, H.M., Cohen, L.G., Buch, E.R., Fritsch, B., Zarahn, E., Celnik, P.A., and Krakauer, J.W. (2009). Noninvasive cortical stimulation enhances motor skill acquisition over multiple days through an effect on consolidation. Proc. Natl. Acad. Sci. U. S. A. 106, 1590–1595.10.1073/pnas.0805413106Search in Google Scholar PubMed PubMed Central
Reis, J., Fischer, J.T., Prichard, G., Weiller, C., Cohen, L.G., and Fritsch, B. (2013). Time-but not sleep-dependent consolidation of tDCS-enhanced visuomotor skills. Cereb. Cortex 25, 109–117.10.1093/cercor/bht208Search in Google Scholar PubMed PubMed Central
Robertson, E.M. (2007). The serial reaction time task: implicit motor skill learning? J. Neurosci. 27, 10073–10075.10.1523/JNEUROSCI.2747-07.2007Search in Google Scholar PubMed PubMed Central
Rroji, O., van Kuyck, K., Nuttin, B., and Wenderoth, N. (2015). Anodal tDCS over the primary motor cortex facilitates long-term memory formation reflecting use-dependent plasticity. PLoS One 10, e0127270.10.1371/journal.pone.0127270Search in Google Scholar PubMed PubMed Central
Saucedo Marquez, C.M., Zhang, X., Swinnen, S.P., Meesen, R., and Wenderoth, N. (2013). Task-specific effect of transcranial direct current stimulation on motor learning. Front Hum. Neurosci. 7, 333.10.3389/fnhum.2013.00333Search in Google Scholar PubMed PubMed Central
Senn, S. (1994). The AB/BA crossover: past, present and future? Stat. Methods Med. Res. 3, 303–324.10.1177/096228029400300402Search in Google Scholar PubMed
Senn, S. (2002). The AB/BA Design With Normal Data. Cross-over Trials in Clinical Research, 2nd ed. (Chichester, UK: John Wiley & Sons), pp. 35–88.10.1002/0470854596.ch3Search in Google Scholar
Shah, B., Nguyen, T.T., and Madhavan, S. (2013). Polarity independent effects of cerebellar tDCS on short term ankle visuomotor learning. Brain Stimul. 6, 966–968.10.1016/j.brs.2013.04.008Search in Google Scholar PubMed
Spieser, L., van den Wildenberg, W., Hasbroucq, T., Richard Ridderinkhof, K., and Burle, B. (2015). Controlling your impulses: electrical stimulation of the human supplementary motor complex prevents impulsive errors. J. Neurosci. 35, 3010–3015.10.1523/JNEUROSCI.1642-14.2015Search in Google Scholar PubMed PubMed Central
Sriraman, A., Oishi, T., and Madhavan, S. (2014). Timing-dependent priming effects of tDCS on ankle motor skill learning. Brain Res. 1581, 23–29.10.1016/j.brainres.2014.07.021Search in Google Scholar PubMed PubMed Central
Stagg, C.J., Jayaram, G., Pastor, D., Kincses, Z.T., Matthews, P.M., and Johansen-Berg, H. (2011). Polarity and timing-dependent effects of transcranial direct current stimulation in explicit motor learning. Neuropsychologia 49, 800–804.10.1016/j.neuropsychologia.2011.02.009Search in Google Scholar PubMed PubMed Central
Stephen, S. (2002). Crossover Trials in Clinical Research (Chichester, UK: John Wiley).Search in Google Scholar
Sun, Y., Lipton, J.O., Boyle, L.M., Madsen, J.R., Goldenberg, M.C., Pascual-Leone, A., Sahin, M., and Rotenberg, A. (2016). Direct current stimulation induces mGluR5-dependent neocortical plasticity. Ann. Neurol. 80, 233–246.10.1002/ana.24708Search in Google Scholar PubMed PubMed Central
Thomas, J.C. and Hersen, M. (2011). Understanding Research in Clinical and Counseling Psychology (Taylor & Francis).10.4324/9780203831700Search in Google Scholar
Ungerleider, L.G., Doyon, J., and Karni, A. (2002). Imaging brain plasticity during motor skill learning. Neurobiol. Learn. Mem. 78, 553–564.10.1006/nlme.2002.4091Search in Google Scholar PubMed
Vahdat, S., Albouy, G., King, B., Lungu, O., and Doyon, J. (2017). Online and offline modulators of motor learning. Front. Hum. Neurosci. 11, 69.10.3389/978-2-88945-166-1Search in Google Scholar
Walker, M.P., Brakefield, T., Seidman, J., Morgan, A., Hobson, J.A., and Stickgold, R. (2003). Sleep and the time course of motor skill learning. Learn. Mem. 10, 275–284.10.1101/lm.58503Search in Google Scholar PubMed PubMed Central
Wellek, S. and Blettner, M. (2012). On the proper use of the crossover design in clinical trials. Dtsch Arztebl Int. 109, 276–281.10.3238/arztebl.2012.0276Search in Google Scholar PubMed PubMed Central
Willian, A.R. and Pater, J.L. (1986). Using baseline measurements in the two-period crossover clinical trial. Controlled Clin. Trials 7, 282–289.10.1016/0197-2456(86)90036-XSearch in Google Scholar
Woods, J.R., Williams, J.G., and Tavel, M. (1989). The two-period crossover design in medical research. Ann. Intern. Med. 110, 560–566.10.7326/0003-4819-110-7-560Search in Google Scholar PubMed
Zimerman, M., Heise, K.F., Hoppe, J., Cohen, L.G., Gerloff, C., and Hummel, F.C. (2012). Modulation of training by single-session transcranial direct current stimulation to the intact motor cortex enhances motor skill acquisition of the paretic hand. Stroke 43, 2185–2289.10.1161/STROKEAHA.111.645382Search in Google Scholar PubMed PubMed Central
Zimerman, M., Nitsch, M., Giraux, P., Gerloff, C., Cohen, L.G., and Hummel, F.C. (2013). Neuroenhancement of the aging brain: restoring skill acquisition in old subjects. Ann. Neurol. 73, 10–15.10.1002/ana.23761Search in Google Scholar PubMed PubMed Central
©2018 Walter de Gruyter GmbH, Berlin/Boston