c o r t e x x x x ( 2 0 1 4 ) 1 e3
Available online at www.sciencedirect.com
ScienceDirect Journal homepage: www.elsevier.com/locate/cortex
Commentary
Commentary regarding: TDCS increases cortical excitability: Direct evidence from TMS-EEG Neil W. Bailey a,*, Richard H. Thomson a, Kate E. Hoy a, Julio C. Hernandez-Pavon b and Paul B. Fitzgerald a a b
Monash Alfred Psychiatry Research Centre, Monash University and The Alfred Hospital, Melbourne, Australia Department of Biomedical Engineering and Computational Science (BECS), Aalto University, Espoo, Finland
Recently Romero Lauro et al. (2014) published the results of a study (‘TDCS increases cortical excitability: Direct evidence from TMS-EEG’) demonstrating altered cortical excitability following tDCS, using a combination of TMS and EEG to assess excitability before, during, and after tDCS. One of their goals was to assess not just whether cortical excitability was altered by tDCS, but whether brain areas that were not directly stimulated by tDCS also exhibited altered excitability. This speaks to the question of whether indirect effects of tDCS occur in regions connected to the directly stimulated region. In other words, Romero Lauro et al.'s research attempts to answer whether tDCS at one location affects activity across diverse regions in the brain, through spreading activation via connected regions. Their results indicated that activity recorded from the scalp over nonstimulated clusters differed following tDCS, so they concluded that tDCS shows spreading activation changes to non-stimulated brain regions. This study is the first to explore the effect of tDCS on cortical excitability with TMS-EEG outside the motor system, and as such we agree that this is a novel and interesting study with excellent experimental design. However, we are concerned that a potentially significant confound was not addressed with enough clarity for readers without significant technical expertise in EEG to understand the limitation. Specifically, the manner in which changes in excitability were assessed in non-stimulated regions from pre to post and be-
tween active and sham conditions did not control for the possible impact of volume conduction, which can result in changes in activity detected at the scalp far removed from the underlying generator of the activity (van den Broek, Reinders, Donderwinkel, & Peters, 1998; Holsheimer & Feenstra, 1977; Nunez et al., 1997; Winter, Nunez, Ding, & Srinivasan, 2007). Volume conduction is the instantaneous passive spread of electrical signal from a source generator through the brain, cerebrospinal fluid, dura mater, and skull to be detected at the scalp (van den Broek et al., 1998; Holsheimer & Feenstra, 1977; Nunez et al., 1997). As such, volume conduction contributes to the activity recorded at a sensor, but does not represent signal from directly under the sensor, nor communication between brain regions (van den Broek et al., 1998; Holsheimer & Feenstra, 1977; Nunez et al., 1997; Winter et al., 2007). In order to assess excitation changes in non-directly stimulated regions, the authors removed the data obtained from sensors over directly stimulated regions from the analysis, and ran the comparisons again. However, because of volume conduction, changes that occurred in stimulated regions could have affected the activity reaching the scalp right across the head. In other words, the measures of amplitude recorded at the scalp above nonstimulated regions may have been altered by changes in excitability in stimulated regions, which project those changes via volume conduction to scalp sites above nonstimulated regions, without any change in the excitability of
* Corresponding author. Monash Alfred Psychiatry Research Centre, Level 4, 607 St Kilda Road, Melbourne, Victoria 3004, Australia. E-mail address: [email protected] (N.W. Bailey). http://dx.doi.org/10.1016/j.cortex.2014.10.022 0010-9452/© 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Bailey, N. W., et al., Commentary regarding: TDCS increases cortical excitability: Direct evidence from TMS-EEG, Cortex (2014), http://dx.doi.org/10.1016/j.cortex.2014.10.022
2
c o r t e x x x x ( 2 0 1 4 ) 1 e3
non-stimulated regions of the brain. The authors allude to this limitation in the manuscript, stating that ‘caution is warranted in interpreting the results of local signal effects, due to the poor spatial resolution of the EEG’. We feel the potential confound is important. As such, volume conduction as an alternative explanation for the changes above non-stimulated brain regions requires specific emphasis so that this possibility is clear for non-experts in EEG, and so that future researchers are aware about the exact details of the questions that remain unanswered. Further, it is unfortunate that the removal of clusters above stimulated regions was the only manner in which changes in excitability in non-stimulated brain regions were assessed, because other currently available analysis methods are able to specify the location of changes in cortical excitability. As mentioned in the article, source localisation has the capacity to detect differences between conditions in the underlying generators of neural activity. This capacity enables researchers to discriminate between volume conduction effects from a stimulated area, and changes in the activation of both the stimulated area and non-directly stimulated areas. Alternatively, RAGU can differentiate between changes in the spatial distribution of the potential and changes in overall neural response strength (Koenig, Kottlow, Stein, & MelieGarcı´a, 2011). This offers an indication of whether changes in activity may have occurred just in the stimulated region, or across the whole head. Also, measures of functional connectivity that exclude zero lag connectivity are available, so that any contribution of volume conduction that might confound the results is excluded from the analysis (Vinck, Oostenveld, van Wingerden, Battaglia, & Pennartz, 2011). These measures could have also been used to determine whether the excitability of connections between regions had been altered by tDCS. Finally the use of stimulation with TMS at .4e.5 Hz during tDCS means that the post measures are not directly assessing the effect of tDCS alone, they are assessing the effect of tDCS plus TMS, two techniques that have been shown to have an interactive effect on cortical excitability (Lang et al., 2004; Siebner et al., 2004). As such, we would suggest that when using TMS to measure excitability pre, during, and post tDCS, the TMS pulses should be applied at a frequency that has been confirmed to be sufficiently low to prevent the possibility of the TMS measurement itself actually moderating cortical excitability. This issue has not been systematically assessed, so it is unclear whether TMS at .4e.5 Hz might modulate cortical excitability. However, physiological research has confirmed that TMS at .1 Hz does not alter cortical excitability, while .9 Hz does alter cortical excitability (Chen et al., 1997), and therapeutic effects in clinical research are suggestive that treatment at .5 Hz leads to neuroplastic changes in cortical excitability (Dragasevic, Potrebic, Damjanovic, Stefanova, & Kostic, 2002; Menkes, Bodnar, Ballesteros, & Swenson, 1999; Misawa, Kuwabara, Shibuya, Mamada, & Hattori, 2005).
Role of funding PBF was supported by a Practitioner Fellowship grant from the National Health and Medical Research Council (NHMRC
606907). KEH was supported by a Post Doctoral Training Fellowship from NHMRC (546229).
Conflicts of interest PBF has received equipment for research from Medtronic Ltd., MagVenture A/S and Brainsway Ltd. NWB, KEH, RHT, and JCH have no relevant conflicts to declare.
references
Chen, R., Classen, J., Gerloff, C., Celnik, P., Wassermann, E. M., Hallett, M., et al. (1997). Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation. Neurology, 48(5), 1398e1403. Dragasevic, N., Potrebic, A., Damjanovic, A., Stefanova, E., & Kostic, V. S. (2002). Therapeutic efficacy of bilateral prefrontal slow repetitive transcranial magnetic stimulation in depressed patients with Parkinson's disease: an open study. Movement Disorders, 17(3), 528e532. Holsheimer, J., & Feenstra, B. W. A. (1977). Volume conduction and EEG measurements within the brain: a quantitative approach to the influence of electrical spread on the linear relationship of activity measured at different locations. Electroencephalography and Clinical Neurophysiology, 43, 52e58. Koenig, T., Kottlow, M., Stein, M., & Melie-Garcı´a, L. (2011). Ragu: a free tool for the analysis of EEG and MEG event-related scalp field data using global randomization statistics. Computational Intelligence and Neuroscience. http://dx.doi.org/10.1155/2011/ 938925. Lang, N., Siebner, H. R., Ernst, D., Nitsche, M. A., Paulus, W., Lemon, R. N., et al. (2004). Preconditioning with transcranial direct current stimulation sensitizes the motor cortex to rapid-rate transcranial magnetic stimulation and controls the direction of after-effects. Biological Psychiatry, 56(9), 634e639. Menkes, D. L., Bodnar, P. B., Ballesteros, R. A., & Swenson, M. R. (1999). Right frontal lobe slow frequency repetitive transcranial magnetic stimulation (SF r-TMS) is an effective treatment for depression: a case-control pilot study of safety and efficacy. Journal of Neurology, Neurosurgery, and Psychiatry, 67, 113e115. Misawa, S., Kuwabara, S., Shibuya, K., Mamada, K., & Hattori, T. (2005). Low-frequency transcranial magnetic stimulation for epilepsia partialis continua due to cortical dysplasia. Journal of the Neurological Sciences, 234(1e2), 37e39. Nunez, P. L., Srinivasan, R., Westdorp, A. F., Wijesinghe, R. S., Tucker, D. M., Silberstein, R. B., et al. (1997). EEG coherency I: statistics, reference electrode, volume conduction, Laplacians, cortical imaging, and interpretation at multiple scales. Electroencephalography and Clinical Neurophysiology, 103, 499e515. Romero Lauro, L. J., Rosanova, M., Mattavelli, G., Convento, S., Pisoni, A., Opitz, A., et al. (2014). TDCS increases cortical excitability: direct evidence from TMS-EEG. Cortex, 58C, 99e111. Siebner, H. R., Lang, N., Rizzo, V., Nitsche, M. A., Paulus, W., Lemon, R. N., et al. (2004). Preconditioning of low-frequency repetitive transcranial magnetic stimulation with transcranial direct current stimulation: evidence for homeostatic plasticity in the human motor cortex. The Journal of Neuroscience, 24(13), 3379e3385. van den Broek, S. P., Reinders, F., Donderwinkel, M., & Peters, M. J. (1998). Volume conduction effects in EEG and MEG.
Please cite this article in press as: Bailey, N. W., et al., Commentary regarding: TDCS increases cortical excitability: Direct evidence from TMS-EEG, Cortex (2014), http://dx.doi.org/10.1016/j.cortex.2014.10.022
c o r t e x x x x ( 2 0 1 4 ) 1 e3
Electroencephalography and Clinical Neurophysiology, 106, 522e534. Vinck, M., Oostenveld, R., van Wingerden, M., Battaglia, F., & Pennartz, C. M. (2011). An improved index of phasesynchronization for electrophysiological data in the presence of volume-conduction, noise and sample-size bias. NeuroImage, 55(4), 1548e1565. Winter, W. R., Nunez, P. L., Ding, J., & Srinivasan, R. (2007). Comparison of the effect of volume conduction on EEG
3
coherence with the effect of field spread on MEG coherence. Statistics in Medicine, 26(21), 3946e3957.
Received 2 September 2014 Reviewed 21 October 2014 Accepted 21 October 2014
Please cite this article in press as: Bailey, N. W., et al., Commentary regarding: TDCS increases cortical excitability: Direct evidence from TMS-EEG, Cortex (2014), http://dx.doi.org/10.1016/j.cortex.2014.10.022
Available online at www.sciencedirect.com
ScienceDirect Journal homepage: www.elsevier.com/locate/cortex
Commentary
Commentary regarding: TDCS increases cortical excitability: Direct evidence from TMS-EEG Neil W. Bailey a,*, Richard H. Thomson a, Kate E. Hoy a, Julio C. Hernandez-Pavon b and Paul B. Fitzgerald a a b
Monash Alfred Psychiatry Research Centre, Monash University and The Alfred Hospital, Melbourne, Australia Department of Biomedical Engineering and Computational Science (BECS), Aalto University, Espoo, Finland
Recently Romero Lauro et al. (2014) published the results of a study (‘TDCS increases cortical excitability: Direct evidence from TMS-EEG’) demonstrating altered cortical excitability following tDCS, using a combination of TMS and EEG to assess excitability before, during, and after tDCS. One of their goals was to assess not just whether cortical excitability was altered by tDCS, but whether brain areas that were not directly stimulated by tDCS also exhibited altered excitability. This speaks to the question of whether indirect effects of tDCS occur in regions connected to the directly stimulated region. In other words, Romero Lauro et al.'s research attempts to answer whether tDCS at one location affects activity across diverse regions in the brain, through spreading activation via connected regions. Their results indicated that activity recorded from the scalp over nonstimulated clusters differed following tDCS, so they concluded that tDCS shows spreading activation changes to non-stimulated brain regions. This study is the first to explore the effect of tDCS on cortical excitability with TMS-EEG outside the motor system, and as such we agree that this is a novel and interesting study with excellent experimental design. However, we are concerned that a potentially significant confound was not addressed with enough clarity for readers without significant technical expertise in EEG to understand the limitation. Specifically, the manner in which changes in excitability were assessed in non-stimulated regions from pre to post and be-
tween active and sham conditions did not control for the possible impact of volume conduction, which can result in changes in activity detected at the scalp far removed from the underlying generator of the activity (van den Broek, Reinders, Donderwinkel, & Peters, 1998; Holsheimer & Feenstra, 1977; Nunez et al., 1997; Winter, Nunez, Ding, & Srinivasan, 2007). Volume conduction is the instantaneous passive spread of electrical signal from a source generator through the brain, cerebrospinal fluid, dura mater, and skull to be detected at the scalp (van den Broek et al., 1998; Holsheimer & Feenstra, 1977; Nunez et al., 1997). As such, volume conduction contributes to the activity recorded at a sensor, but does not represent signal from directly under the sensor, nor communication between brain regions (van den Broek et al., 1998; Holsheimer & Feenstra, 1977; Nunez et al., 1997; Winter et al., 2007). In order to assess excitation changes in non-directly stimulated regions, the authors removed the data obtained from sensors over directly stimulated regions from the analysis, and ran the comparisons again. However, because of volume conduction, changes that occurred in stimulated regions could have affected the activity reaching the scalp right across the head. In other words, the measures of amplitude recorded at the scalp above nonstimulated regions may have been altered by changes in excitability in stimulated regions, which project those changes via volume conduction to scalp sites above nonstimulated regions, without any change in the excitability of
* Corresponding author. Monash Alfred Psychiatry Research Centre, Level 4, 607 St Kilda Road, Melbourne, Victoria 3004, Australia. E-mail address: [email protected] (N.W. Bailey). http://dx.doi.org/10.1016/j.cortex.2014.10.022 0010-9452/© 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Bailey, N. W., et al., Commentary regarding: TDCS increases cortical excitability: Direct evidence from TMS-EEG, Cortex (2014), http://dx.doi.org/10.1016/j.cortex.2014.10.022
2
c o r t e x x x x ( 2 0 1 4 ) 1 e3
non-stimulated regions of the brain. The authors allude to this limitation in the manuscript, stating that ‘caution is warranted in interpreting the results of local signal effects, due to the poor spatial resolution of the EEG’. We feel the potential confound is important. As such, volume conduction as an alternative explanation for the changes above non-stimulated brain regions requires specific emphasis so that this possibility is clear for non-experts in EEG, and so that future researchers are aware about the exact details of the questions that remain unanswered. Further, it is unfortunate that the removal of clusters above stimulated regions was the only manner in which changes in excitability in non-stimulated brain regions were assessed, because other currently available analysis methods are able to specify the location of changes in cortical excitability. As mentioned in the article, source localisation has the capacity to detect differences between conditions in the underlying generators of neural activity. This capacity enables researchers to discriminate between volume conduction effects from a stimulated area, and changes in the activation of both the stimulated area and non-directly stimulated areas. Alternatively, RAGU can differentiate between changes in the spatial distribution of the potential and changes in overall neural response strength (Koenig, Kottlow, Stein, & MelieGarcı´a, 2011). This offers an indication of whether changes in activity may have occurred just in the stimulated region, or across the whole head. Also, measures of functional connectivity that exclude zero lag connectivity are available, so that any contribution of volume conduction that might confound the results is excluded from the analysis (Vinck, Oostenveld, van Wingerden, Battaglia, & Pennartz, 2011). These measures could have also been used to determine whether the excitability of connections between regions had been altered by tDCS. Finally the use of stimulation with TMS at .4e.5 Hz during tDCS means that the post measures are not directly assessing the effect of tDCS alone, they are assessing the effect of tDCS plus TMS, two techniques that have been shown to have an interactive effect on cortical excitability (Lang et al., 2004; Siebner et al., 2004). As such, we would suggest that when using TMS to measure excitability pre, during, and post tDCS, the TMS pulses should be applied at a frequency that has been confirmed to be sufficiently low to prevent the possibility of the TMS measurement itself actually moderating cortical excitability. This issue has not been systematically assessed, so it is unclear whether TMS at .4e.5 Hz might modulate cortical excitability. However, physiological research has confirmed that TMS at .1 Hz does not alter cortical excitability, while .9 Hz does alter cortical excitability (Chen et al., 1997), and therapeutic effects in clinical research are suggestive that treatment at .5 Hz leads to neuroplastic changes in cortical excitability (Dragasevic, Potrebic, Damjanovic, Stefanova, & Kostic, 2002; Menkes, Bodnar, Ballesteros, & Swenson, 1999; Misawa, Kuwabara, Shibuya, Mamada, & Hattori, 2005).
Role of funding PBF was supported by a Practitioner Fellowship grant from the National Health and Medical Research Council (NHMRC
606907). KEH was supported by a Post Doctoral Training Fellowship from NHMRC (546229).
Conflicts of interest PBF has received equipment for research from Medtronic Ltd., MagVenture A/S and Brainsway Ltd. NWB, KEH, RHT, and JCH have no relevant conflicts to declare.
references
Chen, R., Classen, J., Gerloff, C., Celnik, P., Wassermann, E. M., Hallett, M., et al. (1997). Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation. Neurology, 48(5), 1398e1403. Dragasevic, N., Potrebic, A., Damjanovic, A., Stefanova, E., & Kostic, V. S. (2002). Therapeutic efficacy of bilateral prefrontal slow repetitive transcranial magnetic stimulation in depressed patients with Parkinson's disease: an open study. Movement Disorders, 17(3), 528e532. Holsheimer, J., & Feenstra, B. W. A. (1977). Volume conduction and EEG measurements within the brain: a quantitative approach to the influence of electrical spread on the linear relationship of activity measured at different locations. Electroencephalography and Clinical Neurophysiology, 43, 52e58. Koenig, T., Kottlow, M., Stein, M., & Melie-Garcı´a, L. (2011). Ragu: a free tool for the analysis of EEG and MEG event-related scalp field data using global randomization statistics. Computational Intelligence and Neuroscience. http://dx.doi.org/10.1155/2011/ 938925. Lang, N., Siebner, H. R., Ernst, D., Nitsche, M. A., Paulus, W., Lemon, R. N., et al. (2004). Preconditioning with transcranial direct current stimulation sensitizes the motor cortex to rapid-rate transcranial magnetic stimulation and controls the direction of after-effects. Biological Psychiatry, 56(9), 634e639. Menkes, D. L., Bodnar, P. B., Ballesteros, R. A., & Swenson, M. R. (1999). Right frontal lobe slow frequency repetitive transcranial magnetic stimulation (SF r-TMS) is an effective treatment for depression: a case-control pilot study of safety and efficacy. Journal of Neurology, Neurosurgery, and Psychiatry, 67, 113e115. Misawa, S., Kuwabara, S., Shibuya, K., Mamada, K., & Hattori, T. (2005). Low-frequency transcranial magnetic stimulation for epilepsia partialis continua due to cortical dysplasia. Journal of the Neurological Sciences, 234(1e2), 37e39. Nunez, P. L., Srinivasan, R., Westdorp, A. F., Wijesinghe, R. S., Tucker, D. M., Silberstein, R. B., et al. (1997). EEG coherency I: statistics, reference electrode, volume conduction, Laplacians, cortical imaging, and interpretation at multiple scales. Electroencephalography and Clinical Neurophysiology, 103, 499e515. Romero Lauro, L. J., Rosanova, M., Mattavelli, G., Convento, S., Pisoni, A., Opitz, A., et al. (2014). TDCS increases cortical excitability: direct evidence from TMS-EEG. Cortex, 58C, 99e111. Siebner, H. R., Lang, N., Rizzo, V., Nitsche, M. A., Paulus, W., Lemon, R. N., et al. (2004). Preconditioning of low-frequency repetitive transcranial magnetic stimulation with transcranial direct current stimulation: evidence for homeostatic plasticity in the human motor cortex. The Journal of Neuroscience, 24(13), 3379e3385. van den Broek, S. P., Reinders, F., Donderwinkel, M., & Peters, M. J. (1998). Volume conduction effects in EEG and MEG.
Please cite this article in press as: Bailey, N. W., et al., Commentary regarding: TDCS increases cortical excitability: Direct evidence from TMS-EEG, Cortex (2014), http://dx.doi.org/10.1016/j.cortex.2014.10.022
c o r t e x x x x ( 2 0 1 4 ) 1 e3
Electroencephalography and Clinical Neurophysiology, 106, 522e534. Vinck, M., Oostenveld, R., van Wingerden, M., Battaglia, F., & Pennartz, C. M. (2011). An improved index of phasesynchronization for electrophysiological data in the presence of volume-conduction, noise and sample-size bias. NeuroImage, 55(4), 1548e1565. Winter, W. R., Nunez, P. L., Ding, J., & Srinivasan, R. (2007). Comparison of the effect of volume conduction on EEG
3
coherence with the effect of field spread on MEG coherence. Statistics in Medicine, 26(21), 3946e3957.
Received 2 September 2014 Reviewed 21 October 2014 Accepted 21 October 2014
Please cite this article in press as: Bailey, N. W., et al., Commentary regarding: TDCS increases cortical excitability: Direct evidence from TMS-EEG, Cortex (2014), http://dx.doi.org/10.1016/j.cortex.2014.10.022
