IN SYSTEMS NEUROSCIENCE

‘Non-invasive’ brain stimulation is not non-invasive

Nick J. Davis and Martijn Van Koningsbruggen

Journal Name: Frontiers in Systems Neuroscience

ISSN: 1662-5137

Article type: Opinion Article

Received on: 15 Oct 2013

Accepted on: 15 Oct 2013

Provisional PDF published on: 15 Oct 2013

Frontiers website link: www.frontiersin.org

Citation: Davis NJ and Koningsbruggen MV(2013) ‘Non-invasive’ brain

stimulation is not non-invasive. Front. Syst. Neurosci. 7:76.
doi:10.3389/fnsys.2013.00076

Article URL: http://www.frontiersin.org/Journal/FullText.aspx?s=1091&

name=systems%20neuroscience&ART_DOI=10.3389
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 1 ‘Non-invasive’ brain stimulation is not non-invasive
2
3
4
5
6 Nick J. Davis 1*, Martijn van Koningsbruggen 2, 3
7
8 1. Department of Psychology, Swansea University, Swansea, United Kingdom
9 2. Centro Interdipartimentale Mente/Cervello (CIMeC), University of Trento, Rovereto,
10 Italy.
11 3. Department of Cognitive Sciences, University of Trento, Rovereto, Italy.
12
13
14
15
16 Correspondence:
17 Dr Nick Davis
18 Department of Psychology
19 Swansea University
20 Swansea SA2 8PP
21 United Kingdom
22 Email: n.j.davis@swansea.ac.uk
23
24
25
26 Keywords: TMS, tDCS, Non-invasive, Neuroethics, Safety, Human.
27

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29 Introduction
30 The functions of the healthy brain can be studied in two ways. Firstly the changes in the
31 brain’s state can be measured using techniques such as EEG or functional MRI. Secondly, the
32 activity of the brain can be disrupted through the use of brain stimulation. The famous
33 experiments of Wilder Penfield and colleagues in the 1950s showed the power of brain
34 stimulation in people whose brain was exposed in surgery, and highlighted the possibility of
35 inducing changes in the brain's state to demonstrate the involvement of specific brain areas in
36 particular functions (Jasper & Penfield, 1954). Two main techniques are available for human
37 brain stimulation: transcranial magnetic stimulation (TMS) and transcranial current
38 stimulation (tCS). More recently it has been suggested that TMS and tCS might be used to
39 enhance brain function, as well as to disrupt activity.
40 These techniques have collectively become known as “non-invasive brain stimulation”.
41 We argue that this term is inappropriate, as it obscures both the possibility of side-effects
42 from the stimulation, and the longer-term effects (both adverse and desirable) that may result
43 from brain stimulation. We argue that the traditional definition of an invasive procedure, one
44 which requires an incision or insertion in the body, should be re-examined, and we propose
45 that it be widened to include targeted transcutaneous interventions.
46

47 Types of brain stimulation

48 An electric current travelling through a coiled wire creates a magnetic field. This property
49 is used in TMS to create brief magnetic pulses which easily traverse the skull and other
50 matter overlaying the brain. The pulses generate electrical potentials in the brain, depolarising
51 neurones and thereby triggering action potentials (Di Lazzaro et al., 2004). A single pulse of
52 TMS will have two effects: firstly the generation of action potentials in the targeted brain
53 areas underlying the coil; secondly a refractory "silent period" in those same cells as the ion
54 balance is restored. While the effects of a single TMS may only be brief, multiple pulses may
55 induce long term potentiation or depression in the target cells. For example, trains of pulses
56 delivered at 1 Hz result in reduced excitability in the target area for a prolonged period of
57 time. A recent development has been the use of rapid bursts of pulses such as theta-burst
58 stimulation (TBS), which can have opposing effects on excitability depending on the
59 temporal pattern of the bursts (Huang, Edwards, Rounis, Bhatia, & Rothwell, 2005). TMS
60 may be used either “online”, to affect the brain during a task, or “offline”, to compare task
61 performance after versus before longer periods of stimulation.
62
63 tCS is a term that covers several techniques, principally involving direct or alternating
64 current (tDCS or tACS). In a typical tDCS experiment, the participant performs a task to
65 establish a baseline performance level. Then a pair of electrodes is placed on the head, one
66 (or both) of which overlie a target brain area. The experimenter delivers a small electrical
67 current for around 10–20 minutes. Following this the participant performs the task a second

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 68 time to establish whether the stimulation has had an effect on behaviour. The effect depends
69 on a number of factors, including current amplitude and duration (higher currents delivered
70 for more time usually induce a greater effect), the polarity of the electrode over the target
71 area (typically the negative electrode, or cathode, will worsen performance while the positive,
72 anodal, electrode will enhance it), and the brain area and task under study (Nitsche & Paulus,
73 2000, 2001). tACS is less well studied, however the technique offers the possibility of
74 exploring the casual involvement not only of a target brain area, but also of a particular
75 frequency band. For example the beta range (15-35 Hz) is known to be associated with
76 human motor control, however it has only recently been possible to show the causal
77 involvement of beta in maintaining motor state (Fuerra et al., 2011; Pogosyan, Gaynor,
78 Eusebio, & Brown, 2009). These latter studies used tACS to increase the power of the beta
79 band while the motor system was under study, giving somewhat contradictory results (Davis,
80 Tomlinson, & Morgan, 2012).
81
82 The timescale over which the effects of brain stimulation are seen can vary from
83 milliseconds to weeks. At the briefest level, a single pulse of TMS lasts for 100-200 µs,
84 during which time an electric field is induced in the target area. This is enough to generate
85 action potentials in these target cells, and to induce a refractory silent period following the
86 initial burst. Conversely the instantaneous effects of tCS are under-explored, and much of our
87 knowledge of the effects of the electric field on the brain comes from modeling studies (e.g.
88 Miranda, Lomarev, & Hallett, 2006). Most experimental uses of brain stimulation involve the
89 medium-scale effects, which occur on the order of minutes to hours. tDCS experiments
90 exploit the polarizing effect of the electric field on the resting membrane potential, which
91 lasts for around 90 minutes following 13 minutes of stimulation (Nitsche & Paulus, 2001).
92 Similarly, the effects of TBS may last up to one hour (Huang, et al., 2005), which can be
93 extended to more than two hours by slightly adjusting the TBS protocol (Nyffeler et al.,
94 2006).
95
96 There is considerable interest in the therapeutic possibilities of brain stimulation. Both
97 TMS and tDCS have shown some success in the treatment of depression (Slotema, Blom,
98 Hoek, & Sommer, 2010), stroke (Hummel & Cohen, 2006) and tinnitus (Fregni et al., 2006).
99 Most usefully for clinical applications, certain regimes of brain stimulation may lead to
100 longer-lasting changes in brain function. A particularly effective strategy for generating
101 lasting effects is to apply stimulation in multiple sessions spaced around 24 hours apart. This
102 regime makes brain stimulation a possible adjunct therapy for neurological disorders, which
103 can be administered in outpatient clinics, leaving the patient free to return home between
104 stimulation sessions.
105

106 Safety issues in brain stimulation

107 No brain stimulation technique is completely free of side-effects. While the safety limits
108 for brain stimulation are reasonably well mapped (Bikson, Datta, & Elwassif, 2009; Nitsche
109 et al., 2003) there remain real risks of seizure from TMS and tCS, and scalp burns from tCS,
110 if appropriate care is not taken. However the greater risk comes from the “known unknowns”
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111 of brain stimulation: unplanned effects from build-up of stimulating effects in non-target
112 areas, or from build-up of effects across multiple sessions. This latter risk can also be an
113 advantage, as discussed above, however inducing long-lasting changes in cortical excitability
114 can be dangerous to the participant if not properly controlled. Indeed, many institutions that
115 use brain stimulation insist on a minimum interval between sessions to prevent a build-up of
116 effects.
117
118 Brain stimulation of healthy volunteers has recently become an established tool for the
119 study of diverse features of the human brain, from basic neurophysiology (Stagg et al., 2009)
120 to large-scale networks (Polanía, Paulus, Antal, & Nitsche, 2011). It is clear that brain
121 stimulation is a powerful tool in the hands of neuroscientists, and the use and utility of these
122 techniques will increase as we learn more about their effects on the brain and about the
123 optimum parameters for generating these effects. A key feature of brain stimulation is that the
124 effects of stimulation can greatly outlast the stimulation phase, sometimes up to several
125 weeks after the end of a stimulation session.
126

127 Common definitions of invasiveness

128 The common, intuitive definition of the term ‘non-invasive’ implies a procedure where no
129 incision or insertion is made in the body. In most medical contexts this is a sensible
130 distinction; physicians must balance the risks and benefits of invasive and non-invasive
131 procedures for both monitoring (e.g. Shoemaker et al., 1998) and treating (e.g. Medoff, 2008)
132 medical complaints. However invasiveness is not restricted to this definition alone. For
133 example, the Oxford English Dictionary gives two relevant usages for the term ‘non-
134 invasive’: “Chiefly Med[ical] Esp[ecially] of a neoplasm or microorganism: not spreading
135 into adjacent tissue from an initial site of development or colonization. Also: designating or
136 relating to such a pattern of growth”; and “Med[ical] Of a diagnostic or therapeutic
137 procedure: that does not require the insertion of instruments (often including hypodermic
138 needles) through the skin or into a body cavity” (“non-invasive”, Oxford English Dictionary,
139 3rd Edition, 2003).
140
141 The second of these dictionary definitions is what we think of as the intuitive
142 neuroscientific definition of ‘non-invasiveness’. Clearly, in contradistinction to surgical
143 procedures such as deep-brain stimulation or direct cortical stimulation, the application of a
144 coil or electrode to the scalp is non-invasive in the sense that the instrument does not
145 physically enter the body. We believe that transcranial brain stimulation with TMS or tCS fits
146 better with the former definition. Induced currents spread from the point of delivery through
147 the brain (and nearby tissues) to adjacent regions. This retains the dictionary definition’s
148 sense of unwanted diffusion away from a source region.
149
150 Referring to brain stimulation techniques as ‘non-invasive’ likely increases the
151 palatability of the techniques to non-expert participants; an important factor in recruitment, as
152 “brain stimulation” already somewhat raises the stakes when recruiting for experiments or
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153 trials. We do not suggest that recruitment adverts should advertise “invasive brain
154 stimulation”, rather that the use of the term ‘non-invasive’ may create an illusion of comfort
155 in participants’ and non-experts’ minds that may not be warranted.
156

157 Widening access to brain stimulation

158 The widening use of brain stimulation has been much discussed recently. In particular,
159 the relatively low cost and ease of manufacture of tDCS has led to something of a movement
160 in so-called "DIY-tDCS" for self-stimulation. Electrical brain stimulation has been suggested
161 as a promising option for improving human experience in a number of domains, including:
162 numerical skills (Cohen Kadosh, Soskic, Iuculano, Kanai, & Walsh, 2010; Snowball et al.,
163 2013); sport (Banissy & Muggleton, 2013; Davis, 2013); memory capacity (Hoy et al., 2013);
164 and depression (Nitsche, Boggio, Fregni, & Pascual-Leone, 2009). As positive results trickle
165 out of labs and clinics, the likelihood is that a greater number of people will wish to explore
166 the use of brain stimulation. As technologies improve and become more widespread, the
167 ethical implications of (mis)use of brain stimulation must be considered; this concern has not
168 been thoroughly addressed in relation to brain stimulation (but see Cohen Kadosh, Levy,
169 O'Shea, Shea, & Savulescu, 2012; Green, Pascual-Leone, & Wassermann, 1997).
170
171 Recent works have attempted to address the ethical and policy implications of widespread
172 use of enhancing technologies. For example, Fitz & Reiner (2013) propose a stance of
173 “managed technological optimism”, whereby stakeholders (including DIY-tDCS developers)
174 take a share in responsibly determining guidelines for using neuroenhancing technology. We
175 see the issue of self-treatment for neurally-mediated disorders as a potentially more serious
176 issue, as people who are not satisfied with physician-delivered treatment seek adjunct
177 treatment with brain stimulation, without clear guidance about proper controls or interactions
178 with existing treatments (Cabrera, Evans, & Hamilton, 2013; Davis, Gold, Pascual-Leone, &
179 Bracewell, 2013). Potential users should be aware that guidelines and principles have been
180 published that address the safe use of brain stimulation techniques (e.g. Davis, et al., 2013;
181 Green, et al., 1997; Rossi, Hallett, Rossini, Pascual-Leone, & Group, 2009).
182

183 Conclusions
184 Brain stimulation will continue to develop, to the benefit of scientists and of patients, and
185 we foresee its routine use in clinics. We propose that the term ‘non-invasive brain
186 stimulation’ no longer be used, as the term may mislead non-expert users into the view that
187 the effect of the technique is necessarily mild. Any technique which directly affects brain
188 tissue to generate such powerful acute and long-lasting effects should be treated with the
189 same respect as any surgical technique, and proper safety and ethical guidelines should apply
190 in institutions where brain stimulation is in use. We would draw an analogy between brain
191 stimulation and gamma-knife radiotherapy, which is also ‘non-invasive’ in the sense that no
192 incisions or insertions are made in the person, but clinicians and the public have a healthy and

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193 proper respect for the nature of the technique. We propose also that researchers take care to
194 develop good and safe practice for the use of their research, and be mindful that in a climate
195 of wide and open dissemination of scientific results, exciting and beneficial results will reach
196 well beyond the labs and clinics.
197

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199 References
200 Banissy, M., & Muggleton, N. (2013). Transcranial direct current stimulation in sports
201 training: potential approaches. Frontiers in Human Neuroscience, 7, 129.
202 Bikson, M., Datta, A., & Elwassif, M. (2009). Establishing safety limits for transcranial direct
203 current stimulation. Clinical Neurophysiology, 120, 1033–1034.
204 Cabrera, L., Evans, E., & Hamilton, R. (2013). Ethics of the Electrified Mind: Defining
205 Issues and Perspectives on the Principled Use of Brain Stimulation in Medical
206 Research and Clinical Care. Brain Topography, DOI:10.1007/s10548-10013-10296-
207 10548.
208 Cohen Kadosh, R., Levy, N., O'Shea, J., Shea, N., & Savulescu, J. (2012). The neuroethics of
209 non-invasive brain stimulation. Current Biology, 22, R108–R111.
210 Cohen Kadosh, R., Soskic, S., Iuculano, T., Kanai, R., & Walsh, V. (2010). Modulating
211 Neuronal Activity Produces Specific and Long-Lasting Changes in Numerical
212 Competence. Current Biology, 20, 2016-2020.
213 Davis, N. (2013). Neurodoping: Brain Stimulation as a Performance-Enhancing Measure.
214 Sports Medicine, 43, 649-653.
215 Davis, N., Gold, E., Pascual-Leone, A., & Bracewell, R. (2013). Challenges of proper
216 placebo control for noninvasive brain stimulation in clinical and experimental
217 applications. European Journal of Neuroscience, 38(7), 2973–2977.
218 Davis, N., Tomlinson, S., & Morgan, H. (2012). The role of beta-frequency neural
219 oscillations in motor control. Journal of Neuroscience, 32, 403-404.
220 Di Lazzaro, V., Oliviero, A., Pilato, F., Saturno, E., Dileone, M., Mazzone, P., et al. (2004).
221 The physiological basis of transcranial motor cortex stimulation in conscious humans.
222 Clinical Neurophysiology, 115, 255-266.
223 Fitz, N., & Reiner, P. (2013). The challenge of crafting policy for do-it-yourself brain
224 stimulation. Journal of Medical Ethics, doi:10.1136/medethics-2013-101458.
225 Fregni, F., Marcondes, R., Boggio, P. S., Marcolin, M. A., Rigonatti, S. P., Sanchez, T. G., et
226 al. (2006). Transient tinnitus suppression induced by repetitive transcranial magnetic
227 stimulation and transcranial direct current stimulation. European Journal of
228 Neurology, 13(9), 996-1001.
229 Fuerra, M., Bianco, G., Santarnecchi, E., Del Testa, M., Rossi, A., & Rossi, S. (2011).
230 Frequency-dependent tuning of the human motor system induced by transcranial
231 oscillatory potentials. Journal of Neuroscience, 31(34), 12165-12170.
232 Green, R., Pascual-Leone, A., & Wassermann, E. (1997). Ethical Guidelines for rTMS
233 Research. IRB: Ethics and Human Research, 19, 1-7.
234 Hoy, K., Emonson, M., Arnold, S., Thomson, R., Daskalakis, Z., & Fitzgerald, P. (2013).
235 Testing the limits: Investigating the effect of tDCS dose on working memory
236 enhancement in healthy controls. Neuropsychologia,
237 http://dx.doi.org/10.1016/j.neuropsychologia.2013.1005.1018.
238 Huang, Y., Edwards, M., Rounis, E., Bhatia, K., & Rothwell, J. (2005). Theta burst
239 stimulation of the human motor cortex. Neuron, 45, 201-206.
240 Hummel, F. C., & Cohen, L. G. (2006). Non-invasive brain stimulation: a new strategy to
241 improve neurorehabilitation after stroke? Lancet Neurology, 5(8), 708-712.

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242 Jasper, H., & Penfield, W. (1954). Epilepsy and the Functional Anatomy of the Human Brain
243 (2nd ed.): Little, Brown & Co.
244 Medoff, B. (2008). Invasive and Noninvasive Ventilation in Patients With Asthma.
245 Respiratory Care, 53, 740-748.
246 Miranda, P. C., Lomarev, M., & Hallett, M. (2006). Modeling the current distribution during
247 transcranial direct current stimulation. Clinical Neurophysiology, 117(7), 1623-1629.
248 Nitsche, M., Liebetanz, D., Lang, N., Antal, A., Tergau, F., & Paulus, W. (2003). Safety
249 criteria for transcranial direct current stimulation (tDCS) in humans. Clinical
250 Neurophysiology, 114, 2220–2222.
251 Nitsche, M. A., Boggio, P. S., Fregni, F., & Pascual-Leone, A. (2009). Treatment of
252 depression with transcranial direct current stimulation (tDCS): A Review.
253 Experimental Neurology, 219(1), 14-19.
254 Nitsche, M. A., & Paulus, W. (2000). Excitability changes induced in the human motor
255 cortex by weak transcranial direct current stimulation. Journal of Physiology, 527(3),
256 633-639.
257 Nitsche, M. A., & Paulus, W. (2001). Sustained excitability elevations induced by
258 transcranial DC motor cortex stimulation in humans. Neurology, 57(10), 1899-1901.
259 Nyffeler, T., Wurtz, P., Luscher, H.-R., Hess, C., Senn, W., Pflugshaupt, T., et al. (2006).
260 Extending lifetime of plastic changes in the human brain. European Journal of
261 Neuroscience, 24, 2961-2966.
262 Pogosyan, A., Gaynor, L., Eusebio, A., & Brown, P. (2009). Boosting Cortical Activity at
263 Beta-Band Frequencies Slows Movement in Humans. Current Biology, 19, 1637-
264 1641.
265 Polanía, R., Paulus, W., Antal, A., & Nitsche, M. (2011). Introducing graph theory to track
266 for neuroplastic alterations in the resting human brain: A transcranial direct current
267 stimulation study. NeuroImage, 54, 2287-2296.
268 Rossi, S., Hallett, M., Rossini, P., Pascual-Leone, A., & Group, T. S. o. T. C. (2009). Safety,
269 ethical considerations, and application guidelines for the use of transcranial magnetic
270 stimulation in clinical practice and research. Clinical Neurophysiology, 120, 2008–
271 2039.
272 Shoemaker, W., Belzberg, H., Wo, C., Milzman, D., Pasquale, M., Baga, L., et al. (1998).
273 Multicenter Study of Noninvasive Monitoring Systems as Alternatives to Invasive
274 Monitoring of Acutely III Emergency Patients. Chest, 114, 1643-1652.
275 Slotema, C., Blom, J., Hoek, H., & Sommer, I. (2010). Should We Expand the Toolbox of
276 Psychiatric Treatment Methods to Include Repetitive Transcranial Magnetic
277 Stimulation (rTMS)? A Meta-Analysis of the Efficacy of rTMS in Psychiatric
278 Disorders. Journal of Clinical Psychiatry, 71, 873–884.
279 Snowball, A., Tachtsidis, I., Popescu, T., Thompson, J., Delazer, M., Zamarian, L., et al.
280 (2013). Long-Term Enhancement of Brain Function and Cognition Using Cognitive
281 Training and Brain Stimulation. Current Biology, 23, 987–992.
282 Stagg, C. J., Best, J. G., Stephenson, M. C., O'Shea, J., Wylezinska, M., Kineses, Z. T., et al.
283 (2009). Polarity-sensitive modulation of cortical neurotransmitters by transcranial
284 stimulation. Journal of Neuroscience, 29(16), 5202-5206.

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