BJMB
Brazilian Journal of Motor Behavior
Current Opinion
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Neuromodulation by non-invasive brain stimulation (NIBS): a step back to move forward
MIGUEL FERNANDEZ-DEL-OLMO
1
| MARTA SEVILLA-SANCHEZ
2
| GONZALO MARQUEZ-SANCHEZ
2
| DAWSON
KIDGELL
3
| MARIE-HELENE MILOT
4
| RUUD W. SELLES
5,6
| JOHN ROTHWELL
7
| TIBOR HORTOBÁGYI
8
1
Area of Sport Sciences, Faculty of Sports Sciences and Physical Education, Center for Sport Studies, King Juan Carlos University, Madrid, Spain.
2
Department of Physical Education and Sport, Faculty of Sports Sciences and Physical Education, University of A Coruna, A Coruna, Spain.
3
Department of Physiotherapy, School of Primary and Allied Health Care, Faculty of Medicine, Nursing and Health Science, Monash University, Melbourne, Australia.
4
Centre de recherche sur le vieillissement, École de réadaptation, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, QC, Canada.
5
Department of Rehabilitation Medicine, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands.
6
Department of Plastic and Reconstructive Surgery, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands.
7
Sobell Department of Motor Neuroscience and Movement Disorders, University College London, Institute of Neurology, London, United Kingdom.
8
Center for Human Movement Sciences, University Medical Center Groningen, The University of Groningen, Groningen, The Netherlands.
Correspondence to: Miguel Fernandez del Olmo - Area of Sport Sciences, Faculty of Sports Sciences and Physical Education - Center for Sport Studies - King Juan
Carlos University - Camino del Molino, s/n, 28943 Fuenlabrada, Madrid, Spain.
email: miguel.delolmo@urjc.es
https://doi.org/10.20338/bjmb.v15i2.213
ABBREVIATIONS
iTBS Intermittent theta burst (magnetic) stimulation
M1 primary motor cortex
NIBS non-invasive brain stimulation
rTMS repetitive transcranial magnetic stimulation
tDCS transcranial direct current stimulation
PUBLICATION DATA
Received 25 11 2020
Accepted 30 11 2020
Published 01 06 2021
The first studies on non-invasive brain stimulation (NIBS) appeared barely 20
years ago showing lasting changes in cortical excitability of motor areas following repetitive
transcranial magnetic stimulation (rTMS)
1
and transcranial direct current stimulation
(tDCS).
2
These pioneering studies opened up new vistas for the exploration of treatment
alternatives for diverse pathologies (from depression to joint instability) and for the
enhancement of cognitive and motor function. Indeed, the ~2,000 papers published on
NIBS during the past two years is a resolute expression of the effort to fully develop these
techniques of cortical stimulation for quick, customized, reliable, lasting, and most
importantly, corrective modulation of putative brain circuits underlying neurological,
orthopedic, behavioral, and cognitive impairments.
As a result of this immense research effort, NIBS-induced neuromodulatory
treatments are now considered ‘evidence-based’ and have become readily available at
clinics and rehabilitation centers. With exception of rTMS for treating depressive symptoms,
recommendation for therapeutic use of NIBS is based mainly on meta-analytical estimates
of NIBS effects observed in studies using very small and heterogenous samples, and
without randomization, blinding to treatment, or placebo stimulation. The aim of the current
opinion is not to cast a critical light on the NIBS literature. Rather, we wish to reflect on key
features of the purported neuromodulatory effects of NIBS, i.e., the inconsistency in
inducing changes in brain excitability and replicating such changes induced by NIBS.
Depending on the nature (magnetic, electrical) and the wave properties of the
stimulus, NIBS can increase or decrease the excitability of circuits targeted. Intermittent
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theta burst (magnetic) stimulation (iTBS) has excitatory after-effects on the primary motor
cortex (M1). However, several studies, using various rTMS protocols, failed to observe the
expected rise in excitability, while others showing increased excitability revealed that the
effects were unreliable.
3,4
The interneuron networks targeted, shape of the stimulus
waveform, time of day, attention, and genetics are just some of the factors that could
contribute to the inconsistencies between studies. A further complicating factor is that
NIBS can have lasting effects, as was the case after rTMS at 1Hz, which tends to
decrease M1 excitability. When the first rTMS session was repeated after 5 days, there
was a cumulative effect of a deepened M1 inhibition, making session-to-session reliability
assessments questionable.
5
Inter-individual differences in the required current intensity, direction, and the size
of the electric field of NIBS could underlie responsiveness differences across individuals,
potentially contributing to its unreliability. The large inter-individual variation and poor
responsiveness to NIBS was evident after 56 healthy adults received paired associative
stimulation, anodal tDCS, and iTBS, but only ~45% of participants exhibited changes in M1
excitability after each protocol and only 12% responded to all three.
6
Even these response
rates are questionable because the NIBS effects were not compared with sham controls,
leaving the ‘true’ effects undetermined. Therapeutic NIBS effects are believed to rise with
increasing number of sessions, although evidence is inconclusive for such cumulative
effect following repeated NIBS sessions,
7
even if the trial comprises a large sample,
randomization, placebo-control, and double blinding.
8
Brain health state seems to further
increase inter-individual variability in responsiveness to NIBS. For instance, it augmented
the effects of motor training on healthy older adults’ functional outcomes, but not in
individuals at the chronic phase of a stroke following paretic arm strength training.
9,10
The emerging perspective is that NIBS holds promise to become an independent
treatment but, perhaps more likely, as an adjuvant to standard rehabilitation. There is a
need to perform randomized, double-blind, and sham-controlled trials in large sample sizes
with pre-registration of the protocol. Future studies may need to better control the NIBS
application, as for example by including EEG-controlled stimulation and an accurate
modelling of the current flow in the brain. In addition, in many disease applications, we
need a better understanding of the underlying mechanisms of the brain networks that NIBS
aims to modulate and take this into account when designing a personalized NIBS
application. Such approaches could account for variations in brain anatomy and increase
targeting accuracy of the magnetic or electric field, which could then increase the number
of responders, reduce the variation between responders, and produce acceptable reliability
within and between sessions.
Only by taking a step back can we ensure that these promising interventions
improve neurological and cognitive impairments through a ‘real’ neuromodulatory effect.
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Citation: Fernandez-del-Olmo M, Sevilla-Sanchez M, Marquez-Sanchez G, Kidgell D, Milot MH, Selles RW, Rothwell
J, Hortobágyi T. Neuromodulation by non-invasive brain stimulation (NIBS): a step back to move forward. BJMB. 2021.
15(2): 61-64.
Editors: Dr Fabio Augusto Barbieri - São Paulo State University (UNESP), Bauru, SP, Brazil; Dr José Angelo Barela -
São Paulo State University (UNESP), Rio Claro, SP, Brazil; Dr Natalia Madalena Rinaldi - Federal University of
Espírito Santo (UFES), Vitória, ES, Brazil.
Section Editors (Current Opinion): Dr Luis Augusto Teixeira - University of São Paulo (USP), São Paulo, SP, Brazil;
Dr Tibor Hortobágyi - University of Groningen, The Netherlands; Dr Renato de Moraes - University of São Paulo
(USP), Ribeirão Preto, SP, Brazil.
Copyright:© 2021 Fernandez-del-Olmo, Sevilla-Sanchez, Marquez-Sanchez, Kidgell, Milot, Selles, Rothwell and
Hortobágyi and BJMB. This is an open-access article distributed under the terms of the Creative Commons Attribution-
Non Commercial-No Derivatives 4.0 International License which permits unrestricted use, distribution, and
reproduction in any medium, provided the original author and source are credited.
Funding: There was no funding for this study.
Competing interests: The authors have declared that no competing interests exist.
DOI:!https://doi.org/10.20338/bjmb.v15i2.213