Noninvasive Brain Stimulation: Applications and Implications

In March the Institute of Medicine held a workshop on electrical and magnetic modes of Non-Invasive Neuromodulation of the Central Nervous System. I had the pleasure of participating in this dynamic event, which covered a range of relevant topics. Participants discussed the growing number of opportunities as well as challenges and ethical considerations associated with the use of devices to non-invasively stimulate the brain and nervous system.

Though initially developed by scientists and clinicians to probe and modulate brain function, brain stimulation devices are now being sold directly to consumers with the promise they will enhance brain function or wellbeing. These products claim they can increase cognitive performance, mathematical ability, attention span, problem solving, memory, and coordination as well as treat depression and chronic pain. It was clear from the presentations and discussions, however, that much work remains to be done to understand the short- and long-term impact of using these devices for medical and non-medical purposes.

Image

Figure from Dayan et al., Nature Neuroscience, 2013, showing typical noninvasive brain stimulation (NIBS) setups. (Left) Standard figure-eight TMS coil placed over dorsolateral prefrontal cortex. (Right) Bipolar tDCS electrode configuration with one electrode over dorsolateral prefrontal cortex and the other over the contralateral supraorbital region.

History of brain stimulation

In 1831, Michael Faraday discovered electromagnetic induction, in which a varying magnetic field induces electrical current in a conductor placed within the field. The brain makes constant use of electricity to rapidly convey information via action potentials sent along axons – which are elegant biological examples of electrical conductors. Interestingly, humans have been attempting to use electricity to heal the brain since long before this was understood. For example, stone carvings from the Fifth Dynasty of Egypt depict an electric fish being used to treat pain, and during the time of Socrates, electric fish were used to treat headaches and arthritis.

Developed in the 1940s, electroconvulsive therapy (ECT), electrical brain stimulation over one or both hemispheres to create a seizure, is highly effective in treating severe depression¹. In 1985 researchers seized upon Faraday’s law of induction to stimulate discrete regions on the surface of the brain through the skull using a pulsed magnetic field². By connecting a wire coil to a source of electric current and placing the coil on the scalp over the motor cortex, Barker et al. gave us the first example of transcranial magnetic stimulation (TMS). The mechanism by which TMS influences brain function is not completely understood, but we do know that TMS can activate axons and cause them to fire action potentials. TMS effects are not specific to inhibitory vs. excitatory neural activity, but may change the balance between excitation and inhibition^3,4,5.

The development of stimulators able to deliver long trains of closely spaced pulses enabled repetitive transcranial magnetic stimulation (rTMS) in the 1990s. This increased the scope of TMS from a neurophysiological probe to a tool with the potential for altering brain function⁶. The growing scientific and clinical interest in noninvasive brain stimulation generated by TMS also led to the revitalization of transcranial direct current stimulation (tDCS), a technique originally applied to humans and animal models in the mid-20^th century. Unlike TMS, which can produce a direct neurostimulatory effect, tDCS does not usually elicit action potentials. Instead, tDCS is thought to exhibit a modulatory effect on brain function: the externally applied electric field displaces ions within neurons, altering neuronal excitability and modulating the firing rate of individual neurons⁷.  Most of the direct-to-consumer brain stimulation products are tDCS devices.

Medical indications for rTMS

Noninvasive brain stimulation is of great interest to clinicians and researchers, given its potential role in studying brain physiology and in treating diseases of the brain. It offers advantages as a diagnostic tool in that it can be used to observe disease-related changes in brain activation, inhibition, or connectivity. Based upon controlled studies the FDA has cleared TMS devices for therapeutic use with patients suffering from treatment-resistant major depressive disorder⁸. Also, based on a randomized controlled clinical trial, the FDA granted premarket approval of a TMS device for the acute treatment of pain associated with migraine headache with aura⁹. Researchers are also studying rTMS as a potential treatment for a range of other neurological diseases and disorders including stroke rehabilitation, chronic pain, epilepsy, obsessive-compulsive disorder, post-traumatic stress disorder, tinnitus, and movement disorders such as Parkinson’s disease (for an overview, see Wassermann and Zimmermann, 2012). In general, researchers have found that for any given indication, patients need repeated rTMS treatment sessions, and combining rTMS with pharmacological and/or behavioral therapy may improve treatment effects. These observations are perhaps not surprising, given that neuroplasticity is likely fundamental to the therapeutic mechanism of noninvasive brain stimulation. 

Moving the field forward

At the meeting, speakers reported the ability of tDCS to improve learning of specific experimental tasks. Whether these generalize to clinically beneficial improved learning is less clear. Also reported were symptom improvements such as decreased anxiety and fatigue with tDCS. Progress in determining the medical benefit of brain stimulation devices is slowed by the lack of standardization across studies of pulse protocols, devices, and stimulation sites. With some exceptions the large randomized trials that are the norm for testing drugs have not been performed for non-invasive brain stimulation devices. This raises concern that positive results from smaller studies could occur simply by chance, due to natural variation and too small a sample size. Publication bias, which leads to the publication of positive results, but not negative results, adds to the concern. It is clear that for the science of non-invasive neuromodulation to advance, a concerted effort must occur to understand how these interventions affect neural circuit function in animals, and to conduct rigorous human studies with standardized protocols.

Ethics of neurostimulation to enhance performance

An area that was particularly fascinating concerned relevant ethical questions surrounding the distinction between enhancement and treatment. Treatment aims to restore normal functioning to people suffering from neurological, mental, or substance abuse disorders, while enhancement aims to improve the function of normal individuals.

Of course, people use various methods to achieve self-enhancement through neuromodulation, such as drinking coffee, exercising, meditating, and so on. Those methods are fairly universally embraced, but the discussion grows murky if noninvasive brain stimulation is included in the mix. rTMS is an existing technology to treat depression, but how would we think about using rTMS to help people feel ‘better than normal? Or to help school children perform better on standardized testing? In general, are there special issues to consider in applying brain stimulation to the developing brains of children? There is a small but growing contingent of the public that is currently utilizing ‘do it yourself’ brain stimulation devices (see for example this piece that the New York Times produced last year) despite the fact that this area of science is in its infancy and these devices are in no way regulated or approved by any group of technical experts – governmental, academic, or otherwise. Some companies are already positioning themselves to capture a bit of market share.

Going forward, research is necessary to better understand the changes that occur in the brain after both acute and chronic non-invasive brain stimulation.  Not all brains are the same – some patients do not respond to non-invasive brain stimulation, and more studies are needed to determine which individuals are most likely to benefit from treatment. Broad discussions will be needed on not just the scientific, clinical, and regulatory issues, but also ethical questions surrounding noninvasive brain stimulation. Attention is needed not only on the treatment of people with neurological disease, but also the complicated ethical and social landscape of neuroenhancement.

Much thanks to Dr. Mark Hallett for providing the fascinating history of brain stimulation

1. Kellner CH, Greenberg RM, Murrough JW, Bryson EO, Briggs MC, Pasculli RM. ECT in treatment-resistant depression. Am J Psychiatry. 2012 Dec;169(12):1238-44.
2. Barker AT, Jalinous R, Freeston IL. Non-invasive magnetic stimulation of human motor cortex. Lancet. 1985 May 11;1(8437):1106-7.
3. Huerta PT, Volpe BT. Transcranial magnetic stimulation, synaptic plasticity and network oscillations. J Neuroeng Rehabil. 2009 Mar 2;6:7. 
4. Perini F, Cattaneo L, Carrasco M, Schwarzbach JV. Occipital transcranial magnetic stimulation has an activity-dependent suppressive effect. J Neurosci. 2012 Sep 5;32(36):12361-5.
5. Dayan E, Censor N, Buch ER, Sandrini M, Cohen LG. Noninvasive brain stimulation: from physiology to network dynamics and back. Nat Neurosci. 2013 Jul;16(7):838-44.
6. Wassermann EM, Zimmermann T. Transcranial magnetic brain stimulation: therapeutic promises and scientific gaps. Pharmacol Ther. 2012 Jan;133(1):98-107.
7. Ukueberuwa D, Wassermann EM. Direct current brain polarization: a simple, noninvasive technique for human neuromodulation. Neuromodulation. 2010 Jul;13(3):168-73.
8. George MS, Taylor JJ, Short EB. The expanding evidence base for rTMS treatment of depression. Curr Opin Psychiatry. 2013 Jan;26(1):13-8.
9. Lipton RB, Dodick DW, Silberstein SD, Saper JR, Aurora SK, Pearlman SH, Fischell RE, Ruppel PL, Goadsby PJ. Single-pulse transcranial magnetic stimulation for acute treatment of migraine with aura: a randomised, double-blind, parallel-group, sham-controlled trial. Lancet Neurol. 2010 Apr;9(4):373-80.