Thursday, April 14, 2016

Don't Lose Your Head Over tDCS

Recent studies of transcranial electrical stimulation in human cadaver heads showed a 90% loss of current when delivered through the skin (Buzsáki, 2016 CNS meeting).

This is the one song everyone
would like to learn: the song
that is irresistible:

the song that forces men
to leap overboard in squadrons
even though they see the beached skulls

the song nobody knows
because anyone who has heard it
is dead, and the others can't remember.

Better living through electricity. The lure of superior performance, improved memory, and higher IQ without all the hard work. Or at least, in a much shorter amount of time.

Transcranial direct current stimulation (tDCS), hailed as a “non-invasive”1 way to alter brain activity,2 has been hot for years. In fact, peak tDCS is already behind us, with a glut of DIY brain stimulation articles in places like Fortune, CBC, Life Hacker, New Statesman, Wall Street Journal, Wired, Slate, Medical Daily, Mosaic, The Economist, Nature, IEEE Spectrum, and The Daily Dot.

Simply apply a weak electrical current to your head via a pair of saline soaked sponges connected to a 9 volt battery. Current flows between the positive anode, or stimulating electrode (in blue below), and the negative cathode (in red below). Low levels of electrical stimulation travel through the scalp and skull to a region of cortex underneath the anode. Modeling studies suggest that the electric field generated by tDCS in humans is about 1 mV/mm (Neuling et al., 2012). The method doesn't directly induce spiking (the firing of action potentials), but it's thought to alter neuronal excitability. By facilitating neuroplastic changes during cognitive training, tDCS may improve learning, memory, mental arithmetic, and target detection.

Modified from Fig. 1b (Dayan et al., 2013). Bipolar tDCS electrode configuration, with one electrode over left dorsolateral prefrontal cortex and a reference electrode over the contralateral supraorbital region. 

And there you have it. High tech performance enhancement for less than $40. Or a siren song for wannabe brain hackers?

In Symposium Session 7 of the Cognitive Neuroscience Society meeting last week, Dr. György Buzsáki threw a bit of cold water on non-invasive transcranial electrical stimulation (TES) methods, which include tDCS and transcranial alternating current (tACS).

My understanding of his remarks: Studies of transcranial electrical stimulation (TES) in human cadaver heads showed there's a 90% loss of current when delivered through the skin (which is obviously the case in living humans) vs. through the skull. This implies that a current of at least 5 mA on the scalp would be necessary to generate a 1 mV/mm electric field in the human brain. Based on his personal experience, Dr. Buzsáki reported that 4 mA was hard to tolerate even with anesthetized skin. For comparison, 2 mA is the maximum current recommended by an international panel of experts.

Others in the audience had similar interpretations:

This revelation was in the context of work on focused beam stimulation, which is designed to improve the spatial selectivity of TES (Voroslakos et al., 2015):
We recorded TES-generated field potentials in human cadavers and anesthetized rats. Stimulation was applied by placing Ag/AgCl EEG electrodes over the external surface of the skull.  ... We also measured the shunting effect of the skin during transcutaneous stimulation. In addition to our earlier results, we found that the skin dramatically reduced the generated intracranial electric fields, and alters its geometry.

image via Sue Peters, @nomorewires

In turn, the cadaver studies were an extension of very cool research on Closed-Loop Control of Epilepsy by Transcranial Electrical Stimulation. This paper used a rodent model of generalized epilepsy to test a system that (1) records neural activity and (2) triggers TES to quell abnormal activity once it is detected.

Having such a system that works in humans would be a huge advance for those who suffer from intractable seizures. Human heads are very different from rat heads, hence the need for human cadavers. And hence the bombshell that 1-2 mA current may have less of an effect on neurons than previously expected.

“But wait!” you say. “Aren't there literally thousands of peer-reviewed articles on tDCS? Surely it must be doing something.”

How Does It Work?

Shall I tell you the secret
and if I do, will you get me
out of this bird suit?

–Atwood, Siren Song

If the effects of tDCS are not directly via neurons, what's the mechanism of action? It's glia! And calcium! Gliotransmission! Maybe.

“Using a transgenic mouse expressing G-CaMP7 in astrocytes and a subpopulation of excitatory neurons, we find that tDCS induces large-amplitude astrocytic Ca2+ surges across the entire cortex with no obvious changes in the local field potential. Moreover, sensory evoked cortical responses are enhanced after tDCS. These enhancements are dependent on the alpha-1 adrenergic receptor and are not observed in IP3R2 (inositol trisphosphate receptor type 2) knockout mice, in which astrocytic Ca2+ surges are absent. Together, we propose that tDCS changes the metaplasticity of the cortex through astrocytic Ca2+/IP3 signalling.”  (Monai et al., 2016)

The pre-astrocyte version of purported mechanism based on direct modulation of the affected neurons' resting membrane potential is described in the schematic below (click on image for a larger view).

But maybe tDCS doesn't really do much in humans after all, as claimed in two recent review articles (Horvath et al., 2015a,b).3

And remember, transcranial devices are not playthings! (warn Bikson et al., 2013).

This gentleman discusses his burn injuries at the tDCS reddit.


1 But see “Non-invasive” brain stimulation is not non-invasive (Davis & van Koningsbruggen, 2013):
These techniques [TMS and tCS] have collectively become known as “non-invasive brain stimulation.” We argue that this term is inappropriate and perhaps oxymoronic, as it obscures both the possibility of side-effects from the stimulation, and the longer-term effects (both adverse and desirable) that may result from brain stimulation. 

2 But see Evidence that transcranial direct current stimulation generates little-to-no reliable neurophysiologic effect beyond MEP amplitude modulation in healthy human subjects: A systematic review (Horvath et al., 2015a):
Our systematic review does not support the idea that tDCS has a reliable neurophysiological effect beyond MEP amplitude modulation... This work raises questions concerning the mechanistic foundations and general efficacy of this device – the implications of which extend to the steadily increasing tDCS psychological literature.

3 Not too surprisingly, these papers have not gone unopposed...

ADDENDUM (April 15 2016)Antal et al. (2015) published one potent rebuttal to Horvath et al. (2015a):

...We are concerned about the validity of the conclusions for various reasons. Since this paper reviews a whole field of research and comes to debatable assumptions, it is especially important that basic quality requirements are fulfilled, which is unfortunately not the case.

First, this review suffers from numerous conceptual flaws and misunderstandings. Second, the work contains relevant design problems, several errors and many incompletely or incorrectly cited data.

. . .

In summary, as shown by the examples given above, this review suffers from important flaws with regard to citing and interpreting available literature, non-transparent, and in many cases erroneous data aggregation, citation of study specifics, and discussion of the results.

ADDENDUM #2 (April 23 2016)There's a new story in Science News (Cadaver study casts doubts on how zapping brain may boost mood, relieve pain) that has attracted a number of comments, including one by Buzsáki himself. And I have a follow-up post (What We Think We Know and Don't Know About tDCS) that covers more of Buzsáki's CNS talk, along with quotes from tDCS experts who weren't surprised by his results.


Berényi A, Belluscio M, Mao D, Buzsáki G. (2012). Closed-loop control of epilepsy by transcranial electrical stimulation. Science 337(6095):735-7.

Fertonani A, & Miniussi C (2016). Transcranial Electrical Stimulation: What We Know and Do Not Know About Mechanisms. The Neuroscientist.  PMID: 26873962

Monai H, Ohkura M, Tanaka M, Oe Y, Konno A, Hirai H, Mikoshiba K, Itohara S, Nakai J, Iwai Y, & Hirase H (2016). Calcium imaging reveals glial involvement in transcranial direct current stimulation-induced plasticity in mouse brain. Nature communications, 7. PMID: 27000523

M. VOROSLAKOS, A. OLIVA, K. BRINYICZKI, T. ZOMBORI, B. IVÁNYI, G. BUZSÁKI, A. BERÉNYI. (2015). Targeted transcranial electrical stimulation protocols: Spatially restricted intracerebral effects via improved stimulation and recording techniques. Society for Neuroscience. Poster# 257.17/Y3.

Further Reading

Invading the brain to understand and repair cognition – CNS Press Release

When the Hype Doesn’t Pan Out: On Sharing the Highs-and-Lows of Research with the Public – by Jared Cooney Horvath

Non-invasive direct current brain stimulation for depression: 
the evidence behind the hype – by Camilla Nord and Jonathan Roiser

Neurostimulation: Bright sparks – by Katherine Bourzac

DIY tDCS – Keeping Tabs On Transcranial Direct Current Stimulation

Why 2.0 mA as the limit for TDCS? – reddit thread

Brunoni AR, Nitsche MA, Bolognini N, Bikson M, Wagner T, Merabet L, Edwards DJ, Valero-Cabre A, Rotenberg A, Pascual-Leone A, Ferrucci R, Priori A, Boggio PS, Fregni F. (2012). Clinical research with transcranial direct current stimulation (tDCS): challenges and future directions. Brain Stimul. 5(3):175-95.

Davis NJ. (2016). The regulation of consumer tDCS: engaging a community of creative self-experimenters. Journal of Law and the Biosciences. Apr 5:lsw013.

Davis NJ, van Koningsbruggen MG. (2013). "Non-invasive" brain stimulation is not non-invasive. Front Syst Neurosci. 7:76.

Dayan E, Censor N, Buch ER, Sandrini M, Cohen LG. (2013). Noninvasive brain stimulation: from physiology to network dynamics and back. Nat Neurosci. 16(7):838-44.

Edwards D, Cortes M, Datta A, Minhas P, Wassermann EM, Bikson M. (2013). Physiological and modeling evidence for focal transcranial electrical brain stimulation in humans: a basis for high-definition tDCS. Neuroimage 74:266-75.

Horvath JC, Forte JD, Carter O. (2015a). Evidence that transcranial direct current stimulation (tDCS) generates little-to-no reliable neurophysiologic effect beyond MEP amplitude modulation in healthy human subjects: A systematic review. Neuropsychologia 66:213-36.

Horvath JC, Forte JD, Carter O. (2015b). Quantitative Review Finds No Evidence of Cognitive Effects in Healthy Populations From Single-session Transcranial Direct Current Stimulation (tDCS). Brain Stimul. 8(3):535-50.

Kuo MF, Nitsche MA. (2012). Effects of transcranial electrical stimulation on cognition. Clin EEG Neurosci. 43(3):192-9.

Parkin BL, Ekhtiari H, Walsh VF. (2015). Non-invasive human brain stimulation in cognitive neuroscience: a primer. Neuron 87(5):932-45.

Santarnecchi E, Brem AK, Levenbaum E, Thompson T, Kadosh RC, Pascual-Leone A. (2015). Enhancing cognition using transcranial electrical stimulation. Current Opinion Behav Sci. 4:171-8.

Woods AJ, Antal A, Bikson M, Boggio PS, Brunoni AR, Celnik P, Cohen LG, Fregni F, Herrmann CS, Kappenman ES, Knotkova H, Liebetanz D, Miniussi C, Miranda PC, Paulus W, Priori A, Reato D, Stagg C, Wenderoth N, Nitsche MA. (2016). A technical guide to tDCS, and related non-invasive brain stimulation tools. Clin Neurophysiol. 127(2):1031-48.

MORE! (added April 15 2016): Two recent meta-analyses on tDCS and working memory reported “a mix of significant and nonsignificant small effects” and “some evidence of a beneficial effect ... [but] the small effect sizes obtained, coupled with non-significant effects on several analyses require cautious interpretation” (respectively):

Mancuso LE, Ilieva IP, Hamilton RH, Farah MJ. Does Transcranial Direct Current Stimulation Improve Healthy Working Memory?: A Meta-analytic Review. J Cogn Neurosci. 2016 Apr 7:1-27. [Epub ahead of print]

Hill AT, Fitzgerald PB, Hoy KE. Effects of Anodal Transcranial Direct Current Stimulation on Working Memory: A Systematic Review and Meta-Analysis of Findings From Healthy and Neuropsychiatric Populations. Brain Stimul. 2016; 9(2):197-208.

I don't enjoy it here
squatting on this island
looking picturesque and mythical

with these two feathery maniacs,
I don't enjoy singing
this trio, fatal and valuable.

I will tell the secret to you,
to you, only to you.
Come closer. This song

is a cry for help: Help me!
Only you, only you can,
you are unique

at last. Alas
it is a boring song
but it works every time.

–Atwood, Siren Song

from Selected Poems 1965-1975. Copyright © 1974, 1976 by Margaret Atwood. Reprinted with the permission of the author and Houghton Mifflin Company in Poetry (February 1974).

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At April 16, 2016 10:30 AM, Blogger Tiziana Metitieri said...

"“After a small shock to the head, you can achieve happiness, a high mark in school, or the record in your preferred videogame.” I am reading this claim in the newspaper while sitting on the train going to work. I know what they are talking about; this is my field of research! Even so, I find these words persuasive, and I would like to try these shocks. The train has slowed down, a voice announces my stop, and I am back to a daily reality where small shocks have become a significant tool in basic and clinical neuroscience but certainly not to improve the performance of normal people in their everyday activities."
This is the nice opening paragraph of the article written by Carlo Miniussi for the Special Issue of the European Psychologist on Noninvasive Brain Stimulation (
I asked Carlo for comments on your post and I have translated his response (in Italian, with excerpts of your post here “the post is well done because it has a lot of links, but what is reported appear to me not so “new” ( Of course, if the findings obtained by Buzsáki are confirmed, you may think that tDCS has an effect nearly homeopathic on the brain. Certainly, these type of research is the most needed: systematic studies of animal and human models, comparable in terms of the amount of current that stimulates the brain. Luckily, they are coming out, or, well, we know they exist and we are waiting to read them, as for Buzsáki. Now we have some studies on animal models demonstrating that the electrical stimulation affects the level of the basic mechanisms of plasticity ( .....

At April 17, 2016 3:31 AM, Blogger The Neurocritic said...

Dr. Metitieri - Thanks so much for your comment and for translating Dr. Miniussi's remarks on the post. I wasn't familiar with the modeling paper of Miranda et al. I should also reiterate that Buzsáki et al.'s findings haven't been published yet; they've only appeared at conferences thus far (including 2015 SfN).

At April 21, 2016 4:52 AM, Blogger David McGonigle said...

Hi there. Hopefully Buzsáki's presentation will become a paper at one point, and then we can examine the experimental set-up in more detail. But for the moment - as others have already suggested - this may be primarily an issue of comparing apples and oranges. We have the different conductivites of PM and live tissues, for one thing. Another point is that few researchers - I hope - would claim for a direct effect of tES to generate spikes *in the absence of endogenous activity* - unlike TMS. Finally, there are now a great number of papers published on the distributions of current in the brain after tES (although just as many problems with what these actually mean for modulating neuronal activity...!)
The problem with the systematic reviews that you mention are that the field desperately needs to agree on some standardisation of how experimental set-ups are reported in the literature, as at the moment I don't see how it's really possible to compare like with like in this manner. To end, I look forward to seeing Buzsaki's setup in more detail - one thing that struck me was that the electrodes penetrating the scalp may have actually created a scenario where shunts are more likely.


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