Friday, April 22, 2016

What We Think We Know and Don't Know About tDCS

image: Mihály Vöröslakos / University of Szeged

Don't Lose Your Head Over tDCS,” I warned last time. Now the infamous cadaver study has reared its ugly hot-wired head in Science News (Underwood, 2016).

The mechanism of action of transcranial direct current stimulation (tDCS) had been called into question by Dr. György Buzsáki during his presentation at the Cognitive Neuroscience Society meeting.

...Or had it?

To recap, my understanding was that an unpublished study of transcranial electrical stimulation (TES) in human cadaver heads showed a 90% loss of current when delivered through the skin vs. through the skull.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.

But Dr. Tiziana Metitieri left a comment on my post saying this is nothing new. She translated the remarks of Dr. Carlo Miniussi, who said:
...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.  [read more]

Why is this important to cognitive neuroscientists? Because the behavioral effects of tDCS have been vastly overstated, according to some investigators (e.g., Horvath et al., 2015), and the “homeopathic” level of brain stimulation is one likely explanation.

But a common refrain of experts in the field [I am not an expert] is that Buzsáki's results are not surprising the low amount of current is old hat. For instance, Dr. Marom Bikson explained in Science News that...
...many in the field already accepted that the 1 or 2 milliamps the methods use don't directly trigger firing. It can make neurons more likely to fire or form new connections, he and others believe. Unlike techniques that rely on magnetic fields or higher current to actively trigger neurons ... tDCS and tACS likely subtly alter ongoing brain activity, Bikson says. Using cadavers to test these methods is a “complicated choice” because dead tissue conducts electricity differently from living tissue, he adds.

Also quoted is Dr. Vince Clark, who...
...has found that applying 2 milliamps of current to a person’s scalp for just 30 minutes can double the speed at which they learn a game in which players must detect a concealed “threat”... Several labs have replicated those results, he says, adding that the idea that 10% or less of the current gets through to the brain is not new, and doesn’t necessarily mean the methods are ineffective. “If it works, you know 10% is enough,” Clark says.

Although some effects may be replicable, Dr. Vince Walsh dropped a stink bomb by saying that the tDCS field is “a sea of bullshit and bad science—and I say that as someone who has contributed some of the papers that have put gas in the tDCS tank.  ...  It really needs to be put under scrutiny like this.” In Wired, Walsh basically said the reason for the “sea of bullshit and bad science” is that the barrier to enter tDCS research is so darn low.

When Can TES Influence Spiking?

Returning to Buzsáki's talk, he mentioned a study in rats (Ozen et al., 2010) where a TES-induced voltage gradient of 1 mV/mm at the recording sites could phase-locked spiking (action potentials). However, the current was delivered via electrodes placed directly on the skull or even the dura covering the brain. The stimulation protocol was low frequency sinusoid patterns that mimic slow cortical oscillations, to entrain neuronal spiking activity. That was the goal in humans, but similar TES applied to the scalp produced no discernible change in oscillatory activity. Hence, the cadaver tests.

These studies used transcranial alternating current stimulation (tACS), which is designed to influence ongoing cortical oscillations by “entraining” or phase-locking to specific EEG frequency bands (as in Kanai et al., 2008). Buzsáki himself actually commented on the Science piece (which I will quote at length):
"The real question: Is the current which does reach the brain sufficient to perform this ‘extremely weak coupling’ in neural systems?" This is exactly what we investigated. Since we failed to entrain neuronal activity (local fields) repeatedly in the living human brain with the commonly used current intensities, whereas we were very successful in rodents using stimulation electrodes directly on the bone, we looked for answers. The cadaver is the next best possible thing to a living human brain if one wants to know how the currents are distributed inside the brain. We found that most current is lost by the shunting effect of the extracranial tissue. As a result, the voltage gradients that we measured in the brain were way below the values we found in rodents needed to affect population neuronal oscillations. The weak electric fields were just too weak. Of course, there is the principle of stochastic resonance and thus some super weak effect can have some effects occasionally - we cannot and do not want to deny it, but cannot prove it either, therefore cannot rely on it as an explanation for the reported behavioral effects of TES.

In his talk he mentioned possible effects on astrocytes, and my previous post cited the study of Monai et al. (2016). In his Science comment Buzsáki said, “Glia may be more sensitive to polarized currents than neurons and muscles.” He also mentioned possible effects on peripheral nerves in the scalp (edit: "like in the case of vagal stimulation"), which is something that Dr. Jamie Tyler (formerly of Thync) has said for years:
Thync tried to replicate some basic tDCS findings on cognition but could not do so. Dr Tyler now believes that tDCS may not directly stimulate the brain at all but instead modulates cranial nerves in the skull...

During the discussion period at the CNS meeting, Buzsáki was asked about the phenomenon of DIY tDCS. He compared it to alternative medicine.

On that note, I'll conclude with a nod to the tDCS reddit community, some of whom didn't trash my last critical post as much as I expected. Yay! Others? Not so much. Boo: “There are so many inaccuracies in this article, I don't know where to begin.” And then they don't bother to begin...

[EDIT April 24 2016: Later on in the reddit thread, this critic did expand on my potential inaccuracies, but I missed it. Oops, sorry. See the comment below.]

So any- and all-comers can begin by pointing out my inaccuracies in the comments section of this post.

ADDENDUM (April 23 2016): I should mention more specifically that Tyler et al. (2015) proposed that TES affects the ophthalmic and maxillary divisions of the trigeminal nerve and cervical spinal nerve afferents.


Horvath JC, Forte JD, Carter O. (2015). 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.

Kanai R, Chaieb L, Antal A, Walsh V, Paulus W. (2008). Frequency-dependent electrical stimulation of the visual cortex. Curr Biol. 18(23):1839-43.

Ozen, S., Sirota, A., Belluscio, M., Anastassiou, C., Stark, E., Koch, C., & Buzsaki, G. (2010). Transcranial Electric Stimulation Entrains Cortical Neuronal Populations in Rats Journal of Neuroscience, 30 (34), 11476-11485. DOI: 10.1523/JNEUROSCI.5252-09.2010

Underwood, E. (2016). Cadaver study challenges brain stimulation methods. Science, 352 (6284), 397-397 DOI: 10.1126/science.352.6284.397

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At April 23, 2016 5:56 PM, Anonymous Anonymous said...

The measure of whether tDCS works is its efficacy (albeit yet to be proven in some aspects, while there is growing weight supporting others), but NOT whether the amount of current that gets through the skin and skull is what some think it should be in order to work. Not really sure I understood the point of this article, you seem to hem and haw in both directions more than the previous, but you do take the time to ridicule my (urbo10) reddit post "not knowing where to begin" even though I subsequently added some detail (timing issues, I suppose). I'll repeat 2 of my posts in that same thread:

A couple of inaccuracies that jump out at me, or maybe I'm misinformed? the big one is that the author talks about the amount of current that is shunted by the skin. That may be the case where electrodes are close, but for example the DARPA montage, if the current is regulated at 2mA, isn't that the amount of current that must actually pass THROUGH? Second, and this isn't the author's own words, but a copy/paste of a tweet in large prominent print: "FDA approved 2mA"? For what, maybe an IDE? Does that count as FDA approved?

Besides, the question shouldn't be what percentage of current is skin shunted vs. passes through, it should be whether or not what passes through has an efficacy, whatever that current level is. So while it is an interesting issue applicable to understanding different montages, skin shunting really is a red herring.

Additionally, electrodermal activity of living skin is not the same as dead skin, even though the standard supposition is that living skin would shunt more, there are many unknowns.

We really don't know how tDCS works, yet, and how much current needs to get through. So what that the skin shunts some?

At April 24, 2016 1:37 AM, Blogger The Neurocritic said...

Thanks for your comments. Sorry I missed your other reddit posts where you actually did explain yourself.

First, I'll say that György Buzsáki is a brilliant and highly respected neuroscientist, so I'm inclined to believe his experimental results. He's studied hippocampal theta oscillations for 40 years and wrote a 465 page book called 'Rhythms of the Brain' (which you can download for free). It's true that the cadaver study hasn't yet been published in a peer-reviewed journal, but the data have been presented at several conferences. In my post here, I wanted to write more about Buzsáki's talk & what motivated the cadaver study in the first place.

The conference attendee's tweet about 2mA being "FDA approved" was entirely based on what was said during the talk. After the conference I looked it up and didn't find that the FDA had approved tDCS.

I also wanted to include reactions from tDCS researchers (quoted from the Science article), where the theme was "we already knew about the shunting problem." Marom Bikson tweeted: "And we have models validated in *living* humans (for years) on current flow"

and: "And we already have current flow imaged post-mortem with models Fraction, but some amount,reaches brain"

I (and probably others) weren't aware of this earlier work, hence the near-audible gasps during the talk when Buzsáki said 90% loss of current AND zero effect in the human brain. His comment on the Science piece explains the lack of effect with tACS:

"Since we failed to entrain neuronal activity (local fields) repeatedly in the living human brain with the commonly used current intensities, whereas we were very successful in rodents using stimulation electrodes directly on the bone, we looked for answers."

Regarding my waffling, I think it's highly likely that a lot of tDCS research is bad and non-replicable. But at the same time there are careful studies with reproducible findings, and serious research into mechanisms of action (which is extremely important). The developing stories about glia and cranial nerves could also turn out to be quite interesting.

At April 24, 2016 2:18 AM, Blogger The Neurocritic said...

Guess I should also say that skin shunting is NOT a red herring if it's so severe that your stimulation parameters produce zero measurable effect in the living human brain. And Buzsáki said his studies demonstrated that "living tissue (skin and muscles) shunt event MORE" than dead tissue.

I didn't really address your first point (that efficacy is the key measure of whether tDCS works or not), because the talk I attended wasn't about cognitive and clinical applications of tDCS. At the time, someone tweeted: "cosmic irony that the concurrent talk was a meta-analysis of tDCS. ... "

At April 24, 2016 2:25 AM, Blogger The Neurocritic said...

Human Intracranial Electrophysiology: A New Era

Chair: Josef Parvizi, Stanford University
Speakers: Josef Parvizi, György Buzsáki, Xiao-Jing Wang, Dejan Markovic, Sabine Kastner

The purpose of this symposium is to shed light on the basics of neuronal population dynamics and oscillations as well as the new research developments that are taking place in the field of human intracranial electrophysiology. Will invasive recordings and cortical stimulations in human subjects change our view of the functional organization of the human brain?

Talk 2: Rhythms in the Mammalian Brains
György Buzsáki1; 1New York University

Brain rhythms are highly preserved throughout the evolution of mammalian brains and have constrained the evolutionary and ontogenetic scaling of brain structures. This presentation will provide an overview of brain rhythms and how they form a system, tied together by cross-frequency phase coupling. This mechanism allows for bidirectional communication across brain structure in a state-dependent manner. The receiver structure initiates the exchange by a slow frequency rhythm and the messages are conveyed back from the sender to receiver in higher frequency packages, typically gamma and ripples oscillations. Oscillations allow for the segmentation of spike trains-carried information into neurons 'letters' (assemblies) and 'words', which can be concatenated into neuronal 'sentences'.

A competing talk was on: Enhancing Working Memory Training Using Transcranial Direct Current Stimulation

Working memory (WM) is a fundamental cognitive ability that is limited in capacity and constrains complex thought. It is highly predictive of academic and professional success, and thus, in this increasingly complex information age, interventions to increase WM ability are highly valued. A promising intervention that has gained traction over the last decade is transcranial direct current stimulation (tDCS), which is a non-invasive form of brain stimulation that can modulate cortical excitability and temporarily increase brain plasticity. As such, it can boost learning or enhance performance on cognitive tasks. We assessed the value of tDCS as a tool to facilitate working memory training and discovered that stimulation over prefrontal cortex enhanced performance over seven days of training and also had selective effects on transfer to non-trained tasks.

At May 05, 2016 2:29 AM, Blogger David McGonigle said...

Hi again. Just a short comment on your statement here on tACS: 'which is designed to influence ongoing cortical oscillations by “entraining” or phase-locking to specific EEG frequency bands'.

This seems to suggest that, if no entrainment is seen, tACS is therefore ineffective. I would argue that we're still in the early days of linking mechanisms to behavioural effects, and this paper suggests a different way whereby tACS could have physiological effects in the absence of true phase-locking or entrainment.

At May 05, 2016 10:03 AM, Blogger The Neurocritic said...

David - Thanks for the link. File under "what we think we know and don't know..."

At May 20, 2016 8:46 AM, Blogger David McGonigle said...

Indeed! I am currently doing some modelling of how the fields look at the cortex, and I'm amazed at what our 'standard' scalp montages actually look like when one examines their effects on the GM....


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