The Truth About Cognitive Impairment in Retired NFL Players

NINETY-TWO percent of retired National Football League players have decreased cognitive function, according to a new study:

“In the NFL group, baseline neuropsychological assessments showed 92% of players had decreased general cognitive proficiency, 86% had decreased information processing speed, 83% had memory loss, 83% had attentional deficits, and 85% had executive function impairment.”

The Truth?

The study reported on a self-selected sample of 161 current and retired NFL players recruited via a blog (“The NFL concealed the danger of brain injuries!!”), the Los Angeles Chapter of the Retired NFL Players Association, The Summit (??), and possibly other sources. Perhaps these players were motivated to participate because they had cognitive complaints, or because they wanted an evaluation in advance of the $1 billion concussion settlement. The League's Baseline Assessment Program is a required part of the settlement.¹

The quote above is the full extent of the report on the players' neuropsychological assessments. These were done using computerized test batteries (MicroCog or WebNeuro), which are largely unknown to most clinical neuropsychologists. Was there an adequately matched control population? What norms were used? They don't say.

THE TRUTH IS, we don't know the extent of cognitive impairment in these football players, or the percentage of all players who are affected, or the severity of impairment in those who are. This new paper (by Daniel Amen, Bennet Omalu, and others) doesn't give us enough information, but it succeeds in sounding the alarm about the dangers of football and the inevitability of memory loss and attention deficits.

Are blows to the head bad for your brain? Can repeated concussions cause cognitive impairment and chronic traumatic encephalopathy (CTE)? ²  Yes, almost certainly, but we can't rely on biased samples, appeal to celebrity, and Frontline documentaries (“researchers have identified CTE in 96 percent of NFL players that they’ve examined”) as conclusive scientific evidence. What's needed are better sampling methods (in the short term) and longitudinal studies that follow a diverse cohort over time (in the long term).

The Scans

Caption for top figure: SPECT brain scans showing abnormal low blood flow in an NFL player compared to a normal healthy control subject.

The new paper by Amen et al. (2016) was actually focused on SPECT scans, not surprisingly, since these are the backbone of his business at the Amen Clinics. The article claims “90% sensitivity, 86% specificity, and 94% accuracy” in discriminating NFL players from controls. I won't elaborate here, but check out This Neuroimaging Method Has 100% Diagnostic Accuracy (or your money back) and The Dark Side of Diagnosis by Brain Scan for detailed critiques of the methods used here. I will flag one tiny issue, however:

“All NFL players were male, while 56% of the control group were women.”

Why?? The authors have a database of 100,000 SPECT scans...


Footnote

¹  11. What is the Baseline Assessment Program (“BAP”)?

. . .
Retired players who are diagnosed with Level 1 Neurocognitive Impairment (i.e., moderate cognitive impairment) are eligible to receive further medical testing and/or treatment (including counseling and pharmaceuticals) for that condition during the ten-year term of the BAP or within five years from diagnosis, whichever is later.

14. What diagnoses qualify for monetary awards?

Monetary awards are available for the diagnosis of ALS, Parkinson’s Disease, Alzheimer’s Disease, Level 2 Neurocognitive Impairment (i.e., moderate Dementia), Level 1.5 Neurocognitive Impairment (i.e., early Dementia) or Death with CTE (the “Qualifying Diagnoses”). A Qualifying Diagnosis may occur at any time until the end of the 65-year term of the Monetary Award Fund.

² ADDENDUM (May 1 2016): I should say, “...cause CTE and/or other neurodegenerative disorders and dementias.”

Also see: Here’s What We Don’t Know About Head Injuries And Sport
...and A Clinical Approach to the Diagnosis of Traumatic Encephalopathy Syndrome


Reference

Daniel G. Amen, Kristen Willeumier, Bennet Omalu, Andrew Newberg, Cauligi Raghavendra, & Cyrus A. Raji (2016). Perfusion Neuroimaging Abnormalities Alone Distinguish National Football League Players from a Healthy Population Journal of Alzheimer's Disease : 10.3233/JAD-160207

Caption (from press materials): SPECT brain scans showing improvement of abnormal low blood flow in an NFL player compared after 3.5 months on a customized brain rehabilitation program.

ADDENDUM #2 (May 1 2016): The authors' Conflict of Interest statements.

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” (http://www.ncbi.nlm.nih.gov/pubmed/?term=Miranda+PC+2006). 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.


References

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

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).

Siren Song

By Margaret Atwood

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:

90% loss of electrical current between skin and scalp -György Buzsáki #CNS2016

— CNS News (@CogNeuroNews) April 5, 2016

90% charge loss skin-skull using TES. Need 5 mA to affect spiking, FDA approved 2mA, Buzsáki first hand 4mA hard to tolerate. #CNS2016

— Renee M. Symonds (@DatabaseDragons) April 5, 2016

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).

from Fertonani & Miniussi (2016).

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.

Footnotes

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.



References

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).