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To recap, my understanding was that an unpublished study of transcranial electrical stimulation (TES) in human cadaver heads showed a 90% loss of current when delivered through the skin vs. through the skull.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

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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.



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).

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Thursday, March 31, 2016

Sleep Doctoring: Fatigue Amnesia in Physicians



New in the journal journal Cortex: four shocking cases of practicing medicine while exhausted  (Dharia & Zeman, 2016). The authors called this newly discovered syndrome “fatigue amnesia.” Why this is is any different from countless other examples of not remembering things you did while exhausted I do not know. Except amnesia for performing a complex medical procedure is a lot more disturbing than forgetting you did the dishes the night before.

Here are the cases in brief:
Case 1:  A consultant geriatrician, while working as house officer, treated a patient with chest pain and severe pulmonary oedema in the middle of night. She made an entry in the notes, demonstrating successful initial memory acquisition. She does not remember going to bed that night. On the ward round on the following morning the patient was pointed out to her but she had no recollection of seeing the patient or writing the note.

Case 2: A senior house officer, now a consultant neurologist, went to bed in the early hours after a busy shift. She was woken soon afterwards to manage a patient with cardiac arrest. The resuscitation was complex and included an intracardiac adrenaline injection. She documented events in the medical notes immediately, demonstrating successful initial memory acquisition. She returned to bed. She was told on the morning ward round that the patient was well and had his breakfast following the cardiac arrest. She was startled by this information, as she had no recollection of the previous night's events.

Case 3: A consultant microbiologist who was working on a night shift as a house officer clerked in a patient at 11:00 pm and continued to work thereafter throughout the night. On the morning ward round when the patient was pointed out to her she had no recollection of seeing or managing him.

Case 4: A paediatrician reported memory loss for a complex decision made and instructions given over the phone. While working as a registrar he went to bed in the early hours of morning when on call. He was woken by a call about a complex patient. He went to the ward soon afterwards to find out that the trolley was laid out for Swan Ganz catheterisation. Although he was assured that he had done so, he did not remember giving instructions to prepare the trolley.

The incidents were not due to alcohol or drugs. Long hours and sleep deprivation were to blame. And fortunately, the amnesic episodes were isolated and did not recur in any of the doctors. Dharia & Zeman (2016) suggested that:
While the resulting memory gaps can reasonably be described as resulting from a ‘transient amnesic state', the evidence from the medical notes suggest that this phenomenon reflects a novel form of accelerated long-term forgetting (Elliott, Isaac, & Muhlert, 2014), whereby a memory for events is acquired normally but then decays more rapidly than usual.

Sleep Blogging

By tomorrow, I will have forgotten that I wrote this...


Reference

Dharia, S., & Zeman, A. (2016). Fatigue amnesia Cortex DOI: 10.1016/j.cortex.2016.03.001

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Sunday, March 27, 2016

Everybody Loves Dopamine



Dopamine is love. Dopamine is reward. Dopamine is addiction.

Neuroscientists have a love/hate relationship with how this monoamine neurotransmitter is portrayed in the popular press.





[The claim of vagus nerve-stimulating headphones is worth a post in its own right.]



“You can fold your laundry, but you can’t fold your dopamine.”
- James Cole Abrams, M.A. (in Contemplative Psychotherapy)


The word dopamine has become a shorthand for positive reinforcement, whether it's from fantasy baseball or a TV show.

But did you know that a subset of dopamine (DA) neurons originating in the ventral tegmental area (VTA) of the midbrain respond to obnoxious stimuli (like footshocks) and regulate aversive learning?

Sometimes the press coverage of a snappy dopamine paper can be positive and (mostly) accurate, as was the case with a recent paper on risk aversion in rats (Zalocusky et al., 2016). This study showed that rats who like to “gamble” on getting a larger sucrose reward have a weaker neural response after “losing.” In this case, losing means choosing the risky lever, which dispenses a low amount of sucrose 75% of the time (but a high amount 25%), and getting a tiny reward. The gambling rats will continue to choose the risky lever after losing. Other rats are risk-averse, and will choose the “safe” lever with a constant reward after losing.

This paper was a technical tour de force with 14 multi-panel figures.1 For starters, cells in the nucleus accumbens (a VTA target) expressing the D2 receptor (NAc D2R+ cells) were modified to express a calcium indicator that allowed the imaging of neural activity (via fiber photometry). Activity in NAc D2R+ cells was greater after loss, and during the decision phase of post-loss trials. And these two types of signals were dissociable.2 Then optogenetic methods were used to activate NAc D2R+ cells on post-loss trials in the risky rats. This manipulation caused them to choose the safer option.

- click to enlarge -


Noted science writer Ed Yong wrote an excellent piece about these findings in The Atlantic (Scientists Can Now Watch the Brain Evaluate Risk).

Now, there's a boatload of data on the role of dopamine in reinforcement learning and computational models of reward prediction error (Schultz et al., 1997) and discussion about potential weaknesses in the DA and RPE model. So while a very impressive addition to the growing pantheon of laser-controlled rodents, the results of Zalocusky et al. (2016) aren't massively surprising.


More surprising are two recent papers in the highly sought-after population of humans implanted with electrodes for seizure monitoring or treatment of Parkinson's disease. I'll leave you with quotes from these papers as food for thought.

1. Stenner et al. (2015). No unified reward prediction error in local field potentials from the human nucleus accumbens: evidence from epilepsy patients.
Signals after outcome onset were correlated with RPE regressors in all subjects. However, further analysis revealed that these signals were better explained as outcome valence rather than RPE signals, with gamble gains and losses differing in the power of beta oscillations and in evoked response amplitudes. Taken together, our results do not support the idea that postsynaptic potentials in the Nacc represent a RPE that unifies outcome magnitude and prior value expectation.

The next one is extremely impressive for combining deep brain stimulation with fast-scan cyclic voltammetry, a method that tracks dopamine fluctuations in the human brain!

2. Kishida et al. (2016). Subsecond dopamine fluctuations in human striatum encode superposed error signals about actual and counterfactual reward. 
Dopamine fluctuations in the striatum fail to encode RPEs, as anticipated by a large body of work in model organisms. Instead, subsecond dopamine fluctuations encode an integration of RPEs with counterfactual prediction errors, the latter defined by how much better or worse the experienced outcome could have been. How dopamine fluctuations combine the actual and counterfactual is unknown. One possibility is that this process is the normal behavior of reward processing dopamine neurons, which previously had not been tested by experiments in animal models. Alternatively, this superposition of error terms may result from an additional yet-to-be-identified subclass of dopamine neurons.


Further Reading

As Addictive As Cupcakes Mind Hacks (“If I read the phrase ‘as addictive as cocaine’ one more time I’m going to hit the bottle.”)

Dopamine Neurons: Reward, Aversion, or Both? Scicurious

Back to Basics 4: Dopamine! Scicurious (in fact, anything by Scicurious on dopamine)

Why Dopamine Makes People More Impulsive – Sofia Deleniv at Knowing Neurons

2-Minute Neuroscience: Reward System video by Neuroscientifically Challenged


Footnotes

1 For example:
Because decision-period activity predicted risk-preferences and increased before safe choices, we sought to enhance the D2R+ neural signal by optogenetically activating these cells during the decision period. An unanticipated obstacle (D2SP-driven expression of channelrhodopsin-2 eYFP fusion protein (D2SP-ChR2(H134R)-eYFP) leading to protein aggregates in rat NAc neurons) was overcome by adding an endoplasmic reticulum (ER) export motif and trafficking signal29 (producing enhanced channelrhodopsin (eChR2); Methods), resulting in improved expression (Extended Data Fig. 7). In acute slice recordings, NAc cells expressing D2SP-eChR2(H134R)-eYFP tracked 20-Hz optical stimulation with action potentials (Fig. 4c).

2 The human Reproducibility Project: Psychology brigade might be interested to see Pearson’s r2 = 0.86 in n = 6 rats.



References

Kishida KT, Saez I, Lohrenz T, Witcher MR, Laxton AW, Tatter SB, White JP, Ellis TL, Phillips PE, Montague PR. (2016). Subsecond dopamine fluctuations in human striatum encode superposed error signals about actual and counterfactual reward. Proc Natl Acad Sci 113(1):200-5.

Schultz W, Dayan P, Montague PR. (1997). A neural substrate of prediction and reward. Science 275:1593–1599. [PubMed]

Stenner MP, Rutledge RB, Zaehle T, Schmitt FC, Kopitzki K, Kowski AB, Voges J, Heinze HJ, Dolan RJ. (2015). No unified reward prediction error in local field potentials from the human nucleus accumbens: evidence from epilepsy patients. J Neurophysiol. 114(2):781-92.

Zalocusky, K., Ramakrishnan, C., Lerner, T., Davidson, T., Knutson, B., & Deisseroth, K. (2016). Nucleus accumbens D2R cells signal prior outcomes and control risky decision-making Nature DOI: 10.1038/nature17400

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Sunday, March 20, 2016

A Detached Sense of Self Associated with Altered Neural Responses to Mirror Touch



Our bodily sense of self contributes to our personal feelings of awareness as a conscious being. How we see our bodies and move through space and feel touched by loved ones are integral parts of our identity. What happens when this sense of self breaks down? One form of dissolution is Depersonalization Disorder (DPD).1 Individuals with DPD feel estranged or disconnected from themselves, as if their bodies belong to someone else, and “they” are merely a detached observer. Or the self feels absent entirely. Other symptoms of depersonalization include emotional blunting, out-of-body experiences, and autoscopy.


Autoscopy for dummies - Antonin De Bemels (cc licence)


Transient symptoms of depersonalization can occur due to stress, anxiety, sleep deprivation, or drugs such as ketamine (a dissociative anesthetic) and hallucinogens (e.g., LSD, psilocybin). These experiences are much more common than the official diagnosis of DPD, which occurs in only 1-2% of the population.

Research by Olaf Blanke and colleagues (reviewed in Blanke et al., 2015) has tied bodily self-consciousness to the integration of multi-sensory signals in fronto-parietal and temporo-parietal regions of the brain.




The fragmentation or loss of an embodied self raises philosophically profound questions. Although the idea of “mind uploading” is preposterous in my view (whether via whole brain emulation or cryonics), proponents must seriously ask whether the uploaded consciousness will in any way resemble the living person from whom it arose.2 “Minds are not disembodied logical reasoning devices” (according to Andy Clark).  And...
Increasing evidence suggests that the basic foundations of the self lie in the brain systems that represent the body (Lenggenhager et al., 2012).

Lenggenhager et al. asked whether the loss of sensorimotor function alters body ownership and the sense of self. Persons with spinal cord injuries scored higher on Cambridge Depersonalization Scale (CDS) items such as “I have to touch myself to make sure that I have a body or a real existence.” This suggests that disconnecting the brain from somatosensory input can change phenomenological aspects of self-consciousness.




The Stranger in the Mirror

Patients with depersonalization not only feel a change in perception concerning the outside world, but they also have clear-cut changes concerning their own body.  ...  The patient sees his face in the mirror changed, rigid and distorted. His own voice seems strange and unfamiliar to him.  ...  It is in this respect especially remarkable that the estrangement concerning the outside world is often an estrangement in the optic sphere (Schilder, 1935, p. 139).

Depersonalization can involve perceptual distortions of bodily experience in different sensory modalities (e.g., vision, hearing, touch, and pain). Recent research has examined interactions between visual and somatosensory representations of self in the tactile mirroring paradigm (also called visual remapping of touch). Here, the participant views images of a person being touched (or not) while they themselves are touched. Tactile perception is enhanced by simultaneously receiving and observing the same stimulation, especially when the image is of oneself.


Are the symptoms of depersonalization associated with reduced or absent responses in the tactile mirroring paradigm? If so, at what stage of processing (early or late) does this occur? A new study recorded EEG to look at somatosensory evoked potential (SEP) responses to tactile stimuli during mirroring (Adler et al., 2016). The participants scored high (n=14) or low (n=13) on the CDS.

One SEP of interest was the P45, which occurs shortly (25-50 msec) after tactile stimulation. Although the spatial resolution of EEG does not allow firm conclusions about the neural generators, we know from invasive studies in epilepsy patients and animals that P45 originates in the primary somatosensory cortex (S1).

When the participants viewed the other-face, P45 did not differ on touch vs. no-touch trials. But the later N80 component was enhanced for touch vs. no-touch, and the enhancement was similar for low and high depersonalization (DP) participants.



Modified from Figs. 3 and 4 (Adler et al. 2016). SEPs in response to tactile stimuli for low DP (top) and high DP (bottom) while observing touch (thick line) or no-touch (thin line) on another person's face. SEPs are shown for components P45 and N80 at a cluster of central-parietal electrodes located over somatosensory cortex.


Results were different when subjects viewed images of themselves. P45 was enhanced in the low DP group when viewing themselves being touched (vs. no-touch trials). However, those with high DP scores did not show this P45 enhancement.



Modified from Figs. 3 and 4 (Adler et al. 2016). SEPs in response to tactile stimuli while observing touch (thick line) or no-touch (thin line) on the participant's own face. Red arrow indicates no self-mirror enhancement of P45.


These results suggest a very early disturbance in sensory integration of the self in depersonalization:
Measurable effects of mirroring for tactile events on the observer's own face may be absent over P45 because deficits in implicit self-related processing prevent the resulting visual enhancement of tactile processing from taking place in the context of self-related information. An alternative, or additional, explanation for the absence of P45 mirroring effects may be that seeing their own body causes depersonalised individuals to actively inhibit the processing of bodily stimulation via this pathway. This may cause feelings of disembodiment, and is akin to the suggestion that fronto-limbic inhibitory mechanisms acting on emotional processes cause the emotional numbing experienced in depersonalisation (Sierra and David, 2011).
[Although I'm not so sure how much “active inhibition” can occur within 25 msec...]




A later component (P200) did not show the expected effect in the high DP group, either. While these results are intriguing, we must keep in mind that this was a small study that requires replication.3


Our Bodies, Our Selves

Predictive coding models hypothesize that the anterior insular cortex (AIC) provides top-down input to somatosensory, autonomic, and visceral regions and plays a critical role in integrating exteroceptive and interoceptive signals (Seth et al., 2012; Allen et al., 2016). DPD is associated with “pathologically imprecise interoceptive predictive signals,” leading to a disruption of conscious presence (the subjective sense of reality of the world and of the self within the world). Here's the predictive coding model of conscious presence (Seth et al., 2012):
It has been suggested that DPD is associated with a suppressive mechanism grounded in fronto-limbic brain regions, notably the AIC, which “manifests subjectively as emotional numbing, and disables the process by which perception and cognition become emotionally colored, giving rise to a subjective feeling of unreality” (Sierra and David, 2011)...

In our model, DPD symptoms correspond to abnormal interoceptive predictive coding dynamics. ... the imprecise interoceptive prediction signals associated with DPD may result in hypoactivation of AIC since there is an excessive but undifferentiated suppression of error signals.

In contrast, Adler et al. (2016) adopt a very different (Freudian) view:
We speculate that the abnormalities related to depersonalisation may be based on a lack of mirroring interactions in early childhood. Several recent papers culminated in the idea that mirroring experiences in early life - the process of moving and being moved by others, both physically and affectively - give rise to our sense of bodily self... This bodily self forms the core of other forms of self-consciousness, from body ownership to the sense of agency and the ability to mentalise (e.g. Fonagy et al., 2007; Gallese & Sinigaglia, 2010; Markova and Legerstee, 2006; Stern, 1995). ...  Depersonalisation could be a potential consequence of such developmental experiences.

I don't buy it... none of the participants in their study had a clinical diagnosis, and we know nothing of their early childhood. In the end, any model of chronic DPD still has to account for the transient phenomena of disconnection and unreality experienced by so many of us.


Further Reading

Feeling Mighty Unreal: Derealization in Kleine-Levin Syndrome

Fright Week: The Stranger in the Mirror


Footnotes

1 In DSM-5, the syndrome is known as Depersonalization/Derealization Disorder. I wrote about the symptoms of derealization a subjective alteration in one's perception or experience of the outside world in another blog post.

2 For a discussion of the relevant issues, see The False Science of Cryonics and Silicon soul: The vain dream of electronic immortality.

3 Given the requirements for specialized equipment and a specialized population, I don't imagine this study is on the Many Labs or Replication Project lists.


References

Adler, J., Schabinger, N., Michal, M., Beutel, M., & Gillmeister, H. (2016). Is that me in the mirror? Depersonalisation modulates tactile mirroring mechanisms. Neuropsychologia DOI: 10.1016/j.neuropsychologia.2016.03.009

Allen M, Fardo F, Dietz MJ, Hillebrandt H, Friston KJ, Rees G, Roepstorff A. (2016). Anterior insula coordinates hierarchical processing of tactile mismatch responses. Neuroimage 127:34-43.

Blanke O, Slater M, Serino A. (2015). Behavioral, Neural, and Computational Principlesof Bodily Self-Consciousness. Neuron 88(1):145-66.

Lenggenhager, B., Pazzaglia, M., Scivoletto, G., Molinari, M., & Aglioti, S. (2012). The Sense of the Body in Individuals with Spinal Cord Injury. PLoS ONE, 7 (11) DOI: 10.1371/journal.pone.0050757

Schilder, P. (1935). The Image and Appearance of the Human Body. London: Kagan, Paul, Trench, Trubner & Co.

Seth AK, Suzuki K, Critchley HD. (2012). An interoceptive predictive coding model of conscious presence. Front Psychol. 2:395.




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Monday, March 07, 2016

Writing-Induced Fugue State



Who is this, wandering around the crowded street, afraid of everything, trusting no one?

“There must be something wrong, somewhere.”
But maybe I’m safer since I look disheveled.

Who are these people? Where is this place?
Did I write that? When did that happen? I don’t remember.

I can’t stop writing. I can’t stop walking, either, which is a problem because it’s hard to write and walk at the same time.



In the early 1940s, Austrian Psychiatrist Dr. Erwin Stengel wrote a pair of papers on fugue states, a type of dissociative disorder involving loss of personal identity and aimless wandering (Stengel, 1941):
THE peculiar condition designated “fugue state,” of which the main symptom is compulsive wandering, has puzzled psychiatrists since it was first described. Nothing is known of the aetiology of this well-defined condition. Fugue states occur in epileptics, hysterics, and certain psychopaths. Bleuler has described their occurrence in schizophrenia, and they have been recorded in cases of general paralysis and of altered personality due to brain tumour.  ...  Kraepelin recognized that it was impossible to distinguish between the states of compulsive wandering associated with various mental disorders. Janet tried to distinguish between hysterical and epileptic fugues by pointing out that short fugues are more likely to be epileptic than hysterical.  

He was disturbed by inaccurate use of the term, which was widespread (Stengel, 1943):
...the following conditions have been described as fugues: States of wandering, in accordance with the classical conception; states of double personality; all kinds of transitory abnormal behaviour of functional origin; hysterical loss of consciousness and of memory; twilight states; confusional states of hysterical nature; delirious states in schizophrenia. The tendency to call transient states of altered consciousness fugues, irrespective of the behaviour of the patient, is obvious. This is a most unsatisfactory state of affairs. 

Stengel presented dozens of cases in these papers and was obsessed with finding common etiological factors, no matter what the underlying medical condition (e.g., epilepsy, “hysteria”, schizophrenia):
The intimate similarity of fugue states associated with different mental disorders suggests that there must be aetiological factors common to all. However, no attempt has been made hitherto to ascertain such factors. I have been engaged in investigations concerning this problem for more than eight years...
...and (Stengel, 1943):
Clinical studies carried out over many years have convinced me that there is no justification in differentiating between hysterical and epileptic wandering states, as the behaviour of the patients and the majority of the etiological factors are fundamentally the same in all fugues with the impulse to wander (Stengel, 1939, 1941).

Since Stengel was trained as a psychoanalyst and considered Freud as a mentor, you might guess the common etiology:
This was a disturbance of the environment of child life. A serious disturbance in the child-parent relationship, usually of such a nature that the relationship to one or both parents was either completely lacking or only partially developed, had occurred in nearly every case.

Beyond the mommy/daddy issues, symptoms of severe depression (suicide attempts, failure to eat, lack of hygiene) and/or mania (elation, hypersexuality) were commonplace. Here's one especially tragic example:
CASE 9. M. E , female, born 1906. The patient was normal until her twenty first year. At that time she suddenly became unstable and wanted to live apart from her mother, with whom she had been happy hitherto. She went to Paris, where she found employment as a secretary, but after some months she returned home again. When she was 22 she experienced for the first time an urge to wander, which reappeared subsequently two or three times every year. For no adequate reason, sometimes after an insignificant quarrel, she left home and wandered about for some days. During these states she was not fully conscious, slept little, and neglected herself. When normal consciousness returned, after three or four days, she found herself in the country far away from home. These states were followed by profound depression, lasting for several weeks, when the patient indulged in self-reproaches, ate very little, lost weight, and could not work. ... The patient was a typical daydreamer. In her daydreams a fantasy of a man disappointed in love committing suicide often appeared. (Her father had committed suicide.) ... The patient, who was of unusual intelligence, suffered very much from her abnormal states, which appeared at intervals of four to five months, and were always followed by melancholic depression. In one of these depressions she committed suicide by poisoning.

Period Fugue

Stengel (1941) asserted that the majority of his female patients started their wandering premenstrually, but his definition of what this meant was kind of loose (and meaningless): “usually appear before menstruation”, “usually just before menstruation”, “usually commences shortly before her menstrual period”, “at the onset of menstruation”, “about the time of menstruation”.

He had no explanation for this, other than the implication that it's an unstable lady thing. One particularly fun case (Case 14) was a young woman with a previous bout of encephalitis lethargica. But it was determined that her menstrual period and an Oedipus Complex drove her to wander, not her illness.


The report for Case 35 (Miss May S. M, aged 18, member of the women's military service) was accompanied by a four page excerpt from her diary, which is illuminating for what it tells us about bipolar disorder (but fugue, not so much):
1940.  12.1: Had a drink, sang all the way home. 13.1: The matinee went off well. Feeling so horribly sad, a terribly empty feeling, felt like crying my heart out. Home is like the end of the world. 21.1: Tried to commit suicide. Instead wrote to G. telling him to give me some ideas how to get to America. Feeling just frightful, feel dead. 27.1: No feelings at all. 30.1: Have a mad desire to go really common, lipstick, scarlet nails and with as little clothes as possible.

Modern conceptions of fugue states (including dissociative amnesia) focus on trauma, memory systems, and underlying neurobiological causes, instead of dysfunctional child-parent relationships (MacDonald & MacDonald, 2009).



Who is this? How did I end up here?

You mean there’s a world outside my head, beyond the computer, exceeding all page limits and formatting errors?

Writing-Induced Fugue State



ADDENDUM (March 7 2016): I should clarify that in DSM-5, dissociative fugue no longer has its own category. Now it's a subtype of dissociative amnesia (DSM-5 diagnostic code 300.12):

Sub-Specifier: Dissociative Amnesia with dissociative fugue (300.13)


This occurs when an individual travels or wanders, either in a seemingly purposeful or bewildered fashion, without knowing who they are. Dissociative fugue involves amnesia of a person’s entire identity or for other important autobiographical information.

Another salient difference from Stengel's day is that the fugue state must not due to a general medical condition, like temporal lobe epilepsy.



References

Stengel, E. (1941). On the Aetiology of the Fugue States The British Journal of Psychiatry, 87 (369), 572-599 DOI: 10.1192/bjp.87.369.572

Stengel, E. (1943). Further Studies on Pathological Wandering (Fugues with the Impulse to Wander) The British Journal of Psychiatry, 89 (375), 224-241 DOI: 10.1192/bjp.89.375.224




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