Thursday, June 23, 2016

In Oxytocin We Trust

Oh oxytocin, you cuddly hug drug, you fine upstanding moral molecule, why are you so maligned by critics? That's because you're overrated, and misunderstood by those who look to you as a beacon of empathy, trust, love, peace, and prosperity. Sure, you're all about pair bonding in monogamous prairie voles — we have no beef with rigorous animal studies — but in humans, you're downright complicated. Yes, you can be magnanimous and romantic some of the time. But you're not always a moral molecule. You can promote antisocial behaviors such as envy and schadenfreude and aggressive tendencies. And even in voles, too much of a good thing can backfire.

Four new papers on oxytocin in humans have been published this week.1 Collectively, there's something for nearly everyone to complain about:

Oxytocin and Epigenetics

Of the four, the one that has garnered the most media attention is on epigenetics and sociability (Haas et al., 2016, published in PNAS). DNA methylation in the promoter region of the oxytocin gene (OXT) was quantified as an indicator of OXT expression. Lower methylation is presumably associated with higher OXT expression, and all sorts of sociable characteristics such as “more secure attachment styles, improved ability to recognize emotional facial expressions, greater superior temporal sulcus activity during two social-cognitive functional MRI tasks, and larger fusiform gyrus gray matter volume.”

Are these findings plausible from a mechanistic standpoint? Assuming that OXT expression was higher in the sociable sorts, which in turn assumes that methylation in saliva is a good proxy for expression in brain, how did “more“ oxytocin have all these effects? And on what time scale?

The Daily Mail was predictably credulous and hyperbolic,2 using terms like “breakthrough”, “a ‘chatty’ gene which makes people sociable”, and [the kicker] “new treatments for autism”. The autism reference comes from the paper itself (and from the university press release):
"Participants with greater methylation of the OXT gene were less accurate in describing the emotional states of the people they saw in pictures," [first author Brian W. Haas] said. "That's a typical characteristic associated with autism, for example."

But it's not that simple. Let's look at the relationship between emotion recognition and OXT methylation. The task was to view 10 sec video clips of human faces morphing from neutral expressions to happy, sad, fearful and angry, and to identify the emotion as soon as it was detected. This led to 10 different dependent measures: reaction time and accuracy for each of the individual expressions, and for the mean of all expressions. The (conservative) Bonferroni corrected significance level is α = .05/10 = .005 [but the authors said it should be .025]. Overall accuracy is shown below.

Not all that impressive, eh? Another scatterplot was based on self-report questionnaires. The association between an anxious and insecure attachment style and OXT methylation fared better (p=.005), but the association between OXT methylation and avoidant attachment style was not significant. Why?

Oxytocin and Spirituality

The next paper, on oxytocin and spirituality (Van Cappellen et al., 2016), has gained traction on Twitter. Dan Quintana has already written an inspired blog post about it (Spray and pray: Does intranasal oxytocin increase spirituality?), so you should go and check it out. Dan has published at least 7 papers on oxytocin, so his critique is more informed than mine. I'll highlight his main points and then add a few of my own.

Good news:
First, the authors should be congratulated for posting the data for the paper on Open Science Framework (OSF). It’s great to see this dataset online considering the hype surrounding oxytocin...

Here’s a few other things I liked about this paper (or a list of things that oxytocin papers often don’t do): i) Effect sizes and confidence intervals are reported, ii) the alpha for the main outcome was adjusted for multiple tests, and iii) the placebo spray was a “true” placebo that contained all the same ingredients as the oxytocin spray, except the actual oxytocin (i.e, not just saline spray). It’s much easier to taste the difference between oxytocin and saline so this is an important point.

Bad news, genetics:
The authors included an “exploratory analysis” (their words in the intro and a section of the results) of three oxytocin pathway polymorphisms (rs53576, rs6449182, and rs3796863). There are about 10–15 candidate oxytocin pathway SNPs the could be analysed so it’s not clear why these three were chosen rather than others. Sure, rs53576 has been studied a lot, but so have many other oxytocin pathway SNPs (especially rs2254298).

Bad news, religious affiliation: appears that there was a main effect of condition on both spirituality scales. However, a close read of table 1 reveals that this was after correcting for religious affiliation. Now this is reasonable when you consider that someone who’s an atheist is likely to report that spiritually is “not at all” important in my life. In fact, the data bears this out as the average spiritual rating (which can range from 0 to 7) for the atheist/agnostic group was 1.97 during the experimental visit and 1.88 a week later, whereas the average rating for the religiously affiliated group was 4.8 during the first visit and 4.9 during the second visit (I was able to calculate this from their posted dataset — isn’t open data great!).

It’s plausible for someone who identifies as agnostic or atheist to report “not at all” on both occasions — and many did. In fact, when you look at the agnostics/atheist group alone, there’s a statistically significant increase in spirituality after oxytocin compared to placebo both during the lab visit and 1 week later... However, there was no significant difference when assessing the religiously affiliated group.

(or not)

 Dr. Quintana concluded his post by advocating pre-registration and replication.

Oxytocin, Meditation, Positive Emotions, Negative Emotions, Oxytocin Receptor Gene (OXTR rs53576), CD38 (rs6449182 and rs3796863), Religious Affiliation, and Spirituality After Intranasal Oxytocin Administration in 83 Predominantly White Middle Aged Men

My unwieldy subheading includes only a small subset of the 161 variables in the study of Van Cappellen et al. (2016). Granted, some of these variables (e.g, the answers to individual items on questionnaires) were never examined in isolation — they were part of a composite score. Nonetheless, I think we can tick the “Ridiculously large numbers of variables” bullet point. We also have “Intranasal oxytocin administration” and “Small n candidate gene studies” (with n's below 20 in some cells). Bonus bullet point of “Between subjects design” is a personal pet peeve. I'd really like to see some within-subjects studies.

And there's a mysterious element to some of the data not included in this paper:
The data presented here are part of a larger study testing additional hypotheses not related to the present ones. For the larger study and to test a larger model, based on power calculation, a sample of 240 participants was targeted with a breakdown female-male of 125-115... Data collection ... stopped at 239 but despite recruitment effort, the sample is skewed toward females. This report focuses only on the 83 males who took part in the study... Growing evidence suggests that the effects of oxytocin are different for males and females (Feng et al., 2015) and most of the current evidence on intranasal oxytocin’s psychological effects, which support the current hypotheses, come from studies with exclusively male samples. A separate analysis of female participants, controlling for a series of additional variables related to natural variations in oxytocin is ongoing.

The larger study also included a task using Chinese pictographs, since the ability to read Chinese pictographs was an exclusionary criterion “applied to another task unrelated to the current investigation.” I'm generally not a study pre-registration evangelist, but one can really see the point here.

In Oxytocin We Doubt

I'll conclude on a pessimistic note (what else is new?). Some highly critical reviews of the oxytocin literature have appeared recently.

Evans SL, Dal Monte O, Noble P, Averbeck BB. Intranasal oxytocin effects on social cognition: a critique. Brain Res. 2014 Sep 11;1580:69-77.

Leng G, Ludwig M. Intranasal Oxytocin: Myths and Delusions. Biol Psychiatry. 2016 Feb 1;79(3):243-50.
Despite widespread reports that intranasal application of oxytocin has a variety of behavioral effects, very little of the huge amounts applied intranasally appears to reach the cerebrospinal fluid. However, peripheral concentrations are increased to supraphysiologic levels, with likely effects on diverse targets including the gastrointestinal tract, heart, and reproductive tract. The wish to believe in the effectiveness of intranasal oxytocin appears to be widespread and needs to be guarded against with scepticism and rigor. Preregistering trials, declaring primary and secondary outcomes in advance, specifying the statistical methods to be applied, and making all data openly available should minimize problems of publication bias and questionable post hoc analyses. Effects of intranasal oxytocin also need proper dose-response studies, and such studies need to include control subjects for peripheral effects, by administering oxytocin peripherally and by blocking peripheral actions with antagonists. Reports in the literature of oxytocin measurements include many that have been made with discredited methodology. Claims that peripheral measurements of oxytocin reflect central release are questionable at best.
--- there is a retort to Leng and Ludwig by Quintana and Woolley:  Intranasal Oxytocin Mechanisms Can Be Better Understood, but Its Effects on Social Cognition and Behavior Are Not to Be Sniffed At.

Walum H, Waldman ID, Young LJ. Statistical and Methodological Considerations for the Interpretation of Intranasal Oxytocin Studies. Biol Psychiatry. 2016 Feb 1;79(3):251-7.
...Our conclusion is that intranasal OT studies are generally underpowered and that there is a high probability that most of the published intranasal OT findings do not represent true effects. Thus, the remarkable reports that intranasal OT influences a large number of human social behaviors should be viewed with healthy skepticism...

McCullough ME, Churchland PS, Mendez AJ. Problems with measuring peripheral oxytocin: can the data on oxytocin and human behavior be trusted? Neurosci Biobehav Rev. 2013 Sep;37(8):1485-92.

It might be time to order Liquid Trust...


1 Actually, the number of articles is closer to ten, but I'll just list these four for now.
  1. Van Cappellen P, Way BM, Isgett SF, Fredrickson BL. Effects of Oxytocin Administration on Spirituality and Emotional Responses to Meditation. Soc Cogn Affect Neurosci. 2016 Jun 17. PMID: 27317929.
  3. Haas BW, Filkowski MM, Cochran RN, Denison L, Ishak A, Nishitani S, Smith AK. Epigenetic modification of OXT and human sociability. Proc Natl Acad Sci. 2016 Jun 20. PMID: 27325757.
  5. Simons RL, Lei MK, Beach SR, Cutrona CE, Philibert RA. Methylation of the oxytocin receptor gene mediates the effect of adversity on negative schemas and depression. Dev Psychopathol. 2016 Jun 20:1-12. PMID: 27323309.
  7. Gao S, Becker B, Luo L, Geng Y, Zhao W, Yin Y, Hu J, Gao Z, Gong Q, Hurlemann R, Yao D, Kendrick KM. Oxytocin, the peptide that bonds the sexes also divides them. Proc Natl Acad Sci. 2016 Jun 20. PMID: 27325780.
2 Hyperbolic and inaccurate. They called methyl groups "proteins".


Haas BW, Filkowski MM, Cochran RN, Denison L, Ishak A, Nishitani S, Smith AK. Epigenetic modification of OXT and human sociability. Proc Natl Acad Sci. 2016 Jun 20. PMID: 27325757.

Van Cappellen P, Way BM, Isgett SF, Fredrickson BL. Effects of Oxytocin Administration on Spirituality and Emotional Responses to Meditation. Soc Cogn Affect Neurosci. 2016 Jun 17. PMID: 27317929.

Further Reading

The Ed Yong Collection:

Oxytocin: the hype hormone

One Molecule for Love, Morality, and Prosperity?

Oxytocin: Still Not a Moral Molecule

The Weak Science Behind the Wrongly Named Moral Molecule

The Neurocritic Back Catalogue:

Oxytocin and Mind Reading...


ABC News Says: 'Trust Drug' Oxytocin Unbelievable For Now

Paul Zak, Oxytocin Skeptic?

Your Brain on Coupons?

Neuroskeptic Posts:

More Doubts Over The Oxytocin And Trust Theory
(about: Failed Replication of Oxytocin Effects on Trust)

Psychologists Throw Open The “File Drawer”
(about: Is there a publication bias in behavioral intranasal oxytocin research on humans?)

Sofia Deleniv: The Dark Side of Oxytocin

Nature News: Neuroscience: The hard science of oxytocin

Old ad for Liquid Trust

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Monday, June 06, 2016

Advil Increases Social Pain (if you're male)

A recent neuroessay in the New York Times asked, Can Tylenol Help Heal a Broken Heart?
What’s crazy about the pain of a broken heart is that your body perceives it as physical pain.
No it does not. Do you feel heartbroken every time you stub your toe?

Well... I guess the social pain = physical pain isomorphism is a one way street. Anyway, the author continued:
In research published in 2010, scientists found that acetaminophen can reduce physical and neural responses associated with the pain of social rejection, whether in romantic relationships, friendships or otherwise.
The pain reliever Tylenol (acetaminophen) lessens the pain of social rejection, according to the 2010 study in Psychological Science [except when it doesn't].1 Acetaminophen also purportedly soothes the existential angst of watching a David Lynch film, blunts your emotions, and kills your empathy.2

So if you’re hurting from heartache, try popping some Tylenol.
Do not pop Tylenol after a breakup. It can cause serious liver damage if you take too much.

But What About Advil?

A 2014 study in the journal Personal Relationships was the first to break the stranglehold of acetaminophen (Vangelisti et al., 2014). The paper made few headlines (an exception was the Daily Mail), and it was not cited by the Tylenol researchers after its publication. Yet I saw no difference in quality, and even found more to like about it compared to the Tylenol papers (all of which appeared in higher impact journals). One of the Advil authors was Dr. James Pennebaker, chair of Psychology at the University of Texas. Dr. Pennebaker is well-known for his research on text analysis and what word choice can reveal about sex, age, social class, personality, mood, and affective state.

The focus of the study by Dr. Anita Vangelisti and colleagues was on potential sex differences in the effects of a physical pain reliever on social pain. They cited evidence suggesting that women are more sensitive to physical pain, and men might be more responsive to pain relievers like ibuprofen (Walker & Carmody, 1998).

Proposed explanations for sex differences in pain and analgesia include the bullet list below (Mogil & Bailey, 2010). These could potentially influence the effects of ibuprofen (and acetaminophen) on social pain.3
  • Sociocultural manly and stoic machismo
  • Psychological greater negative affect and catastrophizing in women
  • Experiential women may have more experience with clinical pain, which affects current pain perception
  • Opioid receptors and especially their interactions with gonadal hormones
  • Other potential biological factors a long list

Advil Worsened Social Pain in Men

Ibuprofen did indeed increase ratings of social pain in male participants, but decreased ratings in female participants Vangelisti et al. (2014). For more details, read on.

Read more »

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Monday, May 30, 2016

Compulsive Foreign Language Syndrome: Man Becomes Obsessed With Speaking Fake French

You may have seen headlines such as: Florida Man Woke Up In A Motel Room Speaking Only Swedish. Or: Englishman wakes up speaking Welsh after stroke (“Rare brain disorder left English-speaking Alun Morgan only able to communicate in Welsh”). The first case was likely due to a fugue state, a type of dissociative disorder involving loss of personal identity and aimless wandering (Stengel, 1941). The second seems like an unusual example of bilingual aphasia involving loss of the ability to speak one's native language (rather than the more commonly affected second language).

Perhaps you've even seen paranormal claims like:
Under Hypnosis or Past Life Regression, A Physician's Wife Starts Speaking Swedish

. . .  In sessions conducted from 1955 to 1956, when Tania was under hypnosis, a personality emerged who spoke Swedish, a language that neither Tania nor Ken knew. As such, this represents a case of xenoglossy, where an individual can speak a language that has not been learned through normal means.

Tania was born in Philadelphia and as such, English was her native language. Her parents, who were Jewish, were born in Odessa, Russia. No one in the family had ever been to Scandinavia and they knew no one who could speak Swedish.

Xenoglossy is “the putative paranormal phenomenon in which a person is able to speak or write a language he or she could not have acquired by natural means.” Of course, there's always a logical explanation for such cases, but magical thinking leads people to believe that such phenomena are proof of past lives and reincarnation.

A New Case of False Xenoglossy

An amusingly written clinical report describes a 50 year old Italian man who stopped speaking his native Italian and insisted on speaking broken and somewhat fake French after a neurological event (Beschin et al., 2016). An abnormality in his basilar artery blocked the necessary flow of cerebrospinal fluid (CSF), with hydrocephalus and brainstem vascular encephalopathy as a result. A typical example of the condition (known as megadolicho basilar artery) in another patient is shown below.

Fig. 1 (Thiex & Mull, 2006). (A) CSF flow obstruction (arrow). (B) megadolicho basilar artery.

The man had no previous psychiatric history and retained the ability to speak perfect Italian. The clinical report includes the only instance of the word “fling” that I recall seeing in a scientific journal, so I'll quote at length:
He had superficially learned French at school, used it in his 20's due to a fling with a French girl but he has not spoken it for about 30 years. In his professional life he used English as his second language. Before brain damage he never manifested a particular attachment to French culture or French cuisine. His accent is not due to dysarthria and he speaks polished and correct Italian, his mother tongue. However, he now states that French is his preferred language refusing to speak in Italian spontaneously.
. . .

JC's French is maladroit and full of inaccuracies, yet he speaks it in a fast pace with exaggerated intonation using a movie-like prosody and posing as a typical caricature of a French man. His French vocabulary is reduced and he commits several grammatical errors but he does not speak grammelot or gibberish and never inserts Italian terms in his French sentences. He uses French to communicate with everybody who is prepared to listen; he speaks French with his bewildered Italian relatives, with his hospital inmates, with the consultants; he spoke French even in front of the befuddled Committee deciding on his pension scheme. He claims that he cannot but speak in French, he believes that he is thinking in French and he longs to watch French movies (which he never watched before), buys French food, reads French magazines and seldom French books, but he writes only in Italian. He shows no irritation if people do not understand him when he speaks in French.

He performed well on picture naming and verbal fluency tests in Italian, although he first tried to name the item in French (substituting category names like ‘vegetable’ for the low frequency word ‘asparagus’). His episodic memory was poor and he could not recall autobiographical incidents from the previous few years (but could recall earlier memories). He performed well on most other cognitive tests. But he did show some psychiatric symptoms that were secondary to the brain injury.
However, he presents with some delusions of grandeur, sleep disturbances and has some compulsive behaviours: he buys unnecessarily large quantities of objects (e.g., needing two hangers he bought 70) and he makes tons of bread to his wife's chagrin. He also shows unjustified euphoria (which he labels joie de vivre): for example in the morning he opens the windows and shouts bonjour stating that it is a wonderful day. He manifests signs of social disinhibition, for example proposing to organise a singing tour for his daughter's teenage friend or offering French lessons to his neighbours. These symptoms are indicative of secondary mania (Santos, Caeiro, Ferro, & Figueira, 2011) and were drug-resistant.

This is certainly a highly usual consequence of megadolicho basilar artery, but note that the subtitle of Beschin et al.'s article is “A clinical observation not a mystery.” There is no true xenoglossy here (or anywhere else, for that matter).

Further Reading

Man Wakes Up From Coma Speaking New Language: The media’s love of xenoglossy

Foreign Language Syndrome “There actually isn’t a legitimate foreign language syndrome...”


Beschin, N., de Bruin, A., & Della Sala, S. (2016). Compulsive foreign language syndrome: A clinical observation not a mystery. Cortex DOI: 10.1016/j.cortex.2016.04.020

Stengel, E. (1941). On the Aetiology of the Fugue States. British Journal of Psychiatry 87 (369): 572-599.

Thiex R, Mull M. (2006). Basilar megadolicho trunk causing obstructive hydrocephalus at the foramina of Monro. Surg Neurol. 65(2):199-201.

Jen speaks fake Italian on the IT Crowd.

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Wednesday, May 18, 2016

Acetaminophen Probably Isn't an "Empathy Killer"

Left: Belgian physician Dr. Wim Distelmans, a cancer specialist, professor in palliative care and the president of the Belgian federal euthanasia commission. Right: Generic acetaminophen.

What (or who) is an “Empathy Killer“? An Angel of Death Kevorkian-type who helps terminally ill patients with ALS or cancer put an end their excruciating pain? This is a very selfless act that shows extreme empathy for the suffering of others.

Or is an “Empathy Killer” a medication that dulls your numerical ratings of empathic concern for fictional characters ever so slightly? If you guessed the latter, you are correct. Here's the actual title of a new paper in SCAN: “From Painkiller to Empathy Killer: Acetaminophen (Paracetamol) Reduces Empathy for Pain.”

Oh the headlines. Truly painful.

Paracetamol doesn't just kill pain - it makes us less CARING

America's Most Common Drug Ingredient Could Be Making You Less Empathetic

Why Would a Headache Medication Make You Less Empathetic?

A popular line of research in Social Cognitive and Affective Neuroscience examines the commonalities between physical and social/psychological pain. IF there is indeed an overlap,1 one might ask some provocative questions about the underlying neural mechanisms. Do drugs that ease physical pain also soothe the pain of social rejection and existential angst?2 Several recent papers have reported that acetaminophen does exactly that (Dewall et al., 2010; Randles et al., 2013; Durso et al., 2015) although some pundits may beg to differ.3

The latest psychological study on this popular over-the-counter painkiller looks at empathy for another person's pain (Mischkowski et al., 2016). This work is based on the premise that the same neural machinery responsible for feeling our own physical and psychological pain (ACC, AI, mirror neurons don't ask but see Zaki et al., 2016) is invoked when observing the pain of others.

The Mystery of the Sliding Scales

[NOTE: Perceived Pain scores standardized in Tables 1, 3, 4 but not Table 2]

Can Tylenol (aka Parecemetol) lessen the pain you feel for others? I'll go out on a limb here and say probably not. Or not much, especially in a real-world sense. Here's why.

First, you have to understand that the experimental ratings of empathy were based on two different scales that varied from 1 (No pain at all) to 5 (Worst possible pain) OR from -4 (Worst possible pain) to +4 (Most possible pleasure). For the latter scale, the authors “reverse-coded participants’ ratings, so higher ratings indicated higher empathy for pain.”

Participants in Experiment 1 were given a placebo drink (n=40) or 1000 mg liquid acetaminophen (n=40). An hour later, they read short scenarios depicting other people in physical pain (e.g., cutting a finger) or social pain (e.g., getting rejected from college). Two major scores were obtained for perceived pain and personal distress. My reading is that these should yield a mean score between 1 and 5 for each measure.

ADDENDUM (May 18 2016): As pointed out by two Anonymous commenters, the Perceived Pain scores were standardized in Table 1. The same measure was not standardized in Table 2.

PERCEIVED PAIN For each scenario, we measured perceived pain with two measures. First, participants rated the pain of each protagonist using a scale from 1 (No pain at all) to 5 (Worst possible pain). Second, participants rated on three items how much each protagonist felt hurt, wounded, and pained on scales ranging from 1 (Not at all) to 5 (Extremely). We averaged items to create perceived hurt feeling measures across physical and social pain scenarios... Within each scenario type, both perceived pain ratings correlated highly... Therefore, we standardized and averaged these measures into indices of perceived physical and social pain.

PERSONAL DISTRESS Participants also rated their personal distress when reading each scenario. On a scale from 1 (Not at all) to 5 (Extremely), participants rated the extent to which they felt uncomfortable, pained, bothered, unpleasant, distress, as well as wanted to cringe while imagining the feelings of each scenario protagonist. We averaged items to create separate personal distress measures for physical and social pain scenarios...

My guess is that the authors made a mistake in their Tables, or else I misunderstood the scoring scheme. Let's take a look (click on image for a larger view).

For the first Dependent Variable, participants rated their own positive and negative feelings on the PANAS. General Affect ratings didn't differ between drug and placebo.

Next, look at Perceived Pain for Physical Pain Scenarios and Social Pain Scenarios. I won't belabor the p values here. Instead, focus on the red rectangles. [My mistake, Perceived Pain scores were standardized in Table 1. However, this does not affect my next comment.] These values are both close to zero (perhaps not significantly different from zero). But they don't seem to be on the 1 to 5 scale described above. The Personal Distress values ranged from “kind of a little bit” distressed for drug (2.15 and 2.00) to “kind of a little bit more” distressed for placebo (2.75 and 2.45). The participants who received acetaminophen are hardly in the land of the cruel and heartless psychopath. How much would these slight variations in personal distress ratings translate to real world empathy? We simply don't know.

Next, let's figure out the sliding scale issue. In Experiment 2:
Participants read the same eight physical and social pain empathy scenarios as in Experiment 1. After reading each scenario, participants rated perceived pain of the protagonist, using a scale from -4 (Worst possible pain) to +4 (Most possible pleasure). We reverse-coded participants’ ratings, so higher ratings indicated higher empathy for pain.

So here we have a scale that does include negative numbers, perhaps that scale was used for Perceived Pain in Exp. 1. Except ratings in Exp. 2 seems to use the 1 to 5 scale? It's hard to tell at this point. [Perceived Pain scores were not standardized in Table 2.] At any rate, the differences are small, and not significant for some of the comparisons.

There were other conditions involving noise blasts and watching a person being excluded from a round of cyberball (an old-school ball-tossing video game). Some of the values here were confusing as well. Or maybe I'm just confused... [Yes, I was confused. Perceived Pain scores were standardized in Tables 3 and 4.]

Noise blasts rated on a scale from 1 (Not unpleasant at all) to 10 (Extremely unpleasant).

Once again, in Table 4 we see mean values for Perceived Pain that are very close to zero. What does it mean? I will be happy to correct any erroneous interpretations of these Tables.

Now that I have corrected my mistakes, I still think it's hyperbole to say these differences mean that acetaminophen is an empathy killer in real life.

Neuroskeptic points out
Something odd about some of the datapoints... In Table 1, the mean for "perceived pain" for placebo is equal to the mean for acetaminophen * -1 (e.g. 0.22 vs -0.22, 0.19 vs. -0.19). The same is true in Table 4, two different values (e.g. 0.06 vs. -0.06, 0.04 vs -0.04).

Furthermore, does an Empathic Concern for Ostracized Player score of 1.68 (compared to 2.05) mean you're a less caring person? That acetaminophen has dulled your empathy? An empathy score of 2.05 (out of 5) while on placebo isn't exactly a heart-rending level of concern...

I could be wrong, but I don't think the Tylenol-fueled collapse of civilization is neigh. Next up? Ibuprofen! 4


1 Many have argued that the physical-emotional pain isomorphism is vastly overstated (e.g., Hayes and Northoff, 2012; The Neurocritic, 2012; Iannetti et al., 2013; Woo et al., 2014; Wager et al., 2016).

2 Well sure, you say, people have been self-medicating with opiates and alcohol for centuries. BUT here I mean mild nonprescription medications not known for having psychoactive properties.

3 Yeah, I've written about this a lot.

Tylenol Doesn't Really Blunt Your Emotions

Suffering from the pain of social rejection? Feel better with TYLENOL®

Existential Dread of Absurd Social Psychology Studies

Does Tylenol Exert its Analgesic Effects via the Spinal Cord?

Vicodin for Social Exclusion

4 I've wanted to see that study for years.


Dewall CN, Macdonald G, Webster GD, Masten CL, Baumeister RF, Powell C, Combs D, Schurtz DR, Stillman TF, Tice DM, Eisenberger NI. (2010). Acetaminophen reduces social pain: behavioral and neural evidence. Psychological Science 21:931-937.

Durso G, Luttrell A, Way B. (2015). Over-the-Counter Relief From Pains and Pleasures Alike: Acetaminophen Blunts Evaluation Sensitivity to Both Negative and Positive Stimuli. Psychological Science 26:750-758.

Mischkowski, D., Crocker, J., & Way, B. (2016). From Painkiller to Empathy Killer: Acetaminophen (Paracetamol) Reduces Empathy for Pain. Social Cognitive and Affective Neuroscience DOI: 10.1093/scan/nsw057

Randles D, Heine SJ, Santos N. (2013). The common pain of surrealism and death: acetaminophen reduces compensatory affirmation following meaning threats. Psychological Science 24:966-73.

Zaki J, Wager TD, Singer T, Keysers C, Gazzola V. (2016). The Anatomy of Suffering: Understanding the Relationship between Nociceptive and Empathic Pain. Trends Cogn Sci. 20(4):249-59.

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Wednesday, May 04, 2016

Imagine These Experiments in Aphantasia

When you hear the word “apple”, do you picture a Red Delicious apple or a green Granny Smith? Or neither, because you can't conjure up a visual image of an apple (or of anything else, for that matter)?
Aphantasia is the inability to generate visual images, which can be a congenital condition or acquired after brain injury (Farah, 1984). The most striking aspect of this variation in mental life is that those of us with imagery assume that everyone else has it, while those without are flabbergasted when they learn that other people can “see” pictures in their head.

Programming prodigy Blake Ross created a sensation recently with his eloquent essay on what's it's like to discover that all your friends aren't speaking metaphorically when they say, “I see a beach with waves and sand.”

Aphantasia: How It Feels To Be Blind In Your Mind

I just learned something about you and it is blowing my goddamned mind.
. . .

Here it is: You can visualize things in your mind.

If I tell you to imagine a beach, you can picture the golden sand and turquoise waves. If I ask for a red triangle, your mind gets to drawing. And mom’s face? Of course.
. . .

I don’t. I have never visualized anything in my entire life. I can’t “see” my father’s face or a bouncing blue ball, my childhood bedroom or the run I went on ten minutes ago. I thought “counting sheep” was a metaphor. I’m 30 years old and I never knew a human could do any of this. And it is blowing my goddamned mind.

It's worth reading Ross's account in its entirety to gain insight into the vast individual variation in our internal mental lives.

Although the term aphantasia is new (coined by Zeman et al., 2015), the condition isn't; Francis Galton published a paper on the Statistics of Mental Imagery in 1880. Similar to Ross, many of Galton's s friends (male scientists) were shocked to learn that others had imagery:1 
To my astonishment, I found that the great majority of the men of science to whom I first applied, protested that mental imagery was unknown to them, and they looked on me as fanciful and fantastic in supposing that the words 'mental imagery' really expressed what I believed everybody supposed them to mean. They had no more notion of its true nature than a colour-blind man who has not discerned his defect has of the nature of colour. They had a mental deficiency of which they were unaware, and naturally enough supposed that those who were normally endowed, were romancing.

The nature of mental images has been a topic of philosophical debate in cognitive science since the 1970s. Are mental images quasi-perceptual representations that activate visual areas of the brain (Kosslyn and colleagues), or non-pictorial, abstract, symbolic descriptions (Zenon Pylyshyn)? The Stanford Encyclopedia of Philosophy's entry on Mental Imagery provides an indispensable background on the philosophical, theoretical, and empirical debates in the field. As well, extensive research on individual differences in mental imagery (e.g., Kosslyn et al., 1984) can inform new studies on aphantasics.

Aphantasia and Paivio's Dual Coding Theory

To investigate the role of imagery in verbal memory, I propose a return to classic cognitive psychology experiments of the 1970s. Alan Paivio's Dual Coding Theory specifies two types of mental representations, or codes, for words and mental images (Paivio, 1971). The verbal code and imagery code are both activated by pictures, which can account for the picture superiority effect: pictures are better remembered than their verbal referents (i.e., words). The picture superiority effect should be abolished in those who cannot generate visual images.2

Even more interestingly, words that are highly imageable (concrete nouns like elephant) are better remembered than words that are rated low in imageability (abstract nouns like criterion). The original ratings from 1968 and the expanded 2004 version (concreteness, imageability, meaningfulness, familiarity) are available online: Clark and Paivio (2004) Norms. Lists of high and low imageable nouns that are carefully matched on other lexical factors (e.g., number of letters, word frequency, complexity) can be presented in a memory test. The recognition memory (or free recall) advantage for concrete, highly imageable words should be diminished or abolished in relation to self-reported imagery abilities.

I believe this experiment would address the objection of psychogenic aphantasia (“refusing to imagine”), because the concreteness advantage (using imagery during encoding) could not be mobilized as an explicit (or perhaps implicit) strategy. Given the hundreds (if not thousands) of Aphantasics who have made blog comments, joined Facebook groups and other communities, taken surveys, and of course contacted Dr. Zeman, the sample size might be quite respectable.


1 Aphantasia seems bizarrely overrepresented in Galton's cronies. Here's his explanation:
My own conclusion is, that an over-readiness to perceive clear mental pictures is antagonistic to the acquirement of habits of highly generalised and abstract thought, and that if the faculty of producing them was ever possessed by men who think hard, it is very apt to be lost by disuse. The highest minds are probably those in which it is not lost, but subordinated, and is ready for use on suitable occasions. 
2 Of note here, some with aphantasia report severe deficits in autobiographical memory.

ADDENDUM (May 16 2016): see this website on Severely Deficient Autobiographical Memory (SDAM) - research conducted by Dr. Brian Levine.


Farah MJ. (1984). The neurological basis of mental imagery: A componential analysis. Cognition 18:245-72.

GALTON, F. (1880). I.--STATISTICS OF MENTAL IMAGERY Mind, os-V (19), 301-318 DOI: 10.1093/mind/os-V.19.301

Kosslyn SM, Brunn J, Cave KR, Wallach RW. (1984). Individual differences in mental imagery ability: a computational analysis. Cognition 18:195-243.

Paivio A. (1969). Mental imagery in associative learning and memory. Psychological Review 76: 241-263.

Paivio A. (1971, 2013). Imagery and verbal processes. Holt, Rinehart & Winston / Psychology Press.

Zeman, A., Dewar, M., & Della Sala, S. (2015). Lives without imagery – Congenital aphantasia Cortex, 73, 378-380 DOI: 10.1016/j.cortex.2015.05.019

ADDENDUM (May 7 2016): via @vaughanbell, a new review article by the University of Exeter group (part of their project, The Eye's Mind):

MacKisack M, Aldworth S, Macpherson F, Onians J, Winlove C, Zeman A. (2016). On Picturing a Candle: The Prehistory of Imagery Science. Front Psychol. 7:515.

Not only Galton, Paivio, Kosslyn, and Pylyshyn but also Aristotle, Plato, Thomas Aquinas, and more.

- click on image for a larger view -

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Saturday, April 30, 2016

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...


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


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.

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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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