Tuesday, May 05, 2015

Tylenol Doesn't Really Blunt Your Emotions

A new study has found that the pain reliever TYLENOL® (acetaminophen) not only dampens negative emotions, it blunts positive emotions too. Or does it?

Durso and colleagues (2015) reckoned that if acetaminophen can lessen the sting of psychological pain (Dewall et al., 2010; Randles et al., 2013) — which is doubtful in my view then it might also lessen reactivity to positive stimuli. Evidence in favor of their hypothesis would support differential susceptibility, the notion that the same factors govern reactivity to positive and negative experiences.1 This outcome would also contradict the framework of acetaminophen as an all-purpose treatment for physical and psychological pain.

The Neurocritic is not keen on TYLENOL® as a remedy for existential dread or social rejection. In high doses acetaminophen isn't great for your liver, either. And a recent meta-analysis even showed that it's ineffective in treating lower back pain (Machado et al., 2015)...

But I'll try to be less negative than usual. The evidence presented in the main manuscript supported the authors' hypothesis. Participants who took acetaminophen rated positive and negative IAPS pictures as less emotionally arousing compared to a separate group of participants on placebo. The drug group also rated the unpleasant pictures less negatively and the pleasant pictures less positively. “In all, rather than being labeled as merely a pain reliever, acetaminophen might be better described as an all-purpose emotion reliever,” they concluded (Durso et al., 2015).

Appearing in the prestigious Journal of Psychological Acetaminophen Studies, the paper described two experiments on healthy undergraduates, both of which yielded a raft of null results.

Wait a minute..... what? How can that be?

The main manuscript reported the results collapsed across the two studies, and the Supplemental Material presented the results from each experiment separately. Why does this matter?
Eighty-two participants in Study 1 and 85 participants in Study 2 were recruited to participate in an experiment on “Tylenol and social cognition” in exchange for course credit. Our stopping rule of at least 80 participants per study was based on previously published research on acetaminophen (DeWall et al., 2010; Randles et al., 2013), in which 30 to 50 participants were recruited per condition (i.e., acetaminophen vs. a placebo).  ... The analyses reported here for the combined studies are reported for each study separately in the Supplemental Material available online.

What this means is that the authors violated their stopping rule, and recruited twice the number of participants as originally planned. Like the other JPAS articles, this was a between-subjects design (unfortunately), and there were over 80 participants in each condition (instead of 30 to 50).

After running Experiment 1, the authors were faced with results like these:
As expected, however, a main effect of treatment (though not significantly significant in this study) was obtained, F(1,72) = 2.15, p = .147, ηp2 = .029, as was the predicted interaction (although it was not statistically significant in this study), F(3.3, 240.3) = 1.15, p = .330, ηp2 = .016. Contrast analyses indicated that participants taking acetaminophen were marginally significantly less emotionally aroused by extremely pleasant stimuli (M = 5.01, SD = 1.75) than were participants taking placebo (M = 5.65, SD = 1.55), t(72) = 1.67, p = .099. Similarly, participants receiving acetaminophen were less emotionally aroused by extremely unpleasant stimuli (M = 6.88, SD = 1.25) than were participants assigned the placebo condition (M = 7.23, SD = 1.84), although this difference was not statistically significant in this study, t(72) = 0.96, p = .341. Furthermore, participants taking acetaminophen tended to be less emotionally aroused by moderately pleasant stimuli (M = 2.91, SD = 1.64) than participants taking placebo (M = 3.49, SD = 1.89), t(72) = 1.44, p = .155, and participants taking acetaminophen also tended to be less emotionally aroused by moderated unpleasant stimuli (M = 4.68, SD = 1.42) than participants taking placebo (M = 5.25, SD = 2.02), t(72) = 1.42, p = .161, although these differences were not statistically significant in this study. 

Wow, what a disappointment to get these results. Nothing looks statistically significant!

Let's look at Experiment 2:
...Contrast analyses revealed that participants taking acetaminophen tended to rate extremely unpleasant stimuli (M = -3.39, SD = 1.14) less negatively than participants receiving placebo (M = -3.74, SD = 0.74), t(77) = 1.60, p = .115, though this contrast was not itself statistically significant within this study. Participants taking acetaminophen also rated extremely pleasant stimuli (M = +2.51, SD = 1.07) significantly less positively than participants receiving placebo (M = +3.19, SD = 0.88), t(77) = 3.06, p = .003.

Participants taking acetaminophen also tended to evaluate moderately pleasant stimuli (M = +1.15, SD = 0.91) less positively than participants receiving placebo (M = +1.42, SD = 0.89), t(77) = 1.30, p = .198, although this difference was not statistically significant in this study. Finally, participants taking acetaminophen tended to rate moderately unpleasant stimuli less negatively (M = -1.84, SD = 0.99) than participants taking placebo (M = -1.93, SD = 0.95), although this difference was not significant in this study, t(77) = 0.42, p = .678. [NOTE: "tended"? really?] Evaluations of neutral stimuli surprisingly differed as a function of treatment, t(77) = 2.94, p = .004, such that participants taking acetaminophen evaluated these stimuli significantly less positively (M = -0.05, SD = 0.42) than did participants taking placebo (M = +0.22, SD = 0.38).

One of the arguments that acetaminophen affects ratings of emotional stimuli specifically (both positive and negative) is that it does not affect ratings for neutral stimuli. Yet it did here. So in the paragraphs above, extremely pleasant stimuli and neutral stimuli were both rated as less positive by the drug group, but ratings for extremely unpleasant, moderately pleasant, and moderately unpleasant pictures did not differ between drug and placebo groups.

The subjective emotional arousal ratings fared better than the picture ratings in Experiment 2, but there were still some unexpected and non-significant results. Overall, support for the “acetaminophen as an all-purpose emotion reliever” was underwhelming when the studies are examined singly (which is how they were run). 2

[Right about now you're saying, “Hey! I thought you said you'd be less negative here!”]

Let's accept that the combined results reported in the main manuscript present a challenge to the “acetaminophen as a psychological pain reliever” view, and support the differential susceptibility hypothesis. To convince those of us outside the field of social psychology, it would be beneficial to: (1) design within-subjects experiments, and (2) seriously consider possible mechanisms of action, beyond speculations about serotonin and (gasp!) 5-HTTLPR. For instance, why choose acetaminophen (which may act via the spinal cord) and not aspirin or ibuprofen? 3

At the risk of sounding overbearing and pedantic, I hereby issue the following friendly suggestions to all TYLENOL® psychology researchers...

The Proper Pharmacological Study Design Challenge

(1) Please consider using a double-blind, randomized crossover design, like studies that have examined IAPS picture ratings after acute administration of SSRI antidepressants or placebo in healthy participants (Kemp et al., 2004; van der Veen et al., 2012; Outhred et al., 2014).

Speaking of SSRIs, did you know that citalopram did not alter IAPS valence or arousal ratings relative to placebo (Kemp et al., 2004)? Or that paroxetine produced only minor effects on valence and arousal ratings for two of the eight conditions (van der Veen et al., 2012)? 4 What are the implications of these findings for your theoretical framework, that an OTC pain reliever supposedly has a greater impact on emotional processing than a prescription antidepressant? And that before the recent JPAS papers, no one has ever suspected that TYLENOL® affects reactions to emotionally evocative stimuli or David Lynch films?

(2) Please consider that acetaminophen may act via COX-1, COX-2, COX-3, peroxidase, nitric oxide synthase, cannabinoid receptors, and/or descending serotoninergic projections to the spinal cord (Toussaint et al., 2010) before mentioning the anterior cingulate cortex or the serotonin transporter gene. Just another friendly suggestion.

I usually give all my ideas away for free, but if you're interested in hiring me as a consultant, please leave a comment.


1 Turns out differential susceptibility is more or less The Orchid and the Dandelion, or as author David Dobbs puts it, “some of the genes and traits generating our greatest maladies and misdeeds — depression, anxiety, hyper-aggression, a failure to focus — also underlie many of our greatest satisfactions and success." I don't really see how this acetaminophen study informs the differential susceptibility hypothesis, which is based on individual differences (beyond a metaphorical kinship, perhaps).

2 But then I missed the memo from Psych Sci on “recently recommended approaches to presenting the results of multiple studies through combined analyses.”  [paging @mc_hankins...]

3 I know the original social rejection study used Tylenol, but why does everyone persist in doing so?? I was pleased to see that in the press release, first author Geoffrey Durso said they're branching out to test ibuprofen and aspirin.  [There, something positive.]

4 To be precise, participants gave lower arousal ratings to high arousal, low valence pictures and slightly lower valence ratings to high arousal, high valence pictures. The other six cells in the arousal/pleasure ratings of high/low arousal, high/low pleasure were no different on drug vs. placebo.


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. Psychol Sci. 21:931-7.

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 DOI: 10.1177/0956797615570366

Kemp AH, Gray MA, Silberstein RB, Armstrong SM, Nathan PJ. (2004). Augmentation of serotonin enhances pleasant and suppresses unpleasant cortical electrophysiological responses to visual emotional stimuli in humans. Neuroimage 22:1084-96.

Machado GC, Maher CG, Ferreira PH, Pinheiro MB, Lin CW, Day RO, McLachlan AJ, Ferreira ML. (2015). Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo controlled trials. BMJ. 350:h1225.

Outhred T, Das P, Felmingham KL, Bryant RA, Nathan PJ, Malhi GS, Kemp AH. (2014). Impact of acute administration of escitalopram on the processing of emotional and neutral images: a randomized crossover fMRI study of healthy women. J Psychiatry Neurosci. 39:267-75.

Randles D, Heine SJ, Santos N. (2015). The common pain of surrealism and death: acetaminophen reduces compensatory affirmation following meaning threats. Psychol Sci. 24:966-73.

van der Veen FM, Jorritsma J, Krijger C, Vingerhoets AJ. (2012). Paroxetine reduces crying in young women watching emotional movies. Psychopharmacology 220:303-8.

Better get this woman a damn fine cup of coffee and 1000 mg of TYLENOL®

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Sunday, April 26, 2015

FDA says no to marketing FDDNP for CTE

The U.S. Food and Drug Administration recently admonished TauMark™, a brain diagnostics company, for advertising brain scans that can diagnose chronic traumatic encephalopathy (CTE), Alzheimer's disease, and other types of dementia. The Los Angeles Times reported that the FDA ordered UCLA researcher Dr. Gary Small and his colleague/business partner Dr. Jorge Barrio to remove misleading information from their company website (example shown below).

CTE has been in the news because the neurodegenerative condition has been linked to a rash of suicides in retired NFL players, based on post-mortem observations. And the TauMark™ group made headlines two years ago with a preliminary study claiming that CTE pathology is detectable in living players (Small et al., 2013).

The FDA letter stated:
The website suggests in a promotional context that FDDNP, an investigational new drug, is safe and effective for the purpose for which it is being investigated or otherwise promotes the drug. As a result, FDDNP is misbranded under section 502(f)(1) of the FD&C Act...

[18F]-FDDNP1 is a molecular imaging probe that crosses the blood brain barrier and binds to several kinds of abnormal proteins in the brain. When tagged with a radioactive tracer, FDDNP can be visualized using PET (positron emission tomography).

Despite what the name of the company implies, FDDNP is not an exclusive tau marker. FDDNP may bind to tau protein [although this is disputed],2 but it also binds to beta-amyloid, found in the clumpy plaques that form in the brains of those with Alzheimer's disease. Tau is found in neurofibrillary tangles, also characteristic of Alzheimer's pathology, and seen in other neurodegenerative tauopathies such as CTE.

The big deal with this and other radiotracers is that the pathological proteins can now be visualized in living human beings. Previously, an Alzheimer's diagnosis could only be given at autopsy, when the post-mortem brain tissue was processed to reveal plaques and tangles. So PET imaging is a BIG improvement. But still, a scan alone is not completely diagnostic, as noted by the Alzheimer's Association:
Even though amyloid plaques in the brain are a characteristic feature of Alzheimer's disease, their presence cannot be used to diagnose the disease. Many people have amyloid plaques in the brain but have no symptoms of cognitive decline or Alzheimer's disease. Because amyloid plaques cannot be used to diagnose Alzheimer's disease, amyloid imaging is not recommended for routine use in patients suspected of having Alzheimer's disease.

from TauMark's old website

There are currently three FDA-approved molecular tracers that bind to beta-amyloid: florbetapirflutemetamol, and florbetaben (note that none of these is FDDNP). But the big selling point of TauMark™ is (of course) the tau marker part, which would also label tau in the brains of individuals with CTE and frontotemporal dementia, diseases not characterized by amyloid plaques. But how can you tell the difference, when FDDNP targets plaques and tangles (and prion proteins, for that matter)?

A new study by the UCLA team demonstrated that the distribution of FDDNP labeling in the brains of Alzheimer's patients differs from that seen in a selected group of former NFL players with cognitive complaints (Barrio et al., 2015). These retired athletes (and others with a history of multiple concussions) are at risk of developing the brain pathology known as chronic traumatic encephalopathy.

from Fig. 1 (Barrio et al., 2015).  mTBI = mild traumatic brain injury, or concussion. T1 to T4 = progressive FDDNP PET signal patterns.

It's a well-established fact that brains with Alzheimer's disease, frontotemporal lobar degeneration, or Lou Gehrig's disease (for example) all show different patterns of neurodegeneration, so why not extend this to CTE? This may seem like a reasonable approach, but there are problems with some of the assumptions.

Perhaps the most deceptive claim is that “TauMark owns the exclusive license of the first and only brain measure of tau protein...” Au contraire! A review of recent developments in tau PET imaging (Zimmer et al., 2014) said that...
...six novel tau imaging agents—[18F]THK523, [18F]THK5105, [18F]THK5117, [18F]T807, [18F]T808, and [11C]PBB3—have been described and are considered promising as potential tau radioligands.

Note that [18F]FDDNP is not among the six.2,3  In fact, Zimmer et al. (2014) mentioned that in brain slices, “[3H]FDDNP failed to demonstrate overt labeling of tau pathology.” 2

No matter. Former NFL players are clamoring to participate in the TauMark studies.

So to recap, the FDA considered TauMark marketing to be “concerning from a public health perspective.” Their letter warned:
Your website describes FDDNP for use in brain PET scans to diagnose traumatic brain injuries, Alzheimer’s disease, and other neurological conditions. These uses are ones for which a prescription would be needed because they require the supervision of a physician and adequate directions for lay use cannot be written.
(see also Regulatory Focus News and the FDA's own PDF archive of the TauMark site).

At this point, astute followers of The Neurocritic and Neurobollocks might ask, “Hey, how does Dr. Daniel Amen get away with claiming that his SPECT scans can accurately diagnose different types of dementia, each with different ‘treatment plans’?”

Hey FDA, what gives?? Dr. Small and Dr. Barrio have at least 37 peer-reviewed publications on their FDDNP methods and imaging results. Meanwhile, Dr. Amen has two non-peer reviewed poster abstracts on his SPECT results in dementia. With ads like these and appearances on Celebrity Rehab, aren't the Amen Clinics's claims “misbranded” too?

Further Reading

Is CTE Detectable in Living NFL Players?

The Ethics of Public Diagnosis Using an Unvalidated Method

Uncertain Diagnoses, Research Data Privacy, & Preference Heterogeneity

Blast Wave Injury and Chronic Traumatic Encephalopathy: What's the Connection?

Little Evidence for a Direct Link between PTSD and Chronic Traumatic Encephalopathy


1 FDDNP is 2-(1-(6-[(2-[(18)F]fluoroethyl)(methyl)amino]-2-naphthyl)ethylidene)malononitrile.

2 Or what is presumed to be tau. FDDNP is supposedly a tracer for both tau and amyloid, but some experts think it's neither. Zimmer et al. (2014) stated:
Though ... [18F]FDDNP appeared to bind both amyloid plaques and tau tangles, a subsequent study using [3H]FDDNP autoradiography in sections containing neurofibrillary tangles (NFTs) failed to demonstrate overt labeling of tau pathology because of a low affinity for NFTs.
Other studies have shown that it binds to a variety of misfolded proteins.

3 James et al. (2015) were more generous in their review of tau PET imaging, mentioning the existence of seven tau tracers (including FDDNP). But again they noted the lack of specificity.  (Parenthetically speaking, [18F]T807 imaging has been done in a single NFL player, which may be of interest in a future post.)


Barrio, J., Small, G., Wong, K., Huang, S., Liu, J., Merrill, D., Giza, C., Fitzsimmons, R., Omalu, B., Bailes, J., & Kepe, V. (2015). In vivo characterization of chronic traumatic encephalopathy using [F-18]FDDNP PET brain imaging. Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1409952112

Zimmer, E., Leuzy, A., Gauthier, S., & Rosa-Neto, P. (2014). Developments in Tau PET Imaging. The Canadian Journal of Neurological Sciences, 41 (05), 547-553 DOI: 10.1017/cjn.2014.15

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Wednesday, April 15, 2015

Trends in Cognitive, Computational, and Systems Neuroscience 2015

What are the Hot Topics in cognitive neuroscience? We could ask these people, or we could take a more populist approach by looking at conference abstracts. I consulted the program for the recent Cognitive Neuroscience Society meeting (CNS 2015) and made a word cloud using Wordle.1 For comparison, we'll examine the program for the most recent Computational and Systems Neuroscience meeting (Cosyne 2015).

CNS is all about memory, people, and cognitive processing.

Cosyne is about neurons, models, and neural activity.

Read more »

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Monday, April 06, 2015

Cognitive Neuroscience 2015: State of the Union

What can we do to solve the mind/body problem once and for all? How do we cure devastating brain diseases like Alzheimer's, Parkinson's, schizophrenia, and depression? I am steadfast in following the course of my 500 year plan that may eventually solve these pressing issues, to the benefit of all Americans!

There's nothing like attending a conference in the midst of a serious family illness to make one take stock of what's important. My mind/brain has been elsewhere lately, along with my body in a different location. My blogging output has declined while I live in this alternate reality. But aside from the disunion caused by depersonalization/derealization, what is my view of the state of Cognitive Neuroscience in 2015?

But first, let's examine what we're trying to unify. Studies of mind and studies of brain?  Cognition and neuroscience?  Let's start with “neuroscience”.

Wikipedia says:
Neuroscience is the scientific study of the nervous system. Traditionally, neuroscience has been seen as a branch of biology. ... The term neurobiology is usually used interchangeably with the term neuroscience, although the former refers specifically to the biology of the nervous system, whereas the latter refers to the entire science of the nervous system. 

This reminds me of a recent post by Neuroskeptic, who asked: Is Neuroscience Based On Biology? On the face of it, this seemed like an absurd question to me, because the brain is a biological organ and of course we must know its biology to understand how it works. But what he really meant was, Is Cognitive Science Based On Biology? I say this because he adopted a functionalist view and used the brain-as-computer metaphor:
Could it be that brains are only accidentally made of cells, just as computers are only accidentally made of semiconductors? If so, neuroscience would not be founded on biology but on something else, something analogous to the mathematical logic that underpins computer science. What could this be?

See John Searle on Beer Cans & Meat Machines (1984):
This view [the brain is just a digital computer and the mind is just a computer program] has the consequence that there’s nothing essentially biological about the human mind. The brain just happens to be one of an indefinitely large number of different kinds of hardware computers that could sustain the programs which make up human intelligence. ... So, for example, if you made a computer out of old beer cans powered by windmills, if it had the right program. It would have to have a mind.

The infamous argument-by-beer-cans. In the end, Neuroskeptic admitted he's not sure he subscribes to this view. But the post sparked an interesting discussion. There were a number of good comments, e.g. Jayarava said: “Neuro-science absolutely needs to be neuron-science, to focus on brains made of cells because that's what we need to understand in the first place.” Indeed, some neuroscientists don't consider “cognitive neuroscience” to be “neuroscience” at all, because the measured units are higher (i.e., less reductionist) than single neurons.1

A comment by Adam Calhoun gets to the heart of the matter, making a sharp point about the disunity of neuroscience:
Although we use the term 'neuroscience' as though it refers to one coherent discipline, the problem here is that it does not. If you were to pick a neuroscientist at random and ask: "what does your field study?" you will not get the same answer two times in a row.

Neural development? Molecular pathways? Cognition? Visual processing? Are these the same field? Or different fields that have been given the same name?

One of the selling points of neuroscience is its interdisciplinary nature, but it's really hard to talk to each other if we don't speak the same language (or work in the same field). Some graduate programs dwell in an idealized world where students can become knowledgeable in molecular, cellular, developmental, systems, and cognitive neuroscience in one year. The reality is that professors in some subfields couldn't pass the exams given in another subfield. And why would they possibly want to do this, given they're way too busy writing grants.

Sometimes I think cognitive neuroscience is on a completely different planet from the other branches, estranged from even its closest cousin, behavioral neuroscience.2 It's even further away these days from systems neuroscience3 which used to be dominated by the glamour of single unit recordings in monkeys, but now is all about manipulating circuits with opto- and chemogenetics.

But as the Systems/Circuits techniques get more and more advanced (and invasive and mechanistic), the gulf between animal and human studies grows larger and the prospects for clinical translation fade.  [Until the neuroengineers come in and save the day.]

I'll end on a more optimistic note, with a quote from a man who wished to bridge the gap between Aplysia californica and Sigmund Freud.


1 And often not even a direct measure of neural activity at all (e.g. the hemodynamic response in fMRI). The rare exceptions to this are studies in patients with epilepsy, which have revealed the existence of Marilyn Monroe neurons and Halle Berry neurons and (my personal favorite) the rare multimodal Robert Plant neuron in the medial temporal lobe.

2 Though if you look at the mission of the journal called Behavioral Neuroscience, its scope has broadened to include just about anything:
We seek empirical papers reporting novel results that provide insight into the mechanisms by which nervous systems produce and are affected by behavior. Experimental subjects may include human and non-human animals and may address any phase of the lifespan, from early development to senescence.

Studies employing brain-imaging techniques in normal and pathological human populations are encouraged, as are studies using non-traditional species (including invertebrates) and employing comparative analyses. Studies using computational approaches to understand behavior and cognition are particularly encouraged.

In addition to behavior, it is expected that some aspect of nervous system function will be manipulated or observed, ranging across molecular, cellular, neuroanatomical, neuroendocrinological, neuropharmacological, and neurophysiological levels of analysis. Behavioral studies are welcome so long as their implications for our understanding of the nervous system are clearly described in the paper.

3 Actually, systems neuroscience is mostly about engineering and computational modelling these days.

Some Final Definitions (for the record)

The Society for Neuroscience (SfN) explanation of what neuroscientists do:
Neuroscientists specialize in the study of the brain and the nervous system. They are inspired to try to decipher the brain’s command of all its diverse functions. Over the years, the neuroscience field has made enormous progress. Scientists continue to strive for a deeper understanding of how the brain’s 100 billion nerve cells [NOTE: the number is only 86 billion] are born, grow, and connect. They study how these cells organize themselves into effective, functional circuits that usually remain in working order for life.

The SfN mission:
SfN advances the understanding of the brain and the nervous system by bringing together scientists of diverse backgrounds, facilitating the integration of research directed at all levels of biological organization, and encouraging translational research and the application of new scientific knowledge to develop improved disease treatments and cures. 

The CNS mission:
The Cognitive Neuroscience Society (CNS) is committed to the development of mind and brain research aimed at investigating the psychological, computational, and neuroscientific bases of cognition.

The term cognitive neuroscience has now been with us for almost three decades, and identifies an interdisciplinary approach to understanding the nature of thought.

And according to Wikipedia:
Cognitive neuroscience is an academic field concerned with the scientific study of biological substrates underlying cognition,[1] with a specific focus on the neural substrates of mental processes. It addresses the questions of how psychological/cognitive functions are produced by neural circuits in the brain. Cognitive neuroscience is a branch of both psychology and neuroscience, overlapping with disciplines such as physiological psychology, cognitive psychology and neuropsychology.[2] Cognitive neuroscience relies upon theories in cognitive science coupled with evidence from neuropsychology and computational modeling.[2]

Barack Obama, Jan. 24, 2012:
“…We should all want a smarter, more effective government. And while we may not be able to bridge our biggest philosophical differences this year, we can make real progress. With or without this Congress, I will keep taking actions that help the economy grow. But I can do a whole lot more with your help. Because when we act together, there is nothing the United States of America can’t achieve.”

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Saturday, March 28, 2015

Follow #CNS2015

Whether or not you're in sunny San Francisco for the start of Cognitive Neuroscience Society Meeting today, you can follow Nick Wan's list of conference attendees on Twitter: @nickwan/#CNS2015. There's also the #CNS2015 hashtag, and the official @CogNeuroNews account.

Nick will also be blogging from the conference at True Brain. You may see a post or two from The Neurocritic, but I'm usually not very prompt about it. Please comment if you'll be blogging too.

Two of the program highlights are today:

Keynote Address, Anjan Chatterjee:
“The neuroscience of aesthetics and art”

2015 Distinguished Career Contributions Awardee, Marta Kutas:
“45 years of Cognitive Electrophysiology: neither just psychology nor just the brain but the visible electrical interface between the twain”

Here are the CNS interviews with Dr. Chatterjee and Dr. Kutas.

Enjoy the meeting!

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Monday, March 16, 2015

Update on the BROADEN Trial of DBS for Treatment-Resistant Depression

Website for the BROADEN™ study, which was terminated

In these days of irrational exuberance about neural circuit models, it's wise to remember the limitations of current deep brain stimulation (DBS) methods to treat psychiatric disorders. If you recall (from Dec. 2013), Neurotech Business Report revealed that "St. Jude Medical failed a futility analysis of its BROADEN trial of DBS for treatment of depression..."

A recent comment on my old post about the BROADEN Trial1 had an even more pessimistic revelation: there was only a 17.2% chance of a successful study outcome:
Regarding Anonymous' comment on January 30, 2015 11:01 AM, as follows in part:
"Second, the information that it failed FDA approval or halted by the FDA is prima facie a blatant lie and demonstratively false. St Jude, the company, withdrew the trial."

Much of this confusion could be cleared up if the study sponsors practiced more transparency.
A bit of research reveals that St. Judes' BROADEN study was discontinued after the results of a futility analysis predicted the probability of a successful study outcome to be no greater than 17.2%. (According to a letter from St. Jude)

Medtronic hasn't fared any better. Like the BROADEN study, Medtronics' VC DBS study was discontinued owing to inefficacy based on futility Analysis.

If the FDA allowed St. Jude to save face with its shareholders and withdraw the trial rather than have the FDA take official action, that's asserting semantics over substance.

If you would like to read more about the shortcomings of these major studies, please read (at least):
Deep Brain Stimulation for Treatment-resistant Depression: Systematic Review of Clinical Outcomes,
Takashi Morishita & Sarah M. Fayad &
Masa-aki Higuchi & Kelsey A. Nestor & Kelly D. Foote
The American Society for Experimental NeuroTherapeutics, Inc. 2014
DOI 10.1007/s13311-014-0282-1

The Anonymous Commenter kindly linked to a review article (Morishita et al., 2014), which indeed stated:
A multicenter, prospective, randomized trial of SCC DBS for severe, medically refractory MDD (the BROADEN study), sponsored by St. Jude Medical, was recently discontinued after the results of a futility analysis (designed to test the probability of success of the study after 75 patients reached the 6-month postoperative follow-up) statistically predicted the probability of a successful study outcome to be no greater than 17.2 % (letter from St. Jude Medical Clinical Study Management).

I (and others) had been looking far and wide for an update on the BROADEN Trial, whether in ClinicalTrials.gov or published by the sponsors. Instead, the authors of an outside review article (who seem to be involved in DBS for movement disorders and not depression) had access to a letter from St. Jude Medical Clinical Studies.

Another large randomized controlled trial that targeted different brain structures (ventral capsule/ventral striatum, VC/VS) also failed a futility analysis (Morishita et al., 2014):
Despite the very encouraging outcomes reported in the open-label studies described above, a recent multicenter, prospective, randomized trial of VC/VS DBS for MDD sponsored by Medtronic failed to show significant improvement in the stimulation group compared with a sham stimulation group 16 weeks after implantation of the device. This study was discontinued owing to perceived futility, and while investigators remain hopeful that modifications of inclusion criteria and technique might ultimately result in demonstrable clinical benefit in some cohort of severely debilitated, medically refractory patients with MDD, no studies investigating the efficacy of VC/VS DBS for MDD are currently open.
In this case, however, the results were published (Dougherty et al., 2014):
There was no significant difference in response rates between the active (3 of 15 subjects; 20%) and control (2 of 14 subjects; 14.3%) treatment arms and no significant difference between change in Montgomery-Åsberg Depression Rating Scale scores as a continuous measure upon completion of the 16-week controlled phase of the trial. The response rates at 12, 18, and 24 months during the open-label continuation phase were 20%, 26.7%, and 23.3%, respectively.

Additional studies (with different stimulation parameters, better target localization, more stringent subject selection criteria) are needed, one would say. Self-reported outcomes from the patients themselves range from “...the side effects caused by the device were, at times, worse than the depression itself” to “I feel like I have a second chance at life.”

So where do we go now?? Here's a tip: all the forward-looking investors are into magnetic nanoparticles these days (see Magnetic 'rust' controls brain activity)...

UPDATE to the update (March 22 2015): The Vancouver Sun reported (on 3/17/2015) that the sponsor ended the trial:
A procedure that treats depression by using electrodes implanted deep in the brain won’t be available to the public soon, says the researcher who pioneered the procedure more than a decade ago with a team at the University of Toronto.

Neurologist Dr. Helen Mayberg, now at Emory University in Atlanta, said in Vancouver Tuesday that 80 per cent of her recent patients find sustained relief from severe depression after fine wires are surgically implanted to deliver electrical current to a specific part of the brain.

But a medical equipment maker halted its tests to commercialize the discovery six months after implanting devices in 125 recruits in 2013.

Data from that work has not yet been released by St. Jude Medical Inc. based in St. Paul, Minn., although a spokesman for the company said Tuesday that it will be made public. The patients still have the implanted devices and the study was not stopped for safety reasons.


1 BROADEN is an tortured acronym for BROdmann Area 25 DEep brain Neuromodulation. The target was subgenual cingulate cortex (aka BA 25). The trial was either halted by the FDA or withdrawn by the sponsor.


Dougherty DD, Rezai AR, Carpenter LL, Howland RH, Bhati MT, O'Reardon JP, Eskandar EN, Baltuch GH, Machado AD, Kondziolka D, Cusin C, Evans KC, Price LH, Jacobs K, Pandya M, Denko T, Tyrka AR, Brelje T, Deckersbach T, Kubu C, Malone DA Jr. (2014). A Randomized Sham-Controlled Trial of Deep Brain Stimulation of the Ventral Capsule/Ventral Striatum for Chronic Treatment-Resistant Depression. Biol Psychiatry Dec 13. [Epub ahead of print].

Morishita, T., Fayad, S., Higuchi, M., Nestor, K., & Foote, K. (2014). Deep Brain Stimulation for Treatment-resistant Depression: Systematic Review of Clinical Outcomes. Neurotherapeutics, 11 (3), 475-484. DOI: 10.1007/s13311-014-0282-1

DBS for MDD targets as of November 2013
(Image credit: P. HUEY/SCIENCE)

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Monday, March 09, 2015

Daylight Savings Time and "The Dress"

Could one's chronotype (degree of "morningness" vs. "eveningness") be related to your membership on Team white/gold vs. Team blue/black?

Dreaded by night owls everywhere, Daylight Savings Time forces us to get up an hour earlier. Yes, [my time to blog and] I have been living under a rock, but this evil event and an old tweet by Vaughan Bell piqued my interest in melanopsin and intrinsically photosensitive retinal ganglion cells.

I thought this was a brilliant idea, perhaps differences in melanopsin genes could contribute to differences in brightness perception. More about that in a moment.

{Everyone already knows about #thedress from Tumblr and Buzzfeed and Twitter obviously}

In the initial BuzzFeed poll, 75% saw it as white and gold, rather than the actual colors of blue and black. Facebook's more systematic research estimated this number was only 58% (and influenced by probably exposure to articles that used Photoshop). Facebook also reported differences by sex (males more b/b), age (youngsters more b/b), and interface (more b/b on computer vs. iPhone and Android).

Dr. Cedar Riener wrote two informative posts about why people might perceive the colors differently, but Dr. Bell was not satisfied with this and other explanations. Wired consulted two experts in color vision:
“Our visual system is supposed to throw away information about the illuminant and extract information about the actual reflectance,” says Jay Neitz, a neuroscientist at the University of Washington. “But I’ve studied individual differences in color vision for 30 years, and this is one of the biggest individual differences I’ve ever seen.”
“What’s happening here is your visual system is looking at this thing, and you’re trying to discount the chromatic bias of the daylight axis,” says Bevil Conway, a neuroscientist who studies color and vision at Wellesley College. “So people either discount the blue side, in which case they end up seeing white and gold, or discount the gold side, in which case they end up with blue and black.”

Finally, Dr. Conway threw out the chronotype card:
So when context varies, so will people’s visual perception. “Most people will see the blue on the white background as blue,” Conway says. “But on the black background some might see it as white.” He even speculated, perhaps jokingly, that the white-gold prejudice favors the idea of seeing the dress under strong daylight. “I bet night owls are more likely to see it as blue-black,” Conway says.

Melanopsin and Intrinsically Photosensitive Retinal Ganglion Cells

Rods and cones are the primary photoreceptors in the retina that convert light into electrical signals. The role of the third type of photoreceptor is very different. Intrinsically photosensitive retinal ganglion cells (ipRGCs) sense light without vision and:
  • ...contribute to the regulation of pupil size and other behavioral responses to ambient lighting conditions...
  • ...contribute to photic regulation of, and acute photic suppression of, release of the hormone melatonin...

Recent research suggests that ipRGCs may play more of a role in visual perception than was originally believed. As Vaughan said, melanopsin (the photopigment in ipRGCs) is involved in brightness discrimination and is most sensitive to blue light. Brown et al. (2012) found that melanopsin knockout mice showed a change in spectral sensitivity that affected brightness discrimination; the KO mice needed higher green radiance to perform the task as well as the control mice.

The figure below shows the spectra of human cone cells most sensitive to Short (S), Medium (M), and Long (L) wavelengths.

Spectral sensitivities of human cone cells, S, M, and L types. X-axis is in nm.

The peak spectral sensitivity for melanopsin photoreceptors is in the blue range. How do you isolate the role of melanopsin in humans?  Brown et al. (2012) used metamers, which are...
...light stimuli that appear indistinguishable to cones (and therefore have the same color and photopic luminance) despite having different spectral power distributions.  ... to maximize the melanopic excitation achievable with the metamer approach, we aimed to circumvent rod-based responses by working at background light levels sufficiently bright to saturate rods.

They verified their approach in mice, then used a four LED system to generate stimuli that diffed in presumed melanopsin excitation, but not S, M, or L cone excitation. All six of the human participants perceived greater brightness as melanopsin excitation increased (see Fig. 3E below). Also notice the individual differences in test radiance with the fixed 11% melanopic excitation (on the right of the graph).

Modified from Fig. 3E (Brown et al. (2012). Across six subjects, there was a strong correlation between the test radiance at equal brightness and the melanopic excitation of the reference stimulus (p < 0.001).1

Maybe Team white/gold and Team blue/black differ on this dimension? And while we're at it, is variation in melanopsin related to circadian rhythms, chronotype, even seasonal affective disorder (SAD)? 2 There is some evidence in favor of the circadian connections. Variants of the melanopsin (Opn4) gene might be related to chronotype and to SAD, which is much more common in women. Another Opn4 polymorphism may be related to pupillary light responses, which would affect light and dark adaptation. These genetic findings should be interpreted with caution, however, until replicated in larger populations.

Could This Device Hold the Key to “The Dress”?

ADDENDUM (March 10 2015): NO, according to Dr. Geoffry K. Aguirre of U. Penn.: Speaking as a guy with a 56-primary version of This Device to study melanopsin, I think the answer to your question is 'no'…” His PNAS paper, Opponent melanopsin and S-cone signals in the human pupillary light response, is freely available.3

A recent method developed by Cao, Nicandro and Barrionuevo (2015) increases the precision of isolating ipRGC function in humans. The four-primary photostimulator used by Brown et al. (2012) assumed that the rod cells were saturated at the light levels they used. However, Cao et al. (2015) warn that “a four-primary method is not sufficient when rods are functioning together with melanopsin and cones.” So they:
...introduced a new LED-based five-primary photostimulating method that can independently control the excitation of melanopsin-containing ipRGC, rod and cone photoreceptors at constant background photoreceptor excitation levels.

Fig. 2 (Cao et al., 2015). The optical layout and picture of the five-primary photostimulator.

Their Journal of Vision article is freely available, so you can read all about the methods and experimental results there (i.e., I'm not even going to try to summarize them here).

So the question remains: beyond the many perceptual influences that everyone has already discussed at length (e.g., color constancy, Bayesian priors, context, chromatic bias, etc.), could variation in ipRGC responses influence how you see “The Dress”?


1Fig 3E (continued). The effect was unrelated to any impact of melanopsin on pupil size. Subjects were asked to judge the relative brightness of three metameric stimuli (melanopic contrast −11%, 0%, and +11%) with respect to test stimuli whose spectral composition was invariant (and equivalent to the melanopsin 0% stimulus) but whose radiance changed between trials.

2 This would test Conway's quip that night owls are more likely to see the dress as blue and black.

3 Aguirre also said that a contribution from melanopsin (to the dress effect) was doubtful, at least from any phasic effect: “It's a slow signal with poor spatial resolution and subtle perceptual effects.” It remains to be seen whether any bias towards discarding blue vs. yellow illuminant information is affected by chronotype.

Interesting result from Spitschan, Jain, Brainard, & Aguirre 2014):
The opposition of the S cones is revealed in a seemingly paradoxical dilation of the pupil to greater S-cone photon capture. This surprising result is explained by the neurophysiological properties of ipRGCs found in animal studies.


Brown, T., Tsujimura, S., Allen, A., Wynne, J., Bedford, R., Vickery, G., Vugler, A., & Lucas, R. (2012). Melanopsin-Based Brightness Discrimination in Mice and Humans. Current Biology, 22 (12), 1134-1141 DOI: 10.1016/j.cub.2012.04.039

Cao, D., Nicandro, N., & Barrionuevo, P. (2015). A five-primary photostimulator suitable for studying intrinsically photosensitive retinal ganglion cell functions in humans. Journal of Vision, 15 (1), 27-27 DOI: 10.1167/15.1.27

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