Saturday, April 07, 2018

Big Theory, Big Data, and Big Worries in Cognitive Neuroscience

Eve Marder, Alona Fyshe, Jack Gallant, David Poeppel, Gary Marcus
image by @jonasobleser

UPDATE April 9 2018: Video of the entire debate is now available at the CNS blogYouTube, and the end of this post.

What Will Solve the Big Problems in Cognitive Neuroscience?

That was the question posed in the Special Symposium moderated by David Poeppel at the Boston Sheraton (co-sponsored by the Cognitive Neuroscience Society and the Max-Planck-Society). The format was four talks by prominent experts in (1) the complexity of neural circuits and neuromodulation in invertebrates; (2) computational linguistics and machine learning; (3) human neuroimaging/the next wave in cognitive and computational neuroscience; and (4) language learning/AI contrarianism. These were followed by a lively panel discussion and a Q&A session with the audience. What a great format!

We already knew the general answer before anyone started speaking.

But I believe that Dr. Eve Marder, the first speaker, posed the greatest challenges to the field of cognitive neuroscience, objections that went mostly unaddressed by the other speakers. Her talk was a treasure trove of quotable witticisms (paraphrased):
  • How much ambiguity can you live with in your attempt to understand the brain? For me I get uncomfortable with anything more than 100 neurons
  • If you're looking for optimization (in [biological] neural networks), YOU ARE DELUSIONAL!
  • Degenerate mechanisms produce the same changes in behavior, even in a 5 neuron network...
  • Cognitive Neuroscientists should be VERY WORRIED

Dr. Marder started her talk by expressing puzzlement about why she would be asked to speak on such a panel, but she gamely agreed. She initially expressed some ideas that almost everyone endorses:
  • Good connectivity data is essential
  • Simultaneous recordings from many neurons is a good idea [but how many is enough?]
But then she turned to the nightmare of trying to understand large-scale brain networks, as is the fashion these days in human fMRI and connectivity studies.
  • It's not clear what changes when circuits get big
  • Assuming a “return to baseline” is always hiding a change that can be cryptic
  • On the optimization issue... nervous systems can't optimize for one situation if it makes them unable to deal with other [unexpected] situations.
  • How does degeneracy relieve the tyranny?
No one knows...

Dr. Marder was also a speaker at the Canonical Computation in Brains and Machines meeting in mid-March (h/t @neuroecology), and her talk from that conference is available online.

I believe the talks from the present symposium will be on the CNS YouTube channel as well, and I'll update the post if/when that happens.

Speaking of canonical computation, now I know why Gary Marcus was apoplectic at the thought of “one canonical cortical circuit to rule them all.” More on that in a moment...

The next speaker was Dr. Alona Fyshe, who spoke about computational vision. MLE, MAP, ImageNet, CNNs. I'm afraid I can't enlighten you here. Like everyone else, she thought theory vs. data is a false dichotomy. Her memorable tag line was “Kill Your Darlings.” At first I thought this meant delete your best line [of code? of your paper?], but in reality “our theories need to be flexible enough to adapt to data” (always follow @vukovicnikola #cns2018 for the best real-time conference coverage).

Next up was Dr. Gary Marcus, who started out endorsing the famous Jonas and Kording (2017) paper Could a Neuroscientist Understand a Microprocessor? which suggested that current data analysis methods in neuroscience are inadequate for producing a true understanding of the brain. Later, during the discussion, Dr. Jack Gallant quipped that the title of that paper should have been “Neuroscience is Hard” (on Twitter, @KordingLab thought this was unfair). For that matter, Gallant told Marcus, “I think you just don't like the brain.” [Gallant is big on data, but not mindlessly]

image via @vukovicnikola

This sparked a lively debate during the panel discussion and the Q&A.

Anyway, back to Marcus. “Parsimony is a false god,” he said. I've long agreed with this sentiment, especially when it comes to the brain the simplest explanation isn't always true. Marcus is pessimistic that deep learning will lead to great advances in explaining neural systems (or AI). It's that pesky canonical computation again. The cerebral cortex (and the computations it performs) isn't uniform across regions (Marcus et al., 2014).

This is not a new idea. In my ancient dissertation, I cited Swindale (1990) and said:
Swindale (1990) argues that the idea of mini-columns and macro-columns was drawn on insufficient data. Instead, the diversity of cell types in different cortical areas may result in more varied and complex organization schemes which would adequately reflect the different types of information stored there [updated version would be “types of computations performed there”].1

Finally, Dr. Jack Gallant came out of the gate saying the entire debate is silly, and that we need both theory and data. But he also thinks it's silly that we'll get there with theory alone. We need to build better measurement tools, stop faulty analysis practices, and develop improved experimental paradigms. He clearly favors the collection of more data, but in a refined way. For the moment, collect large rich naturalistic data sets using existing technology.

And remember, kids, “the brain is a horror show of maps.”

 image via @vukovicnikola

Big Data AND Big Theory: Everyone Agrees (sorta)

Eve Marder – The Important of the Small for Understanding the Big

Alona Fyshe – Data Driven Everything

Gary Marcus – Neuroscience, Deep Learning, and the Urgent Need for an Enriched Set of Computational Primitives

Jack Gallant – Which Presents the Biggest Obstacle to Advances in Cognitive Neuroscience Today: Lack of Theory or Lack of Data?

Gary Marcus talking over Jack Gallant. Eve Marder is out of the frame.
image by @CogNeuroNews


1 Another quote from the young Neurocritic:
As finer analyses are applied to both local circuitry and network properties, our theoretical understanding of neocortical operation may require further revision, if not total replacement with other metaphors. At our current state of knowledge, a number of different conceptual frameworks can be overlaid on the existing data to derive an order that may not be there. Or conversely, the data can be made to fit into one's larger theoretical view.

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Saturday, March 31, 2018

Automatically-Triggered Brain Stimulation during Encoding Improves Verbal Recall

Fig. 4 (modified from Ezzyat et al., 2018). Stimulation targets showing numerical increase/decrease in free recall performance are shown in red/blue. Memory-enhancing sites clustered in the middle portion of the left middle temporal gyrus.

Everyone forgets. As we grow older or have a brain injury or a stroke or develop a neurodegenerative disease, we forget much more often. Is there a technological intervention that can help us remember? That is the $50 million dollar question funded by DARPA's Restoring Active Memory (RAM) Program, which has focused on intracranial electrodes implanted in epilepsy patients to monitor seizure activity.

Led by Michael Kahana's group at the University of Pennsylvania and including nine other universities, agencies, and companies, this Big Science project is trying to establish a “closed-loop” system that records brain activity and stimulates appropriate regions when a state indicative of poor memory function is detected (Ezzyat et al., 2018).

Initial “open-loop” efforts targeting medial temporal lobe memory structures (entorhinal cortex, hippocampus) were unsuccessful (Jacobs et al., 2016). In fact, direct electrical stimulation of these regions during encoding of spatial and verbal information actually impaired memory performance, unlike an initial smaller study (Suthana et al., 2012).1

{See Bad news for DARPA's RAM program: Electrical Stimulation of Entorhinal Region Impairs Memory}

However, during the recent CNS symposium on Memory Modulation via Direct Brain Stimulation in Humans, Dr. Suthana suggested that “Stimulation of entorhinal white matter and not nearby gray matter was effective in improving hippocampal-dependent memory...” 2

{see this ScienceNews story}

Enter the Lateral Temporal Cortex

Meanwhile, the Penn group and their collaborators moved to a different target region, which was also discussed in the CNS 2018 symposium: “Closed-loop stimulation of temporal cortex rescues functional networks and improves memory” (based on Ezzyat et al., 2018).

Fig. 4 (modified from Ezzyat et al., 2018). Horizontal section. Stimulation targets showing numerical increase/decrease in free recall performance are shown in red/blue. Memory-enhancing sites clustered in the middle portion of the left middle temporal gyrus.

Twenty-five patients performed a memory task in which they were shown a list of 12 nouns, followed by a distractor task, and finally a free recall phase, where they were asked to remember as many of the words as they could. The participants went through a total of 25 rounds of this study-test procedure.

Meanwhile, the first three rounds were “record-only” sessions, where the investigators developed a classifier a pattern of brain activity that could predict whether or not the patient would recall the word at better than chance (AUC = 0.61, where chance =.50).” 3 The classifier relied on activity across all electrodes that were placed in an individual patient.

Memory blocks #4-25 alternated between Simulation (Stim) and No Stimulation (NoStim) lists. In Stim blocks, 0.5-2.25 mA stimulation was delivered for 500 ms when the classifier AUC predicted 0.5 recall during word presentation. In NoStim lists, stimulation was not delivered on analogous trials, and the comparison between those two conditions comprised the main contrast shown below.

Fig. 3a (modified from Ezzyat et al., 2018). Stimulation delivered to lateral temporal cortex targets increased the probability of recall compared to matched unstimulated words in the same subject (P < 0.05) and stimulation delivered to Non-lateral temporal targets in an independent group (P < 0.01).

The authors found that that lateral temporal cortex stimulation increased the relative probability of item recall by 15% (using a log-binomial model to estimate the relative change in recall probability). {But if you want to see all of the data, peruse the Appendix below. Overall recall isn't that great...}

Lateral temporal cortex (n=18) meant MTG, STG, and IFG (mostly on the left). Non-lateral temporal cortex (n=11) meant elsewhere (see Appendix below). The improvements were greatest with stimulation in the middle portion of the left middle temporal gyrus. There are many reason for poor encoding, and one could be that subjects were not paying enough attention. The authors didn't have the electrode coverage to test that explicitly. This leads me to believe that electrical stimulation was enhancing the semantic encoding of the words. The MTG is thought to be critical for semantic representations and language comprehension in general (Turken & Dronkers, 2011).

Thus, my interpretation of the results is that stimulation may have boosted semantic encoding of the words, given the nature of the stimuli (words, obviously), the left lateralization with a focus in MTG, and the lack of an encoding task. The verbal memory literature clearly demonstrates that when subjects have a deep semantic encoding task (e.g., living/non-living decision), compared to shallow orthographic (are there letters that extend above/below?) or phonological tasks, recall and recognition are improved. Which led me to ask some questions, and one of the authors kindly replied (Dan Rizzuto, personal communication). 4

  1. Did you ever have conditions that contrasted different encoding tasks? Here I meant to ask about semantic vs orthographic encoding (because the instructions were always to “remember the words” with no specific encoding task).
    • We studied three verbal learning tasks (uncategorized free recall, categorized free recall, paired associates learning) and one spatial navigation task during the DARPA RAM project. We were able to successfully decode recalled / non-recalled words using the same classifier across the three different verbal memory tasks, but we never got sufficient paired associates data to determine whether we could reliably increase memory performance on this task.
  2. Did you ever test nonverbal stimuli (not nameable pictures, which have a verbal code), but visual-spatial stimuli? Here I was trying to assess the lexical-semantic nature of the effect. 
    • With regard to the spatial navigation task, we did observe a few individual patients with LTC stimulation-related enhancement, but we haven't yet replicated the effect across the population.

Although this method may have therapeutic implications in the future, at present it is too impractical, and the gains were quite small. Nonetheless, it is an accomplished piece of work to demonstrate closed-loop memory enhancement in humans.


1 Since that time, however, the UCLA group has reported that theta-burst microstimulation of....
....the right entorhinal area during learning significantly improved subsequent memory specificity for novel portraits; participants were able both to recognize previously-viewed photos and reject similar lures. These results suggest that microstimulation with physiologic level currents—a radical departure from commonly used deep brain stimulation protocols—is sufficient to modulate human behavior and provides an avenue for refined interrogation of the circuits involved in human memory.

2 Unfortunately, I was running between two sessions and missed that particular talk.

3 This level of prediction is more like a proof of concept and would not be clinically acceptable at this point.

4 Thanks also to Youssef Ezzyat and Cory Inman, whom I met at the symposium.


Ezzyat Y, Wanda PA, Levy DF, Kadel A, Aka A, Pedisich I, Sperling MR, Sharan AD, Lega BC, Burks A, Gross RE, Inman CS, Jobst BC, Gorenstein MA, Davis KA, Worrell GA, Kucewicz MT, Stein JM, Gorniak R, Das SR, Rizzuto DS, Kahana MJ. (2018). Closed-loop stimulation of temporal cortex rescues functional networks and improves memory. Nat Commun. 9(1): 365.

Jacobs, J., Miller, J., Lee, S., Coffey, T., Watrous, A., Sperling, M., Sharan, A., Worrell, G., Berry, B., Lega, B., Jobst, B., Davis, K., Gross, R., Sheth, S., Ezzyat, Y., Das, S., Stein, J., Gorniak, R., Kahana, M., & Rizzuto, D. (2016). Direct Electrical Stimulation of the Human Entorhinal Region and Hippocampus Impairs Memory. Neuron 92(5): 983-990.

Suthana, N., Haneef, Z., Stern, J., Mukamel, R., Behnke, E., Knowlton, B., & Fried, I. (2012). Memory Enhancement and Deep-Brain Stimulation of the Entorhinal Area. New England Journal of Medicine 366(6): 502-510.

Titiz AS, Hill MRH, Mankin EA, M Aghajan Z, Eliashiv D, Tchemodanov N, Maoz U, Stern J, Tran ME, Schuette P, Behnke E, Suthana NA, Fried I. (2017). Theta-burstmicrostimulation in the human entorhinal area improves memory specificity. Elife Oct 24;6.

Turken AU, Dronkers NF. (2011). The neural architecture of the language comprehension network: converging evidence from lesion and connectivity analyses. Front Syst Neurosci. Feb 10;5:1.

Appendix (modified from Supplementary Table 1)  

- click on image for a larger view - 

In the table above, Stim and NoStim recall percentages are for ALL words in the blocks. But:
  • Only half of the words in each Stim list were stimulated, however, so this comparison is conservative. The numbers improve slightly if you compare just the stimulated words with the matched non-stimulated words. Not all subjects exhibited a significant within-subject effect, but the effect is reliable across the population (Figure 3a)

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Friday, March 23, 2018

25 Years of Cognitive Neuroscience in Boston

The 25th Annual Meeting of the Cognitive Neuroscience Society starts off with a big bang on Saturday afternoon with the Big Theory versus Big Data Debate, moderated by David Poeppel.1

Big Theory versus Big Data: What Will Solve the Big Problems in Cognitive Neuroscience?

My non-commital answers are:

(1) Both.

(2) It depends. (on what you want to do: predict behavior2 (or some mental state), explain behavior, control behavior, etc.)

Abstract: All areas of the sciences are excited about the innovative new ways in which data can be acquired and analyzed. In the neurosciences, there exists a veritable orgy of data – but is that what we need? Will the colossal datasets we now enjoy solve the questions we seek to answer, or do we need more ‘big theory’ to provide the necessary intellectual infrastructure? Four leading researchers, with expertise in neurophysiology, neuroimaging, artificial intelligence, language, and computation will debate these big questions, arguing for what steps are most likely to pay off and yield substantive new explanatory insight.

Talk 1: Eve Marder The Important of the Small for Understanding the Big

Talk 2: Jack Gallant Which Presents the Biggest Obstacle to Advances in Cognitive Neuroscience Today: Lack of Theory or Lack of Data?

Talk 3: Alona Fyshe Data Driven Everything

Talk 4: Gary Marcus Neuroscience, Deep Learning, and the Urgent Need for an Enriched Set of Computational Primitives

Levels of analysis! Marr! [Poeppel is the moderator] New new new! Transformative techniques, game-changing paradigms, groundbreaking schools of thought, and multiple theories for myriad neural circuits. There is no single computational system that can possibly explain brain function at all levels of analysis (gasp! not even the Free Energy Prinicple).3

A Q&A or panel discussion would be nice... (although not on the schedule)

This Special Symposium will be preceded by the ever-exciting Data Blitz (a series of 5 minute talks) and followed by a Keynote Address by the Godfather of Cognitive Neuroscience:

Michael Gazzaniga

The Consciousness Instinct

How do neurons turn into minds? How does physical “stuff”—atoms, molecules, chemicals, and cells—create the vivid and various alive worlds inside our heads? This problem has gnawed at us for millennia. In the last century there have been massive breakthroughs that have rewritten the science of the brain, and yet the puzzles faced by the ancient Greeks are still present. In this lecture I review the the history of human thinking about the mind/brain problem, giving a big-picture view of what science has revealed. Understanding how consciousness could emanate from a confederation of independent brain modules working together will help define the future of brain science and artificial intelligence, and close the gap between brain and mind.

Plus there is a jam packed schedule of posters, talks, and prestigious award recipients/presenters on Sunday through Tuesday. Another highlight:

Symposium 3 The Next 25 Years of Cognitive Neuroscience: Opportunities and Challenges (Brad Postle, Chair)4

I belong to the school of slow blogging, so I probably won't have immediate recaps. Follow #CNS2018 and enjoy the conference!


1 The passenger next to me was watching the Big Bang Theory, so yay for repetition priming.

2 At multiple levels of analysis, e.g. from molecular processes to motor output and all in between. Not daunting or anything. Perhaps not even possible...

3 Although Poster A87 suggests otherwise. {I think}

4 Unfortunately, this conflicts with Symposium 1 Memory Modulation via Direct Brain Stimulation in Humans which I really want to attend as well.

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Sunday, March 18, 2018

Universal Linguistic Decoders are Everywhere

Pereira et al. (2018) - click image to enlarge

No, they're not. They're really not. They're “everywhere” to me, because I've been listening to Black Celebration. How did I go from “death is everywhere” to “universal linguistic decoders are everywhere”? I don't imagine this particular semantic leap has occurred to anyone before. Actually, the association travelled in the opposite direction, because the original title of this piece was Decoders Are Everywhere.1 {I was listening to the record weeks ago, the silly title of the post reminded me of this, and the semantic association was remote.}

This is linguistic meaning in all its idiosyncratic glory, a space for infinite semantic vectors that are unexpected and novel. My rambling is also an excuse to not start out by saying, oh my god, what were you thinking with a title like, Toward a universal decoder of linguistic meaning from brain activation (Pereira et al., 2018). Does the word “toward” absolve you from what such a sage, all-knowing clustering algorithm would actually entail? And of course, “universal” implies applicability to every human language, not just English. How about, Toward a better clustering algorithm (using GloVe vectors) for inferring meaning from the distribution of voxels, as determined by an n=16 database of brain activation elicited by reading English sentences?

But it's unfair (and inaccurate) to suggest that the linguistic decoder can decipher a meandering train of thought when given a specific neural activity pattern. Therefore, I do not want to take anything away from what Pereira et al. (2018) have achieved in this paper. They say:
  • “Our work goes substantially beyond prior work in three key ways. First, we develop a novel sampling procedure for selecting the training stimuli so as to cover the entire semantic space. This comprehensive sampling of possible meanings in training the decoder maximizes generalizability to potentially any new meaning.”
  • “Second, we show that although our decoder is trained on a limited set of individual word meanings, it can robustly decode meanings of sentences represented as a simple average of the meanings of the content words. ... To our knowledge, this is the first demonstration of generalization from single-word meanings to meanings of sentences.”
  • “Third, we test our decoder on two independent imaging datasets, in line with current emphasis in the field on robust and replicable science. The materials (constructed fully independently of each other and of the materials used in the training experiment) consist of sentences about a wide variety of topics—including abstract ones—that go well beyond those encountered in training.”

Unfortunately, it would take me days to adequately pore over the methods, and even then my understanding would be only cursory. The heavy lifting would need to be done by experts in linguistics, unsupervised learning, and neural decoding models. But until then...

Death is everywhere
There are flies on the windscreen
 For a start
 Reminding us
 We could be torn apart

---Depeche Mode, Fly on the Windscreen


1 Well, they are super popular right now.


Pereira F, Lou B, Pritchett B, Ritter S, Gershman SJ, Kanwisher N, Botvinick M, Fedorenko E. (2018). Toward a universal decoder of linguistic meaning from brain activation. Nat Commun. 9(1):963.

Come here
Kiss me
Come here
Kiss me


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Sunday, February 11, 2018

Policy Insights from The Neurocritic: Alarm Over Acetaminophen, Ibuprofen Blocking Emotion Is Overblown

Just in time for Valentine's Day, floats in a raft of misleading headlines:

Scientists have found the cure for a broken heart

Painkillers may also mend a broken heart

Taking painkillers could ease heartaches - as well as headaches

Paracetamol and ibuprofen could ease heartaches - as well as headaches

If Tylenol and Advil were so effective in “mending broken hearts”, “easing heartaches”, and providing a “cure for a broken heart”, we would be a society of perpetually happy automatons, wiping away the suffering of breakup and divorce with a mere dose of acetaminophen. We'd have Tylenol epidemics and Advil epidemics to rival the scourge of the present Opioid Epidemic.

Really, people,1 words have meanings. If you exaggerate, readers will believe statements that are blown way out of proportion. And they may even start taking doses of drugs that can harm their kidneys and livers.

These media pieces also have distressing subtitles:

Common painkillers that kill empathy
... some popular painkillers like ibuprofen and acetaminophen have been found to reduce people’s empathy, dull their emotions and change how people process information.

A new scientific review of studies suggests over-the-counter pain medication could be having all sorts of psychological effects that consumers do not expect.

Not only do they block people’s physical pain, they also block emotions.

The authors of the study, published in the journal Policy Insights from the Behavioral and Brain Sciences, write: “In many ways, the reviewed findings are alarming. Consumers assume that when they take an over-the-counter pain medication, it will relieve their physical symptoms, but they do not anticipate broader psychological effects.”

Cheap painkillers affect how people respond to hurt feelings, 'alarming' review reveals
Taking painkillers could ease the pain of hurt feelings as well as headaches, new research has discovered.

The review of studies by the University of California found that women taking drugs such as ibuprofen and paracetamol reported less heartache from emotionally painful experiences, compared with those taking a placebo.

However, the same could not be said for men as the study found their emotions appeared to be heightened by taking the pills.

Researchers said the findings of the review were 'in many ways...alarming'.

I'm here to tell you these worries are greatly exaggerated. Just like there's a Trump tweet for every occasion, there's a Neurocritic post for most of these studies (see below).

A new review in Policy Insights from the Behavioral and Brain Sciences has prompted the recent flurry of headlines. Ratner et al. (2018) reviewed the literature on OTC pain medications.
. . . This work suggests that drugs like acetaminophen and ibuprofen might influence how people experience emotional distress, process cognitive discrepancies, and evaluate stimuli in their environment. These studies have the potential to change our understanding of how popular pain medications influence the millions of people who take them. However, this research is still in its infancy. Further studies are necessary to address the robustness of reported findings and fully characterize the psychological effects of these drugs.

The studies are potentially transformative, yet the research is still in its infancy. The press didn't read the “further studies are necessary” caveat. But I did find one article that took a more modest stance:

Do OTC Pain Relievers Have Psychological Effects?
Ratner wrote that the findings are “in many ways alarming,” but he told MD Magazine that his goal is not so much to raise alarm as it is to prompt additional research. “Something that I want to strongly emphasize is that there are really only a handful of studies that have looked at the psychological effects of these drugs,” he said.

Ratner said a number of questions still need to be answered. For one, there is not enough evidence out there to know to what extent these psychological effects are merely the result of people being in better moods once their pain is gone.

. . .

Ratner also noted that the participants in the studies were not taking the medications because of physical pain, and so the psychological effects might be a difference in cases where the person experienced physical pain and then relief.

For now, Ratner is urging caution and nuanced interpretation of the data. He said stoking fears of these drugs could have negative consequences, as could a full embrace of the pills as mood-altering therapies.

Ha! Not so alarming after all, we see on a blog with 5,732 Twitter followers (as opposed to 2.4 million and 2.9 million for the most popular news pieces). I took 800 mg of ibuprofen before writing this post, and I do not feel any less anxious or disturbed about events in my life. Or even about feeling the need to write this post, with my newly “out” status and all.

There's a Neurocritic post for every occasion...

As a preface to my blog oeuvre, these are topics I care about deeply. I'm someone who has suffered heartache and emotional pain (as most of us have), as well as chronic pain conditions, four invasive surgeries, tremendous loss, depression, anxiety, insomnia, etc.... My criticism does not come lightly.

I'm not entirely on board with studies showing that one dose (or 3 weeks) of Tylenol MAY {or may not} modestly reduce social pain or “existential distress” or empathy as sufficient models of human suffering and its alleviation by OTC drugs. In fact, I have questions about all of these studies.

Suffering from the pain of social rejection? Feel better with TYLENOL® – My first question has always been, why acetaminophen and not aspirin or Advil? Was there a specific mechanism in mind?

Existential Dread of Absurd Social Psychology Studies – Does a short clip of Rabbits (by David Lynch) really produce existential angst and thoughts of death? [DISCLAIMER: I'm a David Lynch fan.]

Tylenol Doesn't Really Blunt Your Emotions – Why did ratings of neutral stimuli differ as a function of treatment (in one condition)?

Does Tylenol Exert its Analgesic Effects via the Spinal Cord? – and perhaps brainstem

Acetaminophen Probably Isn't an "Empathy Killer" – How do very slight variations in personal distress ratings translate to real world empathy?

Advil Increases Social Pain (if you're male) – Reduced hurt from Cyberball exclusion in women, but a disinhibition effect in men (blunting their tendency to suppress their emotional pain)?

...and just for fun:

Vicodin for Social Exclusion – not really – but social pain and physical pain are not interchangeable

Use of Anti-Inflammatories Associated with Threefold Increase in Homicides – cause/effect issue, of course

Scene from Rabbits by David Lynch


1 And by “people” I mean scientists and journalists alike. Read this tweetstorm from Chris Chambers, including:


Ratner KG, Kaczmarek AR, Hong Y. (2018). Can Over-the-Counter Pain Medications Influence Our Thoughts and Emotions? Policy Insights from the Behavioral and Brain Sciences. Feb 6:2372732217748965.

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Monday, February 05, 2018

Head Impact and Hyperphosphoralated Tau in Teens

We all agree that repeated blows to the head are bad for the brain. What we don't yet know is:
  • who will show lasting cognitive and behavioral impairments
  • who will show only transient sequelae (and for how long)
  • who will manifest long-term neurodegeneration
  • ...and by which specific cellular mechanism(s)

Adding to the confusion is the unclear terminology used to describe impact-related head injuries. Is a concussion the same as a mild traumatic brain injury (TBI)? Sharp and Jenkins say absolutely not, and contend that Concussion is confusing us all:
It is time to stop using the term concussion as it has no clear definition and no pathological meaning. This confusion is increasingly problematic as the management of ‘concussed’ individuals is a pressing concern. Historically, it has been used to describe patients briefly disabled following a head injury, with the assumption that this was due to a transient disorder of brain function without long-term sequelae. However, the symptoms of concussion are highly variable in duration, and can persist for many years with no reliable early predictors of outcome. Using vague terminology for post-traumatic problems leads to misconceptions and biases in the diagnostic process, producing uninterpretable science, poor clinical guidelines and confused policy. We propose that the term concussion should be avoided. Instead neurologists and other healthcare professionals should classify the severity of traumatic brain injury and then attempt to precisely diagnose the underlying cause of post-traumatic symptoms.

In an interview about the impressive mega-paper by Tagge, Fisher, Minaeva, et al. (2018), co-senior author Dr. Lee Goldstein also said no, but had a different interpretation:
When it comes to head injuries and CTE, Goldstein spoke of three categories that are being jumbled: concussions, TBI and CTE. Concussion, he says, is a syndrome defined “by consensus really every couple of years, based on the signs and symptoms of neurological syndrome, what happens after you get hit in the head. It’s nothing more than that, a syndrome...

A TBI is different. “it is an injury, an event,” he said. “It’s not a syndrome. It’s an event and it involves damage to tissue. If you don’t have a concussion, you can absolutely have brain injury and the converse is true.”
. . .

“So concussion may or may not be a TBI and equally important not having a concussion may or may not be associated with a TBI. A concussion doesn’t tell you anything about a TBI. Nor does it tell you anything about CTE.”

I think I'm even more confused now... you can have concussion (the syndrome) without an injury or an event?

But I'm really here to tell you about 8 post-mortem brains from teenage males who had engaged in contact sports. These were from Dr. Ann McKee's brain bank at BU, and were included in the paper along with extensive data from a mouse model (Tagge, Fisher, Minaeva, et al., 2018). Four brains were in the acute-subacute phase after mild closed-head impact injury and had previous diagnoses of concusion. The other 4 brains were control cases, including individuals who also had previous diagnoses of concussion. Let me repeat that. The controls had ALSO suffered head impact injuries at unknown (“not recent”) pre-mortem dates (>7 years prior in one case).

This amazing and important work was made possible by magnanimous donations from grieving parents. I am very sorry for the losses they have suffered.

Below is a summary of the cases.

Case 1
  • 18 year old multisport athlete American football (9 yrs), baseball, basketball, weight-lifting
  • history of 10 sports concussions
  • died by suicide (hanging) 4.2 months after a snowboarding accident with head injury
  • evidence of hyperphosphorylated tau protein 

    Fig. 1 (Tagge, Fisher, Minaeva, et al., 2018). Case 1. (C) and (D) Hemosiderin-laden macrophages indicated by arrows, consistent with subacute head injury. (E)  microhemorrhage surrounded by neurites immunoreactive for phosphorylated tau protein (asterisks).

    Case 2
    • 18 year old multisport athlete American football (3 yrs), rugby, soccer, hockey
    • history of 4 concussions
    • one “severe concussion” 1 month before death, followed by “a second rugby-related head injury that resulted in sideline collapse and a 2-day hospitalization”
    • died a week later after weightlifting 
    • neuropathology not shown

    Case 3
    • 17 year old multisport athlete American football, lacrosse
    • history of 2 concussions, the second resulting in confusion and memory loss
    • small anterior cavum septum pellucidum (associated with CTE in other studies)
    • died by suicide (hanging) 2 days after second concussion

    Fig. 1 (Tagge, Fisher, Minaeva, et al., 2018). Case 3. (F)-(H) amyloid precursor protein (APP)-immunostaining in the corpus callosum (arrows).

    Case 4
    • 17 year old American football player
    • history of 3 concussions (26 days, 2 days, 1 day before death)
    • final head injury was fatal, due to swelling and brain herniation
    • evidence of hyperphosphorylated tau protein
    • diagnosed with early-stage CTE

    Fig. 1 (Tagge, Fisher, Minaeva, et al., 2018). Case 4. (O) Phosphorylated tau protein-containing neurofibrillary tangles, pretangles, and neurites in the sulcal depths of the cerebral cortex consistent with neuropathological diagnosis of early-stage CTE.

    CONTROLS none showed evidence of microvascular or axonal injury, astrocytosis, microgliosis, or phosphorylated tauopathy indicative of CTE or other neurodegenerative disease

    Case 5
    • 19 year old American football player 
    • history of concussion not reported (but can assume possible “blows to the head”)
    • died from multiple organ failure and cardiac arrest

    Case 6
    • 19 year old hockey player 
    • history of 6 concussions (time pre-mortem unknown)
    • died from cardiac arrhythmia

    Case 7
    • 17 year old American football player
    • history of concussion not reported (but can assume “blows to the head”)
    •  0.3-cm cavum septum pellucidum (consistent with impact injury)
    • died from oxycodone overdose (a factor neglected in previous studies)

    Case 8
    • 22 year old former American football player
    • history of 3 concussions (one with loss of consciousness) at least 7 years before death
    • history of bipolar disorder and 2 prior suicide attempts
    • died by suicide of unknown mechanism (also neglected in previous studies, but we don't know if asphyxiation was involved)

    Fig. 1 (Tagge, Fisher, Minaeva, et al., 2018). Case 8. (K) Minimal GFAP-immunoreactive astrocytosis in white matter. (N) Few activated microglia in brainstem white matter [NOTE: not an acute-subacute case].

    The goal of this study was to look at pathology after acute-subacute head injury (e.g., astrocytosis, macrophages, and activated microglia). Only 2 of the cases showed hyperphosphorylated tau protein, which is characteristic of CTE. But in the media (e.g., It's not concussions that cause CTE. It's repeated hits), all of these changes have been conflated with CTE, a neurodegenerative condition that presumably develops over a longer time scale. Overall, the argument for a neat and tidy causal cascade is inconclusive in humans (in my view), because hyperphosphoralated tau was not observed in any of the controls, including those with significant histories of concussion. Or in Cases 2 and 3. Are we to assume, then, that concussions do not produce tauopathy in all cases? Is there a specific “dose” of head impact required? The mouse model is more precise in this realm, and those results seemed to drive the credulous headlines.

    Importantly, the authors admit that “Clearly, not every individual who sustains a head injury, even if repeated, will develop CTE brain pathology.” Conversely, CTE pathology can occur without having suffered a single blow to the head (Gao et al., 2017).

    Clearly, there's still a lot to learn.


    Gao AF, Ramsay D, Twose R, Rogaeva E, Tator C, Hazrati LN. (2017). Chronic traumatic encephalopathy-like neuropathological findings without a history of trauma. Int J Pathol Clin Res. 3:050.

    Sharp DJ, Jenkins PO. (2015). Concussion is confusing us all. Practical neurology 15(3):172-86.

    Tagge CA, Fisher AM, Minaeva OV, Gaudreau-Balderrama A, Moncaster JA, Zhang XL, Wojnarowicz MW, Casey N, Lu H, Kokiko-Cochran ON, Saman S, Ericsson M, Onos KD, Veksler R, Senatorov VV Jr, Kondo A, Zhou XZ, Miry O, Vose LR, Gopaul KR, Upreti C, Nowinski CJ, Cantu RC, Alvarez VE, Hildebrandt AM, Franz ES, Konrad J, Hamilton JA, Hua N, Tripodis Y, Anderson AT, Howell GR, Kaufer D, Hall GF, Lu KP, Ransohoff RM, Cleveland RO, Kowall NW, Stein TD, Lamb BT, Huber BR, Moss WC, Friedman A, Stanton PK, McKee AC, Goldstein LE. (2018). Concussion, microvascular injury,and early tauopathy in young athletes after impact head injury and an impact concussion mouse model. Brain 141: 422-458.

    Super Bowl Confetti Made Entirely From
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    Saturday, January 27, 2018

    I should have done this by now...

    Today marks the day of 12 years of blogging. Twelve years! During this time, I've managed to remain a mysterious pseudonym to almost everyone. Very few people know who I am.

    But a lot has changed since then. The Open Science movement, the rise of multiple platforms for critique, the Replication Crisis in social psychology, the emergence of methodological terrorists, data police, and destructo-critics. Assertive psychologists and statisticians with large social media presences have openly criticized flawed studies using much harsher language than I do. Using their own names. It's hard to stay relevant...

    Having a pseudonym now seems quaint.

    The most famous neuro-pseudonym of all, Neuroskeptic, interviewed me 2 years ago in a post on Pseudonyms in Science. He asked:

    What led you to choose to blog under a pseudonym?

    My answer:
    It was for exactly the same reason that reviewers of papers and grants are anonymous: it gives you the ability to provide an honest critique without fear of retaliation. If peer review ever becomes completely open and transparent, then I’d have no need for a pseudonym any more.

    In an ideal world, reviewers should be identified and held accountable for what they write. Then shoddy reviews and nasty comments would (presumably) become less common. We’ve all seen anonymous reviews that are incredibly insulting, mean, and unprofessional. So it’s hypocritical to say that bloggers are cowardly for hiding under pseudonyms, while staunchly upholding the institution of anonymous peer review. ...

    Neuroskeptic also interviewed Neurobonkers (who went public) and Dr. Primestein (who has not).

    Have you ever been tempted to drop the pseudonym and use your real name? What do you think would happen (positive and negative if you did?)

    My answer:
    . . .

    If I were to drop the pseudonym, it might be good (and bad) for my career as a neuroscientist. I could finally take credit for my writing, but then I’d have to take all the blame too! But overall, it’s likely that less would happen than I currently imagine.

    {At this point, most people probably don't care who I am.}

    So what has changed? Have I left the field? No. But some serious and tragic life events have rendered my anonymity irrelevant. I just don't care any more.

    In September, my closest childhood friend died from cancer (see Survival and Grief).

    I'm on the right.

    Then a month later, my wife was diagnosed with stage 4 cancer. My sadness and depression and anxiety over this is beyond words.

    I don't want to go into any more detail right now, but I'd like to show you who we are. We met via our blogs in 2006.

    Snowshoeing on Mt. Seymour, December 2016
    I'm on the left.

    So yeah, think of this as my “coming out”. Sorry if I've offended anyone with my ability to blend into male-dominated settings.

    Thank you for reading, and for your continued support during this difficult time.

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