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
    Shredded Concussion Studies

    A gift from The Onion

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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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    Wednesday, January 10, 2018

    Sexual Violence is Horrible, But First Look at Causes Outside the Brain

    "At the brain level, empathy for social exclusion of personalized women recruited areas coding the affective component of pain (i.e., anterior insula and cingulate cortex), the somatosensory components of pain (i.e., posterior insula and secondary somatosensory cortex) together with the mentalizing network (i.e., middle frontal cortex) to a greater extent than for the sexually objectified women. This diminished empathy is discussed in light of the gender-based violence that is afflicting the modern society" (Cogoni et al., 2018).

    A new brain imaging paper on Cyberball, social exclusion, objectification, and empathy went WAY out on a limb and linked the results to sexual violence, despite the lack of differences between male and female participants. It's quite a leap from watching a video of women in differing attire, comparing levels of empathy when “objectified” vs. “personalized” women are excluded from the game, and actually perpetrating violence against women in the real world.

    modified from Fig. 1 (Cogoni et al., 2018). (A) objectified women in little black dresses; (B) personalized women in pants and t-shirt. Note: the black bar didn't appear in the actual videos.

    I'm not a social psychologist (so I've always been a bit skeptical), but Cyberball is a virtual game designed as a model for social rejection and ostracism (Williams et al., 2000). The participant is led to believe they are playing an online ball-tossing game with other people, who then proceed to exclude them from the game. It's been widely used to study exclusion, social pain, and empathy for another's person's pain.

    The present version went beyond this simple animation and used 1521 second videos (see still image in Fig. 1) with the “self” condition represented by a pair of hands. More important, though, was a comparison of the two “other person” conditions.

    “Each video displayed either a ‘social inclusion’ or a ‘social exclusion’ trial.  ...  At the end of each trial, the participant was asked to rate the valence of the emotion felt by themselves (self condition), or by the other person (other conditions), during the game on a  Likert-type rating scale going from −10 = ‘very negative’ over 0 to +10 = ‘very positive’.”

    The participants were 19 women and 17 men, who showed no differences in their emotion ratings. Curiously, the negative emotion ratings on exclusion trials did not differ between the Self, Objectified, and Personalized conditions. So there appears to be no empathy gap for objectified women who were excluded from Cyberball. The difference was on the inclusion trials, when the subjects didn't feel as positively towards women in little black dresses when they were included in the game (in comparison to when women in pants were included, or when they themselves were included).

    Fig. 3 (Cogoni et al., 2018).

    At this point, I won't delve deeper into the neuroimaging results, because the differences shown at the top of the post were for the exclusion condition, when behavioral ratings were the all same. And any potential sex differences in the imaging data weren't reported.1 Or else I'm confused. At any rate, perhaps an fMRI study of perpetrators would be more informative in the future. But ultimately, culture and social conditions and power differentials (all outside the brain) are the major determinants of violence against women.

    When discussing the objectification of women in the present era, it's hard to escape the Harvey Weinstein scandal. One of the main purposes of Miramax2 was to turn young women inro sex objects. Powerful essays by Lupita Nyong’o, Salma Hayek, and Brit Marling (to name just a few) describe the indignities, sexual harassment, and outright assault they endured from this highly influential career-maker or breaker. Further, they describe the identical circumstances, the lingering doubt, the self-blame, and the commodification of themselves. Here's Marling:
    Hollywood was, of course, a rude awakening to that kind of idealism. I quickly realized that a large portion of the town functioned inside a soft and sometimes literal trafficking or prostitution of young women (a commodity with an endless supply and an endless demand). The storytellers—the people with economic and artistic power—are, by and large, straight, white men. As of 2017, women make up only 23 percent of the Directors Guild of America and only 11 percent are people of color.
    . . .

    Once, when I was standing in line for some open-call audition for a horror film, I remember catching my reflection in the mirror and realizing that I was dressed like a sex object. Every woman in line to audition for “Nurse” was, it seemed. We had all internalized on some level the idea that if we were going to be cast we’d better sell what was desired—not our artistry, not our imaginations—but our bodies.

    Dacher Keltner wrote about empathy deficits of the rich and famous in Sex, Power, and the Systems That Enable Men Like Harvey Weinstein. But he emphasized the abuse of power: “The challenge, then, is to change social systems in which the abuses of power arise and continue unchecked.” 


    1 Although they listed a variety of reasons, the authors didn't do themselves any favors with this explanation for the lack of sex differences:
    “Although this issue is still debated, in this study we refer to gender violence as a phenomenon that mainly entails not only active participation, but also passive acceptance or compliance and therefore involving both men and women’ behaviors.”

    2 And Hollywood in general...


    Cogoni C, Carnaghi A, Silani G. (2018). Reduced empathic responses for sexually objectified women: an fMRI investigation. Cortex  99: 258–272.  {PDF}

    Williams KD, Cheung CK, Choi W. (2000). Cyberostracism: effects of being ignored over the Internet. J Pers Soc Psychol. 79:748-62.

    Further Reading: The Cyberball Collection (by The Neurocritic)

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

    Vicodin for Social Exclusion

    Existential Dread of Absurd Social Psychology Studies

    The Mental Health of Lonely Marijuana Users

    Acetaminophen Probably Isn't an "Empathy Killer"

    Advil Increases Social Pain (if you're male)

    Oh, and... Spanner or Sex Object?

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    Sunday, December 31, 2017

    Least Popular Posts of 2017

    2017 was a really bad year. The U.S. is more divided than ever, the truth is meaningless, well-researched journalism is called FAKE NEWS, the President lies once every minute, white supremacist rallies have been normalized, some tech companies1 continue to invade our privacy/extract personal data, exploit the middle and lower classes,2 and displace long-time residents from urban areas. And who knows what health care and Alaska will look like in 2018.

    Yes, this is classic Neurocritic pessimism.3

    While everyone else rings in the New Year by commemorating the best and brightest of 2017 in formulaic Top Whatever lists, The Neurocritic has decided to wallow in shame. To mark this Celebration of Failure, I have compiled a Bottom Five list,4 the year's least popular posts as measured by Google Analytics. The last time I compiled a “Worst of” list was in 2012.

    Methods: The number of pageviews per post was copied and pasted into an Excel file, sorted by date. Then the total pageviews for each post was prorated by the vintage of the post, to give an estimate of daily views.5 

    Results: The posts are listed in inverse order, starting with #5 and ending with #1 (least popular).

    5 Most Unpopular Posts of 2017

    5. Terrorism and the Implicit Association Test – I actually worked pretty hard on this one. It's about the stereotyping of Muslims, the importance of language (e.g., Theresa May: “the single, evil ideology of Islamist extremism that preaches hatred, sows division, and promotes sectarianism”), a demonstration that semantics derived automatically from language corpora contain human-like biases, the Arab-Muslim IAT (which found little to no bias against Muslims), and some general problems with the IAT.

    4. Smell as a Weapon, and Odor as Entertainment – This was from my two-part olfactory series, which covered the interesting history of Olfactory Warfare (e.g, stink bombs, stealth camouflage) and the use of smell in cinematic and VR contexts. {or at least, it was interesting to me}.

    3. The Big Bad Brain – This featured a fun and catchy music video (High) by Sir Sly, which was an earworm for me. But too esoteric and not much staying power.

    2. What's Popular at #CNS2017? – This falls under the perennially unpopular category of “yearly conference announcements”, which is only relevant around the time of the meeting.

    1. Olfactory Deterrence – This was about the prospect of nuclear war and how putrid smells might deter the use of nuclear weapons, along with eradicating cavalier attitudes about them.

    Discussion: We can easily see some themes emerging: the IAT, olfaction, music videos, and the Cognitive Neuroscience Society meeting.

    Conclusion: People are sick of the IAT, aren't thrilled about the sense of smell (especially in relation to nuclear war), and do not like music videos or CNS Meeting announcements. However, they do like meeting recaps, as shown by the popularity of What are the Big Ideas in Cognitive Neuroscience? and The Big Ideas in Cognitive Neuroscience, Explained.


    1 Uber deserves special mention.

    2 This one is from 2016, but it's a real eye-opener: The Not-So-Wholesome Reality Behind The Making of Your Meal Kit.

    3 This has been the worst-ever year for me personally as well, so I see no reason to be optimistic.

    4 Actually, #5 is Survival and Grief. I cannot bear to feature this one, so the closely ranked #6 is a stand-in.

    5 The post with the absolute lowest number of views (Brief Guide to the CTE Brains in the News. Part 2: Fred McNeill) was written on 12/11/2017. For a true reading of yearly “staying power” we'd need to follow all posts for 365 days.

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    Saturday, December 23, 2017

    Amygdala Stimulation in the Absence of Emotional Experience Enhances Memory for Neutral Objects

    The amygdala is a small structure located within the medial temporal lobes (MTL), consisting of a discrete set of nuclei. It has a reputation as the “fear center” or “emotion center” of the brain, although it performs multiple functions. One well-known activity of the amygdala, via its connections with other MTL areas, involves an enhancement of memories that are emotional in nature (compared to neutral). Humans and rodents with damaged or inactivated amygdalae fail to show this emotion-related enhancement, although memory for neutral items is relatively preserved (Adolphs et al., 1997; Phelps & Anderson, 1997; McGaugh, 2013).

    A new brain stimulation study (Inman et al., 2017) raises interesting questions about the necessity of subjective emotional experience in the memory enhancement effect. A group of 14 refractory epilepsy patients underwent surgery to implant electrodes in the left or right amygdala (and elsewhere) for the sole purpose of monitoring the source of their seizures. In a boon for affiliated research programs everywhere, patients are able to participate in experiments while waiting around for seizures to occur.

    The stimulating electrodes were located in or near the basolateral complex of the amygdala (BLA), shown below. The stimulation protocol was developed from similar studies in rats, which demonstrated that direct electrical stimulation of BLA can improve memory for non-emotional events when tested on subsequent days (Bass et al., 2012; 2014; 2015).

    Fig. 1A and B (modified from Inman et al., 2017). 
    (A) A representative postoperative coronal MRI showing electrode contacts in the amygdala (white square). (B) Illustration of left amygdala with black circles indicating estimated centroids of bipolar stimulation in or near the BLA in all 14 patients. White borders denote right-sided stimulation.

    The direct translation from animals to humans is a clear strength of the paper (Inman et al., 2017): activation of the BLA modulated neuronal activity and markers of synaptic plasticity in the hippocampus and perirhinal cortex, two structures important for declarative memory that are directly innervated by the BLA.  ... These and other studies [in animals] have led to the view that an emotional experience engages the amygdala, which in turn enhances memory for that experience through modulation of synaptic plasticity-related processes underlying memory consolidation in other brain regions. This model predicts that direct stimulation of the human amygdala could enhance memory in a manner analogous to emotion’s enhancing effects on long-term memory.

    The experimental task was a test of object recognition memory. Pictures of 160 neutral objects were presented on Day 1 while the participants made “indoor” or “outdoor” decisions (which were quite ambiguous in many cases). The purpose of this task was to engage a deep level of semantic encoding of each object, which was presented for 3 seconds. Immediately after stimulus offset for half the items (n=80), a train of electrical stimulation pulses was presented for 1 second (each pulse = 500 μs biphasic square wave; pulse frequency = 50 Hz; train frequency = 8 Hz). For the other half (n=80), no stimulation was presented. Each trial was separated by a 5 second interval.

    Fig. 1D (modified from Inman et al., 2017).

    An immediate recognition memory test was presented after completion of the study phase. Yes/no decisions were made on 40 old objects with post-stimulation, 40 old objects with no stimulation, and 40 new objects (“foils”). Then 24 hours later, a similar yes/no recognition test was presented, but this time with the other set of items not tested previously, along with a new set of foils. The prediction was that electrical stimulation of the amygdala would act as an artificial “boost” of performance on the 24 hour test, after memory consolidation had occurred.

    This prediction was (mostly) supported as shown below, with one caveat I'll explain shortly. In Panel A, a commonly used measure of discrimination performance (d′) is shown for the Immediate and One-Day tests, with red dots indicating stimulation and blue dots no stimulation (one dot per patient). Most participants performed better on stimulated items regardless of whether on the Immediate test or One-Day test, although variability was higher on the Immediate test. Panel B shows a summary of the performance difference for stimulation no stimulation trials. Paired-samples t-tests (two sided) were conducted for each recognition-memory interval. The result for One-Day was significant (p=.003), but the result for Immediate was not (p=.30). This would seem to be convincing evidence that amygdala stimulation during encoding enhanced delayed recognition memory selectively.

    Fig. 2A and B (modified from Inman et al., 2017).

    HOWEVER, from the statistics presented thus far, we don't know whether the memory enhancement effect was statistically larger for the One-Day test. My guess is not, because an ANOVA showed a main effect of test day (p< 0.001) and a main effect of stimulation (p= 0.03). But no interaction between these variables was reported.

    Nonetheless, the study was fascinating because the patients were unable to say whether or not stimulation was delivered in a subsequent test of awareness (10 trials of each condition):
    All 14 patients denied subjective awareness of the amygdala stimulation on every trial. In addition, no patient reported emotional responses associated with amygdala stimulation during the stimulation awareness test or during recognition-memory testing. Moreover, similar amygdala-stimulation parameters caused no detectable autonomic changes in patients (n = 7) undergoing stimulation parameter screening.

    The take-home message is that subjective and objective indicators of emotion were not necessary for amygdala stimulation during encoding to enhance subsequent recognition of neutral material. “This memory enhancement was accompanied by neuronal oscillations during retrieval that reflected increased interactions between the amygdala, hippocampus, and perirhinal cortex”1 (as had been shown previously in animals).2

    So it seems that subjective emotional experience may be an unnecessary epiphenomenon for the boosting effect of emotion in the formation of declarative memories. Or at least in this limited (albeit impressive) laboratory setting. And here I will step aside from being overly critical. Anyone who wants to slam the reproducibility of an n=14 rare patient sample size should be prepared to run the same study with 42 individuals with amygdala depth electrodes.


    1 Inman et al., 2017:
    For [n = 5 patients] with electrodes localized concurrently in the amygdala, hippocampus, and perirhinal cortex), local field potentials (LFPs) from each region were recorded simultaneously during the immediate and one-day recognition-memory tests... LFP oscillations were apparent in the theta (here 5–7 Hz) and gamma (30–55 Hz) ranges...  ...  Recognition during the one-day test but not during the immediate test exhibited increased power in perirhinal cortex in the gamma frequency range for remembered objects previously followed by stimulation compared with remembered objects without stimulation. Furthermore, LFPs during the one-day test, but not during the immediate test, revealed increased coherence of hippocampal–perirhinal oscillations in the theta frequency range for remembered objects previously followed by stimulation compared with remembered objects without stimulation.

    2 If you think the 14 patients with epilepsy were variable, wait until you see the [overly honest] results from even smaller studies with rats.

    Fig. S7 (Inman et al., 2017).

    Conveniently, Professor Dorothy Bishop has a new blog post on Using simulations to understand the importance of sample size. So yes, sample size matters...


    Adolphs R, Cahill L, Schul R, Babinsky R. (1997). Impaired declarative memory for emotional material following bilateral amygdala damage in humans. Learn Mem. 4(3):291-300.

    Bass DI, Manns JR. (2015). Memory-enhancing amygdala stimulation elicits gamma synchrony in the hippocampus. Behav Neurosci. 129(3):244-56.

    Bass DI, Nizam ZG, Partain KN, Wang A, Manns JR. (2014). Amygdala-mediated enhancement of memory for specific events depends on the hippocampus. Neurobiol Learn Mem. 107:37-41.

    Bass DI, Partain KN, Manns JR. (2012). Event-specific enhancement of memory via brief electrical stimulation to the basolateral complex of the amygdala in rats. Behav Neurosci. 126(1):204-8.

    Ikegaya Y, Saito H, Abe K. (1996). The basomedial and basolateral amygdaloid nuclei contribute to the induction of long-term potentiation in the dentate gyrus in vivo. Eur J Neurosci. 8(9):1833-9.

    Inman CS, Manns JR, Bijanki KR, Bass DI, Hamann S, Drane DL, Fasano RE, Kovach CK, Gross RE, Willie JT. (2017). Direct electrical stimulation of the amygdala enhances declarative memory in humans. Proc Natl Acad Sci.  Dec 18. [Epub ahead of print]

    McGaugh JL.(2013). Making lasting memories: remembering the significant. Proc Natl Acad Sci 110 Suppl 2:10402-7.

    Phelps EA, Anderson AK. (1997). Emotional memory: what does the amygdala do? Curr Biol. 7(5):R311-4.

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    Monday, December 11, 2017

    Brief Guide to the CTE Brains in the News. Part 2: Fred McNeill

    Chronic traumatic encephalopathy (CTE) is the neurodegenerative disease of the moment, made famous by the violent and untimely deaths of many retired professional athletes. Repeated blows to the head sustained in contact sports such as boxing and American football can result in abnormal accumulations of tau protein (usually many years later). The autopsied brains from two of these individuals are shown below.

    Left: courtesy of Dr. Ann McKee in NYT.  Right: courtesy of Dr. Bennett Omalu in CNN. These are coronal sections1 from the autopsied brains of: (L) Aaron Hernandez, aged 27; and (R) Fred McNeill, aged 63.

    Part 1 of this series looked at complicating factors in the life of Aaron Hernandez PCP abuse, death by asphyxiation that presumably had some impact on his brain beyond the effects of concussions in football.

    Part 2 will discuss the tragic case of Fred McNeill, former star linebacker for the Minnesota Vikings. He died in 2015 from complications of Amyotrophic Lateral Sclerosis (ALS), suggesting that his was not a “pure” case of CTE, either.

    Fred McNeill

    McNeill in 1974 (Mike Zerby / Minneapolis Star Tribune).

    Obituary: Standout of the 1970s and 1980s was suffering from dementia and died from complications from ALS, according to Matt Blair [close friend and former teammate]

    ALS is a motor neuron disease that causes progressive wasting and death of neurons that control voluntary muscles of the limbs and ultimately the muscles that control breathing and swallowing. Around 30-50% of individuals with ALS show cognitive and behavioral impairments.

    According to a recent review (Hobson and McDermott, 2016):
    Overlap between ALS and other neurodegenerative diseases, in particular frontotemporal dementia (FTD) and parkinsonism, is increasingly recognized. ...

    Approximately 10–15% of patients with ALS show signs of FTD ... typically behavioural variant of FTD. A further 50% experience mild cognitive or behavioural changes. Patients with executive dysfunction have a worse prognosis, and behavioural changes have a negative impact on carer quality of life.

    This raises the issue that repetitive head trauma can result in multiple neurodegenerative diseases, not only CTE. In fact, this has been recognized by other researchers who studied 14 retired soccer players who were experts at heading the ball (Ling et al., 2017). Only four had pathologically confirmed CTE:
    ...concomitant pathologies included Alzheimer's disease (N = 6), TDP-43 (N = 6), cerebral amyloid angiopathy (N = 5), hippocampal sclerosis (N = 2), corticobasal degeneration (N = 1), dementia with Lewy bodies (N = 1), and vascular pathology (N = 1); and all would have contributed synergistically to the clinical manifestations. ...   Alzheimer's disease and TDP-43 pathologies are common concomitant findings in CTE, both of which are increasingly considered as part of the CTE pathological entity in older individuals.

    So the blanket term of “CTE” can include build-up of not only tau, but other abnormal proteins typically seen in Alzheimer's disease (Aβ) and the ALS-FTD spectrum (TDP-43). This lowers the utility of an in vivo marker specific to tau in diagnosing CTE in living individuals, an important enterprise because definitive diagnosis is only obtained post-mortem.

    This brings us to the problematic report on Mr. McNeill's brain and the news coverage surrounding it.

    CTE confirmed for 1st time in live person, according to exam of ex-NFL player

    The recent study by Omalu and colleagues (2017) performed a PET scan on Mr. Neill almost 4.5 years before he died. This was before any motor signs of ALS had appeared. Clearly, 4.5 years is a very long time in the course of progressive neurodegenerative diseases, so right off the bat a comparison of his PET scan and post-mortem pathology is highly problematic.

    Former Vikings linebacker Fred McNeill identified as subject of breakthrough CTE study

    Another reason this study was not the “breakthrough” of news headlines is because the type of pathology plainly visible on MRI, and the type of cognitive deficits shown on neuropsychological tests, were quite typical of Alzheimer's disease and perhaps also vascular dementia. The MRI scan taken at the time of PET “showed mild, global brain atrophy with enlarged ventricles, moderate bilateral hippocampal atrophy, and diffuse white matter hyperintensities.”

    Among his worst cognitive deficits at the time of testing were memory and picture naming, which is characteristic of Alzheimer's disease (AD). Likewise, the behavioral deficits reported by his wife are typically seen in AD.

    Two years after the PET scan, he developed motor symptoms of ALS. His wife noted he could no longer tie his shoes or button his shirts. He developed muscle twitching in his arms and showed decreased muscle mass in his arms and shoulders. He was diagnosed with ALS 17 months prior to death, which was in addition to his presumed diagnosis of CTE.

    FDA says no to marketing FDDNP for CTE

    Finally, the molecular imaging probe used to identify abnormal tau protein in the living brain, [18F]-FDDNP, is not specific for tau. It also binds to beta-amyloid and a variety of other misfolded proteins. Or maybe not!

    As I've written before, the brain diagnostics company TauMark™ was admonished by the FDA for making false claims. Six authors on the current paper hold a financial interest in the company. Most other research groups use more specific tau imaging tracers such as [18F]T807 (aka [18F]AV-1451 or Flortaucipir).

    I certainly acknowledge that theses types of pre- and post-mortem studies are very difficult to conduct, and although the n=1 is a known weakness, you have to start somewhere. Nonetheless, the stats relating FDDNP binding to tau pathology were very thin and not all that believable. The paragraph below presents the results in their entirety. Note that p=.0202 was considered “highly correlated” while p=.1066 was not significant.
    Correlation analysis was performed to investigate whether the in vivo regional [F-18]FDDNP binding level agreed with the density of tau pathology based on autopsy findings. Spearman rank-order correlation coefficient (rs) was calculated for the regional [F-18]FDDNP DVRs (Figure 1) and the density of tau pathology, as well as for amyloid and TDP-43 substrates (Table 5). Our results showed that the tau regional findings and densities obtained from antemortem [F-18]FDDNP-PET imaging and postmortem autopsy were highly correlated (rs = 0.592, P = .0202). However, no statistical correlation was found with the presence of amyloid deposition (r s = -0.481; P = .0695) or of TDP-43 (rs = 0.433; P = .1066).

    Also, FDDNP-PET showed that in cortical regions, the medial temporal lobes showed the highest distribution volume ratio (DVR), along with anterior and posterior cingulate cortices. Isn't this typical of the Aβ distribution in AD?

    I'm not denying the existence of CTE as a complex clinical entity, or saying that multiple concussions don't harm your brain. Along with others (e.g., Iverson et al., 2018), I'm merely suggesting that the clinical, cognitive, behavioral, and pathological sequelae of repeated head trauma should be carefully studied, and not presented in a sensationalistic manner.


    1 Illustration of the coronal plane of section.

    2 Note that most cases of ALS and FTD are not caused by concussions.

    Read Part 1 of the series:

    Brief Guide to the CTE Brains in the News. Part 1: Aaron Hernandez


    Hobson EV, McDermott CJ. (2016). Supportive and symptomatic management of amyotrophic lateral sclerosis. Nat Rev Neurol. 12(9):526-38.

    Iverson GL, Keene CD, Perry G, Castellani RJ. (2018). The Need to Separate ChronicTraumatic Encephalopathy Neuropathology from Clinical Features. J Alzheimers Dis. 61(1):17-28.

    Ling H, Morris HR, Neal JW, Lees AJ, Hardy J, Holton JL, Revesz T, Williams DD. (2017). Mixed pathologies including chronic traumatic encephalopathy account fordementia in retired association football (soccer) players. Acta Neuropathol. 133(3):337-352.

    Omalu B, Small GW, Bailes J, Ercoli LM, Merrill DA, Wong KP, Huang SC, Satyamurthy N, Hammers JL, Lee J, Fitzsimmons RP. (2017). Postmortem Autopsy-Confirmation of Antemortem [F-18] FDDNP-PET Scans in a Football Player With Chronic Traumatic Encephalopathy. Neurosurgery. 2017 Nov 10.

    Further Reading I've written about CTE a lot, you can read more below.

    FDA says no to marketing FDDNP for CTE

    Is CTE Detectable in Living NFL Players?

    The Ethics of Public Diagnosis Using an Unvalidated Method

    The Truth About Cognitive Impairment in Retired NFL Players

    Lou Gehrig Probably Died of Lou Gehrig's Disease

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

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

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