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Deconstructing the most sensationalistic recent findings in Human Brain Imaging, Cognitive Neuroscience, and Psychopharmacology
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  • 06/19/17--02:10: The Big Bad Brain

  • I’m high, staring at the ceiling
    Sending my love, what a wonderful feeling
    What comes next, I see a light
    I’m along for the ride as I’m taking flight




    Plus a cool brain tattoo to boot. AND the song is an earworm (at least it is for me).


    It feels good to be running from the devil
    Another breath and I'm up another level
    It feels good to be up above the clouds
    It feels good for the first time in a long time now







    A monument to love unspoken
    Carved into stone “Unwilling to come undone”


    Here's what singer Landon Jacobs had to say about those specific lyrics:
    “in the face of what I incorrectly assumed was an impending brain aneurysm, I decided that the best way to spend my final moments was to push my love through the universe to the people I cared about. I was terrified of dying, but that’s not reason to squander a potential death bed situation.”

    (he had gotten way too high on one occasion and had a panic attack... he thought he was dying)







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  • 06/30/17--03:47: What Is Thought?


  • Is that some sort of trick question? Everyone knows what thought is. Or do they...  My questions for you today are:

    • How do you define “a thought” (yes, a single thought)? Where is the boundary from one thought to the next?
    • What is “thought” more generally? Does this cognitive activity require conscious awareness? Or language? We don't want to be linguistic chauvinists, now do we, so let's assume mice have them. But how about shrimp? Or worms?

    What is “a thought”?

    Can you define what a discrete “thought” is?  This question was motivated by a persistent brain myth:
    You have an estimated 70,000 thoughts per day.
    Where did this number come from? How do you tally up 70,000 thoughts? Do some thoughts last 10 seconds, while others are finished in one tenth of a second?

    Over 24 hours, one thought per second would yield 86,400 thoughts. If “thoughts” are restricted to 16 waking hours, the number would be 57,600. But we're almost certainly thinking while we're dreaming (for about two hours every night), so that would be 64,800 seconds, with an ultimate result of one thought every 0.9257 seconds, on average.

    LONI®, the Laboratory of Neuroimaging at USC, included this claim on their Brain Trivia page, so perhaps it's all their fault.1

    How many thoughts does the average person have per day?
    *70,000

    *This is still an open question (how many thoughts does the average human brain processes in 1 day). LONI faculty have done some very preliminary studies using undergraduate student volunteers and have estimated that one may expect around 60-70K thoughts per day. These results are not peer-reviewed/published. There is no generally accepted definition of what "thought" is or how it is created. In our study, we had assumed that a "thought" is a sporadic single-idea cognitive concept resulting from the act of thinking, or produced by spontaneous systems-level cognitive brain activations.

    Neuroskeptic tried to find the origin of The 70,000 Thoughts Per Day Myth five years ago. He found a very bizarre post by Charlie Greer (“Helping Plumbing, HVAC, and Electrical service contractors Sell More at Higher Profits”):
    Several years ago, the National Science Foundation put out some very interesting statistics. We think a thousand thoughts per hour. When we write, we think twenty-five hundred thoughts in an hour and a half. The average person thinks about twelve thousand thoughts per day. A deeper thinker, according to this report, puts forth fifty thousand thoughts daily.

    If this “NSF report” exists, no one can find it (NSF is a funding agency, not a research lab). Were the LONI® researchers funded by NSF?  No one knows...





    Maybe we're approaching this in the wrong way. We shouldn't be relying on descriptions of mental events to define a thought, but rather discrete brain states.


    Using this definition, “a thought” is what you can capture with your fancy new imaging technique. Therefore, a thought conveniently occupies the available temporal resolution of your method:
    “A thought or a cognitive function usually lasts 30 seconds or a minute. That’s the range of what we’re hoping to be able to capture,” says Kay Tye, an assistant professor in the Department of Brain and Cognitive Sciences at MIT.
    In this case, the method is FLARE, “an engineered transcription factor that drives expression of fluorescent proteins, opsins, and other genetically encoded tools only in the subset of neurons that experienced activity during a user-defined time window” (Wang et al., 2017).


    But what if your method records EEG microstates, “short periods (100 ms) during which the EEG scalp topography remains quasi-stable” (Van De Ville et al., 2010). In this case, thoughts are assembled from EEG microstates:
    One characteristic feature of EEG microstates is the rapid transition from one scalp field topography into another, leading to the hypothesis that they constitute the “basic building blocks of cognition” or “atoms of thought” that underlie spontaneous conscious cognitive activity.

    And for good measure, studies of mind wandering, spontaneous thought, and the default mode network are flourishing. To learn more, a good place to start is Brain signatures of spontaneous thoughts, a blog post by Emilie Reas.

    What is “thought”?

    What is called thinking? The question sounds definite. It seems unequivocal. But even a slight reflection shows it to have more than one meaning. No sooner do we ask the question than we begin to vacillate. Indeed, the ambiguity of the question foils every attempt to push toward the answer without some further preparation.

    - Martin Heidegger, What Is Called Thinking?

    Philosophers have filled thousands of pages addressing this question, so clearly we're way beyond the depth and scope of this post. My focus here is more narrow, “thought” in the sense used by cognitive psychologists. Is thought different from attention

    Once we look at the etymology and usage of the word, no wonder we're so confused...

    Does Beauty Require Thought?

    Speaking of philosophy, a recent study tested Kant's views on aesthetics, specifically the claim that experiencing beauty requires thought (Brielmann & Pelli, 2017).




    Participants in the study rated the pleasure they felt from seeing pictures (IKEA furniture vs. beautiful images), tasting Jolly Rancher candy, and touching a soft alpaca teddy bear. In one condition, they had to perform a working memory task (an auditory 2-back task) at the same time. They listened to strings of letters and identified when the present stimulus matched the letter presented two trials ago. This is distracting, obviously, and the participants' ratings of pleasure and beauty declined. So in this context, the authors effectively defined thought as attention or working memory (Brielmann & Pelli, 2017).2 


    Alternate Titles for the paper (none of which sound as exciting as the original Beauty Requires Thought)

    Aesthetic Judgments and Pleasure Ratings Require Attention

    Judgments of Beauty Require Working Memory and Cognitive Control

    ...or the especially clunky Ratings of “felt beauty” Require Attention — but only for beautiful items.


    Dual task experiments are pretty popular. Concurrent performance of the n-back working memory task also disrupts the execution of decidedly non-beautiful activities, such as walking and timed ankle movements. So I guess walking and ankle movements require thought...



    Footnote

    1This claim was still on their site as recently as March 2017, but it's no longer there.

    2They did, however, show that working memory load on its own (a digit span task) didn't produce the same alterations in beauty/pleasure ratings.


    References

    Brielmann, A., & Pelli, D. (2017). Beauty Requires Thought. Current Biology, 27 (10), 1506-1513.

    Van de Ville D, Britz J, Michel CM. (2010). EEG microstate sequences in healthy humans at rest reveal scale-free dynamics. Proc Natl Acad Sci 107(42):18179-84.

    Wang W, Wildes CP, Pattarabanjird T, Sanchez MI, Glober GF, Matthews GA, Tye KM, Ting AY. (2017). A light- and calcium-gated transcription factor for imaging andmanipulating activated neurons. Nat Biotechnol. Jun 26.



    gif from palerlotus


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    How do we construct a unified self-identity as a thinking and feeling person inhabiting a body, separate and unique from other entities? A “self” with the capacity for autobiographical memory and complex thought? Traditionally, the field of cognitive science has been concerned with explaining the mind in isolation from the body.

    The growing field of embodied cognition, on the other hand, seeks to rejoin them. One major strand has focused on grounding higher-order semantics and language understanding in perceptual and sensory-motor representations. This view is distinct from theories of knowledge based on abstract, amodal representations divorced from sensory-motor experience. Another wing of the embodied approach is concerned with how interoception the inner sense of your physical state grounds your feelings and emotions in the body. Interoceptive awareness of visceral functions such as heartbeat has been related to core consciousness and awareness of self, including body image.

    A relatively neglected yet critical aspect of any grand theory of the embodied self is the vestibular system. The vestibular system is the set of sensory organs responsible for maintaining our balance and keeping our visual field in a stable position while our head moves around. These organs are located in the inner ear and include...
    ...two otolith organs (the saccule and utricle), which sense linear acceleration (i.e., gravity and translational movements), and the three semicircular canals, which sense angular acceleration in three planes. The receptor cells of the otoliths and semicircular canals send signals through the vestibular nerve fibers to the neural structures that control eye movements, posture, and balance.

    The quote above is from Kathleen Cullen and Soroush Sadeghi (2008), who have an excellent review on the vestibular system in Scholarpedia.



    We take the vestibular system for granted until something goes wrong, like motion sickness (a mismatch of movement perceived by the vestibular and visual systems) or a rare disorder of the inner ear such as Menière’s disease. But how can a dysfunction of the inner ear influence our sense of self?

    Song, Jáuregui-Renaud, and colleagues (2008) looked at symptoms of depersonalization (a feeling of detachment from oneself) in 50 patients with peripheral vestibular disease and 121 healthy controls. The participants were given the Depersonalization/Derealization Inventory of Cox and Swinson (2002) to assess symptoms of these conditions:
    1. Depersonalization: Experiences of unreality, detachment, or being an outside observer with respect to one's thoughts, feelings, sensations, body, or actions (e.g.,perceptual alterations, distorted sense of time, unreal or absent self, emotional and/or physical numbing.)" 
    2. Derealization: "Experiences of unreality or detachment with respect to surroundings (e.g., individuals or objects are experienced as unreal, dreamlike, foggy, lifeless, or visually distorted."

    Beyond the expected high frequency of dizziness, the patients were much more likely to experience feelings of Shifting Ground, Spaced Out, Body Feels Strange, and Not Being in Control of Self than were controls (see bottom half of the figure below).



    The authors suggest that abnormal vestibular signals disrupt the relationship of the self to the environment, leading to strange feelings of detachment:
    Vestibular disease causes primary symptoms of vertigo and feelings that the ground is unstable ... which are more marked in distinct, acute episodes. These immediate symptoms are, by definition, unreal experiences since the body is not spinning and the ground is not heaving, but they are readily understandable as perceptions derived directly from abnormal sensory signals. Vestibular dysfunction could also compromise more general precepts of stable relationships between the self and the environment...

    Symptoms of depersonalization/derealization can be induced experimentally in healthy people via caloric stimulation. This procedure is used medically to check the vestibulo-ocular reflex, which stabilizes the visual image while the head is moving. The test involves delivering warm or cold water into the ear canal and observing the resultant eye movements (or lack thereof).

    Song et al. (2008) administered caloric stimulation to 20 of their vestibular patients and 20 controls. After stimulation, many healthy participants reported feelings of detachment/separation from their surroundings (40%), and that their body feels strange/different (50%). These were novel experiences for most. Conversely, the patients reported no such changes after stimulation because they already experience these symptoms.

    An even more extreme way to stimulate the vestibular system is through unilateral centrifugation (i.e., spinning around in a specialized chair). NOTE: this has nothing to do with the fictional Centrifuge Brain Project. See more about that here.



    (I don't think I'd be smiling)


    A recent study subjected 100 healthy participants to unilateral centrifugation to stimulate the utricles (Aranda-Moreno & Jáuregui-Renaud, 2016). The target of this test differs from the caloric procedure, which stimulates the semicircular canals. The utricles and the semicircular canals detect different types of motion (linear acceleration and angular acceleration, respectively), and the authors wanted to see if unilateral centrifugation would produce the same effects as caloric stimulation. And indeed, after centrifugation, symptoms of depersonalization and derealization were reported with increased frequency e.g., Surroundings seem strange and unreal; Time seems to pass very slowly; Body feels strange or different in some way (see Table below for details).


    - click on image for a larger view -


    modified from Table 2 (Aranda-Moreno & Jáuregui-Renaud, 2016). Frequency (Freq) and severity (score range) for each of the symptoms of the Cox and Swinson (2002) depersonalization/derealization inventory reported by 100 subjects.


    These results provide further evidence that the vestibular system contributes to the construction of the self. The sense of inhabiting one's body is assembled from many different inputs, of course. These can go awry in epilepsy, migraine, focal brain injury, psychiatric disturbances, and under extreme stress. Although rare, out-of-body experiences are more frequent in persons who suffer from dizziness due to vestibular disorders (Lopez & Elzière, 2017). In these instances, the vestibular system is unable to ground the self within the body.


    References

    Aranda-Moreno C, Jáuregui-Renaud K. (2016). Derealization during utricular stimulation. Journal of Vestibular Research 26(5-6):425-431.

    Cullen K, Sadeghi S (2008). Vestibular system. Scholarpedia, 3(1):3013.

    Lopez C, Elzière M. (2017). Out-of-body experience in vestibular disorders - A prospective study of 210 patients with dizziness.Cortex Jun 8.

    Sang FY, Jauregui-Renaud K, Green DA, Bronstein AM, Gresty MA. (2006). Depersonalisation/derealisation symptoms in vestibular disease. Journal of Neurology, Neurosurgery & Psychiatry 77(6):760-6.


    Further Reading

    Research Topic: The Vestibular System in Cognitive and Memory Processes in Mammalians (collection edited by Besnard et al., 2015)

    Personality changes in patients with vestibular dysfunction (review by Smith & Darlington, 2013)

    Feeling Mighty Unreal: Derealization in Kleine-Levin Syndrome (blog post by The Neurocritic)

    A Detached Sense of Self Associated with Altered Neural Responses to Mirror Touch (blog post by The Neurocritic)

    Theme issue ‘Interoception beyond homeostasis: affect, cognition and mental health’ (edited by Manos Tsakiris and Hugo D. Critchley).

    The poverty of embodied cognition (Goldinger et al., 2016).

    Arguments about the nature of concepts: Symbols, embodiment, and beyond (Mahon & Hickok, 2016).

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  • 08/13/17--05:18: Olfactory Deterrence

  • A military aide carries the “nuclear football” aboard the Marine One helicopter in which President Trump was waiting to depart the South Lawn of the White House on Feb. 3. (Michael Reynolds/European Pressphoto Agency). via Washington Post.


    August 6, 1945 President Harry S. Truman, announcing the bombing of Hiroshima:

    “If they do not now accept our terms they may expect a rain of ruin from the air, the like of which has never been seen on this earth.” (video)
    [Trump was less than a year old.]


    August 8, 2017 President Donald Trump:

    “North Korea best not make any more threats to the United States. They will be met with fire and fury like the world has never seen... he has been very threatening beyond a normal state[ment]. They will be met with fire, fury and frankly power the likes of which this world has never seen before.” (video)

    Issuing a threat of nuclear war is not something to cheer about (“We're number one! We're number one!”). Jesus does not condone such an action, despite what pastor Robert Jeffress says.

    “The mixture of foreign policy, golf and veiled threats about nuclear war is unprecedented and jarring,” said BBC reporter Tara McKelvey.

    I would like to think that most Americans are horrified by the prospect of nuclear war. But many are pleased with the blunt, bracing talk and feel “protected by the vastness of America” “It doesn’t concern me,” said [a guy] at the Morgan County Fair in Brush, Colo. “We live in the safest part of the whole country.”

    WHAT IS WRONG WITH YOU?!! I shout to myself.1 The people interviewed for that article were between the ages of 45 and 76 (mean = 64.5 yrs), so they were all alive during the Cold War and probably watched The Day After on TV (now on YouTube). Mushroom clouds, incineration, radiation sickness, utter devastation. In Kansas. The apocalyptic wasteland of suffering encouraged by a younger generation of trolls immune to actual footage of melting bodies and acute radiation syndrome.


    Olfactory VR

    The callous Gamergate set requires a more visceral and disgusting approach to the gravity of the Trump-Kim Jong-un escalation. My near-future sci-fi solution to nuclear trolling would involve delivering odorants that carry the stench of death (e.g., cadaverine, putrescine) each and every time these jokers spread anxiety and discord. This would require immersive virtual reality (or some preposterous way to deliver odorants via smart phone) and real-time monitoring of social media streams for key phrases. Exposure to the nauseating, inescapable smell of rotting flesh might be punishing enough to initiate a change in behavior...




    ...but this could ultimately backfire in the event of an actual Zombie Apocalypse, because they would be protected from the marauding undead hoards. And that's not what we want.






    For a very different view on ironic amusement, see this essay:
    Today, the younger generations that will determine our future did not experience terrifying emotions as part of their nuclear education. For them, the gigantic mutant ants and degenerate war survivors that stalk the memories of their grandparents are obvious myths, evoking only the kind of ironic amusement that young people find in video games, TV shows and superhero movies. These post-Cold War generations should therefore be more ready than their elders to face nuclear missiles dispassionately, not as supernatural prodigies but as plain machinery.


    Footnote

    1But wait. Don't Conservatives Scare More Easily Than Liberals? (“Say Scientists” so it must be true). Or not. There were a lot of problems with that study, see Conservatives Are Neurotic and Liberals Are Antisocial.


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    The use of smell as a weapon, or a deterrent, was explored in a fanciful way in my previous post on nuclear threats. While poking around the literature, I found a fascinating unclassified document from the Army Research Laboratory, Olfaction Warfare: Odor as Sword and Shield (PDF). The authors provide a sweeping overview of odor, from chemical tactics in the natural world to the use of scents in the beauty and entertainment industries. The primary military application discussed by Schmeisser et al. (2013) is the use of odor in stealth operations. These are designed to deceive the enemy by masking current location or projecting smells to a false location. Although the document does not propose putrid odor as an offensive weapon, the authors discuss the history of such efforts.


    Stink Bombs

    Stink bombs are “devices designed to create an unpleasant smell forcing people to leave an area or protecting off-limits areas against being entered.”

    One unsavory application during WWII was used to make German officers smell like rotten meat, but unfortunately, “this substance was so volatile that it could not be confined to specific targets and contaminated everything in the area.”

    Another unsuccessful project from 1966 tried to develop “culturally specific stink bombs, which would affect Vietnamese guerillas, leaving the U.S. troops unaffected. The project was abandoned due to technical barriers.”

    But a more contemporary program reached the pinnacle of olfactory deterrence:
    In 2001 the U.S. announced the development of the ultimate stink bomb aimed at driving away hostile forces by a stench so foul that it results not only in disgust or aversion but also fear. The odorant used in the bomb has been developed by a team of researchers led by Dr. Pamela Dalton at the Monell Chemical Senses Center in Philadelphia and is a mixture of two agents: the U.S. Government Standard Bathroom Malodor (a mixture of eight chemicals with a stench similar to human feces but much stronger) and the Who-Me?, a sulphur-based odorant that smells like rotting carcasses...

    Scratch-and-Sniff

    Schmeisser et al.'s technical report makes for surprisingly entertaining reading. It's highly unlikely that any other military document praises Polyester, John Waters' 1981 multimodal film event that provided viewers with scratch-and-sniff cards.
    The cards had 10 numbered spots (1.roses, 2.flatulence, 3.model airplane glue, 4.pizza, 5.gasoline, 6.skunk, 7.natural gas, 8.new car smell, 9.dirty shoes, and 10.air freshener) that the audience scratched and sniffed when the appropriate number flushed at the corner of the screen. This system, called Odorama, solved the problem with hanging odors that was the main problem of the early smell-distributing systems.

    Waters' Odorama succeeded where the older scent distributions systems had failed. Smell-O-Vision (1939) and AromaRama (1959) were financial disasters for movie theaters, because “the odors were weak, the smells persisted longer than was desired, and the molecules were distributed by noisy systems.”


    OloramaTM

    Present day technology for odor delivery has advanced beyond scratch-and-sniff, of course, and Olorama offers an enhanced cinematic experience (“the smells jump off the screen”). The kits feature “very compact, hidden aromatization devices that are installed under seats (1 device for every 5-7 seats, depending on their size).”

    They also sell a product for home use. Olfactory enhancement of virtual reality is not a new development, but this VR system looks stylish, at the very least.





    The company stocks over 70 scents in categories such as Fantasy, Food, Wild, and...

    ACTION

    FIRE - RAIN - FOREST

    (AND COMING SOON...):
    GUNPOWDER - BLOOD - BURNING RUBBER


    Reference

    Schmeisser E, Pollard KA, Letowski T. Olfaction warfare: odor as sword and shield. ARMY RESEARCH LAB. ABERDEEN PROVING GROUND MD. HUMAN RESEARCH AND ENGINEERING DIRECTORATE; 2013 Mar.

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  • 09/04/17--17:15: Survival and Grief


  • There is no transcendent moment of growth or meaning in watching a childhood friend die of cancer. There is no learning experience that will somehow make me stronger. Only horror, helplessness, loss, and grief. I am deriving no spiritual uplift from this experience, only depression and despair. If someone wants to talk to me about post-traumatic growth, I will spray paint their car.

    Others disagree with me, I'm sure of it. For religious reasons. And I will respect their beliefs. There is no point in being a skeptical asshole to a grieving family.

    The most important point here is that dying patients should not have to suffer this much. I wrote about this and related issues seven years ago, as my father was dying of cancer.

    Ketamine for Depression: Yay or Neigh?

    Limbaugh/Palin "death panels" extend the lives of terminally ill patients

    2009 Lie of the Year Redux: Palin's so-called Death Panels

    Update on Ketamine in Palliative Care Settings


    I had more of a voice back then. Today I feel hopeless about the state of the world and my ability to have any impact on it. But I will try to keep my happy memories alive.



    I love you.
    RIP.



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    [image from Huth et al., 2016]

    No, not “meaning” in the semantic sense... 


    “Neuroexistentialism” is the angst that some humans feel upon realizing that the mind and spirit have an entirely physical basis. At a personal level I don't understand all the hubbub, because I accepted that mind = brain when I entered graduate school to study neuroscience. But for others:
    “Coming to terms with the neural basis of who we are can be very unnerving. It has been called “neuroexistentialism”, which really captures the essence of it. We’re not in the habit of thinking about ourselves that way” (Churchland, 2013). 

    It's very 2013.




    Neuroexistentialism is also the title of a forthcoming volume of essays edited by Caruso and Flanagan. In their introductory chapter, Flanagan and Caruso define this philosophical variant in the progression of existentialisms to the present third-wave:
    “There are three kinds of existentialism that respond to three different kinds of grounding projects—grounding in God’s nature, in a shared vision of the collective good, or in science. The first-wave existentialism of Kierkegaard, Dostoevsky, and Nietzsche expressed anxiety about the idea that meaning and morals are made secure because of God’s omniscience and good will. The second-wave existentialism of Sartre, Camus, and de Beauvoir, was a post-holocaust response to the idea that some uplifting secular vision of the common good might serve as a foundation. Today, there is a third-wave existentialism, neuroexistentialism, which expresses the anxiety that even as science yields the truth about human nature it also disenchants. The theory of evolution together with advances in neuroscience remove the last vestiges of an immaterial soul or self that can know the nature of what is really true, good, and beautiful.”

    But I don't understand why the neuroscientific view must be so disenchanting. (But then again I'm a neuroscientist.) I knew fellow students who went to church yet easily reconciled their cell culture day jobs with their religious beliefs.

    Professor Patricia Churchland is the best at explaining the “Don't Worry, Be Happy” response to neuroexistential terror:
    Q - Some might say the idea that you are just your brain makes life bleak, unforgiving and ultimately futile. How do you respond to that?
    A - It’s not at all bleak. I don’t see how the existence of a god or a soul confers any meaning on my life. How does that work, exactly? Nobody has ever given an adequate answer. My life is meaningful because I have family, meaningful work, because I love to play, I have dogs, I love to dig in the garden. That’s what makes my life meaningful, and I think that’s true for most people.


    Word cloud for the 18 chapter titles in Neuroexistentialism


    The Scope of Neuroexistentialsim

    In brief, it's about free will, morality, meaning, and purpose. And of course neuroscience.

    Back to my puzzlement about who suffers from a modern-day ailment caused by science spoilers. I found the below sentence to be both condescending and hyperbolic (Flanagan and Caruso):
    But for most ordinary folk and many members of the nonscientific academy, the idea that humans are animal and that the mind is the brain is destabilizing and disenchanting, quite possibly nauseating, a source of dread, fear and trembling, sickness unto death even.

    Perhaps the authors overascribe the illness and exaggerate the depth of ennui experienced by “most ordinary folk” who are too busy to grapple with the scientific implications of social neuroscience.

    Honestly, I don't mean to be overly snarky but right now I'm grappling with Survival and Grief, and with second-wave existential crises caused by crazed leaders with bad hair who wave around their phallic symbols of nuclear destruction, and with persisting racism that divides the country, and with the hypocrisy of anti-immigration Christians, and with a future of toxic air and coastal regions underwater. Maybe what I'm experiencing is actually fourth-wave existentialism...




    Medicating Neuroexistential Angst

    If neuroexistentialism is a narrow form of generalized anxiety or even panic, can't we use our scientific knowledge to sooth these troubled brains? Why not apply psychopharmacological principles (and/or psychotherapy) to calm the fearful and trembling mind? We have already presupposed that mind = brain (which brought us “sickness unto death even”), and that medications can alter brain function in psychiatric disorders.

    But this is not the correct way forward (see Flanagan and Caruso).
    “...Are there naturalistic resources that can quell the anxiety produced by the ascendancy of the scientific image generally, and specifically, the picture that comes from combining neo-Darwinism with neuroscience, which produces the new and nerve-wracking anxiety associated with neuroexistentialism?

    One promising approach is to pursue a kind of descriptive-normative inquiry into the causes and conditions of flourishing for material beings living in a material world, whose self-understanding includes the idea that such a world is the only kind of world that there is and thus that the meaning and significance of their lives, if there is any, must be found in such a world. We can call such an inquiry eudaimonics (Flanagan 2007, 2009).”

    So the solution to third-wave existentialism is positive psychology (as opposed to despair).1


    Footnote

    1Despair:
    What sets the existentialist notion of despair apart from the conventional definition is that existentialist despair is a state one is in even when he isn't overtly in despair. So long as a person's identity depends on qualities that can crumble, he is considered to be in perpetual despair. And as there is, in Sartrean terms, no human essence found in conventional reality on which to constitute the individual's sense of identity, despair is a universal human condition.


    Further Reading



    Existential Neuroscience: a field in search of meaning

    Earlier in 2013, the field of Existential Neuroscience (distinct from Neuroexistentialism) took the journal SCAN by storm, with neuroimaging studies focused on terror management theory (which describes how we deal with the inevitability of death). At the time,
    I asked:
    But what is Existential Neuroscience, exactly? A group of French intellectuals discussing brain research in a cafe while smoking and sipping espresso? An authentic neuroscience of utter freedom that embraces a state of perpetual despair1 over the meaninglessness of existence? Or independent groups of German-speaking neuroscientists who scan subjects while they ponder death?

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    Website for the BROADEN™ study, which was terminated by
    the sponsor.


    A multi-site, randomized, double-blind, placebo-controlled clinical trial of deep brain stimulation (DBS) for treatment-resistant depression has failed, according to a new article in Lancet Psychiatry. The targeted brain region was bilateral subcallosal cingulate white matter, which had been called the “Depression Switch” based on acute stimulation studies at Emory. These disappointing results were not surprising, since they were covered by Neurotech Business Report in December 2013 and then in depth by my posts here and here. The new paper followed the patients for a longer period of time, up to 24 months for some in the cohort.

    The main portion of the trial was six months in length. All patients received implantation surgery. Two weeks later, they were randomized to either the treatment group (n=60), who received stimulation right away, or the “sham” control group (n=30), who did not. After six months, the blinding was uncovered and both sham and treatment groups were offered open label DBS for another six months.

    In the figure below, Control (red line) and Stimulation (blue line) groups both showed slight improvements over time, with no significant difference in depression severity measured by the Montgomery-Åsberg Depression Rating Scale (MADRS). This was the primary endpoint. We don't see a difference between groups at six months or any other time.


    - click on image for a larger view -


    Fig. 2. (Holtzheimer et al., 2017).At months 9 and 12, the control group was receiving active stimulation; therefore, for the control group, 9 months refers to 3 months of active stimulation, and 12 months refers to 6 months of active stimulation. Error bars indicate standard deviations.


    Concerning the endpoint more specifically (Holtzheimer et al., 2017):
    The primary efficacy endpoint for the study was defined as difference in proportion of patients achieving a response between the stimulation and control groups. Response was defined as a 40% or greater reduction in MADRS and no worsening in GAF from baseline (average of three baseline MADRS assessments) to the average scores at months 4, 5, and 6.


    Table 3 (modified from Holtzheimer et al., 2017).


    Here's the full scoop for the futility analysis that put an end to the trial (because of the low probability of success). I had erroneously stated in January 2014 that the trial was halted by the FDA. It wasn't. It was stopped by the sponsor, St. Jude Medical (Holtzheimer et al., 2017):
    For the futility analysis, based on the first 6 months' data, the proportion of patients with response for the stimulation group was predicted to be 40%, and for the control group was predicted to be 18·5%. In the actual futility analysis, these figures were 20% for the stimulation group and 17% for the control group. It was concluded that the study had a 17% chance of success if continued. Although this did not meet the prespecified definition for futility (<10% chance of success), the sponsor chose to end study enrolment following the futility analysis.

    Although “These findings are disappointing given the encouraging data from earlier open-label studies of subcallosal cingulate DBS,” all was not lost, according to the authors. They offered a number of possible explanations (which can be summarized as long duration of illness, suboptimal stimulation parameters, and lack of tractography):
    • “participants in this study had an average current episode duration of about 12 years, which is much longer than the average duration of current episode in previous studies of subcallosal cingulate DBS (approximately 5 years) and might have contributed to the low overall proportion of patients achieving a response.”
    • “possible that stimulation contacts and parameters were suboptimal during the first 12 months of this study, given the somewhat restrictive programming algorithm used. Greater improvement in depression occurred after the 12-month endpoint when more flexibility in stimulation contacts and parameters was allowed.”
    • “Neurosurgical placement of the DBS electrodes, based on this algorithm, was highly accurate and did not differ between eventual responders and non-responders.”
    [NOTE: placement was verified by at least two of three experts: HSM, CH, PEH. Nonetheless, the authors argue that placement could improve with more detailed tractography, e.g. Riva-Posse et al. 2017. This refinement of protocol has been discussed for the last 10 years; see Johansen-Berg 2007 and ...But My Subgenual Cingulate Is Sad.]
    • “for maximal efficacy, the active electrode for subcallosal cingulate DBS must be placed such that it affects a crucial network of white matter tracts connecting key brain regions, including the forceps minor, cingulum bundle, and uncinate fasciculus. Therefore, it is possible that prospective targeting on the basis of individual diffusion tensor imaging tractography could optimise electrode placement in subcallosal cingulate DBS.”

    In an earlier paper, a group of DBS investigators and ethics experts advised other researchers, industry mavens, and even bloggers on “Being open minded about neuromodulation trials: Finding success in our 'failures'.” (Finns et al., 2017)
    “Similarly, another randomized double blind clinical trial comparing active versus sham stimulation for the treatment of severe depression targeting Brodmann Area 25 was also halted for futility prior to completion of the planned study (St Jude Medical sponsored BROADEN trial). While there are neither publications nor official industry statements, uninformed speculations as to causes of the failure are in the public domain [28,29] to the detriment of the scientific process and progress.

    In each of these instances, different combinations of variables can lead to disappointing results. For example, patient characteristics, surgical variability, stimulation algorithms, outcome metrics, and institutional variance, can all contribute to negative outcomes in complex trials that initially seem promising. Further, once a negative report is published, the work can become ‘toxic’, and there is little incentive to engage in small subset analyses that have a limited market.
    Finally,
    “We believe that investigators, industry, regulators and society need to fully understand what is casually described as success and failure in order to maximize return on investment, all the more so when opportunities for additional knowledge generation remain in place. To do otherwise, would be irresponsible.”

    So to call the BROADEN trial a failure is “irresponsible”? Personally, I am aware that a multi-site trial using invasive new technology to treat intractable psychiatric patients with a terrible and (ultimately) ill-defined syndrome is a massive undertaking. And very, very, very expensive. I have no problem with the investigators trying to glean what they can from individual differences to move forward with better targets/parameters/etc. I wanted to see this procedure help a majority of patients.

    The bottom line here is that the primary preregistered endpoint was as follows: 12/60 (20%) improved with stimulation, 5/30 (17%) improved with no stimulation, 8/60 (12%) patients with stimulation reported an increase in depressive symptoms (this was not defined or quantified), and 1/30 (3%) patients with no stimulation reported an increase in depressive symptoms.

    Let's take a look at the registered clinical trial. Oh we can't.


    Clinical Trial NCT00617162

    [Trial of device that is not approved or cleared by the U.S. FDA]




    However, we can look at other clinical trials using the same device (Libra Deep Brain Stimulation System) with the same sponsor (St. Jude Medical) in Europe and Canada. Oh by the way, an April 2016 news release announced: Abbott to Acquire St Jude Medical (DBS was not mentioned). In January 2017 Abbott Completes the Acquisition of St. Jude Medical (no DBS here, either). I won't speculate any further. I'm too tired.


    I'd like to conclude with an upbeat tweet from a prominent neuroscientist who studies pain and the placebo effect.



    References

    Choi KS, Riva-Posse P, Gross RE, Mayberg HS. (2015). Mapping the "Depression Switch" During Intraoperative Testing of Subcallosal Cingulate Deep Brain Stimulation. JAMA Neurol. 72(11):1252-60.

    Fins JJ, Kubu CS, Mayberg HS, Merkel R, Nuttin B, Schlaepfer TE. (2017). Being open minded about neuromodulation trials: Finding success in our "failures". Brain Stimul. 10(2):181-186. 

    Holtzheimer PE, Husain MM, Lisanby SH, Taylor SF, Whitworth LA, McClintock S, Slavin KV, Berman J, McKhann GM, Patil PG, Rittberg BR. (2017). Subcallosal cingulate deep brain stimulation for treatment-resistant depression: a multisite, randomised, sham-controlled trial. The Lancet Psychiatry. 2017 Oct 4.

    Riva-Posse P, Choi KS, Holtzheimer PE, Crowell AL, Garlow SJ, Rajendra JK, McIntyre CC, Gross RE, Mayberg HS. (2017). A connectomic approach for subcallosal cingulate deep brain stimulation surgery: prospective targeting in treatment-resistant depression. Mol Psychiatry. 2017 Apr 11. [Epub ahead of print].


    Further Reading

    BROADEN Trial of DBS for Treatment-Resistant Depression Halted by the FDA
     NOTE: the trial was actually halted by the sponsor, not the FDA

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

    Deep Brain Stimulation for Bipolar Depression

    Modern Tract-Tracing for Historical Psychosurgery

    ...But My Subgenual Cingulate Is Sad

    The Sad Cingulate

    Sad Cingulate on 60 Minutes and in Rats

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    The devil always experienced malicious pleasure in imposing himself in neuropsychiatric nosology


    Olry and Haines (2017) published a mischievous article in the Journal of the History of the Neurosciences:
    Having an inquiring mind by nature, the Devil always managed to interfere in all spheres of human activity, including the sciences. ... Biologists use an enzyme called “luciferase” — Lucifer has been described as the “light-bearing” fallen angel, hence the bioluminescence — to spot certain proteins by chromogenous reactions (Lodish et al., 2005, p. 92). ...

    But how did the Devil get a foot — of course cloven (!) — into the door of the neurosciences?

    Demonic possession plays an important role, of course, even in modern day psychiatric nosology (see the debate over Possession Trance Disorder in DSM-5). Does it make any sense to use DSM-5 (or DSM-IV) criteria to diagnose spirit possession across cultures? Transcultural psychiatry takes a much more inclusive and sensitive approach to such phenomena, which are often precipitated by trauma.

    Olry and Haines (2017) avoid this literature entirely and suggest that:
    The concept of demonic possession has been mainly of theological (Omand, 1970; Balducci, 1975; Rodewyk, 1988; Amorth, 1999, 2002; Bamonte, 2006; Fortea, 2006, 2008) and/or historical concern (Villeneuve, 1975; Pigin, 1998; Kelly, 2010; Kiely & McKenna, 2007).  ...

    Although conservative theologians might not question the reality of diabolical possession (see Haag, 1969; Cortès & Gatti, 1975, for the few exceptions), many psychiatrists and psychologists admit being interested in the concept though, of course, not declaring themselves in favor of a supernatural etiology...

    But being diabolical sorts themselves, the authors namedrop and show off their autographed copy of The Exorcist.



    Figure 1. Title page of William Peter Blatty’s The Exorcist, with signed dedication by the actress Linda Blair. Author’s (R.O.) copy.



    They continue:
    However, literature and the movie industry — let’s remember William Peter Blatty’s The Exorcist (Blatty, 1971) (see Fig. 1) and the sociological impact of William Friedkin’s screen adaptation two years later (Bozzuto, 1975) — not only generated impassioned movie critics ... but also brought back scientific discussions involving neurosciences and, more specifically, psychology, neurology, and psychiatry (Montgomery, 1976).



    Häxan (1922)entire film available at archive.org


    Deadly exorcisms have been reported recently in the medical literature, including several cases of Fatal Hypernatraemia from Excessive Salt Ingestion During Exorcism. One 20-year-old woman received a prescription for Prozac to treat her postpartum depression, but her family also advised her to undergo an exorcism. She reportedly drank six glasses of a mixture of 1 kg table salt in a liter of water.

    The Church itself involved physicians many centuries ago in the differential diagnosis between possession and mental disease, as exemplified by the 1583 Rheims National Synod:

    [Before he undertakes to exorcize, the priest has to inquire diligently about the life of the possessed [. . .], of his health [. . .], because melancholics, lunatics often need much more cures of the physician than the ministry of exorcists.] (Tonquédec, 1948, p. 330)

    Physicians, and in actual fact, clinical neuroscientists, then had to name a phenomenon — nosology oblige — about which most did not believe.


    The Devil's Influence Over Neuropsychiatry – “some lexicological compromises”
    ...neuropsychiatrists sometimes allow themselves the use of theological concepts (e.g., possession, diabolical, demonological), provided that an additional term — medical or not — grants them a little more scientific credibility. This addition may be “neurosis” (demonological neurosis: Hélot, 1898; Freud, 1923), “psychosis” (diabolical possession psychosis: Lhermitte, 1944), “delirium” (diabolical possession delirium: Gayral, 1944; Delay, 1945), “syndrome” (possession syndrome: Yap, 1960), “phenomenon” (phenomenon of possession: Bron, 1975), “state” (possession state: Wittkower, 1970), or “experience” (possession experience: Pattison, 1969, p. 323).

    Or sometimes the patient may feel like they are literally in hell.



    Self-Portrait in Hell, by Edvard Munch (1903)



    Reference

    Olry R, Haines DE. (2017). The devil always experienced malicious pleasure in imposing himself in neuropsychiatric nosology. J Hist Neurosci. 26(3):329-335.


    Further Reading

    Possession Trance Disorder in DSM-5

    Spirit Possession as a Trauma-Related Disorder in Uganda

    "The spirit came for me when I went to fetch firewood" - Personal Narrative of Spirit Possession in Uganda

    Possession Trance Disorder Caused by Door-to-Door Sales

    Fatal Hypernatraemia from Excessive Salt Ingestion During Exorcism

    Diagnostic Criteria for Demonic Possession



    The Wailing (aka 곡성, , Gokseong)


    ...and to make your Halloween nightmares complete...



    Although it's certainly not for everybody, The Wailing is an amazing film.

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    Death by suicide is a preventable tragedy if the suicidal individual is identified and receives appropriate treatment. Unfortunately, some suicidal individuals do not signal their intent, and others do not receive essential assistance. Youths with severe suicidal ideation are not taken seriously in many cases, and thus are not admitted to emergency rooms. A common scenario is that resources are scarce, the ER is backed up, and a cursory clinical assessment will determine who is admitted and who will be triaged. From a practical standpoint, using fMRI to determine suicide risk is a non-starter.

    Yet here we are, with media coverage blaring that an Algorithm can identify suicidal people using brain scans and Brain Patterns May Predict People At Risk Of Suicide. These media pieces herald a new study claiming that fMRI can predict suicidal ideation with 91% accuracy (Just et al. 2017). The authors applied a complex algorithm (machine learning) to analyze brain scans obtained using a highly specialized protocol to examine semantic and emotional responses to life and death concepts.

    Let me unpack that a bit. The scans of 17 young adults with suicidal ideation (thoughts about suicide) were compared to those from another 17 participants without suicidal ideation. A computer algorithm (Gaussian Naive Bayes) was trained on the neural responses to death-related and suicide-related words, and correctly classified 15 out of 17 suicidal ideators (88% sensitivity) and 16 out of 17 controls (94% specificity). Are these results too good to be true? Yes, probably. And yet they're not good enough, because two at-risk individuals were not picked up.




    The computational methods used to classify the suicidal vs. control groups are suspect, according to manymachine learningexpertsonsocialmedia. One problem is known as “overfitting using too many parameters taken from small populations that may not generalize to unique samples. The key metric is whether the algorithm will be able to classify individuals from independent, out-of-sample populations. And we don't know that for sure. Another problem is that the leave-one-out cross validation is problematic. I'm not an expert here, so the Twitter threads that start below (and here) are your best bet.


    For the rest of this post, I'll raise other issues about this study that concerned me.


    Why use an expensive technology in the first place?

    The rationale for this included some questionable statements.
    • ...predictions by both clinicians and patients of future suicide risk have been shown to be relatively poor predictors of future suicide attempt2,3.
    One of the papers cited as a poor predictor (Nock et al., 2010) was actually touted as a breakthrough when it was published: Implicit Cognition Predicts Suicidal Behavior. [n.b. Nock is an author on the Just et al. paper that trashes his earlier work]. Anyway, Nock et al. (2010) developed the death/suicide Implicit Association Test (IAT)1which was able to identify ER patients at greatest risk for another suicide attempt in the future:
    ...the implicit association of death/suicide with self was associated with an approximately 6-fold increase in the odds of making a suicide attempt in the next 6 months, exceeding the predictive validity of known risk factors (e.g., depression, suicide-attempt history) and both patients’ and clinicians’ predictions.
    But let's go ahead with an fMRI study that will be far more accurate than a short and easy-to-administer computerized test!

    • Nearly 80% of patients who die by suicide deny suicidal ideation in their last contact with a mental healthcare professional4.
    This 2003 study was based on psychiatric inpatients who died by suicide while in hospital (5-6% of all suicides) or else shortly thereafter, and may not be representative of the entire at-risk population. Nonetheless, other research shows that current risk scales are indeed of limited use and may even waste valuable clinical resources. The scales “may be missing important aspects relevant to repeat suicidal behaviour (for example social, cultural, economic or psychological processes).” But a focus on brain scans would also miss social, cultural, and economic factors.


    How do you measure the neural correlates of suicidal thoughts?

    This is a tough one, but the authors propose to uncover the neural signatures of specific concepts, as well as the emotions they evoke:
    ...the neural signature of the test concepts was treated as a decomposable biomarker of thought processes that can be used to pinpoint particular components of the alteration [in participants with suicidal ideation]. This decomposition attempts to specify a particular component of the neural signature that is altered, namely, the emotional component...

    How do you choose which concepts and emotions to measure?

    The “concepts” were words from three different categories (although the designation of Suicide vs. Negative seems arbitrary for some of the stimuli). The set of 30 words was presented six times, with each word shown for three seconds followed by a four second blank screen. Subjects were “asked to actively think about the concepts ... while they were displayed, thinking about their main properties (and filling in details that come to mind) and attempting consistency across presentations.”




    The “emotion signatures” were derived from a prior study (Kassam et al., 2013) that asked method actors to self-induce nine emotional states (anger, disgust, envy, fear, happiness, lust, pride, sadness, and shame). The emotional states selected for the present study were anger, pride, sadness, and shame (all chosen post hoc). Should we expect emotion signatures that are self-induced by actors to be the same as emotion signatures that are evoked by words? Should we expect a universal emotional response to Comfort or Evil or Apathy?

    Six words (death, carefree, good, cruelty, praise, and trouble in descending order) and five brain regions (left superior medial frontal, medial frontal/anterior cingulate, right middle temporal, left inferior parietal, and left inferior frontal) from a whole-brain analysis (that excluded bilateral occipital lobes for some reason) provided the most accurate discrimination between the two groups. Why these specific words and voxels? Twenty-five voxels, specifically. It doesn't matter.
    The neural representation of each concept, as used by the classifier, consisted of the mean activation level of the five most stable voxels in each of the five most discriminating locations.
    ...and...
    All of these regions, especially the left superior medial frontal area and medial frontal/anterior cingulate, have repeatedly been strongly associated with self-referential thought...
    ...and...
    ...the concept of ‘death’ evoked more shame, whereas the concept of ‘trouble’ evoked more sadness in the suicidal ideator group. ‘Trouble’ also evoked less anger in the suicidal ideator group than in the control group. The positive concept ‘carefree’ evoked less pride in the suicidal ideator group. This pattern of differences in emotional response suggests that the altered perspective in suicidal ideation may reflect a resigned acceptance of a current or future negative state of affairs, manifested by listlessness, defeat and a degree of anhedonia (less pride evoked in the concept of ‘carefree’) [why not less pride to 'praise' or 'superior'? who knows...]

    Not that this involves circularity or reverse inference or HARKing or anything...


    How can a method that excludes data from 55% of the target participants be useful??

    This one seems like a showstopper. A total of 38 suicidal participants were scanned, but those who did not show the desired semantic effects were excluded due to “poor data quality”:
    The neurosemantic analyses ... are based on 34 participants, 17 participants per group whose fMRI data quality was sufficient for accurate (normalized rank accuracy > 0.6) identification of the 30 individual concepts from their fMRI signatures. The selection of participants included in the primary analyses was based only on the technical quality of the fMRI data. The data quality was assessed in terms of the ability of a classifier to identify which of the 30 individual concepts they were thinking about with a rank accuracy of at least 0.6, based on the neural signatures evoked by the concepts. The participants who met this criterion also showed less head motion (t(77) = 2.73, P < 0.01). The criterion was not based on group discriminability.

    This logic seems circular to me, despite the claim that inclusion wasn't based on group classification accuracy. Seriously, if you throw out over half of your subjects, how can your method ever be useful? Nonetheless, the 21 “poor data quality” ideators with excessive head motion and bad semantic signatures were used in an out-of-sample analysis that also revealed relatively high classification accuracy (87%) compared to the data from the same 17 “good” controls (the data from 24 “bad” controls were excluded, apparently).
    We attribute the suboptimal fMRI data quality (inaccurate concept identification from its neural signature) of the excluded participants to some combination of excessive head motion and an inability to sustain attention to the task of repeatedly thinking about each stimulus concept for 3 s over a 30-min testing period.

    Furthermore, another classifier was even more accurate (94%) in discriminating between suicidal ideators who had made a suicide attempt (n=9) from those who had not (n=8), although the out-of-sample accuracy for the excluded 21 was only 61%. Perhaps I'm misunderstanding something here, but I'm puzzled...

    I commend the authors for studying a neglected clinical group, but wish they were more rigorous, didn't overinterpret their results, and didn't overhype the miracle of machine learning.


    Crisis Text Line [741741 in the US] uses machine learning to prioritize their call load based on word usage and emojis. There is a great variety of intersectional risk factors that may lead someone to death by suicide. At present, no method can capture the full scope of diversity of who will cross the line.

    If you are feeling suicidal or know someone who might be, here is a link to a directory of online and mobile suicide help services.



    Footnote

    1I won't discuss the problematic nature of the IAT here.


    References

    Just MA, Pan L, Cherkassky VL, McMakin DL, Cha c, Nock MK, & Brent D (2017). Machine learning of neural representations of suicide and emotion concepts identifies suicidal youth. Nature Human Behaviour. Published online: 30 October 2017

    Kassam KS, Markey AR, Cherkassky VL, Loewenstein G, Just MA. (2013). Identifying Emotions on the Basis of Neural Activation. PLoS One. 8(6):e66032.

    Nock MK, Park JM, Finn CT, Deliberto TL, Dour HJ, Banaji MR. (2010). Measuring the suicidal mind: implicit cognition predicts suicidal behavior. Psychol Sci. 21(4):511-7.

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    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 O'Neill, aged 63.


    Both men played professional football in the NFL. Both came upon some troubled times after leaving the game. And although the CTE pathology in their brains has been attributed directly to football — repeated concussive and sub-concussive events — other potential factors have been mostly ignored. Below I'll discuss these events and phenomena, and whether they could have contributed to the condition of the post-mortem brains.


    Aaron Hernandez


    Illustration by Sean McCabe for Rolling Stone


    Talented ex-NFL football star, PCP addict, convicted murderer, and suicide by hanging. The Rolling Stone ran two riveting articles that detailed the life (and death) of Mr. Hernandez. Despite a difficult upbringing surrounded by violence and tragedy, he was a serious and stellar athlete at Bristol High School. The tragic death of his father from a medical accident led Aaron to hang out with a less savory crowd. He fortunately ended up at the University of Florida for college football. There he failed several drug tests, but the administration mostly looked the other way. He was on a national championship team, named an all-American, and involved in a shooting where he was not charged.

    Most NFL teams took a pass because of his use of recreational drugs and reputation as a hot-head:
    After seeing his pre-draft psychological report, where he received the lowest possible score, one out of 10, in the category of “social maturity” and which also noted that he enjoyed “living on the edge of acceptable behavior,” a handful of teams pulled him off their boards, and 25 others let him sink like a stone on draft day.

    But he ended up signing with the New England Patriots in a $40 million deal. He smoked pot constantly and avoided hanging out with the other players. “Instead of teammates, Hernandez built a cohort of thugs, bringing stone-cold gangsters over to the house to play pool, smoke chronic and carouse.” Things spiraled downwards, in terms of thug life, use of PCP (angel dust), and ultimately the murder of a friend that ended in a life sentence without parole.

    He was also tried and acquitted of a separate double homicide, but his days were numbered. Two days later he hanged himself with a bedsheet in his jail cell. He was rumored to have smoked K2 (nasty synthetic cannabis) just before his death, but this was ultimately unsubstantiated.

    These complicating factors lengthy history of drug abuse, death by asphyxiation must have had some effect on his brain, I mused in another post.




    Meanwhile, the New York Times had a splashy piece about how the pristine brain of Aaron Hernandez presented an opportunity to study a case of “pure” CTE:
    What made the brain extraordinary, for the purpose of science, was not just the extent of the damage, but its singular cause. Most brains with that kind of damage have sustained a lifetime of other problems, too, from strokes to other diseases, like Alzheimer’s. Their samples are muddled, and not everything found can be connected to one particular disease.

    This was a startling statement, as I said in my secondary blog:
    I’ve been struggling to write a post that highlights the misleading nature of this claim. How much of that was [the writer's] own hyperbole? Or was he merely paraphrasing the famous neuropathologists who presented their results to the media, not to peer reviewers? Is it my job to find autopsied brains from PCP abusers and suicides by hanging? Searching for the latter, by the way, will turn up some very unsavory material in forensic journals and elsewhere. At any rate, I think much of this literature glosses over any complicating elements, and neglects to mention all of the cognitively intact former football players whose brains haven’t been autopsied.

    In the next post, I'll discuss the case of Fred O'Neill.


    Footnote

    1Illustration of the coronal plane of section.





    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




    New York Times: A neuropathologist and her associate examined slices of the brain of a 27-year-old man. Credit: Boston University.

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    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.


    Footnotes

    1Illustration 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


    References

    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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    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):
    ...direct 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.


    Footnotes

    1Inman 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...


    References

    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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  • 12/31/17--14:19: 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.


    Footnotes

    1Uber deserves special mention.

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

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

    4Actually, #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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    "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.” 


    Footnotes

    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...


    References

    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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    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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    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.


      References

      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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      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,1words 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


      Footnote

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





      Reference

      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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      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
      Tonight

      ---Depeche Mode, Fly on the Windscreen


      Footnote

      1 Well, they are super popular right now.


      Reference

      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
      Now
      Come here
      Kiss me
      Now

      ---ibid



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      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 presenters on Sunday through Tuesday. Another highlight:

      Symposium 3The 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!



      Footnotes


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

      2At 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.

      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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      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.
       
    • 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.


      Footnotes

      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.


      References

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


      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...
      • ..so 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


      Footnote

      1Another 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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      How is semantic knowledge represented and stored in the brain? A classic way of addressing this question is via single-case studies of patients with brain lesions that lead to a unique pattern of deficits. Agnosia is the inability to recognize some class (or classes) of entities such as objects or persons. Agnosia in the visual modality is most widely studied, but agnosias in the auditory and olfactory modalities have been reported as well. A key element is that basic sensory processing is intact, but higher-order recognition of complex entities is impaired.

      Agnosias that are specific for items in a particular category (e.g., animals, fruits/vegetables, tools, etc.) are sometimes observed. An ongoing debate posits that some category-specific dissociations may fall out along sensory/functional lines (the Warrington view), or along domain-specific lines (the Caramazza view).1 The former suggests that knowledge of living things is more reliant on vision (you don't pick up and use an alligator), while knowledge of tools is more reliant on how you use them. The latter hypothesis suggests that evolutionary pressures led to distinct neural systems for processing different categories of objects.2

      Much less work has examined how nonverbal auditory knowledge is represented in the brain. A new paper reports on a novel category-specific deficit in an expert bird-watcher who developed semantic dementia (Muhammed et al., 2018). Patient BA lost the ability to identify birds by their songs, but not by their appearance. As explained by the authors:

      BA is a dedicated amateur birder with some 30 years’ experience, including around 10 weeks each spring spent in birdwatching expeditions and over the years had also regularly attended courses in bird call recognition, visual identification and bird behaviour. He had extensive exposure to a range of bird species representing all major regions and habitats of the British Isles. He had noted waning of his ability to name birds or identify them from their calls over a similar timeframe to his evolving difficulty with general vocabulary. At the time of assessment, he was also becoming less competent at identifying birds visually but he continued to enjoy recognising and feeding the birds that visited his garden. There had been no suggestion of any difficulty recognising familiar faces or household items nor any difficulty recognising the voices of telephone callers or everyday noises. There had been no evident change in BA's appreciation of music.

      BA's brain showed a pattern of degeneration characteristic of semantic dementia, with asymmetric atrophy affecting the anterior, medial, and inferior temporal lobes, to a greater extent in the left hemisphere.



      Fig. 1 (modified from Muhammed et al., 2018).Note that L side of brain shown on R side of scan. Coronal sections of BA's T1-weighted volumetric brain MRI through (A) temporal poles; (B) mid-anterior temporal lobes; and (C) temporo-parietal junctional zones. There is more severe involvement of the left temporal lobe.



      The authors developed a specialized test of bird knowledge in the auditory, visual, and verbal modalities. The performance of BA was compared to that of three birders similar in age and experience.


      Results indicated that “BA performed below the control range for bird knowledge derived from calls and names but within the control range for knowledge derived from appearance.” There was a complicated pattern of results for his knowledge of specific semantic characteristics in the different modalities, but the basic finding suggested an agnosia for bird calls. Interestingly, he performed as well as controls on tests of famous voices and famous face pictures.

      Thus, the findings suggest separate auditory and visual routes to avian conceptual knowledge, at least in this expert birder. Also fascinating was the preservation of famous person identification via voice and image. The authors conclude with a ringing endorsement of single case studies in neuropsychology:
      This analysis transcends the effects of acquired expertise and illustrates how single case experiments that address apparently idiosyncratic phenomena can illuminate neuropsychological processes of more general relevance.

      link via @utafrith


      References

      Caramazza A, Mahon BZ. (2003). The organization of conceptual knowledge: the evidence from category-specific semantic deficits. Trends Cogn Sci. 7(8):354-361.

      Muhammed L, Hardy CJD, Russell LL, Marshall CR, Clark CN, Bond RL, Warrington EK, Warren JD. (2018). Agnosia for bird calls. Neuropsychologia 113:61-67.

      Warrington EK, McCarthy RA. (1994). Multiple meaning systems in the brain: a case for visual semantics. Neuropsychologia 32(12):1465-73.

      Warrington EK, Shallice T. (1984). Category specific semantic impairments. Brain 107(Pt 3):829-54.


      Footnotes

      1 I'm using this nomenclature as a shorthand, obviously, as many more researchers have been involved in these studies. And this is an oversimplification based on the origins of the debate.

      2 In fact, the always-argumentative Prof. Caramazza gave a lecture on The Representation of Objects in the Brain: Nature or Nurture for winning the Fred Kavli Distinguished Career Contributions in Cognitive Neuroscience Award (#CNS2018). Expert live-tweeter @vukovicnikola captured the following series of slides, which summarizes the debate as resolved in Caramazza's favor (to no one's surprise).








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      Deep brain stimulation (DBS) of the subthalamic nucleus in Parkinson's disease (PD) has been highly successful in controlling the motor symptoms of this disorder, which include tremor, slowed movement (akinesia), and muscle stiffness or rigidity. The figure above shows the electrode implantation procedure for PD, where a stimulating electrode is placed in either the subthalamic nucleus, (STN), a tiny collection of neurons within the basal ganglia circuit, or in the internal segment of the globus pallidus, another structure in the basal ganglia (Okun, 2012). DBS of the STN is more common, and more often a source of disturbing non-motor side effects.

      In brief, DBS of the STN alters neural activity patterns in complex cortico-basal-ganglia-thalamo-cortical networks (McIntyre & Hahn, 2010).

      DBS surgery may be recommended for some patients in whom dopamine (DA) replacement therapy has become ineffective, usually after a few years. DA medications include the classic DA precursor L-DOPA, followed by DA agonists such as pramipexole, ropinirole, and bromocriptine. But unfortunately, impulse control disorders (ICDs, e.g., compulsive shopping, excessive gambling, binge eating, and compulsive sexual behavior) occur in about 17% of PD patients on DA agonists (Voon et al., 2017).

      There are many first-person accounts from PD patients who describe uncharacteristic and embarrassing behavior after taking DA agonists, like this grandpa who started seeing prostitutes for the first time in his life:
      'I have become an embarrassment'

      For most of his life John Smithers was a respected family man who ran a successful business. Then he started paying for sex. Now, in his 70s, he explains how his behaviour has left him broke, alone and tormented

      I am 70 years old and used to be respectable. I was a magistrate for 25 years, and worked hard to feed my children and build up the family business. I was not the most faithful of husbands, but I tried to be discreet about my affairs.1 Now I seem to be a liability. Over the last two decades I have spent a fortune on prostitutes and lost two wives. I have made irrational business decisions that took me to the point of bankruptcy. I have become an embarrassment to my nearest and dearest.

      Also reports like: Drug 'led patients to gamble'.


      New-onset ICDs can also occur in patients receiving STN DBS, but the effects are mixed across the entire population: ICD symptoms can also improve or remain unchanged. Why this is the case is a vexing problem that includes premorbid personality, genetics, family history, past and present addictions, and demographic factors (Weintraub & Claassen).


      - click on image for a larger view -



      Neuroethicists are weighing in on the potential side effects of DBS that may alter a patient's perception of identity and self. A recent paper included a first-person account of altered personality and a sense of self-estrangement in a 46 year old woman undergoing STN DBS for PD (Gilbert & Viaña, 2018):
      The patient reported a persistent state of self-perceived changes following implantation. More than one year after surgery, her narratives explicitly refer to a persistent perception of strangeness and alteration of her concept of self. For instance, she reported:
      "can't be the real me anymore—I can't pretend . . . I think that I felt that the person that I have been [since the intervention] was somehow observing somebody else, but it wasn't me. . . . I feel like I am who I am now. But it's not the me that went into the surgery that time. . . . My family say they grieve for the old [me]. . . ."

      Many of her quotes are striking in their similarity to behaviors that occur in the manic phase of bipolar disorder {loss of control, grandiosity}:
      The patient also reported developing severe postoperative impulsivity: "I cannot control the impulse to go off if I'm angry." In parallel, while describing a sense of loss of control over some impulsions, she has also recognized that DBS gave her increased feelings of strength: "I never had felt this lack of power or this giving of power—until I had deep brain stimulation."

      {also uncharacteristic sexual urges and hypersexuality; excessively energetic; compulsive shopping}:
      ...she experienced radically enhanced capacities, in the form of increased uncontrollable sexual urges:
      "I know this is a bit embarrassing. But I had 35 staples in my head, and we made love in the hospital bathroom and that wasn't just me. It was just I had felt more sexual with the surgery than without."
      And greater physical energy:
      "I remember about a week after the surgery, I still had the 35 staples in my head and I was just starting to enter the cooler months of winter but my kids had got me winter clothes so I had nothing to wear to the follow up appointment and when I went back there of the morning, I thought "I can walk into the doctor's" even though it was 5 kilometers into town. It's like the psychologist said: "For a woman who had a very invasive brain surgery 9 days ago and you've just almost walked 10 kilometers."And on the way, I stopped and bought a very uncharacteristic dress, backless—completely different to what I usually do."

      Examining the DSM-5 criteria for bipolar mania, it seems clear (to me, at least) that the patient is indeed having a prolonged manic episode induced by STN DBS.
      In order for a manic episode to be diagnosed, three (3) or more of the following symptoms must be present:
      • Inflated self-esteem or grandiosity
      • Decreased need for sleep (e.g., one feels rested after only 3 hours of sleep)
      • More talkative than usual or pressure to keep talking
      • Flight of ideas or subjective experience that thoughts are racing
      • Attention is easily drawn to unimportant or irrelevant items
      • Increase in goal-directed activity (either socially, at work or school; or sexually) or psychomotor agitation
      • Excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments)

      It's also notable that she divorced her husband, moved to another state, ruptured the therapeutic relationship with her neurologist and surgical team, and made a suicide attempt. She also took up painting and perceived the world in a more vibrant, colorful way {which resembles narratives of persons experiencing manic episodes}:
      "I don't know, all the senses came alive. I wanted to listen to Paul Kelly and all of my favorite music really loud in the toilet. And you know, also everything was colourful. . . . Well, since brain surgery I can. I didn't bother before. I can see the light . . . the light that is underlying every masterpiece in photography. . . . I've seen it like I've never seen it before . . . I am a totally different person. I like it that I love photography and music and colourful clothes, but where is the old me now?"

      However, she appears to display more insight into her altered behavior than {most} people in the midst of bipolar mania. Perhaps her reality monitoring abilities are more intact? Or it's because her symptoms wax and wane.2 But like in many manic individuals, she did not want this feeling to stop:
      "I went to the psychiatrist, and he said, 'Right, well, this is bordering on mania[NOTE: that is an understatement], you need to turn the settings right down to manage it.'I said to him, 'Please don't, this is not over the top—this is just joy.'"

      I think this line of research studying individuals with Parkinson's who have impulse control disorders due to DA replacement or DBS   can provide insight into bipolar mania. Certainly, drugs that act as antagonists at multiple DA receptor subtypes (typical and atypical antipsychotics) are used in the management of bipolar disorder.

      Patient narratives are also informative in this regard, and provide critical information for individuals considering various types of therapies for PD. In this paper, the patient was not informed by the medical team that there could be undesirable psychiatric side effects. She has taken legal action against the lead neurosurgeon, and the proceedings were ongoing when the article was written.


      ADDENDUM (May 14 2018): The study was conducted in accordance with Human Research Ethics Committee regulations. The patient provided consent to have her narratives included in publications on neuropsychiatric side effects of DBS for PD.


      Footnotes

      1One might wonder whether Mr. Smithers' premorbid propensity for affairs made him more vulnerable for compulsive sexual activity after DA agonists. And that is one consideration displayed in the box and circle diagram above.

      2 She did experience bouts of depression as well as mania, perhaps related to the stimulation parameters and precise location. And bipolar individuals also gain insight once the manic episode subsides.


      References

      Gilbert F, Viaña JN. (2018). A Personal Narrative on Living and Dealing with Psychiatric Symptoms after DBS Surgery. Narrat Inq Bioeth. 8(1):67-77.

      McIntyre CC, Hahn PJ. (2010). Network perspectives on the mechanisms of deep brain stimulation. Neurobiol Dis. 38(3):329-37.

      Voon V, Napier TC, Frank MJ, Sgambato-Faure V, Grace AA, Rodriguez-Oroz M, Obeso J, Bezard E, Fernagut PO. (2017). Impulse control disorders and levodopa-induceddyskinesias in Parkinson's disease: an updateLancet Neurol. 16(3):238-250.

      Weintraub D, Claassen DO. (2017). Impulse Control and Related Disorders in Parkinson's Disease. Int Rev Neurobiol. 133:679-717.


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      Do Plants Have “Memory”?


      A new paper by Bédécarrats et al. (2018) is the latest entry into the iconoclastic hullabaloo claiming a non-synaptic basis for learning and memory. In short, “RNA extracted from the central nervous system of Aplysia given long-term sensitization training induced sensitization when injected into untrained animals...” The results support the minority view that long-term memory is not encoded by synaptic strength, according to the authors, but instead by molecules inside cells (à la Randy Gallistel).

      Adam Calhoun has a nice summary of the paper at Neuroecology:
      ...there is a particular reflex1(memory) that changes when they [Aplysia] have experienced a lot of shocks. How memory is encoded is a bit debated but one strongly-supported mechanism (especially in these snails) is that there are changes in the amount of particular proteins that are expressed in some neurons. These proteins might make more of one channel or receptor that makes it more or less likely to respond to signals from other neurons. So for instance, when a snail receives its first shock a neuron responds and it withdraws its gills. Over time, each shock builds up more proteins that make the neuron respond more and more. These proteins are built up by the amount of RNA (the “blueprint” for the proteins, if you will) that are located in the vicinity of the neuron that can receive this information.  ...

      This new paper shows that in these snails, you can just dump the RNA on these neurons from someone else and the RNA has already encoded something about the type of protein it will produce.

      Neuroskeptic has a more contentious take on the study, casting doubt on the notion that sensitization of a simple reflex to any noxious stimulus (a form of non-associative “learning”) produces “memories” as we typically think of them. But senior author Dr. David Glanzman tolerated none of this, and expressed strong disagreement in the comments:
      “I’m afraid you have a fundamental misconception of what memory is. We claim that our experiments demonstrate transfer of the memory—or essential components of the memory—for sensitization. Now, although sensitization may not comport with the common notion of memory—it’s not like the memory of my Midwestern grandmother’s superb blueberry pies, for example—it nevertheless has unambiguous status as memory.  ...  [didactic lesson continues] ...  We do not claim in our paper that declarative memories—such as my memory of my grandmother’s blueberry pies—or even simpler forms of associative memories like those induced during classical conditioning—can be transferred by RNA. That remains to be seen.”

      OK, so Glanzman gets to define what memory is. But later on he's caught in a trap and has to admit:
      “Of course, there are many phenomena that can be loosely regarded as memory—the crease in folded paper, for example, can be said to represent the memory of a physical action.”

      That was in response to who said:
      “So a transfer of RNA that activates a cellular mechanism associated with touch isn't memory, but rather just exogenously turning on a cellular pathway. By that logic, gene therapy to treat sickle cell anemia changes blood "memory".” 2

      However, my favorite comment was from Smut Clyde:
      “Kandel set the precedent that reflexes in Aplysia are "memories", and now we're stuck with it.”

      This reminded me of Dr. Kandel's bold [outlandish?] attempt to link psychoanalysis, Aplysia withdrawal reflexes, and human anxiety (Kandel, 1983). I was a bit flabbergasted that gill withdrawal in a sea slug was considered “mentation” (thought) and could support Freudian views.3
      In the past, ascribing a particular behavioral feature to an unobservable mental process essentially excluded the problem from direct biological study because the complexity of the brain posed a barrier to any complementary biological analysis. But the nervous systems of invertebrates are quite accessible to a cellular analysis of behavior, including certain internal representations of environmental experiences that can now be explored in detail; This encourages the belief that elements of cognitive mentation relevant to humans and related to psychoanalytic theory can be explored directly [in Aplysia] and need no longer be merely inferred.

      - click on image for a larger view -



      So anticipatory anxiety in humans is isomorphic to invertebrate responses in a classical aversive conditioning paradigm, and chronic anxiety is recreated by long-term sensitization paradigms. Perhaps I missed the translational advances here, and any application to Psychoanalytic and Neuropsychoanalytic practice that has been fully realized.

      If we want to accept a flexible definition of learning and memory in animals, why not consider associative learning experiments in pea plants, where a neutral cue predicting the location of a light source had a greater effect on the direction of plant growth than innate phototropism (Gagliano et al., 2016)? Or review the literature on associative and non-associative learning in Mimosa? (Abramson & Chicas-Mosier, 2016). Or evaluate the field of ‘plant neurobiology’ and even the ‘Philosophy of Plant Neurobiology’ (Calvo, 2016). Or are the possibilities of chloroplast-based consciousness and “mentation” without neurons too threatening (or too fringe)?

      But in the end, we know we've reached peak plant cognition when a predictive coding model appears — Predicting green: really radical (plant) predictive processing (Calvo & Friston, 2017).


      Further Reading

      The Big Ideas in Cognitive Neuroscience, Explained (especially the sections on Gallistel and Ryan)

      What are the Big Ideas in Cognitive Neuroscience? (you can watch the videos of their 2017 CNS talks)


      Footnotes

      1edited to indicate my emphasis on reflex more specifically, the gill withdrawal reflex in Aplysia which can only go so far as a model of other forms of memory, in my view.

      Another skeptic (but for different reasons) is Dr. Tomás Ryan, who was paraphrased in Scientific American:
      But [Ryan] doesn’t think the behavior of the snails, or the cells, proves that RNA is transferring memories. He said he doesn’t understand how RNA, which works on a time scale of minutes to hours, could be causing memory recall that is almost instantaneous, or how RNA could connect numerous parts of the brain, like the auditory and visual systems, that are involved in more complex memories.

      3But I haven't won the Nobel Prize, so what do I know?


      References

      Abramson CI, Chicas-Mosier AM. (2016). Learning in plants: lessons from Mimosa pudica. Frontiers in psychology Mar 31;7:417.

      Bédécarrats A, Chen S, Pearce K, Cai D, Glanzman DL. (2018). RNA from Trained Aplysia Can Induce an Epigenetic Engram for Long-Term Sensitization in Untrained Aplysia. eNeuro. May 14:ENEURO-0038.

      Calvo P. (2016). The philosophy of plant neurobiology: a manifesto. Synthese 193(5):1323-43.

      Calvo P, Friston K. Predicting green: really radical (plant) predictive processing. Journal of The Royal Society Interface. 14(131):20170096.

      Gagliano M, Vyazovskiy VV, Borbély AA, Grimonprez M, Depczynski M. (2016). Learning by association in plants. Scientific Reports Dec 2;6:38427.

      Kandel ER. (1983). From metapsychology to molecular biology: explorations into the nature of anxiety. Am J Psychiatry 140(10):1277-93.