Tuesday, October 10, 2017

BROADEN Trial of DBS for Treatment-Resistant Depression No Better than Sham

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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Tuesday, September 19, 2017

Neuroexistentialism: A Brain in Search of Meaning

[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

1 Despair:
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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Monday, September 04, 2017

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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Saturday, August 19, 2017

Smell as a Weapon, and Odor as Entertainment



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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Sunday, August 13, 2017

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

1 But 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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Sunday, July 16, 2017

Role of the Vestibular System in the Construction of Self



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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Friday, June 30, 2017

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

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

2 They 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.



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