Thursday, September 20, 2018

Dr. Bernard Carroll: blogger, funny tweeter, and critic of scientific and ethical lapses in psychiatry


Dr. Bernard Carroll (Nov 21, 1940 – Sep 10, 2018)




I was friends with Dr. Carroll (“Barney”) on Twitter, and always enjoyed his wit.



Before that he was an early commenter and supporter of my blog, The Neurocritic. Which pleased me to no end, given this brief biography from his blogger site.


My blogs Health Care Renewal
Occupation Psychopharmacology
Introduction Past chairman FDA Psychopharmacologic Drugs Advisory Committee.
Past chairman, department of psychiatry Duke University Medical Center.
Interests Professional ethics, medicine


He didn't know who I was and didn't care. He assessed me by the quality of my writing, and allowed me entrée into a world I would have no access to otherwise.1

As I'm facing the most catastrophic loss of my life, I will miss him too. He was a brilliant, principled, and compassionate man.


Remembrance from Health Care RenewalRemembering Dr Bernard Carroll


Obituary in BMJ by Dr. Allen Frances (and Dr. Barney Carroll):

Barney Carroll: the conscience of psychiatry
A pioneer in biological psychiatry, more recently Bernard Carroll (‘‘Barney’’) became a withering critic of its compromised ethics and corruption by industry. Shortly before his death, he helped prepare this obituary—his last chance to help correct the perverse incentives that too often influence the conduct and reporting of scientific research.
. . .

Barney rejected grand biological theories that offered neat, simple-but-wrong explanations of psychopathology. Ever aware of the complexity of the human brain, he was an early rejecter of blind optimism that any simple imbalance of monoamine transmitters could account for the wide variety of mental disorders. More recently, he deplored the ubiquitous hype that suggested that genetics or neuroimaging or big data mining could provide simple answers to deeply complex questions. He predicted—presciently—that these powerful new tools would have great difficulty in producing solid, replicable findings that could be translated to clinical practice.





Footnote

1 i.e., Very senior male psychiatrists. When I wrote my blog post about being female, and my wife's diagnosis of stage 4 cancer...

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.

...Barney was the first to comment, with his usual wit and grace: “I am pretty sure we can handle that. Bless you both.”

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Monday, September 10, 2018

Brain stimulation during sleep does not enhance memory for learned material



“Learn while you sleep” has been the claim of snake oil salesmen since the 1950s. The old pseudoscience methods involved listening to tapes and records. From a 1958 article by Lester David:
Max Sherover, president of the Linguaphone Institute of New York ... coined the word “dormiphonics,” defining it as a “new scientific method that makes quick relaxed learning possible, awake or asleep.” Dormiphonics, declares Mr. Sherover, works by “repeated concentrated impact of selected material on the conscious and subconscious mind.”

An “experiment” was conducted at the Tulare County Prison, where 100 convicts “volunteered to act as guinea pigs” (considered completely unethical by today's standards). During sleep, they were subjected to low-volume recordings that exhorted them to be better human beings: “Love shall rule your life. You shall love God, your family and others. You shall do unto others as you want others to do unto you. . .” The low voice also warned them away from the evils of alcohol.


Knight Education Recordings (1960s)
a commercially available product of the era


Even earlier, the Psycho-Phone (Salinger, 1927) played wax cylinders with different self-help messages, e.g., “Prosperity” and “Life Extension” on a phonograph while the unwitting customer slept. The Cummings Center Blog has a great post on this odd contraption. Salinger sold the machines for the whopping price of $235 (the equivalent of $3,250 in 2017). He didn't need Kickstarter or Indiegogo.




In the modern era, DIY brain stimulation enthusiasts promote self-experimentation with battery-driven devices. These transcranial direct current stimulation (tDCS) kits are available online, with a primary goal of enhancing cognitive performance. Using state-of-the-art professionally manufactured devices, scientists have published thousands of peer-reviewed papers, with mixed results as to the efficacy of different tDCS protocols.

A newer method is transcranial alternating current stimulation (tACS), which delivers stimulation within precise frequency bands with the aim of synchronizing oscillations within that band (e.g., ~10 Hz for alpha, ~1-4 Hz for delta, etc.). The goal is to modulate ongoing oscillatory brain rhythms to affect behavior.1

Today, the importance of sleep for the consolidation of previously learned material has been well-documented. Conceptually, this is quite different from the discredited “subliminal sleep learning” from days of yore. New research aims to improve retention of information learned during the day by delivering precisely timed and calibrated tACS during slow wave sleep (Ketz et al., 2018).



Fig. 1 (modified from Ketz et al., 2018). (A) Target detection task. (B) Memory was tested on two image types: Repeated (identical to Original) and Generalized (same as Original but from different viewpoint). (C) tDCS montage used during training (left), and tACS montage used to augment slow waves during sleep (right).


During the day, participants were trained on a difficult military task that required them to detect hidden targets (explosive devices, snipers, suicide bombers) that were concealed or disguised (Clark et al, 2012). As in their earlier study, tDCS or sham stimulation was delivered during the training phase (over right frontal or right parietal cortices). Previous findings indicated that significant improvements in learning and performance were observed after 30 min tDCS (anodal 2.0 mA) vs. “sham” (0.1 mA). However, this tDCS finding did not replicate in the current study (see Fig, 3A, left below). Why? The authors speculated that possible differences in current generation between their previous iontophoresis system (2.0 mA) and the present use of StarStim (1.0 mA) could explain the failure to replicate.

After training, tACS was delivered during sleep. The authors' cool closed-loop approach recorded the dominant slow wave (SW) frequency, and then delivered stimulation to match the phase and frequency of this dominant oscillation (range of 0.5 to 1.2 Hz). Fig. 3A (right) doesn't look terribly impressive, however. tACS did not improve performance for Repeated images, and had highly variable effects for Generalized images. Nonetheless, the two- and three-way interactions were significant, as was the pairwise comparison between active tACS vs. sham for Generalized images (all p's ≈ .015 for n=16).



Fig. 3 (modified from Ketz et al., 2018). (A) Waking tDCS effects (left) and SW tACS effects during sleep (right). (B) SW events broken down per sleep stage (left) and total SW events for each stimulation condition (right). Note that active stimulation had fewer total SW events compared with sham.


Why was there no change in performance for Repeated images but a small improvement for Generalized images? The authors recognize this conundrum and say:
...it is unclear why there was no improvement in Repeated images induced by SW tACS, as might be expected based on previous studies.

Then they speculate that consolidation of essential ‘gist’ — rather than recognition of specific items — was impacted by tACS.

Media coverage of this modest finding was predictably overblown, and originated with the Society for Neuroscience press release, Overnight Brain Stimulation Improves Memory: Non-invasive technique enhances memory storage without disturbing sleep. If it enhances memory storage, then why were Repeated images unaffected? Anyway, most commenters at Hacker News were pretty skeptical, which was a pleasant surprise.


Footnote

1 However, there is some question whether tACS delivered at typical stimulation intensities can really entrain endogenous rhythms (Lafon et al., 2017).


References

Clark VP, Coffman BA, Mayer AR, Weisend MP, Lane TD, Calhoun VD, Raybourn EM, Garcia CM, Wassermann EM. (2012). TDCS guided using fMRI significantly accelerates learning to identify concealed objects. Neuroimage 59(1):117-28.

Ketz N, Jones AP, Bryant NB, Clark VP, Pilly PK (2018). Closed-Loop Slow-Wave tACS Improves Sleep-Dependent Long-Term Memory Generalization by Modulating Endogenous Oscillations. J Neurosci. 38(33):7314-7326.

Lafon B, Henin S, Huang Y, Friedman D, Melloni L, Thesen T, Doyle W, Buzsáki G, Devinsky O, Parra LC, A Liu A. (2017). Low frequency transcranial electrical stimulation does not entrain sleep rhythms measured by human intracranial recordings. Nat Commun. 8(1):1199.





Hugo Gernsback
December 1921

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Sunday, August 19, 2018

A Preventable Tragedy in a Man with Semantic Dementia


TAKE HOME MESSAGE: All suicide attempts and parasuicidal gestures should be taken very seriously in patients with dementia.
“Previous parasuicide is a predictor of suicide. The increased risk of subsequent suicide persists without decline for at least two decades.”

A new case report on a 53 year old man1 with semantic dementia (SD) presented his prior parasuicidal gestures as “stereotypic behaviour” [ed. NOTE: repeated attempts to hang himself with a cord is “stereotyped behavior”], with tragic consequences:
The patient showed abnormal behaviours such as following around his wife and frequently visiting a drug store to purchase sleeping pills, which necessitated hospitalization. Despite having no depressive symptoms including suicidal ideation, he repeatedly attempted to hang himself with a cord during a temporary stay at home. At the time of the interview, he stated, ‘I found a cord suspended from the ceiling, and so just played with it by hanging myself. It was just a play’, indicating an absence of suicidal ideation and lack of seriousness for the event. In March 2012, he died by hanging himself with a towel inside his hospital room.

...Despite the fact that the man had been severely depressed for two years before his SD diagnosis, had a well-documented history of suicidal ideation, and had made several suicide attempts (Kobayashi et al., 2018):
In April 2009, the patient started to express suicidal ideation such as ‘I would like to hang myself’. From May to June, he was admitted to a psychiatric hospital because of a deliberate overdose. After being discharged, the patient started to show lack of ability to understand what others were saying, kept insisting on his own way, and became excessively fixated on certain things. In July 2010, he was dismissed from his job because of poor performance. In September 2010, the patient was hospitalized after multiple attempts to hang himself with a cord. During this hospitalization, he was found to have difficulty in naming familiar objects.

His difficulty in naming familiar objects could be an early sign of neurodegeneration (especially in a 53 year old man), but by itself is not diagnostic. But he also had difficulty understanding what other people were saying, i.e. a problem in language comprehension. These symptoms are characteristic of semantic dementia, a type of frontotemporal lobar degeneration associated with a profound loss of meaning words and objects don't make sense any more. He did very poorly on subsequent neuropsychological testing. Neuroimaging results revealed atrophy in bilateral (but L > R) anterior and inferior temporal cortices that is characteristic of SD.



Now, it's easy for me to sit back and be all critical. BUT: I am not a clinician, I was not involved in this case, and hindsight is often 20/20. But it always pays to err on the side of caution when suicidal actions are expressed, even in a person who denies being suicidal, but especially in one who may no longer understand exactly what he's doing.


If you are contemplating suicide or know someone who is, please consult:

Online Suicide Help directory


Footnote

1 They say he's 50 in the Abstract, but the Case Presentation starts out by saying he's 53.


Reference

Kobayashi R, Hayashi H, Tokairin T, Kawakatsu S, Otani K. (2018). Suicide as a result of stereotypic behaviour in a case with semantic dementia. Psychogeriatrics Jul 30. [Epub ahead of print]

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Sunday, August 12, 2018

Improved Brain Health for All! (update on the BRAIN initiative)


adapted from Figure 3 (Koroshetz et al., 2018). Magnetic resonance angiography highlighting the vasculature in the human brain in high resolution, without the use of any contrast agent, on a 7T MRI scanner. Courtesy of Plimeni & Wald (MGH). [ed. note: here's a great summary on If, how, and when fMRI goes clinical, by Dr. Peter Bandettini.]


The Journal of Neuroscience recently published a paywalled article on The State of the NIH BRAIN Initiative. This paper reviewed the research and technology development funded by the “moonshot between our ears” [a newly coined phrase]. The program has yielded a raft of publications (461 to date) since its start in 2014. Although the early emphasis has not been on Human Neuroscience, NIH is ramping up its funding for human imaging and neuromodulation.



They've developed a Neuroethics Division, because...
...neuroscience research in general and the BRAIN Initiative specifically, with its focus on unraveling the mysteries of the human brain, generate many important ethical questions about how these new tools could be responsibly incorporated into medical research and clinical practice.

I don't think most of the current grant recipients are focused on “unraveling the mysteries of the human brain”, however. They're interested in cell types, circuit diagrams, and monitoring and manipulating neural activity in model organisms such as Drosophila, zebrafish, and mice. There are aspirations for a Human Cell Atlas, but many of the other tools are very far away (or impossible) for use in humans.

- click on image to enlarge -



Some aspects of the terminology used by Koroshetz et al., (2018) are vague to the savvy but non-expert eye. What is a neural circuit? The authors never actually define the term. You'll get different answers depending on who you ask. We know that “individual neuroscientists have chosen to work at specific spatial scales, ranging from .. ion channels ... to systems level” and we know there is a range of temporal scales, “from the millisecond of synaptic firing to the entire lifespan” (Koroshetz et al., 2018):
Within this diverse set of scales, the circuit is a key point of focus for two primary reasons: (1) neural circuits perform the calculations necessary to produce behavior; and (2) dysfunction at the level of the circuit is the basis of disability in many neurological and psychiatric disorders.

So maybe key point #1 is a generic working definition of a neural circuit, and is the focus of many NIH BRAIN-funded neuroscientists. But there's a huge leap from the impressive work on e.g. mapping, manipulating, and controlling stress-related feeding behaviors in rodents, and key point #2: isolating circuit dysfunction and ultimately treating eating disorders in humans. There is a lot of “promise” and many “aspirational goals”, but the concluding sentence is just too aspirational and promises too much:
With diverse scientists jointly working in novel team structures, often in partnership with industry, and sharing unprecedented types and quantities of data, the BRAIN Initiative offers a unique opportunity to open the door to a golden age in brain science and improved brain health for all.

The research that gets closest to bridging this gap is electocorticography (ECoG) and deep brain stimulation (DBS) in human patients.1 The exemplar cited in the NIH paper is by Swann et al. (2018), and involved testing a closed-loop DBS system in two Parkinson's patients. The Activa PC + S system (Medtronic) is able to both stimulate the brain target region (subthalamic nucleus, STN) and record neural activity at the same time. The local field potential (LFP) activity is then fed back to the stimulator, which adjusts its parameters based on a complex control algorithm derived from the neural data.

Fig. 4 (Swann et al., 2018). Adaptive DBS.


The unique aspect here is that the authors recorded gamma oscillations (60–90 Hz in this case) from a subdural lead over motor cortex to adjust stimulation. In earlier work, they showed this gamma power was indicative of dyskinesia (abnormal, uncontrolled, involuntary movement), so STN stimulation was adjusted when gamma was above a certain threshold. The study demonstrated feasibility, and its greatest benefit at this early point was energy savings that preserved the battery.

It's cool work that has been promoted by NIH, but unfortunately the first author was not mentioned in the press release, not featured in the accompanying video, and her name isn't even visible on a shot of the poster that appears in the video.2  [the last author gets all the credit.]

Future NIH BRAIN studies will address essential tremor, epilepsy, obsessive-compulsive disorder, major depressive disorder, traumatic brain injury, stroke, tetraplegia, and blindness (apparently).


Returning to key point #1, some have criticized the distinct lack of emphasis on behavior, which echos recent papers (see An epidemic of "Necessary and Sufficient" neurons).


The next tweet is critical too, and an interesting discussion ensued.


And given all the technology development funded by BRAIN, it's a great time to be a neuroengineer, but not a neuropsychologist, ethologist, or behavioral specialist.
Indeed, the BRAIN Initiative funded an equal number of investigators trained in engineering relative to those trained in neuroscience in 2016 (Koroshetz et al., 2018).

Footnotes

1 DARPA is the biggest investor here.

2 We interrupt the NIH press coverage of this paper to acknowledge the first author, Dr. Nicki Swann. Dr. Swann and many of her female colleagues have described the difficulties of traveling and attending conferences while being a new mother, and offered some possible solutions. If the BRAIN Initiative is serious about addressing Neuroethics (for animals and futuristic sci-fi applications to human patients), they should also be actively involved in issues affecting women and minority researchers. And I imagine they are, it just wasn't apparent here.


References

Koroshetz W, Gordon J, Adams A, Beckel-Mitchener A, Churchill J, Farber G, Freund M, Gnadt J, Hsu N, Langhals N, Lisanby S. (2018). The State of the NIH BRAIN Initiative. Journal of Neuroscience Jun 19:3174-17.  NOTE: this should really be open access...

Swann NC, de Hemptinne C, Thompson MC, Miocinovic S, Miller AM, Gilron R, Ostrem JL, Chizeck HJ, Starr PA. (2018). Adaptive deep brain stimulation for Parkinson's disease using motor cortex sensing. J Neural Eng. 15(4):046006.

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Friday, July 13, 2018

An epidemic of "Necessary and Sufficient" neurons

A great deal of neuroscience has become “circuit cracking.”
— Alex Gomez-Marin


A miniaturized holy grail of neuroscience is discovering that activation or inhibition of a specific population of neurons (e.g., prefrontal parvalbumin interneurons) or neural circuit (e.g., basolateral amygdala nucleus accumbens) is “necessary and sufficient” (N&S) to produce a given behavior.



from: Optogenetics, Sex, and Violence in the Brain: Implications for Psychiatry 1 


In the last year or so, it has become acceptable to question the dominant systems/circuit paradigm of “manipulate and measure” as THE method to gain insight into how the brain produces behavior (Krakauer et al., 2017; Gomez-Marin, 2017). Detailed analysis of an organism's natural behavior is indispensable for progress in understanding brain-behavior relationships. Claims that optogenetic and other manipulations of a neuronal population can demonstrate that it is “N&S” for a complex behavior have also been challenged. Gomez-Marin (2017) pulled no punches and stated:
I argue that to upgrade intervention to explanation is prone to logical fallacies, interpretational leaps and carries a weak explanatory force, thus settling and maintaining low standards for intelligibility in neuroscience. To claim that behavior is explained by a “necessary and sufficient” neural circuit is, at best, misleading.

The latest entry into this fault-fest goes further, indicating that most N&S claims in biology violate the principles of formal logic and should be called ‘misapplied-N&S’ (Yoshihara & Yoshihara, 2018). They say the use of “necessary and sufficient” terminology should be banned and replaced with “indispensable and inducing” (except for a handful of instances). 2



modified from Fig. 1A (Yoshihara & Yoshihara, 2018). The relationship between squares and rectangles as a typical example of true necessary (being a rectangle; pale green) and sufficient condition (being a square; magenta) in formal logic.


N&S claims are very popular in optogenetics, which has become a crucial technique in neuroscience. But demonstrating true N&S is nearly impossible, because the terminology disregards: activity in the rest of the brain, whether all the activated neurons are “necessary” (instead of only a subset), what actually happens under natural conditions (rather than artificially induced), the requirement of equivalence, etc. Yoshihara & Yoshihara (2018) are especially disturbed by the incorrect use of “sufficient”, which leads to results being overstated and misinterpreted:
The main problem comes from the word ‘sufficient,’ which is often used to emphasize that artificial expression of only a single gene or activation of only a single neuron can cause a substantial and presumably relevant effect on the whole process of interest. Although it may be sufficient as an experimental manipulation for triggering the effect, it is not actually sufficient for executing the whole effect itself.

And for optogenetics:
Rather, the importance of ‘sufficiency’ experiments lies in demonstrating a causal link through optogenetic activation of neurons... Thus, words such as triggers, promotes, induces, switches, or initiates may better reflect or express the desired nuance without creating such confusion.

Y & Y (2018) aren't shy about naming names in their Commentary, and even say that misapplied-N&S has generated unproductive and misleading studies that offer no scientific insight whatsoever. Although one could say that N&S has a different meaning in biology, or is merely a figure of speech, such strong statements have consequences for the future directions of a field.

Thanks to BoOrg Lab for the link to Gomez-Marin.


Footnotes

1 “...neurons necessary and sufficient for inter-male aggression are located within the ventrolateral subdivision of the ventromedial hypothalamic nucleus (VMHvl)...”

2 One of the instances uses the old discredited “command neuron” concept of Ikeda & Wiersma (1964). They call it A‘Witch Hunt’ of Command Neurons and note that only three command neurons meet the true N&S criteria (one each in lobster, Aplysia, and Drosophila).


References

Gomez-Marin A. (2017). Causal circuit explanations of behavior: Are necessity and sufficiency necessary and sufficient? In: Decoding Neural Circuit Structure and Function (pp. 283-306). Springer, Cham.  {PDF}

Krakauer JW, Ghazanfar AA, Gomez-Marin A, MacIver MA, Poeppel D. (2017). Neuroscience Needs Behavior: Correcting a Reductionist Bias. Neuron. 93(3):480-490.

Yoshihara M, Yoshihara M. (2018). 'Necessary and sufficient' in biology is not necessarily necessary - confusions and erroneous conclusions resulting from misapplied logic in the field of biology, especially neuroscience. J Neurogenet. 32(2):53-64.

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Sunday, June 24, 2018

The Lie of Precision Medicine



This post will be my own personalized rant about the false promises of personalized medicine. It will not be about neurological or psychiatric diseases, the typical topics for this blog. It will be about oncology, for very personal reasons: misery, frustration, and grief. After seven months of research on immunotherapy clinical trials, I couldn't find a single [acceptable] one1 in either Canada or the US that would enroll my partner with stage 4 cancer. For arbitrary reasons, for financial reasons, because it's not the “right” kind of cancer, because the tumor's too rare, because it's too common, because of unlisted exclusionary criteria, because one trial will not accept the genomic testing done for another trial.2 Because of endless waiting and bureaucracy.

But first, I'll let NIH explain a few terms. Is precision medicine the same as personalized medicine? Yes and no. Seems to me it's a bit of a branding issue.
What is the difference between precision medicine and personalized medicine?

There is a lot of overlap between the terms "precision medicine" and "personalized medicine." According to the National Research Council, "personalized medicine" is an older term with a meaning similar to "precision medicine."

Here's a startling paper from 1971, Can Personalized Medicine Survive? (by W.M. GIBSON, MB, ChB in Canadian Family Physician).




[it's a defense of the old-fashioned family doctor (solo practitioner) by Gibson]:
...will the solo practitioner's demise be welcomed, his replacement being a battery of experts in the fields of medicine, surgery, psychiatry and all the new allied health sciences, infinitely better trained than their singlehanded predecessor?

We wouldn't want any confusion between a $320 million dollar initiative and the ancient art of medicine. NIH again:
However, there was concern that the word "personalized" could be misinterpreted to imply that treatments and preventions are being developed uniquely for each individual; in precision medicine, the focus is on identifying which approaches will be effective for which patients based on genetic, environmental, and lifestyle factors.

The Council therefore preferred the term "precision medicine" to "personalized medicine." However, some people still use the two terms interchangeably.

So “precision medicine” is considered a more contemporary and cutting-edge term.


Archived from The White House Blog (Obama edition), January 30, 2015.


What about pharmacogenomics? 
Pharmacogenomics is a part of precision medicine. Pharmacogenomics is the study of how genes affect a person’s response to particular drugs. This relatively new field combines pharmacology (the science of drugs) and genomics (the study of genes and their functions) to develop effective, safe medications and doses3 that are tailored to variations in a person’s genes.

At present, precision pharmacogenomics is just a “tumor grab” with no promise of treatment in most cases. There are some serious and admirable efforts, but accessibility and costs are major barriers.


But we've been promised such a utopia for quite a while.
Personalized medicine in oncology: the future is now (Schilsky, 2010):

Cancer chemotherapy is in evolution from non-specific cytotoxic drugs that damage both tumour and normal cells to more specific agents and immunotherapy approaches. Targeted agents are directed at unique molecular features of cancer cells, and immunotherapeutics modulate the tumour immune response; both approaches aim to produce greater effectiveness with less toxicity. The development and use of such agents in biomarker-defined populations enables a more personalized approach to cancer treatment than previously possible and has the potential to reduce the cost of cancer care.



IT'S 2018, WHERE IS THAT FUTURE YOU PROMISED US?

But wait, let's go back further, to 1999:
New Era of Personalized Medicine 
Targeting Drugs For Each Unique Genetic Profile

Certainly, there are success stories for specific types of cancer (e.g., Herceptin). A more recent example is the PD-1 inhibitor pembrolizumab (Keytruda®), which has shown remarkable results in patients with melanoma, including Jimmy Carter. The problem is, direct-to-consumer marketing creates false hope about the probability that a patient with another form of cancer will respond to this treatment, or one of the many other immunotherapies with PR machines. But if there's a 25% chance or even a 10% chance it'll extend the life of your loved one, you'll go to great lengths to try to acquire it, one way or another. Speaking from personal experience.



But exaggerated claims and the use of the superlatives in describing massively expensive cancer drugs (e.g., “breakthrough,” “game changer,” “miracle,” “cure,” “home run,” “revolutionary,” “transformative,” “life saver,” “groundbreaking,” and “marvel”) are highly questionable (Abola & Prasad, 2016) and even harmful.

It's a truly horrible feeling when you realize there are no options available, and all your hope is gone.


References

Abola MV, Prasad V. (2016). The use of superlatives in cancer research. JAMA oncology. 2(1):139-41.

Gibson WM. (1971). Can personalized medicine survive? Can Fam Physician. 17(8):29-88.

Langreth R, Waldholz M. (1999). New era of personalized medicine: targeting drugs for each unique genetic profile. Oncologist 4(5):426-7.

Schilsky RL. (2010). Personalized medicine in oncology: the future is now. Nat Rev Drug Discov. 9(5):363-6.  {PDF}


Footnotes

1 

2  But hey, we'll do yet another biopsy of your tumor, and let you know the results in 2-3 months, when you're too ill to be enrolled in any trial. Here's a highly relevant article The fuzzy world of precision medicine: deliberations of a precision medicine tumor board but I'm afraid to read it.

3 OMFG, you have got to be kidding me. Here is a subset of the possible side effects from one toxic monoclonal antibody duo:

Very likely (21% or more, or more than 20 people in 100):
  • fatigue/tiredness
  • decrease or loss of appetite, which may result in weight loss
  • cough
  • inflammation of the small intestine and / or large bowel causing abdominal pain and diarrhea which may be severe and life threatening

Less likely (5 – 20% or between 5 and 20 people in 100):
  • pain and or inflammation in various areas including: muscles , joint, belly, back, chest, headache
  • flu-like symptoms such as body aches, fever, chills, tiredness, loss of appetite, cough
  • constipation
  • dizziness
  • shortness of breath
  • infection which may rarely be serious and become life threatening
  • nausea and vomiting
  • dehydration
  • skin inflammation causing hives or rash which may rarely be severe and become life threatening
  • anemia which may cause tiredness, or may require blood transfusion
  • itching
  • abnormal liver function seen by blood tests. This may rarely lead to jaundice (yellowing of the skin and whites of eyes) and be severe or life threatening
  • abnormal function of your thyroid gland which cause changes in hormonal levels. A decrease in thyroid function as seen on blood tests may cause you to feel tired, cold or gain weight while an increase in thyroid function may cause you to feel shaky, have a fast pulse or lose weight.
  • Swelling of arms and/or legs (fluid retention)
  • Changes in the level of body salts as seen on blood tests. You may not have symptoms.
  • Inflammation of the pancreas that results in increased level of digestive enzymoes (lipase, amylase) seen in bloods and may cause abdominal pain
  • Inflammation of the lungs (including fluid in the lungs) which could cause shortness of breath, chest pain, new or worse cough. It could be serious and/or life threatening. May occur more frequently if you are receiving radiation treatment to your chest or if you are Japanese.
  • Serious bleeding events leading to death may occur in patients with head and neck tumors. Please talk to your doctor immediately if you are experiencing bleeding.
  • Decrease of a protein in your blood called albumin that may cause fluid retention and results in swelling of your legs or arms

You get the idea. I'll skip:

Rarely (1 – 4% or less than 5 in 100 people)

Very Rare (less than 1% or less than 1 in 100 people)

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Sunday, June 17, 2018

Citric Acid Increases Balloon Inflation (aka sour taste makes you more risky)


from Balloon Analog Risk Task (BART) – Joggle Research for iPad


Risk taking and risk preference1 are complex constructs measured by self-report questionnaires (“propensity”), laboratory tasks, and the frequency of real-life behaviors (smoking, alcohol use, etc).  A recent mega-study of 1507 healthy adults by Frey et al. (2017) measured risk preference using six questionnaires (and their subscales), eight behavioral tasks, and six frequency measures of real-life behavior.


Table 1 (Frey et al., 2017). Risk-taking measures used in the Basel-Berlin Risk Study.

-- click on image for a larger view --


The authors were interested in whether they could extract a general factor of risk preference (R), analogous to the general factor of intelligence (g). They used a bifactor model to account for the general factor as well as specific, orthogonal factors (seven in this case). The differing measures above are often used interchangeably and called “risk”, but the general factor R only...
...explained substantial variance across propensity measures and frequency measures of risky activities but did not generalize to behavioral measures. Moreover, there was only one specific factor that captured common variance across behavioral measures, specifically, choices among different types of risky lotteries (F7). Beyond the variance accounted for by R, the remaining six factors captured specific variance associated with health risk taking (F1), financial risk taking (F2), recreational risk taking (F3), impulsivity (F4), traffic risk taking (F5), and risk taking at work (F6).

In other words, the behavioral tasks didn't explain R at all, and most of them didn't even explain common variance across the tasks themselves (F7 below).



Fig. 2 (Frey et al., 2017). Bifactor model with all risk-taking measures, grouped by measurement tradition. BART is outlined in red.


Here's where we come to the recent study on “risk” and taste. The headlines were either misleading (A Sour Taste in Your Mouth Means You’re More Likely to Take Risks) or downright false no lemons were used (When Life Gives You Lemons, You Take More Risks) and this doozy (The Fruit That Helps You Take Risks – May Help Depressed And Anxious).

To assess risk-tasking, Vi and Obrist (2018) administered the Balloon Analog Risk Task (BART) to 70 participants in the UK and 71 in Vietnam. They were randomly assigned to one of five taste groups [yes, n=14 each] of Bitter (caffeine), Salty (sodium chloride), Sour (citric acid), Umami (MSG), and Sweet (sugar, presumably). They were given two rounds of BART and consumed 20 ml of flavored drink or plain water before each (in counterbalanced order).

[Remember that BART didn't load on a general factor of risk-taking, nor did it capture common variance across behavioral tasks.]

As in the animation above (and a video made by the authors)2, the participant “inflates” a virtual balloon via mouse click until they either stop and win a monetary reward, or else they pop the balloon and lose money. The number of clicks (pumps) indicates risk-taking behavior. Overall, the Vietnamese students (all recruited from the School of Biotechnology and Food Technology at Hanoi University) appeared to be riskier than the UK students (but I don't know if this was tested directly). The main finding was that both groups clicked more after drinking citric acid than the other solutions.



Why would this this balloon pumping be more vigorous after tasting a sour solution? We could also ask, why were the Vietnamese subjects more risk-averse after drinking salt water, and riskier (relative to UK subjects) after drinking sugar water?3 We simply don't know the answer to any of these questions, but the authors weren't shy about extrapolating to clinical populations:
For example, people who are risk-averse (e.g., people with anxiety disorders or depression) may benefit from a sour additive in their diet.

Smelling lemon oil is relaxing, but tasting citric acid promotes risk:
Prior work has, for instance, shown that in cases of psychiatric disorders such as depression, anxiety, or stress-related disorders the use of lemon oils proved efficient and was further demonstrated to reduce stress. While lemon and sour are not the same, they share common properties that can be further investigated with respect to risk-taking.

We're really not sure how any of this works. The authors offered many more analyses in the Supplementary Materials, but they didn't help explain the results. Although the sour finding was interesting and observed cross culturally, would it replicate using groups larger than n=14?


Footnotes

1 From Frey et al. (2017):
The term “risk” refers to properties of the world, yet without a clear agreement on its definition, which has ranged from probability, chance, outcome variance, expected values, undesirable events, danger, losses, to uncertainties. People’s responses to those properties, on the other hand, are typically described as their “risk preference.”

2 The video conveniently starts by illustrating risk as skydiving, which bears no relation to being an adventurous eater.

3 The group difference in umami had a cultural explanation.


References

Frey R, Pedroni A, Mata R, Rieskamp J, Hertwig R. (2017). Risk preference shares the psychometric structure of major psychological traits. Science Advances 3(10):e1701381.

Vi CT, Obrist M. (2018). Sour promotes risk-taking: an investigation into the effect of taste on risk-taking behaviour in humans. Scientific Reports 8(1):7987.




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