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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Monday, May 21, 2018

What counts as "memory" and who gets to define it?


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 reflex 1 (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

1 edited 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.

3 But 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.

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Sunday, May 13, 2018

“My family say they grieve for the old me” – profound personality changes after deep brain stimulation



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

1 One 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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Sunday, April 29, 2018

The Fractionation of Auditory Semantic Knowledge: Agnosia for Bird Calls




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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