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Channel: The Neurocritic

Thoughts of Blue Brains and GABA Interneurons

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An unsuccessful planto create a computer simulation of a human brain within 10 years. An exhaustive catalog of cell types comprising a specific class of inhibitory neurons within mouse visual cortex. What do these massive research programs have in common? Both efforts were conducted by large multidisciplinary teams at non-traditional research institutions: the Blue Brain Project based in Lausanne, Switzerland and the Allen Institute for Brain Science in Seattle, Washington.

BIG SCIENCE is the wave of the future, and the future is now. Actually, that future started 15-20 years ago. The question should be, is there a future for any other kind of neuroscience?
 

Despite a superficial “BIG SCIENCE” similarity, the differences between funding sources, business models, leadership, operation, and goals of Blue Brain and the Allen Institute are substantial. Henry Markram, the “charismatic but divisive” visionary behind Blue Brain (and the €1 billion Human Brain Project) has been criticized for his “autocratic” leadership, “crap” ideas, and “ill-conceived, ... idiosyncratic approach to brain simulation” in countless articles. His ambition is undeniable, however:

“I realized I could be doing this [eg., standard research on spike-timing-dependent plasticity] for the next 25, 30 years of my career, and it was still not going to help me understand how the brain works.”

 

I'm certainly not a brilliant neuroscientist in Markram's league, but I commented previously on how a quest to discover “how the brain works” might be futile:

...the search for the Holy Grail of [spike trains, network generative models, manipulated neural circuit function, My Own Private Connectome, predictive coding, the free energy principle (PDF), or a computer simulation of the human brain promised by the Blue Brain Project] that will “explain” how “The Brain” works is a quixotic quest. It's a misguided effort when the goal is framed so simplistically (or monolithically).


In his infamous 2009 TED talk, Markram stated that a computer simulation of the human brain was possible in 10 years:
“I hope that you are at least partly convinced that it is not impossible to build a brain. We can do it within 10 years, and if we do succeed, we will send to TED, in 10 years, a hologram to talk to you.”


This claim would come back to haunt him in 2019, because (of course) he was nowhere close to simulating a human brain. In his defense, Markram said that his critics misunderstood and misinterpreted his grandiose proclamations.1

Blue Brain is now aimed at“biologically detailed digital reconstructions and simulations of the mouse brain.”

In Silico

Documentary filmmaker Noah Hutton2undertook his own 10 year project that followed Markram and colleagues as they worked towards the goals of Blue Brain. He was motivated by that TED talk and its enthralling prediction of a brain in a supercomputer (hence in silico). Originally entitled Bluebrain and focused on Markram, the documentary evolved over time to include more realistic viewpoints and interviews with skeptical scientists, including Anne Churchland, Terry Sejnowski, Stanislas Dehaene, and Cori Bargmann. Ironically, Sebastian Seung was one of the loudest critics (ironic because Seung has a grandiose TED talk of his own, I Am My Connectome).


 

In Silico was available for streaming during the DOC NYC Festival in November (in the US only), and I had the opportunity to watch it. I was impressed by the motivation and dedication required to complete such a lengthy project.  Hutton had gathered so much footage that he could have made multiple movies from different perspectives.

Over the course of the film, Blue Brain/Human Brain blew up, with ample critiques and a signed petition from hundreds of neuroscientists (see archived Open Letter).

And Hutton grew up. He reflects on the process (and how he changed) at the end of film. He was only 22 at the start, and 10 years is a long time at any age.

Some of the Big Questions in In Silico:

  • How do you make sure all this lovely simulated activity would be relevant for an animal's behavior?
  • How do you build in biological imperfections (noise) or introduce chaos into your perfect pristine computational model? “Tiny mistakes” are critical for adaptable biological systems.

  • “You cannot play the same soccer game again,” said one of the critics (Terry Sejnowski, I think)

  • “What is a generic brain?”
  • What is the vision? 

The timeline kept drifting further and further into the future. It was 10 years in 2009, 10 years in 2012, 10 years in 2013, etc. 

Geneva 2019, and it's Year 10 only two Principals left, 150 papers published, and a model of 10 million neurons in mouse cortex. Stunning visuals, but still disconnected from behavior.

In the end, “What have we learned about the brain? Not much. The model is incomprehensible,” to paraphrase Sejnowski.


GABA Interneurons

Another brilliant and charismatic neuroscientist, Christof Koch, was interviewed by Hutton. “Henry has two personalities. One is a fantastic, sober scientist … the other is a PR-minded messiah.”

Koch is Chief Scientist of the MindScope Program at the Allen Institute for Brain Science, which focuses on how neural circuits produce vision. Another major unit is the Cell Types Program, which (as advertised) focuses on brain cell types and connectivity.3

The Allen Institute core principles are team science, Big Science, and open science. An impressive recent paper by Gouwens and 97 colleagues (2020) is a prime example of all three. Meticulous analyses of structural, physiological, and genetic properties identified 28 “met-types” of GABAergic interneurons that have congruent morphological, electrophysiological, and transcriptomic properties. This was winnowed down from more than 500 morphologies in 4,200 GABA-containing interneurons in mouse visual cortex. With this mind-boggling level of neuronal complexity in one specific class of cells in mouse cortex — along with the impossibility of “mind uploading” — my inclination is to say that we will never(never say never) be able to build a realistic computer simulation of the human brain.


Footnotes 

1 Here's another gem: “There literally are only a handful of equations that you need to simulate the activity of the neocortex.”

2 Most of Hutton's work has been as writer and director of documentary films, but I was excited to see that his first narrative feature, Lapsis, will be available for streaming next month. To accompany his film, he's created an immersive online world of interlinked websites that advertise non-existent employment opportunities, entertainment ventures, diseases, and treatments. It very much reminds me of the realistic yet spoof websites associated with the films Eternal Sunshine of the Spotless Mind (LACUNA, Inc.) and Ex Machina (BlueBook). In fact, I'm so enamored with them that they've appeared in several of my own blogposts.

3 Investigation of cell types is big in the NIH BRAIN Initiative ® as well.



References

Abbott A. (2020). Documentary follows implosion of billion-euro brain project. Nature 588:215-6.

[Alison Abbott covered the Blue Brain/Human Brain sturm und drang for years]

Gouwens NW, Sorensen SA, Baftizadeh F, Budzillo A, Lee BR, Jarsky T, Alfiler L, Baker K, Barkan E, Berry K, Bertagnolli D ... Zeng H et al. (2020). Integrated morphoelectric and transcriptomic classification of cortical GABAergic cells. Cell 83(4):935-53.

Waldrop M. (2012). Computer modelling: Brain in a box. Nature News 482(7386):456.


Further Reading

The Blue Brain Project (01 February 2006), by Dr. Henry Markram

“Alan Turing (1912–1954) started off by wanting to 'build the brain' and ended up with a computer. ... As calculation speeds approach and go beyond the petaFLOPS range, it is becoming feasible to make the next series of quantum leaps to simulating networks of neurons, brain regions and, eventually, the whole brain.”

A brain in a supercomputer (July 2009), Henry Markram's TED talk
“Our mission is to build a detailed, realistic computer model of the human brain. And we've done, in the past four years, a proof of concept on a small part of the rodent brain, and with this proof of concept we are now scaling the project up to reach the human brain.”


Blue Brain Founder Responds to Critics, Clarifies His Goals (11 Feb 2011), Science news

Bluebrain: Noah Hutton's 10-Year Documentary about the Mission to Reverse Engineer the Human Brain (9 Nov 2012), an indispensable interview with Ferris Jabr in Scientific American

European neuroscientists revolt against the E.U.'s Human Brain Project (11 July 2014), Science news

Row hits flagship brain plan (7 July 2014), Nature news

Brain Fog (7 July 2014), Nature editorial

Human Brain Project votes for leadership change (4 March 2015), Nature news

'In Silico:' Director Noah Hutton reveals how one neuroscientist's pursuit of perfection went awry (10 Nov 2020), another indispensable interview, this time with Nadja Sayej in Inverse

“They still haven’t even simulated a whole mouse brain. I realized halfway through the 10-year point that the human brain probably wasn’t going to happen.” ...

In the first few years, I followed only the team. Then, I started talking to critics.

 

 


Overview of 'The Spike': an epic journey through failure, darkness, meaning, and spontaneity

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from Princeton University Press (March 9, 2021)


THE SPIKE is a marvelously unique popular neuroscience book by Professor Mark Humphries, Chair of Computational Neuroscience at the University of Nottingham and Proprietor of The Spike blog on Medium. Humphries' novel approach to brain exposition is built around — well— the spike, the electrical signal neurons use to communicate. In this magical rendition, the 2.1 second journey through the brain takes 174 pages (plus Acknowledgments and Endnotes).

I haven't read the entire book, so this is not a proper book review. But here's an overview of what I might expect. The Introduction is filled with inventive prose like, “We will wander through the splendor of the richly stocked prefrontal cortex and stand in terror before the wall of noise emanating from the basal ganglia.” (p. 10).


Did You Know That Your Life Can Be Reduced To Spikes?

Then there's the splendor and terror of a life reduced to spikes (p. 3):

“All told, your lifespan is about thirty-four billion billion cortical spikes.”


Spike Drama

But will I grow weary of overly dramatic interpretations of spikes? “Our spike's arrival rips open bags of molecules stored at the end of the axon, forcing their contents to be dumped into the gap, and diffuse to the other side.” (p. 29-30).

Waiting for me on the other side of burst vesicles are intriguing chapters on Failure (dead end spikes) and Dark Neurons, the numerous weirdos who remain silent while their neighbors are “screaming at the top of [their] lungs.” (p. 83). I anticipate this story like a good mystery novel with wry throwaway observations (p. 82):

“Neuroimaging—functional MRI—shows us Technicolor images of the cortex, its regions lit up in a swirling riot of poorly chosen colors that make the Pantone people cry into their tasteful coffee mugs.”


Pantone colors of 2021 are gray and yellow

 

Wherever it ends up – with a mind-blowing new vision of the brain based on spontaneous spikes, or with just another opinion on predictive coding theory – I predict THE SPIKE will be an epic and entertaining journey. 

 


Overinterpreting Computational Models of Decision-Making

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Bell (1985)



Can a set of equations predict and quantify complex emotions resulting from financial decisions made in an uncertain environment? An influential paper by David E. Bell considered the implications of disappointment, a psychological reaction caused by comparing an actual outcome to a more optimistic expected outcome, as in playing the lottery. Equations for regret, disappointment, elation, and satisfaction have been incorporated into economic models of financial decision-making (e.g., variants of prospect theory).

Financial choices comprise one critical aspect of decision-making in our daily lives. There are so many choices we make every day, from the proverbial option paralysis in the cereal aisle...

...to decisions about who to date, where to go on vacation, whether one should take a new job, change fields, start a business, move to a new city, get married, get divorced, have children (or not).

And who to trust. Futuristic scenario below...


Decision to Trust

I just met someone at a pivotal meeting of the Dryden Commission. We chatted beforehand and discovered we had some common ground. Plus he's brilliant, charming and witty.

“Are you looking for an ally?” he asked. 


Neil, Laura and Stanley in Season 3 of Humans

 

Should I trust this person and go out to dinner with him? Time to ask my assistant Stanley, the orange-eyed (servile) Synthetic, an anthropomorphic robot with superior strength and computational abilities.


Laura:“Stanley, was Dr. Sommer lying to me just then, about Basswood?”


Stanley, the orange-eyed Synth: “Based on initial analysis of 16 distinct physiological factors, I would rate the likelihood of deceit or misrepresentation in Dr. Sommer's response to your inquiry at... EIGHTY-FIVE PERCENT.”

The world would be easier to navigate if we could base our decisions on an abundance of data and well-tuned weighting functions accessible to the human brain. Right? Like a computational model of trust and reputation or a model of how people choose to allocate effort in social interactions. Right?

I'm out of my element here, so this will limit my understanding of these models. Which brings me to a more familiar topic: meta-commentary on interpretation (and extrapolation).

Computational Decision-Making


My motivation for writing this post was annoyance. And despair. A study on probabilistic decision-making under uncertain and volatile conditions came to the conclusion that people with anxiety and depression will benefit from focusing on past successes, instead of failures. Which kinda goes without saying. The paper in eLife was far more measured and sophisticated, but the press release said:

The more chaotic things get, the harder it is for people with clinical anxiety and/or depression to make sound decisions and to learn from their mistakes. On a positive note, overly anxious and depressed people’s judgment can improve if they focus on what they get right, instead of what they get wrong...

...researchers tested the probabilistic decision-making skills of more than 300 adults, including people with major depressive disorder and generalized anxiety disorder. In probabilistic decision making, people, often without being aware of it, use the positive or negative results of their previous actions to inform their current decisions.


The unaware shall become aware. Further advice:

“When everything keeps changing rapidly, and you get a bad outcome from a decision you make, you might fixate on what you did wrong, which is often the case with clinically anxious or depressed people...”

...individualized treatments, such as cognitive behavior therapy, could improve both decision-making skills and confidence by focusing on past successes, instead of failures...

 

The final statement on individualized CBT could very well be true, but it has nothing to do with the outcome of the study (Gagne et al., 2021), wherein participants chose between two shapes associated with differential probabilities of receiving electric shock (Exp. 1), or financial gain or loss (Exp. 2).
 


With that out of the way, I will say the experiments and the computational modeling approach are impressive. The theme is probabilistic decision-making under uncertainty, with the added bonus of volatility in the underlying causal structure (e.g., the square is suddenly associated a higher probability of shocks). People with anxiety disorders and depression are generally intolerant of uncertainty. Learning the stimulus-outcome contingencies and then rapidly adapting to change was predictably impaired.

Does this general finding differ for learning under reward vs. punishment? For anxiety vs. depression? In the past, depression was associated with altered learning under reward, while anxiety was associated with altered learning under punishment (including in the authors'own work). For reasons that were not entirely clear to me, the authors chose to classify symptoms using a bifactor model designed to capture “internalizing psychopathology” common to both anxiety and depression vs. symptoms that are unique to each disorder [ but seeFried (2021) ]1

Overall, high scores on the common internalizing factor were associated with impaired adjustments to learning rate during the volatile condition, and this held whether the outcomes were shocks, financial gains, or financial losses. Meanwhile, high scores on anxiety-unique or depression-unique symptoms did not show this relationship. This was determined by computational modeling of task performance, using a hierarchical Bayesian framework to identify the model that best described the participants' behavior:

We fitted participants’ choice behavior using alternate versions of simple reinforcement learning models. We focused on models that were parameterized in a sufficiently flexible manner to capture differences in behavior between experimental conditions (block type: volatile versus stable; task version: reward gain versus aversive) and differences in learning from better or worse than expected outcomes. We used a hierarchical Bayesian approach to estimate distributions over model parameters at an individual- and population-level with the latter capturing variation as a function of general, anxiety-specific, and depression-specific internalizing symptoms. 


We've been living in a very uncertain world for more than a year now, often in a state of loneliness and isolation. Some of us have experienced loss after loss, deteriorating mental health, lack of motivation, lack of purpose, and difficulty making decisions. My snappish response to the press release concerns whether we can prescribe individualized therapies based on the differences between the yellow arrows on the left (“resilient people”) compared to the right (“internalizing people” — i.e., the anxious and depressed), given that the participants may not even realize they're learning anything.



 Footnote

1 I will leave it to Dr. Eiko Fried (2021) to explain whether we should accept (or reject) this bifactor model of “shared symptoms” vs. “unshared symptoms”.



References

Bell DE. (1985) Disappointment in decision making under uncertainty. Operations research 33(1):1-27.

Gagne C, Zika O, Dayan P, Bishop SJ. (2020). Impaired adaptation of learning to contingency volatility in internalizing psychopathology. Elife 9:e61387.

Further Reading

Fried EI. (2020). Lack of theory building and testing impedes progress in the factor and network literature. Psychological Inquiry 31(4):271-88.

Guest O, Martin AE. (2021) How computational modeling can force theory building in psychological science. Perspect Psychol Sci. Jan 22:1745691620970585.

van Rooij I, Baggio G. (2021). Theory before the test: How to build high-verisimilitude explanatory theories in psychological science. Perspect Psychol Sci. Jan 6:1745691620970604.

Hoarders and Collectors

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Andy Warhol's collection of dental models

 
Pop artist Andy Warhol excelled in turning the everyday and the mundane into art. During the last 13 years of his life, Warhol put thousands of collected objects into 610 cardboard boxes. These Time Capsules were never sold as art, but they were meticulously cataloged by museum archivists and displayed in a major exhibition at the Andy Warhol Museum. “Warhol was a packrat. But that desire to collect helped inform his artistic point of view.” Yet Warhol was aware of his compulsion, and it disturbed him: “I'm so sick of the way I live, of all this junk, and always dragging home more.”

Where does the hobby of collection cross over into hoarding, and who makes this determination? 

Artists get an automatic pass into the realm of collectionism, no matter their level of compulsion. The Vancouver Art Gallery held a major exhibition of the works of Canadian writer and artist Douglas Coupland in 2014. One of the sections consisted of a room filled with 5,000 objects collected over 20 years and carefully arranged in a masterwork called The Brain. Here's what the collection looked like prior to assembly.
 

Materials used in the The Brain, 2000–2014, mixed-media installation with readymade objects. Courtesy of the Artist and Daniel Faria Gallery. Photo: Trevor Mills, Vancouver Art Gallery.


Hoarding, on the other had, lacks the artistic intent or deliberate organization of collection. Collectors may be passionate, but their obsessions/compulsions do not hinder their everyday function (or personal safety). According to Halperin and Glick (2003):
“Characteristically, collectors organize their collections, which while extensive, do not make their homes dysfunctional or otherwise unlivable. They see their collections as adding a new dimension to their lives in terms of providing an area of beauty or historical continuity that might otherwise be lacking.”
 
The differential diagnosis for the DSM-5 classification of Hoarding Disorder vs. non-pathological Collecting considers order and value of primary importance.



Fig. 2 (Nakao & Kanba, 2019).
If possessions are well organized and have a specific value, the owner is defined as a ‘collector.’ Medical conditions that cause secondary hoarding are excluded from Hoarding Disorder. The existence of comorbidities such as obsessive-compulsive disorder (OCD), autism spectrum disorder (ASD), and attention deficit hyperactivity disorder (ADHD) must be excluded as well.


I've held onto the wish of writing about this topic for the last eight months...


...because of the time I spent sorting through my mother's possessions between July 2020 and November 2020 after she died on July 4th. This process entailed flying across the country five times in a total of 20 different planes in the midst of a pandemic.
 
Although my mother showed some elements of  hoarding, she didn't meet clinical criteria. She had various collections of objects (e.g., glass shoes, decorator plates, snuff bottles, and ceremonial masks), but what really stood out were her accumulations— organized but excessive stockpiles of useful items such as flashlights, slippers, sweatshirts, kitchen towels, and watches (although most of the latter were no longer useful).
 

Ten pairs of unworn gardening gloves


During the year+ of COVID sheltering-in-place, some people wrote books, published papers, started nonprofits, engaged in fundraising, held Zoom benefit events, demonstrated for BLM, home-schooled their kids, taught classes, cared for sick household members, mourned the loss of their elder relatives, or endured COVID-19 themselves.
 
I dealt with the loss of a parent, along with the solo task of emptying 51 years of accumulated belongings from her home. To cope with this sad and lonely and emotionally grueling task, I took photos of my mother's accumulations and collections. It became a mini-obsession unto itself. I tried to make sense of my mother's motivations, but the trauma of her suffering and the specter of an unresolved childhood were too overwhelming. Besides, there's no computational model to explain the differences between Collectors, Accumulators and Hoarders.
 

Additional Reading

Compulsive Collecting of Toy Bullets

Compulsive Collecting of Televisions

The Neural Correlates of Compulsive Hoarding

Welcome to Douglas Coupland's Brain


References

Halperin DA, Glick J. (2003). Collectors, accumulators, hoarders, and hoarding perspectives. Addictive Disorders & Their Treatment 2(2):47-51.

Nakao T, Kanba S. (2019). Pathophysiology and treatment of hoarding disorder. Psychiatry Clin Neurosci. 73(7):370-375. doi:10.1111/pcn.12853





Did dreams evolve to transcend overfitting?

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A fascinating new paper proposes that dreams evolved to help the brain generalize, which improves its performance on day to day tasks. Incorporating a concept from deep learning, Erik Hoel (2021):

“...outlines the idea that the brains of animals are constantly in danger of overfitting, which is the lack of generalizability that occurs in a deep neural network when its learning is based too much on one particular dataset, and that dreams help mitigate this ubiquitous issue. This is the overfitted brian [sic] hypothesis.”

 

The Overfitted Brain Hypothesis (OHB) proposes that the bizarre phenomenology of dreams is critical to their functional role. This view differs from most other neuroscientific theories, which treat dream content as epiphenomenal — a byproduct of brain activity involved in memory consolidation, replay, forgetting, synaptic pruning, etc.  

In contrast, Hoel suggests that “it is the very strangeness of dreams in their divergence from waking experience that gives them their biological function.”

The hallucinogenic, category-breaking, and fabulist quality of dreams means they are extremely different from the “training set” of the animal (i.e., their daily experiences).
. . .

To sum up: the OBH conceptualizes dreams as a form of purposefully corrupted input, likely derived from noise injected into the hierarchical structure of the brain, causing feedback to generate warped or “corrupted” sensory input. The overall evolved purpose of this stochastic activity is to prevent overfitting. This overfitting may be within a particular module or task such a specific brain region or network, and may also involve generalization to out-of-distribution (unseen) novel stimuli.


Speaking of overfitting, I was reminded of Google's foray into artificial neural networks for image classification, which was all the rage in July 2015. The DeepDream program is a visualization tool that shows what the layers of the neural network have learned:

One way to visualize what goes on is to turn the network upside down and ask it to enhance an input image in such a way as to elicit a particular interpretation.


The image above is characteristic of the hallucinogenic output from the DeepDream web interface, and it illustrates that the original training set was filled with dogs, birds, and pagodas.  DeepDream images inspired blog posts with titles like, Do neural nets dream of electric sheep? and Do Androids Dream of Electric Bananas? and my favorite, Scary Brains and the Garden of Earthly Deep Dreams.


Reference

Hoel E. (2021). The overfitted brain: Dreams evolved to assist generalization. Patterns 2(5):100244.

 


The rs-FC fMRI Law of Attraction (i.e., Resting-State Functional Connectivity of Speed Dating Choice)

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Feeling starved for affection after 15 months of pandemic-mandated social distancing? Ready to look for a suitable romantic partner by attending an in-person speed dating event? Just recline inside this noisy tube for 10 minutes, think about anything you like, and our algorithm will Predict [the] Compatibility of a Female-Male Relationship!

This new study by Kajimura and colleagues garnered a lot of attention on Twitter, where it was publicized by @INM7_ISN (Simon Eickhoff) and @Neuro_Skeptic. The prevailing sentiment was not favorable (check the replies)...

 

 

Full disclosure: I was immediately biased against the claims made in this study...

This research emphasizes the utility of neural information to predict complex phenomena in a social environment that behavioral measures alone cannot predict.

...and have covered earlier attempts at linking speed dating choice to a proxy of neural activity. But I wanted to be fair and see what the authors did, since their results reflect an enormous amount of work.

Here I will argue that a 10 minute brain scan cannot predict who you will choose at a speed dating event. The resultant measures are even further away from identifying a compatible mate for you, since only 5% of speed dating interactions result in a relationship of any sort (6% for sexual relationships and 4% for romantic relationships, according to one study).

I was flabbergasted that anyone would think a “resting” state MRI scan (looking at “+” for 10 min) and its resulting pattern of correlated BOLD signal fluctuations would reflect a level of superficial desirability that can be detected by a potential mate at greater than chance level. Another disclosure: this is far from my field of expertise. So I searched the literature. Apparently, “patterns of functional brain activity during rest encode latent similarities (e.g., in terms of how people think and behave) that are associated with friendship” (Hyon et al., 2020). However, that study was conducted in a small town in South Korea (total population 860), allowing a detailed social network analysis. Plus, people knew each other well and experienced many of the same day to day events, which could shape their functional connectomes. Not exactly relevant for predicting strangers' speed dating choices, eh?

Another paper identified a “global personality network” based on data from 984 participants in the Human Connectome Project (Liu et al., 2019). The sample was large enough to support a training set of n=801 and a “hold-out” dataset (n=183) for validation purposes. The results supported the authors'“similar brain, similar personality” hypothesis. But in the dating world, how much do “similars” attract (compared to the popular saying, “opposites attract”)? Well why not construct (dis)similarity profiles between potential pairs by taking the absolute value of differences in functional connectivity (FC), and combine those with values of similarities in FC? Does that make sense?? And in order to arrive at this metric, there's a whole lot of machine learning (but with much smaller training sets)...

Identity Classification 

A separate sample of 44 individuals from the Human Connectome Project was used to construct the Similarity of Connectivity Pattern between pairs (Kajimura et al., 2021). These 44 participants had each been scanned twice, allowing 44 self-self pairs (Jessica at time 1 vs. Jessica at time 2), which were compared to 44 self-other pairs (Jessica at time 1 vs. Jennifer at time 2). Self-self “feature values” always show a positive correlation, and these were used to define “individual-specific information.”

26,680 feature values?

To start, 116 regions of interest (ROIs) were defined by Automated Anatomical Labeling (AAL). Pairwise comparisons of these for Self scan #1 vs. Self scan #2 (or vs. Other scan #2) resulted in a vector of 6,670 functional connectivities for each data point [(116 × 115)/2]. Then multiply this by four (!!) and you get 26,680 values fed into a machine learning classifier. Why four? Because the slow fluctuating BOLD signals were decomposed into four frequency bands for the classification procedure. Was this necessary? Does it add robustness, or merely more opportunities for false positive results?


Fig. 3 (Kajimura et al., 2021). Top 100 feature values, i.e. absolute values of differences between functional connectivity that contributed to identity classification for three frequency bands [the fourth was eliminated because the classifier could not distinguish between self-self and self-other pairs].

The machine learning algorithm was sparse logistic regression with elastic-net regularization (SLR-EN), which usually prevents overfitting, but I don't know if the algorithm can overcome 26,680 feature values with only 44 subjects. Maybe I'm misunderstanding (and others can correct me if I'm wrong), but the number of participants is rather low for SLR-EN given the number of input parameters? Then...
The classification accuracy was evaluated using a stratified k-fold cross-validation procedure. ... The ratio of the number of correctly classified labels was then obtained as the classification accuracy.


The regional results are below, showing a 7 x 7 brain network matrix with similarity in red (positive coefficients) and dissimilarity in blue (negative coefficients). We're still in the realm of correctly classifying self-self, so dissimilarites were considered artifacts of overfitting [but similarities were not?]. If the contribution from similar > dissimilar with binomial tests, this was considered an indicator of self. This was true of F1 (53 out of 67, p<.001) and F2 (52 out of 67, p<.001), but not F3, which was at chance (33 out of 67).


Fig. 4 (modified from Kajimura et al., 2021). Ratio of self-self classification connectivity in terms of brain networks. Red and blue matrices display the results of similarity- and dissimilarity-based contributions [at three frequency bands]. ... Vis, visual network; Som, somatosensory-motor network; Sal, salience network; Lim, limbic system; Con, executive control network; Def, default mode network; Cer, cerebellum.


Separate Statistical Analysis — a bevy of Pearsons 

Before we turn to speed dating, two more analyses are shown below for the identity classification study. The first involved a boatload of FDR-corrected Pearson’s correlations of the functional connectivity vectors for self–self pairs vs. self–other pairs (Fig 2A). The next shows the effectiveness of the machine learning (ML) algorithm in classifying these pairs (Fig 2B).

 

Fig. 2 (modified from Kajimura et al., 2021).Identity classification. (A) Similarities in overall functional connectivity profile was significantly higher for the self–self pair (dark-colored distribution) than the self–other pair (light-colored distribution) for all frequency bands. [I've included arrows to point out where they start to diverge] (B) Distribution of differences between ML classification accuracy.

As the authors predicted, self-self comparisons yielded more similar connectivites than self-other pairs. The ML algorithm identified self for three of the frequency bands (F1-F3) at greater than chance levels (12.4%. 14.8%, and 16.3% better than chance, respectively). However, the algorithm is still wrong a lot of the time. This is especially important for the matchmaking study...


Speed Dating

The authors provided a nice self-explanatory graphic presenting an overview of the Speed Dating study (click on image for a larger view). Data collection and analysis followed the flow of the Identity experiment.



Participants and Social Event

The participants were 42 heterosexual young adults (20-23 yrs), with 20 females and 22 males. Why these numbers were not perfectly matched, I do not know. The resting state fMRI scan was several days before the first speed dating session. [I'm assuming it was the first, because the Methods say there were three speed dating events. There was also a post-dating scan, which was described in another paper]. The three hour event was held in a large room where pairs of participants had 3 min long conversations with every member of the opposite sex. After each conversation, all the men moved to the next table. When all the speed dates were over, each person was asked to identify at least half of the opposite sex individuals they'd like to chat with again.

Well, there's a problem here — a requirement to select half the dates could result in less-than-optimal choices in some individuals. This requirement was necessary for sampling purposes, but it makes you wonder about the quality of the matches. Also, there was a strong possibility of unilateral matches — one individual thinks they've found their dream partner but that feeling was not reciprocated. When both members of a pair said "yes" they were considered compatible. Out of a total of 440 possible pairs, 158 were compatible and 282 incompatible.

The Compatible vs. Incompatible comparisons are the key findings of the study (Fig. 5, with A and B panels as above). Unlike the Identity comparison, compatible male-female pairs did not show more similar functional connnectivity patterns than incompatible pairs (Fig. 5A).

Well then...

“This indicates that the compatibility of female–male relationships is not necessarily represented by the similarity of functional connectivity patterns.”

Yes.

“Unlike identity classification, compatibility classification was supported by the considerable negative coefficients of the features” (shown in Fig. 6 of the paper). We shall not interpret this as opposites attract

 


 
Fig. 5 (Kajimura et al., 2021). Compatibility classification. (A) Similarity of overall functional connectivity profile. There was no significant difference between compatible (dark-colored distribution) and incompatible (light-colored distribution) pairs. (B) Distribution of differences between the classification accuracy with true labels of pairs and that with a randomized label for each frequency band. Vertical lines indicate chance levels.


Fig. 5B shows classification accuracy for compatible pairs, which was above chance for F1 and F2. Before investing in a commercial venture,  however, you should know that the benefit beyond guessing is only 5.47% and 4.95%, respectively. Thus, I disagree with the claim that...
...the current results indicate that resting-state functional connectivity has information about behavioral tendencies that two individuals actually exhibit during a dyadic interaction, which cannot be measured by self-report methods and thus may remain hidden unless we use neuroimaging methods concurrently.

To review the potential limitations of the study, we can't assess the quality of matches (meh vs. enthusiastic), we don't know what the participants were thinking about during their rsfMRI scan (see Gonzalez-Castillo et al., 2021), and we don't know their mental state during the scan. Although rs-FC fMRI is often considered a stable trait”, state factors and motion artifacts can affect the results on a given day (Geerligs et al., 2015). Indeed, ~35% of the time, the present paper was unsuccessful in classifying the same person run on two different days (and that's excluding one of four frequencies that was not above chance).

Is there something intrinsic encoded in BOLD signal fluctuations that can predict who we will find appealing (and a potential “match) after a three minute interaction?  Decisions at speed dating events are mostly based on physical attractiveness, so it seems very implausible to me.


Further Reading (the Speed Dating Collection)

The Neuroscience of Speed Dating Choice

The Electroencephalogram Cocktail Party

EEG Speed Dating

The Journal of Speed Dating Studies

Winner of Best Title

How I Meditated with Your Mother: Speed Dating at Temples and Shrines in Contemporary Japan

 

References

Geerligs L, Rubinov M, Henson RN. (2015). State and trait components of functional connectivity: individual differences vary with mental state. Journal of Neuroscience 35(41):13949-61.

Gonzalez-Castillo J, Kam JW, Hoy CW, Bandettini PA. (2021). How to Interpret Resting-State fMRI: Ask Your Participants. Journal of Neuroscience 41(6):1130-41.
 
Hyon R, Youm Y, Kim J, Chey J, Kwak S, Parkinson C. (2020). Similarity in functional brain connectivity at rest predicts interpersonal closeness in the social network of an entire village. Proceedings of the National Academy of Sciences 117(52):33149-60.

 
 
 

Why would nasally-transferred coronavirus only affect the left side of the brain?

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WE GET QUESTIONS!

Q– “I survived a mild case of COVID. Should I be worried about the volume of gray matter in olfactory-related structures in the left hemisphere of my brain?”

A– Most of what you've read on social media may be overstated.

One of the scariest things about SARS-CoV-2 (other than possible death) is that it affects multiple organs, including the brain. The vast majority of studies have compared measures in COVID survivors to those obtained from participants without COVID. These cross-sectional studies cannot determine whether pre-existing differences can account for disease-related 'changes'.

An important new preprint by Douaud and colleagues reported results from a longitudinal study that obtained MRIs from participants before and during the pandemic. Carefully matched cohorts of COVID+ (n=394) and COVID- (n=388) people were given a second scan 3 years after their initial entry into the study. The majority of patients were not hospitalized. The authors hypothesized that brain areas related to smell and taste, senses which show notable decrements in infected patients, would be altered in the COVID-19 population.

 


from Vaughan & Jackson (2014).The “piriform axis” is an unusual oblique angle that shows primary olfactory cortex (Pir, piriform cortex) in the orbitofrontal region of the frontal lobe and nearby medial temporal lobe structures related to emotion and memory (Am, amygdala and Hip, hippocampus).


The frightening entrée of the virus into the brain may be through the nose. In mice, the S1 subunit of the coronavirus spike protein crosses the protective blood brain barrier and ends up in the olfactory bulb within 10-30 min (Rhea et al., 2021). After that, we don't really know what happens. So it's a stretch to suggest that neurotropism (viral infection of brain cells) causes alterations at a macro level in humans that can be detected by structural MRI. Anyway, that's the hypothesis.

What was unclear to me, however, was the number of other analyses conducted as part of the study. Other than the smell/taste regions of interest (ROIs), there were 2,360 distinct measures of brain structure or function (including resting-state fMRI and task-related fMRI, which we assume were not significantly different in the patients).

Sticking to the ROIs, the authors ran permutation tests that corrected for multiple comparisons and found that only the left hemisphere was affected. WHY?? Despite the Proustian speculation...

“...where the left hemisphere seem [sic] to be more involved in the emotional aspect of olfactory memory (the famous madeleine de Proust association that seemed particularly targeted in COVID-19).”

...it's mysterious why the virus would have deleterious effects on the brain by only invading the left nostril.

 

Fig. 1. (Douaud et al., 2021). The three main regions showing significant loss of grey matter (thickness, volume) between the two time-points specifically for the COVID patients are the parahippocampal gyrus, the lateral orbitofrontal cortex, and the superior insula. All results were localised to the left hemisphere.


The other notable aspect of the results was the massive overlap in distribution between the COVID+ and COVID- participants (see snarky commentary in the first figure). The authors helpfully showed the full spread of values for the time 1 vs. time 2 difference (clustered around zero). But did gray matter volume and thickness actually increase in some people? Although the group differences were statistically significant, were there any functional consequences? Severity of smell/taste loss? Effects on memory or emotion? We don't know.

COVID-19 can have persistent, disabling effects in some people, including young and previously healthy individuals (the “long haulers”, see Davis et al., 2021). There is no doubt about the reality of Long Covid.

On the other hand, alarmist coverage of preliminary neuroimaging findings is not helpful. The differences in Fig. 1 of Douaud et al. do not depict a shrinkage of 4 standard deviations, despite what some widely circulated tweets may claim.As one of the authors explains:


 

In fact, the exploratory analysis showed the largest loss of brain volume was non-specific (and not discussed). And perhaps not due to neurotropic invasion?

 


Longitudinal studies are extremely valuable, and the authors are to be commended for this. We'll wait for future papers to verify these findings, but for now I'm not totally convinced.


References

Davis HE, Assaf GS, McCorkell L, Wei H, Low RJ, Re'em Y, Redfield S, Austin JP, Akrami A. (2021). Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. EClinicalMedicine. 2021 Jul 15. Epub ahead of print. PMID: 34308300.
 
Douaud G, Lee S, Alfaro-Almagro F, Arthofer C, Wang C, Lange F, Andersson JL, Griffanti L, Duff E, Jbabdi S, Taschler B. (preprint). Brain imaging before and after COVID-19 in UK Biobank. medRxiv. June 20, 2021.

Rhea EM, Logsdon AF, Hansen KM, Williams LM, Reed MJ, Baumann KK, Holden SJ, Raber J, Banks WA, Erickson MA. (2021). The S1 protein of SARS-CoV-2 crosses the blood–brain barrier in mice. Nature Neuroscience 24(3):368-78.

Reading Aloud without a Mask, Olfactory Bulbs, Omega Variant

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Here's the latest alarming COVID news to distract you from fires and hurricanes.
{I'm very sorry if you are experiencing either of these disasters personally. Donations ideas: El Dorado Community Foundation and The Mutual Aid Response Network.}


Caldor Fire: Karl Mondon/Bay Area News Group. Hurricane Ida: Edmund D. Fountain/New York Times.

 

Masklessness

Outbreak Associated with SARS-CoV-2 B.1.617.2 (Delta) Variant in an Elementary School — Marin County, California, May–June 2021

An unvaccinated elementary school teacher was experiencing nasal congestion and fatigue but continued working. The teacher read aloud to the students while maskless and two days later received a positive test for the Delta variant. Half of the class was infected, with the greatest risk among those sitting in front. Transmission to siblings and parents ensued, for a total of 27 cases.

"Among the five infected adults, one parent and the teacher were unvaccinated; the others were fully vaccinated. The vaccinated adults and one unvaccinated adult were symptomatic with fever, chills, cough, headache, and loss of smell."

 

The CDC created a figure showing the seating chart, transmission pattern, and whether the individual was symptomatic. The desks were six feet apart, an air filter in front, and the door and windows were open. All five children in the front row were infected.

 

from the CDC: Classroom layout and seating chart for 24 students in index patient’s class, by SARS-CoV-2 testing date, result or status, and symptoms—Marin County, California, May–June 2021

Conclusion and recommendation:

"Ineligibility because of age and lack of vaccination contribute to persistent elevated risk for outbreaks in schools, especially as new SARS-CoV-2 variants emerge. However, implementation of multiple prevention strategies within schools can mitigate this risk."



Olfactory Bulbs 

Speaking of smell, over 20 papers show MRI signal abnormalities in the olfactory bulbs of COVID-19 patients with anosmia (loss of smell). This isn't new, but anosmia has been reported in breakthroughcasesas well. The images below show some resolution in a patient from time 1 to time 2.

Magnetic Resonance Imaging Alteration of the Brain in a Patient With Coronavirus Disease 2019 (COVID-19) and Anosmia

"...we can speculate that SARS-CoV-2 might invade the brain through the olfactory pathway and cause an olfactory dysfunction of sensorineural origin."

 

modified from Fig 2 (Politi et al., 2020). A coronal 2-dimensional FLAIR image shows a slight reduction of the hyperintensity and the thickness of the olfactory bulbs [right side], suggesting a postinfection olfactory loss.


modified from Fig 2 (Politi et al., 2020). FLAIR image showing complete resolution of the previously seen signal alteration within the cortex of the right gyrus rectus [bottom image].



Omega Variant 

OK, I made that up. However (alpha, beta, delta, epsilon, iota, gamma, OTHER):



Predominance of antibody-resistant SARS-CoV-2 variants in vaccine breakthrough cases from the San Francisco Bay Area, California (preprint):

"These findings suggest that vaccine breakthrough cases are preferentially caused by circulating antibody-resistant SARS-CoV-2 variants, and that symptomatic breakthrough infections may potentially transmit COVID-19 as efficiently as unvaccinated infections, regardless of the infecting lineage."

 


A Curious Case of Auditory-Gustatory Synesthesia... in someone who can't smell

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A fascinating case study from 1907 describes the self-reported sensory “taste” experiences evoked by hearing specific words, names, or sounds (Pierce, 1907). The subject was a young woman about to graduate from college. As far as she could tell, she's always had these experiences, and for most of her life she didn't know they were unusual. This surprise upon discovering the uniqueness of one's one internal experience is similar to what is reported by many contemporary individuals with less typical phenomenology, such as aphantasia (the inability to generate visual images).

Pierce noted that the subject was anosmic (had a loss of smell), although this was not formally tested. Nonetheless, he observed:

Coffee burning upon a stove is not noticed, though she may be close by. Camphor placed in the nostrils gives only a stinging sensation. Ammonia can be sniffed without discomfort. And, as with all anosmics, foods are discriminated on the basis of the pure taste qualities, or by the characters of texture, astringency, and so on, which any food-complex may possess. These sensory defects are worth noting for their possible significance in connection with the theory of this special case of synæsthesia.

 

Some aspects of the report were rather quaint by modern standards (e.g., the first person narration), but others were quite prescient.

But what evidence have we that an actual case of synæsthesia is here being reported, and not a case of artificial association due to a lively dramatic fancy? This is a point that must be raised, for it is very easy to entertain a suspicion that these phenomena are essentially ungenuine. Now, of course, in matters of this kind general impressions and personal knowledge of the subject count heavily. And on both these grounds I have no hesitation in asserting my conviction that the above-cited equivalents are the expression of a genuine synæsthesia.



One key piece of evidence was the consistency of gustatory experiences associated with the same words at a later date:

...the equivalents possess a constancy which would hardly be possible apart from a true synæsthesia. After an interval of six months a number of words were given at random from the original list, with the result that the identical equivalents were described in almost precisely the same language.

 

Also, there was a somatotopic-like arrangement for some of the gustatory experiences:

Many of the experiences are given quite definite locations in the mouth. Thus the equivalents of Ethel and Hall (tactual) are felt at the tip of the tongue; of lox (irritation) at the back of the throat; of Judith (salt) at the sides of the tongue; of Sarah (cold) on the lips; of amethyst (bitter) "at the back of the mouth, on the roof, where the root of the tongue seems to hit it" ...

 

Pierce tried to discern whether similar sounds could be related to similar gustatory experiences, but that wasn't the case. Nor were they related to similarities in articulation. He still preferred a physiological explanation, yet...
In attempting to decide whether the above-cited experiences are to be explained by the physiological or by the psychological theory, we are, apparently, in no better and in no worse case than in respect to all varieties of synæsthesia. No decisive facts are at hand.

 

An interesting commentary in JAMA predated MRI connectivity studies of synesthesia by nearly a century in its speculation about alternative brain wiring:

There is little evidence one way or the other as to whether or not this phenomenon is to be explained on purely physiologic grounds, depending on a cross circuiting of the association fibers between different brain centers.



Pierce concludes his paper with a pithy aphorism that acknowledges the inconclusiveness of the study:
Still, here no less than in all known cases of synaesthesis, we can only regret that our theory is so lame while our facts are so secure.


References

Pierce AH. (1907). Gustatory audition; a hitherto undescribed variety of synæsthesia. The American Journal of Psychology. Jul 1:341-52.

Commentary (1907). GUSTATORY AUDITION. JAMA. XLIX(10):857-858.


Xylological Delusions of Being a Tree

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The mythology surrounding reverse inter-metamorphosis, a delusional syndrome that involves transformation into a beast, has frightened and fascinated for hundreds of years. A special instance of reverse inter-metamorphosis is clinical lycanthropy, the delusion that one has been transformed into a wolf (or another animal). A recent review identified 43 cases in the literature between 1852 and today (Guessoum et al., 2021). Psychotic depression and schizophrenia were the most common co-existing psychiatric diagnoses in these individuals.



The article advocates a cultural and person-centered approach to treatment, as did many of the original authors. The wolf has different characteristics and symbolic meanings across various cultures. As in other realms, popular media and folklore shape the content of the delusion. Occasionally, there may be a literal event that triggers the belief of transmogrification.


Clinical Kynanthropy After a Dog Bite

This case report of kynanthropy delusional transformation into a dog was notable because the COVID-19 lockdown might have exacerbated the condition. The patient was a 28-year-old single male who started grinning, barking, and walking on four legs after being bitten by a dog... but not until two years later (Jain et al., 2021).

He was apparently alright until two months before the presentation, when, due to the COVID-19-related nationwide lockdown, he read excessively on the internet about dog bites. ... he developed a feeling that his tongue is moving like a dog’s and began having repetitive thoughts about converting into a dog. Gradually, his sleep reduced to 1–2 hours/day, and he expressed fear that if he sleeps, he might get up as a dog. He sought repeated reassurance from his family that he hasn’t transformed into a dog, to the extent that they got irritated and asked him to see a doctor. These repetitive thoughts would be present for the whole day, and he would chant God's name to get relief from them.


The man had no history of rabies, mood disorder, or substance use. Upon examination, he was anxious but did not present with depression or psychotic features. Instead, he had repetitive doubts about turning into a dog. The patient was diagnosed with moderate OCD (with poor insight) and given a prescription of 20 mg fluoxetine (Prozac). A month later, he reported improvement in his repetitive thoughts, and at three months showed an improvement in social and occupational function. He realized he had spent way too much time on the internet reading and watching videos about dog bites.

 

Botanical Inter-metamorphosis

A unique arboreal delusion was briefly described in a recent abstract (Bakhshi & Hirsch, 2021): a depressed young woman believed she had been transformed into a tree. The major manifestations were standing still for long periods of time and repeating, "I am a tree."

A 21-year-old right-handed cisgender female, two months prior to presentation, noted stiffness and difficulty with ambulation. One-month prior to admission, she experienced recurrent depression with myriad vegetative and nonvegetative symptoms of depression. On admission her chief complaint was "I am a tree", standing motionless and minimally responding to query. After treatment with quetiapine, mirtazapine and hydroxyzine for a one-week period, her perception of being a tree fully resolved.

 

The authors considered a range of delusional diagnoses for her condition:

  • Cotard’s syndrome– NO, she did not think she was dead
  • Ekbom syndrome (delusional parasitosis) – NO, she did not think her body was infested with bugs
  • Reverse Inanimate Capgras Syndrome– MAYBE? (but "instead of an imposter replacing a close friend, who then is inserted into the sufferer; a tree has replaced the sufferer.")
  • Intermetamorphosis– NO, misindentification of another, not self
  • Botanical Intermetamorphosis– NO, another person transformed into a plant, not self
  • Reverse Intermetamorphosis– MAYBE? ("However, in this situation, the objects are all human or animate animals not botanicals.") – but isn't this the point, to report on a botanical?
  • Fregoli syndrome– NO, altered physical identity of another, not self
  • Reverse Fregoli syndrome– NO, patient assumes the physical identity of another person, not a plant
  • Botanical Variant of Interparietal Syndrome– NO, she did not have parietal lobe damage. ("In this condition, parts of the body are perceived to be lifeless, due to lesions of the inferior parietal lobe...")


The groundbreaking conclusion was that doctors should check for delusions involving plant life in all of these syndromes, because botanical variants have not been described before.

 
Further Reading

Werewolves of London, Ontario

Haunting Delusions of Identity

Ophidianthropy: The Delusion of Being Transformed into a Snake

Psychopharmacology of Lycanthropy

The oldest remaining werewolf movie 


Keanu Reeves as Ortiz the Dog Boy in Freaked



References

Bakhshi HS, Hirsch AR. (2021). Xylological Variant of Reverse Fregoli Syndrome, Delusions of Being a Tree. CNS Spectrums 26(2):145.

Guessoum SB, Benoit L, Minassian S, Mallet J, Moro MR. (2021). Clinical Lycanthropy, Neurobiology, Culture: A Systematic Review. Frontiers in Psychiatry Oct. 13, 1693.

Jain VP, Gupta N, Kale VP. (2021). Clinical Kynanthropy: A Case Report of Psychological Manifestation of a Dog Bite. Indian Journal of Psychological Medicine. Oct 13:02537176211047132.

 


 

Is Precision Psychiatry Realistic?

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Fig. 1 (Fernandes et al., 2017). Domains related to ‘precision psychiatry’.


The right drug for the right patient” was a catch phrase in the early years of the personalized medicine movement (2000), represented by the emerging field of pharmacogenomics. No more “one size fits all” prescribing — the Human Genome Project will allow doctors to predict how you will respond to any given medication.

The last time I went to the drug store, I picked up my cheap generic prescription without the benefit of genomic testing.

The term “personalized medicine” was outdated by 2011. The National Research Council (PDF) preferred the new and improved “precision medicine” brand because...

...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.


What is Precision Psychiatry?

If you believe the hype (circa 2017), it's a paradigm shift! It's perfection! [yes, really]...
...a high level of exactness in measurement will be achieved such that, eventually, it will be personalised. It can be conceptualised as a highly sophisticated and intricate classification system, where infinitesimal categories will, ideally, attain perfection in a detailed multidimensional classification.


...It's quixotic (if taken to those lofty extremes). Precision psychiatry is an incredibly popular topic for review papers, but don't hold your breath awaiting its implementation. Especially if you're a patient. 


What is Stratified Psychiatry?

Fig. 1 (Arns et al., 2021). An infographic summarizing the more ‘diagnostic based one-size-fits-all psychiatry’ that is currently in use (left), to more ‘prognostic’ models such as Stratified Psychiatry (right-top) and Precision Psychiatry (right-bottom).


Perhaps Stratified Psychiatry is more realistic, where subgroups of patients with similar biomarker profiles are assigned to treatments predicted to show a higher probability of clinical response. But the infographic above may be conflating precision psychiatry and personalized psychiatry (it seems that way in the text as well). So is stratified psychiatry a more modest version of precision psychiatry, with only a few biomarkers (vs. 35 or so)? Without the grandiosity of anticipating infinitesimal categories with perfect diagnostic accuracy or the absolute faith in RDoC (NIMH Research Domain Criteria)? 


In the end, making promises you can't keep helps no one (see The Lie of Precision Medicine).


References

Arns M, van Dijk H, Luykx JJ, van Wingen G, Olbrich S. Stratified psychiatry: Tomorrow's precision psychiatry?European Neuropsychopharmacology. 2022 Feb 1;55:14-9.
 
Fernandes BS, Williams LM, Steiner J, Leboyer M, Carvalho AF, Berk M. The new field of ‘precision psychiatry’. BMC medicine. 2017 Dec;15(1):1-7.
 

Your Own Personal DBS

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The second calendar year of COVID surges to a close, and hospital personnel continue their frenetic pace of caring for the infected (most of whom are defiantly unvaccinated). For the rest of us, Vaccine Scientists are the 2021 Heroes of the Year... surely they will outsmart the latest variant of the sneaky virus. Their astonishing achievements built on less glamorous (and less recognized) work conducted over the course of 20 years. As told by Time magazine:

In 2005, [Dr. Katalin] Kariko and [Dr. Drew] Weissman reported their findings in what they thought would be a landmark paper in the journal Immunity, then waited for the accolades to flood in. “I told Kati the night before the paper was published, Tomorrow our phones are going to ring off the hook,” says Weissman. No one called.


Clinical Neuroscience Heroes of the Year

Another remarkable achievement in 2021 was the demonstration of a “closed-loop” deep brain stimulation (DBS) protocol in a patient with refractory depression (Scangos et al., 2021a, 2021b). This new personalized treatment modality was based on devices and procedures first used in patients with intractable epilepsy. An implanted responsive neurostimulation (RNS) system detects brain waves that predict the onset of a seizure and then delivers pulses to quell the aberrant electrical activity. The device provides stimulation only when needed, thereby “closing the loop” on a self-contained, personalized neurotherapy.

NeuroPace Next Gen RNS® System

 

Application of this concept to major depressive disorder (MDD) was based on years of research in basic neurophysiology, neural circuits and biomarkers, electrocorticography (ECoG), cognitive neuroscience, neuroengineering, and machine learning. Some of this work was funded by the 2013 BRAIN Initiative, specifically DARPA's SUBNETS program. The goals of DARPA were rather lofty and unattainable (as they usually are) and outlined in a detailed funding announcement. Or, as I quipped at the time:

To elaborate, over a 5 year period, the successful applicants must conduct clinical trials in human patients with 7 specified psychiatric and neurological disorders (not including PD), some of which have never been treated with DBS. The successful teams will use devices that both stimulate and record neural activity, and provide real-time data that can be decoded as reflecting a particular behavioral state... basically, a futuristic implant that can adjust its own stimulation parameters based on how the patient is doing.

 

O ye of little faith!

“Someone to hear your prayers
Someone who cares”


Bypassing the “paradigm shift” of another brand of precision psychiatry, a group of scientists and clinicians at UCSF actually achieved this goal in a proof-of-concept n=1 clinical trial, taking personalized psychiatry to its ultimate (albeit prohibitively expensive) destination (Scangos et al., 2021a, 2021b).

 

The first step in establishing a personalized deep brain stimulation protocol in a single patient with treatment-resistant depression involved 10 days of “mood mapping” while EEG activity was recorded from 160 contacts in 10 target brain regions (Fig 1a, Scangos et al. 2021a).

Electrodes were implanted bilaterally in orbitofrontal cortex, amygdala, hippocampus, ventral capsule/ventral striatum (VC/VS), and subgenual cingulate for 10 days to map mood and identify a “depressive state” biomarker that correlated with symptom ratings. Cross-validated supervised machine learning models identified gamma power in left and right amygdala as the most reliable indicators. Additional results from the mapping of brain stimulation → emotional response are shown below in a schematic figure (click on image for a larger view).



Fig. 1 (Scangos et al. 2021b). Mapping mood across the corticolimbic circuit.(a) Examples of the clinical responses to ~90 s of stimulation. Electrodes that demonstrated a positive or negative mood response to stimulation are enlarged for emphasis and shaded with color of respective region.

Three positive protocols were identified: ‘tingles of pleasure’ with 100-Hz VC/VS stimulation, ‘neutral alertness… less cobwebs and cotton’ with 100-Hz SGC stimulation, and calm pleasure ‘like … reading a good book’ with 1-Hz OFC stimulation.

The team's earlier work on mood mapping was initiated in patients with epilepsy, who were under neurosurgical observation to localize seizure foci using recordings from intracranial electrodes (Kirby et al., 2018; Rao et al., 2018). This actually follows the path outlined by DARPA in their Systems-Based Neurotechnology for Emerging Therapies (SUBNETS) précis:
Through measuring pathways involved in complex systems-based brain disorders [such as MDD] ... SUBNETS will pursue the capability to record and model how these systems function in both normal and abnormal conditions, among volunteers seeking treatment for unrelated neurologic disorders [such as epilepsy] and impaired clinical research participants. SUBNETS will then use these models to determine safe and effective therapeutic stimulation methodologies. These models will be adapted onto next-generation, closed-loop neural stimulators that exceed currently developed capacities for simultaneous stimulation and recording...


Ultimately, stimulation of the right VC/VS was associated with the most consistent and sustained improvement in symptoms (Scangos et al. 2021a). A combination of techniques (evoked potential mapping, graph theory, and deterministic tractography) identified the connectivity between right VC/VS and the amygdala sites. Further sessions suggested that right VC/VS stimulation may be associated with a reduction in gamma activity on trials that saw an improvement in mood. 



After all these mapping sessions, the DBS sites were selected: the NeuroPace RNS System was placed with stimulating leads in right VC/VS and recording leads in right amygdala. Most impressive of all is that detection of the “depressive” gamma biomarker in the amygdala would trigger six seconds of 1 mA intermittent stimulation in VC/VS.


The authors found that the number of detections, defined as gamma power crossing a threshold of 0.8% of full amplitude scale within 10-min recording periods was 87% predictive of symptom severity state and highly correlated with [the patient's self-report on standardized scales]” (Scangos et al. 2021a). The patient's depression improved dramatically within 12 days, and full remission was reached several months later.

The 2021 papers presented an overview of procedures and the results obtained from one patient (Sarah), who was identified by first name and masked photo in press releases and news articles. The n=1 trial was the culmination of hundreds of millions of dollars of federal research funding, so I was kinda fascinated by why the clinical team chose this particular patient (which is protected health information, of course). In an interview, Sarah said, “I was at the end of the line. I was severely depressed. I could not see myself continuing if this was all I’d be able to do, if I could never move beyond this. It was not a life worth living.”

The inclusion criteria for the trial required that the current depressive episode is two or more years in length and treatment-resistant (failure to respond to four adequate trials (including ECT), three classes of medications, one augmentation strategy, and psychotherapy). In the present case, her most recent 4-year episode did not adequately respond to four antidepressants, augmentation with five other meds, electroconvulsive therapy, transcranial magnetic stimulation, or psychotherapy. In other words, closed-loop DBS is only appropriate for the most severe unrelenting cases of depression.
 

The Future of Depression Treatment is here, but will it work in other patients? And at what cost?
 
. . .


2035

DARPA has mandated that all depressed Americans must be implanted with its CyberNeuroTron WritBit device, which cost $100 billion to develop. CNTWB is a closed-loop DBS system that automatically adjusts the stimulation parameters at 12 different customized target locations. It uses state-of-the-art syringe-injectable mesh electronics, incorporating silicon nanowires and microvoltammetry. Electrical and chemical signals are continuously recorded and uploaded to a centralized data center, where machine learning algorithms determine with high accuracy whether a given pattern of activity signals a significant change in mood.

The data are compiled, analyzed, and stored by the global search engine conglomerate BlueBook, which in 2032 swallowed up Google, Facebook, Apple, and every other internet data mining company.
 

Further Reading

A Tale of Two BRAINS: #BRAINI and DARPA's SUBNETS

And the DARPA deep brain stimulation awards go to...

New Deep Brain Stimulation System Measures Neurotransmitter Release

Who Will Pay for All the New DBS Implants?

BROADEN Trial of DBS for Treatment-Resistant Depression Halted by the FDA

Will machine learning create new diagnostic categories, or just refine the ones we already have?


References

Scangos KW, Khambhati AN, Daly PM, Makhoul GS, Sugrue LP, Zamanian H, Liu TX, Rao VR, Sellers KK, Dawes HE, Starr PA, Krystal AD, Chang EW. (2021a). Closed-loop neuromodulation in an individual with treatment-resistant depression. Nature Medicine 27(10):1696-700.

Scangos KW, Makhoul GS, Sugrue LP, Chang EF, Krystal AD. (2021b). State-dependent responses to intracranial brain stimulation in a patient with depression. Nature Medicine 27(2):229-31.



"Reach out, touch faith"

Vortioxetine for Post-COVID Brain Fog

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If you're relatively young and healthy, is a mild case of COVID-19 really “mild”, like a cold or the flu? Are you still at risk for long COVID a persistent state of fatigue, anxiety, insomnia, exercise intolerance, and “brain fog” (impairments in memory, attention, and concentration) even if you're fully vaccinated?

If you have post-COVID brain fog and live in Toronto, you might be eligible for a clinical trial run by the Brain and Cognition Discovery Foundation. The study will assess the effects of vortioxetine (brand name Trintellix), an FDA-approved antidepressant that may improve cognitive function in people with depression. It has a complex mechanism of action as a “serotonin reuptake inhibitor, agonist of the 5-HT1A receptor, and antagonist of the 5-HT3 and 5-HT7 receptors.” The clinical trial is a randomized, double-blind, placebo-controlled study that plans to enroll 200 participants.


Trintellix™ was approved by Health Canada in 2014, meaning it's fully covered by the government if you have major depressive disorder (MDD). It's an expensive drug ($423 a month) with no generic version, so too bad if you live in the US and suffer from MDD-related cognitive dysfunction, since most forms of insurance won't cover it.

 


Are there any differences in outcome between the delta and omicron variants? What about all the long haulers who weren't able to obtain a definitive COVID-19 test? These are only two of many important questions.


Meanwhile, it's well-documented that unvaccinated individuals are 13 times more likely to be hospitalized and 20 times more likely to die than fully vaccinated individuals. Why is this so hard to understand??

The Ongoing Debate about Hippocampal Neurogenesis in Adult Humans is over.

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modified from Franjic et al. (2022). Cross-species comparison shows transcriptomic signatures of neurogenesis in the hippocampus of adult mouse, pig, and monkey but not human.


Does the adult brain generate new neurons throughout the lifespan? The prevailing view in most of the 20th century was that no new neurons are born in the mammalian brain once development ceases. A series of studies in the 1960s showed otherwise, but these were ignored until the 1990s. A now-historical paper from 2000 recounted the death of a dogma: adult neurogenesis is here to stay, even in humans. Thousand of studies in animals (mostly rodents) demonstrated that new neurons are born in the dentate gyrus region of the adult hippocampus, and they can play an important role in learning and memory.

More recently, several papers have questioned whether adult humans really do generate new neurons in the hippocampus (Sorrells et al, 2018, 2021; Franjic et al., 2022). One such paper examined the morphology of dentate gyrus cells taken from post-mortem brains and from tissue surgically removed from epilepsy patients, with ages ranging from prenatal to elderly (Sorrells et al, 2018). The presence of progenitor cells and young neurons was determined using immunohistochemistry (selective staining methods, visible in green and yellow below).

click on images for larger view

modified from Fig 2a (Sorrells et al, 2018). Human dentate gyrus (DG) proliferation declines sharply during infancy.


modified from Fig 3d (Sorrells et al, 2018). The number of young neurons declines in the human DG from infancy into childhood.


The paper's title succinctly summarized the findings: “Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults.”Immature neurons were rare in the 7 yr old and 13 yr old samples, and absent entirely in adults.

Despite these seemingly convincing results, critiques have identified shortcomings in the way that post-mortem human brain samples are typically processed, as well as other technical issues that affect immunostaining of neurogenic markers (Moreno-Jiménez et al., 2021).


Transcriptomics to the Rescue?

The latest study used different methodology: single-nucleus RNA-sequencing (snRNA-seq) of neurogenic markers in adult hippocampal subregions (Franjic et al., 2022). In a technical tour de force, the authors microdissected samples from five hippocampal subregions from the brains of pigs, macaque monkeys, and humans. Single brain cell nuclei were isolated according to an incredible complex protocol, followed by cellular barcoding, cDNA amplification, sequencing of libraries, single nuclei expression quantification, and hierarchical tree construction. The goal was to create a taxonomy of cell types categorized by gene expression.

 

  click on image for larger view

Fig 1 (Franjic et al., 2022). Cell type diversity in the human hippocampal-entorhinal system revealed by snRNA-seq. (E)Dendrogram depicting the hierarchical taxonomy across all cell subtypes.


As a cognitive neuroscientist, this level of cellular diversity is astounding and humbling. If you ever feel like you're learning a lot about the how the brain works from fMRI, take a look at the dendrogram above.

Iterative clustering identified 69 transcriptomically distinct cell clusters across all donors that were organized into a dendrogramatic taxonomy reflecting their unique gene expression patterns.


snRNA-seq reveals a neurogenic trajectory in the macaque, pig, and mouse DG that is virtually absent in humans

Using more comprehensive and less disputed methods than previous studies, and incorporating cross-species comparisons, Franjic and colleagues did not observe any signs of neurogenesis in the hippocampus of adult humans. A companion preview article concluded that human adult neurogenesis is unlikely (Nano & Bhaduri, 2022).


These results don't negate or diminish the excellent and informative work on neurogenesis in rodents, but they suggest that the human hippocampus relies on other forms of neuroplasticity to learn and remember.

 

References

Franjic D, Skarica M, Ma S, Arellano JI, Tebbenkamp AT, Choi J, Xu C, Li Q, Morozov YM, Andrijevic D, Vrselja Z. et al. (2022). Transcriptomic taxonomy and neurogenic trajectories of adult human, macaque, and pig hippocampal and entorhinal cells. Neuron 110: 452-469
 
Moreno-Jiménez EP, Terreros-Roncal J, Flor-García M, Rábano A, Llorens-Martín M. (2021). Evidences for adult hippocampal neurogenesis in humans. Journal of Neuroscience 41(12):2541-53.
 
Nano PR, Bhaduri A. (2022). Mounting evidence suggests human adult neurogenesis is unlikely. Neuron 110(3):353-5.
 
Snyder JS. (2018). Questioning human neurogenesis. Nature 555: 315-316
 
Sorrells SF, Paredes MF, Cebrian-Silla A, Sandoval K, Qi D, Kelley KW, James D, Mayer S, Chang J, Auguste KI, Chang EF. (2018). Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature 555(7696):377-81.
 
Sorrells SF, Paredes MF, Zhang Z, Kang G, Pastor-Alonso O, Biagiotti S, Page CE, Sandoval K, Knox A, Connolly A, Huang EJ. (2021). Positive controls in adults and children support that very few, if any, new neurons are born in the adult human hippocampus. Journal of Neuroscience 41(12):2554-65.



Must-see experiment from Snyder Lab (2014)!  

Machine Yearning - Sad Robots and Prolonged Grief

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What is 'machine yearning'?


Intense longing exhibited by cartoon robots? 



Or a clever pun that describes a network analysis of prolonged grief symptoms? (Malgaroli et al., 2022).


My late wife was a writer who was very fond of robots and Futurama. This post is an opportunity to incorporate them all into a brief narrative about the computational psychiatry of prolonged grief disorder.



Prolonged Grief Disorder (PGD) is an ICD-11 diagnosis that overlaps with other formulations of “pathological grief” including “persistent complex bereavement disorder” (PCBD) and “complicated grief”. The ICD-11 definition and symptoms can be found here.

Prolonged grief disorder is a disturbance in which, following the death of a partner, parent, child, or other person close to the bereaved, there is persistent and pervasive grief response characterised by longing for the deceased or persistent preoccupation with the deceased accompanied by intense emotional pain (e.g. sadness, guilt, anger, denial, blame, difficulty accepting the death, feeling one has lost a part of one’s self, an inability to experience positive mood, emotional numbness, difficulty in engaging with social or other activities).”

 

The symptoms must persist for at least six months, with consideration of differing cultural norms for bereavement. The overlap between PGDand PCBD is shown in purple in the figure below.

click on image for a larger view

Infographic. Disturbed grief: prolonged grief disorder and persistent complex bereavement disorder (BMJ).


Painful and prolonged yearning for the lost loved one is an obvious core symptom.

[NOTE: A celebration of life is viewed as a more adaptive response.]

 

But there's so much more... An aptly titled paper by Lenferink and Eisma (2018) indicated there are 37,650 ways to have “persistent complex bereavement disorder” yet only 48 ways to have “prolonged grief disorder”. 1 For a PCBD diagnosis (a DSM-5 construct), an individual must have at least one of four Cluster I symptoms and at least six of twelve Cluster II symptoms. For a a PGD diagnosis, an individual must have at least one of two Cluster I symptoms and at least three of five Cluster II symptoms. This is a rather stunning degree of symptom heterogeneity, and much more complicated than the Infographic suggests. It might even limit the usefulness of these diagnostic categories, which may be true of psychiatric diagnoses in general (see RDoC).

Here is where computational methods may assist with understanding symptom profiles and trajectories of grief (Malgaroli et al., 2022). Data driven analyses using unsupervised machine learning methods can identify patterns within the heterogeneity. Network analyses have identified the centrality of loneliness (Fried et al., 2015) and a social/identity symptom cluster that includes role confusion and meaninglessness (Malgaroli et al., 2018). In the review article, the authors thought this was novel and stated that, “A more surprising and emergent result showed meaninglessness and role confusion to be strongly central elements.” 

But I am not surprised at all.


My wife (@blueberrio) wrote microfiction — miniature standalone stories as well as longer collections. Her book Reliant was an entire apocalypse in tweets. After the nuclear crisis occurs in Part 2, the main character channels the agony of loss in a heartbreaking (and prophetic) way.

Bereaved
The bright, hollow sky absorbs my grief as I mourn our lost love. I wail and hug my knees, wishing to die. You can't soothe me, gone.


I don't feel that way too often any more. Which is good, because it's unbearable. But I still feel anxious, confused, disoriented, sad, and lonely.

 

Footnote

1This paper is the younger sibling of 636,120 Ways to Have Posttraumatic Stress Disorder.


References

Fried EI, Bockting C, Arjadi R, Borsboom D, Amshoff M, Cramer AO, Epskamp S, Tuerlinckx F, Carr D, Stroebe M. (2015). From loss to loneliness: The relationship between bereavement and depressive symptoms. Journal of abnormal psychology 124(2):256.

Lenferink LI, Eisma MC. (2018). 37,650 ways to have “persistent complex bereavement disorder” yet only 48 ways to have “prolonged grief disorder”. Psychiatry Research 261:88-9. [PDF]

Malgaroli M, Maccallum F, Bonanno GA. (2018). Symptoms of persistent complex bereavement disorder, depression, and PTSD in a conjugally bereaved sample: a network analysis. Psychological Medicine 48(14):2439-48.

Malgaroli M, Maccallum F, Bonanno GA. (2022). Machine yearning: How advances in computational methods lead to new insights about reactions to loss. Current Opinion in Psychology 43:13-7. [PDF]


Nostalgia and Its Analgesia

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“Nostalgia is a sentiment of loss and displacement, but it is also a romance with one’s own fantasy. Nostalgic love can only survive in a long-distance relationship. A cinematic image of nostalgia is a double exposure, or a superimposition of two images—of home and abroad, of past and present, of dream and everyday life. The moment we try to force it into a single image, it breaks the frame or burns the surface.”

–Svetlana Boym, Nostalgia and Its Discontents


Nostalgia means different things to different groups of scholars. To historians, nostalgia is bad, “...essentially history without guilt ... an abdication of personal responsibility, a guilt-free homecoming, an ethical and aesthetic failure” (Boym, 2007). To social psychologists, nostalgia is good, “a meaning-providing resource [that] may serve an existential function” by helping us avoid thoughts of death (Routledge et al., 2008).

To cognitive neuroscience types, nostalgia is encapsulated in an fMRI experiment that compares brain responses to pictures of “nostalgic” objects (from childhood) vs. contemporary objects (Yang et al., 2021).1


In this post, my authority on cultural nostalgia is Svetlana Boym, who was the Curt Hugo Reisinger Professor of Slavic and Comparative Literatures at Harvard, a Russian émigré, and an extraordinary thinker, writer, cultural theorist, and photographer. Her 2007 essay was adapted from her influential book, The Future of Nostalgia (2001). She viewed nostalgia as a manifestation of collective memory and longing, with two contrasting types. Reflective nostalgia is exemplified by the displacement of immigrants, who may long for a home that no longer exists (or perhaps never existed). Restorative nostalgia, on the other hand, is a dangerous impulse to return to a “pure” (or nationalistic) state of a distant past. Is it fair for psychologists to consider nostalgia as a private reminiscence devoid of a larger context?


A Blast from the Past

The reconciliation between these different views of nostalgia used to be terror management theory (TMT). In this theory, reminders of death (mortality salience) increase in-group favoritism and defense of one's own world view as a way to assuage existential fear. Thus, restorative nostalgia might be seen in the light (or darkness) of TMT. Indeed, instructing participants to write about a nostalgic event lessened mortality salience (Routledge et al., 2008). However, TMT has failed to replicate in several large studies, so there goes that idea (i.e., the link between social psychology experiments and restorative nostalgia, not the concept of restorative nostalgia itself).


Escape from the Pandemic

The COVID memory vortex altered our perception of time and space and warped the horizon of past and future. A restricted sense of the present (and the lack of new cultural output) caused TV nostalgia and musical nostalgia:

Nostalgia became a default listening mode — and for me, the cumulative oldness felt distressingly new. The old problem with nostalgia was that it made it harder to imagine the future. The new problem with nostalgia was that it made it harder to experience the present.

But wasn't this also a way to avoid ubiquitous thoughts of death and constant media coverage (and lived experience) of overwhelmed essential workers, illness, hospitalization, and relatives dying alone? Was there anything special about nostalgia, or would any absorbing distraction suffice? Nostalgia intervention studies during COVID-19 demonstrated improvements in well-being (Wildschut & Sedikides, 2022), but the control conditions didn't include sourdough bread baking, home improvement projects, or Zoom Peloton sessions.


Comfortably Numb

A fleeting feeling of nostalgia can lessen the perception of physical pain, apparently (Zhang et al., 2022) — although the effect looks quite modest to me.

 


In this study, visual cues were presented for 8 sec (e.g., childhood or contemporary gum), followed by 3 sec of thermal stimulation (low vs. high), a 7 sec wait, and then a rating of perceived pain intensity on that trial. The next picture-pain cycle would occur 10 sec later. Very small downward modulations of cortical activity were observed with nostalgia, but the impressive associations were in the thalamus.

 

modified from Fig. 4 (Zhang et al., 2022). During pain encoding, the thalamus showed a positive correlation between the BOLD response and the analgesic effect.


While acknowledging that nostalgia is a complicated emotion, the authors stated that...

These findings suggest that the thalamus might play a key role in the nostalgia and pain information encoding process in the possible brain circuit for nostalgia-induced analgesia.


But nostalgia can also induce feelings of emotional pain and sadness. On the very last day I spent at my childhood home, I walked around the backyard and was struck by a staggering sense of loss. My memories of running around and playing wiffle ball - badminton - croquet - nerf football - frisbee — and building a minimalistic tree house and burying dead animals under a cross — were dim and lonely. I just sold the house and my best friend (who used to live next door) was dead and my mother was dead. I mourned in a way that I never did while inside the house, emptying it of all my mother's possessions.

“Nostalgia is a sentiment of loss and displacement...”

 

Footnote

1This study found that presentation of nostalgic pictures was associated with enhanced mortality salience, along with increased activation in the right amygdala (Yang et al., 2021). Which is the opposite of previous studies...

 

References

Boym S. (2007). Nostalgia and its discontents. The Hedgehog Review. 9(2):7-19.

Routledge C, Arndt J, Sedikides C, Wildschut T. (2008). A blast from the past: The terror management function of nostalgia. Journal of Experimental Social Psychology 44(1):132-40.

Wildschut T, Sedikides C. (2022). Benefits of nostalgia in vulnerable populations. European Review of Social Psychology 27:1-48.

Yang Z, Sedikides C, Izuma K, Wildschut T, Kashima ES, Luo YL, Chen J, Cai H. (2021). Nostalgia enhances detection of death threat: neural and behavioral evidence. Scientific Reports 11(1):1-8.

Zhang M, Yang Z, Zhong J, Zhang Y, Lin X, Cai H, Kong Y. (2022). Thalamocortical mechanisms for nostalgia-induced analgesia. Journal of Neuroscience 42(14):2963-72.

 
 

THIS device may not nudge your brain into deep sleep

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The Washington Post used this picture of a saline-filled 280-channel Geodesic Head Web1 to illustrate a new wearable device that aims to enhance slow wave sleep (SWS). The device delivers low-level current (0.5 mA) at 0.5 Hz to mimic the frequency of EEG naturally recorded during SWS (0.5-1 Hz). However, this is impossible with saline sensors, which would also dry out well before the night is over. 


 

The WaPo article accurately showed different stages of applying the net, including measuring the head, checking impedences, and filling sensors with saline (above). A published journal article used similar Geodesic technology but using 256 electrodes filled with conductive gel (Hathaway et al., 2021). This setup was able to deliver transcranial electrical stimulation (TES) at 0.5 Hz.  Time spent in deep sleep was increased by 13% for active vs. sham stimulation. The BEL website shows people snoozing while wearing this headgear.

 

Footnote

1 This net is made by BEL Company and is the latest iteration of the 256-channel Geodesic Sensor Net made by EGI/Philips. Both designs were developed by Dr. Don Tucker at the University of Oregon. In 2017 he sold his company Electrical Geodesics, Inc. to Philips for $37 million. He now runs Brain Electrophysiology Laboratory (BEL) Company.



Reference
 
Hathaway E, Morgan K, Carson M, Shusterman R, Fernandez-Corazza M, Luu P, Tucker DM. (2021). Transcranial Electrical Stimulation targeting limbic cortex increases the duration of human deep sleep. Sleep Medicine 81:350-7.
 

ABCT Apologizes for Past Support of Gay Conversion Therapy

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It's 2022, and the Association for Behavioral and Cognitive Therapies (ABCT) has just issued a belated apology because two of their past Presidents published papers on “aversion therapies” for “converting” gay and transgender individuals to the socially prescribed norms of sexuality and gender identity. 

Well, they didn't actually say this, nor did they name the prominent and distinguished clinical psychologists who authored these papers. Although these luminaries signed on to the mea culpa, there was no direct admission of the harm caused by these ill-advised practices. Instead, the document focused on “the courageous and historic role that some of our members have played in advancing SGM [sexual and gender minority] rights and mental health (e.g., Drs. Charles Silverstein and Gerald Davison).” 

Which is great and all.

But. 

This covert history has been hiding in plain sight for 50 years, and I'm surprised the reckoning hasn't come any earlier. I'm not a clinician, nor am I in the field of cognitive behavior therapy research. But in 2013 I wrote a post on Dr. David H. Barlow and Aversion Therapy for Gays. Dr. Barlow had received a prestigious award for his contributions to clinical psychology, which are indeed extensive. But he was also an author on papers that examined aversion therapy in gay men (Barlow et al., 1969; Barlow, 1973; Barlow et al., 1975; Herman et al., 1974; Barlow et al., 1975; Hayes et al., 1983) and exorcism for transsexualism (Barlow et al., 1977). Dr. Barlow and Dr. Steven C. Hayes were Past Presidents of ABCT in 1978-1979 and 1997-1998, respectively. Hayes subsequently developed Acceptance and Commitment Therapy (ACT) and Barlow is known for his work on the treatment of anxiety disorders.


Sorry Seems to Be the Hardest Word

I first learned about the ABCT apology on Twitter, via Lorenzo Lorenzo-Luaces, PhD (@lluaces) and Aaron Fisher (aaronjfisher).

ABCT Apology for Behavior Therapy’s Contribution to the Development and Practice of Sexual Orientation and Gender Identity and Expression Change Efforts

The ABCT Board of Directors and past leadership have released an apology for behavior therapy’s contributions to the development and practice of sexual orientation and gender identity and expression change efforts [SOGIECEs].


More details are in the Full Apology PDF.

...[ABCT] apologizes for our historic role in the development and use of so-called “conversion therapies,” practices that have caused untold harm to members of the sexual and gender minority (SGM) community for over 50 years. To this day, publications written by ABCT members – including members in prominent leadership roles – are used by anti-SGM activists to justify their ongoing use of these damaging so-called “therapies.” ABCT deeply regrets behavior therapists’ role in the creation, study, and use of these practices, and recognizes and accepts responsibility for the ways in which both our actions and inactions have harmed SGM people. ABCT recognizes it is time for us to document our history and legacy and say that we are truly sorry.1


But documentation of this history and legacy is rather sketchy... Without naming names, the Apology cited the recent review of Capriotti and Donaldson (2022), which in turn asked “Why don’t behavior analysts do something?” about retracting the unethical paper of Rekers and Lovaas (1974). The conversion therapy work of Barlow and Hayes was mentioned here as well. 

 

I wrote to Barlow in 2013 to ask him about this early research on SGM people.2  I didn't really expect an answer, especially since I'm an obscure anonymous blogger. Nonetheless, I wanted to give him the opportunity to respond before I posted about his work.

Dear Dr. Barlow,

Congratulations on your receipt of the 2012 James McKeen Cattell Fellow Award from the APS for your distinguished contributions to the field.

I am a blogger writing a post about past treatments for homosexuality and came across references to your early work on aversion therapy in gay men, which I found unfortunate.

I wondered whether you had a statement about that work in light of contemporary views of homosexuality, or whether you had issued such a statement in the past.

Thank you very much for your time.

Sincerely,
The Neurocritic


Then a reader (Jordon) commented on my post in 2015, saying Barlow wrote back when he was asked about aversion therapy. Barlow sent a forthcoming book chapter from his 2016 retrospective, The Neurotic Paradox, Volume 1: Progress in Understanding and Treating Anxiety and Related Disorders. A sort-of not-really apology appeared on p. 6-7:

But it was also during this time [late 60s-early 70s] that I undertook what has come to be from my own personal point of view the most regrettable initiative in my clinical research career. Specifically ... I began treating and evaluating the effects of [covert sensitization]  treatment in individuals with what came to be called paraphilias but what was then called sexual deviation (Barlow, 1974a). While our focus was mostly on pedophilia (e.g. Barlow, Leitenberg, & Agras, 1969), the aggressive behavior of rapists (e.g. Abel, Barlow, Blanchard, & Guild, 1977), and other paraphilias (e.g. Hayes, Brownell, & Barlow, 1978), included in this series of studies were participants presenting with same-sex arousal patterns with consenting adults. (e.g., Barlow, Leitenberg, & Agras, 1969). At that time homosexuality was considered a disorder in all systems of nosology and, under extreme pressures from society and the associated stigma, these individuals sought out treatment; so very few clinicians even gave it a second thought. But by the mid-1970s several individuals began questioning these treatment goals.

 

These practices were “embedded in the continually shifting landscape of cultural values and mores” and homosexuality wasn't de-pathologized until “later in the decade” of the 1970s [it was actually 1973] and“most of the work was on paraphilias” [but many papers were on attempted conversion of gay men and transgender women (who were called male transsexuals)]. Most importantly, Barlow did not acknowledge the harm inflicted on the recipients of his treatments.

Besides the bizarre exorcism in a transsexual article, three more papers described covert modeling procedures and a “therapeutic package” to change the gender identity of transgender youth and young women (Barlow et al., 1973, 1979; Hay et al., 1981). Given the Increasing Criminalization of Gender-Affirming Care for Transgender Youth in many Southern states, it's critical for all psychological organizations to disown past practices used to justify such discriminatory and inhumane treatment.

 

What else should I be?
All apologies
What else could I say?
Everyone is gay

--Nirvana


Footnotes

1One of the action items is that disclaimers will be added to SOGIECE papers previously published in ABCT journals. My initial search turned up only one. Barlow DH (1973). Increasing heterosexual responsiveness in the treatment of sexual deviation: A review of the clinical and experimental evidence. Behavior Therapy 4:655-671

2The SGM terminology was unfamiliar to me before now. I also wondered whether the acronym SOGIECE was real, but apparently it is.

 

ADDENDUM (June 12 2022): Dr. Hayes has issued a personal apology for his role in conversion therapy. Also, he has published on ACT to lessen the impact of internalized homophobia (which is quite common in LGBTQ+ persons, as I know from personal experience).

Yadavaia JE, Hayes SC. (2012). Acceptance and commitment therapy for self-stigma around sexual orientation: A multiple baseline evaluation. Cognitive and behavioral practice 19(4):545-59.
 

Bibliography
(refs discussed in Dr. David H. Barlow and Aversion Therapy for Gays)

Barlow DH (1973). Increasing heterosexual responsiveness in the treatment of sexual deviation: A review of the clinical and experimental evidence. Behavior Therapy 4:655-671.

Barlow DH, Abel GG, & Blanchard EB (1977). Gender identity change in a transsexual: an exorcism. Archives of sexual behavior, 6 (5), 387-95. PMID: 921523

Although the prevention of transsexualism is the ideal, work in this area has been fraught with ethical problems, and data on the possibility of prevention, or even what to prevent, are not available...

Barlow DH, Agras WS, & Leitenberg H (1972). The contribution of therapeutic instruction of covert sensitization. Behaviour research and therapy, 10 (4), 411-5. PMID: 4637499

Barlow DH, Agras WS, Abel GG, Blanchard EB, Young LD. (1975). Biofeedback and reinforcement to increase heterosexual arousal in homosexuals. Behav Res Ther. 13:45-50.

The patient descriptions are distressing, e.g. a boy raped by a male relative: “The first S was a 15-yr-old male who had engaged in homosexual behavior for 4 yr after being seduced [sic] by an uncle.”

Barlow DH, Leitenberg H, & Agras WS (1969). Experimental control of sexual deviation through manipulation of the noxious scene in covert sensitization. Journal of abnormal psychology, 74 (5), 597-601. PMID: 5349402

Hayes SC, Brownell KD, & Barlow DH (1983). Heterosocial-skills training and covert sensitization. Effects on social skills and sexual arousal in sexual deviants. Behaviour research and therapy, 21 (4), 383-92, PMID: 6138027

Herman SH, Barlow DH, Agras WS. (1974). An experimental analysis of exposure to "explicit" heterosexual stimuli as an effective variable in changing arousal patterns of homosexuals. Behav Res Ther. 12:335-45.


Additional References

Barlow DH, Abel GG, Blanchard EB. (1979). Gender identity change in transsexuals: Follow-up and replications. Archives of General Psychiatry 36(9):1001-7.

Barlow DH, Agras WS. (1973). FADING TO INCREASE HETEROSEXUAL RESPONSIVENESS IN HOMOSEXUALS. Journal of Applied Behavior Analysis. 6(3):355-66.

“Heterosexual responsiveness, measured by penile responses and reports of behavior, was strengthened in three homosexuals through a fading procedure [slides of nude females superimposed on slides of nude males.]. ... The results suggest that fading was responsible for altering stimulus control of sexual arousal and that aversive techniques may not be necessary in the treatment of sexual deviation.” [well that's a relief...]

Barlow DH, Hayes SC, Nelson RO, Steele DL, Meeler ME, Mills JR. (1979). Sex role motor behavior: A behavioral checklist. Behavioral Assessment. 1:119-38. [I could not find a copy of this; however, the items appear in Hayes et al. 1984].  Examples:

  • Firm Wrist Action Versus Limp Wrist Action.
  • Hand(s) in Pocket. 
  • Frequent or Exaggerated Hand or Arm Movements.
Barlow DH, Reynolds EJ, Agras WS. (1973). Gender identity change in a transsexual. Archives of General Psychiatry 28(4):569-76.

Brownell KD, Hayes SC, Barlow DH. (1977). Patterns of appropriate and deviant sexual arousal: the behavioral treatment of multiple sexual deviations. Journal of Consulting and Clinical Psychology 45(6):1144.

  • one cis-male cross-dresser into BDSM (among the rapists, pedophiles, and exhibitionists) listened to arousing scenarios followed by humiliating consequences while his penile circumference was measured.
  • no gay or trans subjects here, but other papers have used the D word (“deviant”).
Hay WM, Barlow DH, Hay LR. (1981). Treatment of stereotypic cross-gender motor behavior using covert modeling in a boy with gender identity confusion. Journal of consulting and clinical psychology 49(3):388.

Hayes SC, Nelson RO, Steele DL, Meeler ME, Barlow DH. (1984). Instructional control of sex-related motor behavior in extremely masculine or feminine adults. Sex Roles 11(3):315-31.


Leonard SR, Hayes SC. (1983). Sexual fantasy alternation. Journal of behavior therapy and experimental psychiatry. 14(3):241-9.

  • four bisexual men (three white, one black) who were “confused” about their sexual orientation
  • but only the black man was medicated (with a potent antipsychotic)
“Subject 3 was a 32 yr old, black, married, blue collar worker and father of five. His heterosexual history was extensive. He reported a 3 yr history of homosexual activity ocurring during drinking episodes. At the time of referral and throughout the study, he received medication (Thorazine 25 mg daily) from a physician at the referring agency.”

 


 

 

Extracting reliable neurobiological biomarkers for complex subjective experiences isn't easy

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"The self is the psychological counterpart of the default mode functionality of the brain." (Scalabrini et al., 2021).


The self studying how "The Self" is represented and constructed by the brain is apex meta-neuroscience.1 We can say that the self is a manifestation (or an illusory byproduct) of activity in the default mode network (medial prefrontal cortex, posterior cingulate cortex/precuneus, and angular gyrus), but what does this really mean? How do we relate specific neural states to aspects of a changeable self? In a field increasingly focused on remote control of genetically-defined microciruits, pinning down subjective internal phenomena seems presumptuous and hopelessly overambitious.

But of course, the inherent challenge of studying complex subjective experiences hasn't stopped scientists from trying. One active area of research involves characterizing the neural correlates of internal responses to traumatic events. This is of great clinical relevance, because the long-term persistence of fear, hypervigilance, negative affect, and intrusive memories after trauma can be disabling (post-traumatic stress disorder, PTSD). Alterations in one's sense of self (dissociation) can also occur in PTSD, and is the focus of the rest of this post. Dissociative symptoms can include:

  1. Depersonalization: Persistent or recurrent experiences of feeling detached from, and as if one were an outside observer of, one’s mental processes or body (e.g., feeling as though one were in a dream; feeling a sense of unreality of self or body or of time moving slowly).
     
  2. Derealization: Persistent or recurrent experiences of unreality of surroundings (e.g., the world around the individual is experienced as unreal, dreamlike, distant, or distorted). 


In states of depersonalization/derealization (which can occur independently of PTSD), one feels disconnected from the self and/or external reality. Dissociative symptoms are considered a maladaptive (but protective) response to stress and trauma. The standard method of eliciting dissociative symptoms during fMRI scanning is script-driven imagery (SDI), a highly unpleasant manipulation. Before the experiment, the participant recounts a narrative of the traumatic event, which is subsequently read back to them in the scanner. The presence of acute dissociative symptoms is determined by questionnaires and interviews before, during, and after the scan.

Early studies reported increased activity in prefrontal (and other) cortical regions in the SDI condition compared to baseline (Lanius et al., 2002) or a neutral script condition (Hopper et al., 2007), which was related to the severity of dissociative symptoms. This fits a theoretical perspective where higher cortical regions are tamping down limbic (and emotional) responses to the trauma induction. It should be mentioned that dissociative responses to SDI are generally less common than vivid re-experiencing of the trauma (30% vs. 70% in Lanius et al., 2002). Drawbacks of these studies include small samples sizes and inconsistencies in the fMRI results.

Mertens and colleagues (2022) set out to replicate these findings in a larger, more homogeneous population of 51 female survivors of childhood abuse. The study included additional questionnaires and separation of the SDI condition into “script listening” and “focused recall” phases (previous studies only included the latter). The experimental design included three runs of neutral script (30 sec each of listening/imaging and focused recall of the event) and three runs of trauma script, which was effective in increasing self-reported ratings of dissociative symptoms, e.g. “Did what you were experiencing seem unreal to you, like you were in a dream or watching a movie or play?” and “Did you feel like you were a spectator watching what was happening to you, like an observer or outsider?” (rated on a 0-6 scale).


click on image for a larger view
 

The fMRI results indicated that a wide swath of left cerebellum, occipital cortex, and supramarginal gyrus (parietal lobe) were more active in the trauma script than neutral condition, and this was specific to the script listening phase (no differences were observed during the focused recall phase). The same pattern was seen in the amygdala in a region of interest analysis. Importantly, there was no relationship between any of the clusters and any dissociation measure (amygdala and insula shown below).2



Fig. 2 (Mertens et al., 2022). Script-elicited signal activation clusters and corresponding brain-behaviour correlates (N = 51).


The authors tried a number of different analytic techniques to try and find a relationship between activation clusters and dissociative symptoms, but they could not. In their conclusions, they mentioned the significance of the replication crisis in neuroimaging and noted that “the current (null) findings highlight the difficulty of extracting reliable neurobiological biomarkers for complex subjective experiences such as dissociation.” Identifying who we are and what we experience via spatio-temporal patterns of brain activity are problems that do not have an imminent solution.


Footnotes

1Self = a self-aware entity with fully-realized consciousness (whatever this means) 

2Here, the number of self-report and clinician-rated measures was impressive, e.g. Dissociative Experiences scale (trait dissociation), Cambridge Depersonalization Scale, Clinician Administered Dissociative States Scale, Responses to Script-Driven Imagery, etc.

 

Further Reading

Feeling Mighty Unreal: Derealization in Kleine-Levin Syndrome

A Detached Sense of Self Associated with Altered Neural Responses to Mirror Touch

Role of the Vestibular System in the Construction of Self

Derealization / Dying

'I Do Not Exist' - Pathological Loss of Self after a Buddhist Retreat

The Stranger in the Mirror

Writing-Induced Fugue State


References

Hopper JW, Frewen PA, van der Kolk BA, Lanius RA. (2007). Neural correlates of reexperiencing, avoidance, and dissociation in PTSD: Symptom dimensions and emotion dysregulation in responses to script‐driven trauma imagery. Journal of Traumatic Stress 20(5):713-25.

Lanius RA, Williamson PC, Boksman K, Densmore M, Gupta M, Neufeld RW, Gati JS, Menon RS. (2002). Brain activation during script-driven imagery induced dissociative responses in PTSD: a functional magnetic resonance imaging investigation. Biological Psychiatry 52(4):305-11.

Lebois LA, Harnett NG, van Rooij SJ, Ely TD, Jovanovic T, Bruce SE, House SL, Ravichandran C, Dumornay NM, Finegold KE, Hill SB et al. (2022). Persistent dissociation and its neural correlates in predicting outcomes after trauma exposure. American Journal of Psychiatry Jun 22.

Mertens YL, Manthey A, Sierk A, Walter H, Daniels JK. (2022). Neural correlates of acute post-traumatic dissociation: a functional neuroimaging script-driven imagery study. BJPsych Open 8(4).

Northoff G, Scalabrini A. (2021). “Project for a Spatiotemporal Neuroscience”–Brain and Psyche Share Their Topography and Dynamic. Frontiers in Psychology 2021:4500.

Scalabrini A, Schimmenti A, De Amicis M, Porcelli P, Benedetti F, Mucci C, Northoff G. (2022). The self and its internal thought: In search for a psychological baseline. Consciousness and Cognition 97:103244.

 

Nested hierarchy of self in the brain

Fig. 4 (Northoff & Scalabrini, 2021). Nested hierarchy of self in the brain.


The Human Protein Atlas (Neuropeptide Edition)

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The more you study the brain, the more unknowable it becomes. The level of complexity is baffling, and this is true whether the brain belongs to a human or a crab.1 The latest uptick in human brain complexity was revealed from analysis of postmortem tissue in 17 subregions of prefrontal cortex (PFC). Zhong and colleagues (2022) found that 60 neuropeptides and 60 neuropeptide receptors are expressed in at least one of the PFC subregions.

 

All the data are freely available (links are in the open access article) and incorporated into the Human Protein Atlas which has about 15 million individual web pages (according to Wikipedia).


Footnote

1Marder et al., 2022:

There is a growing literature that suggests that circuits can have degenerate solutions, that is similar looking behavior with different underlying parameters across individuals. ...  Moreover, repeated performance of the same task is often associated with variable activity in the network generating this task [57∗∗].

 

Reference

Zhong, W., Barde, S., Mitsios, N., Adori, C., Oksvold, P., Feilitzen, K. V., ... & Hökfelt, T. (2022). The neuropeptide landscape of human prefrontal cortex. Proceedings of the National Academy of Sciences, 119(33), e2123146119. 



modified from Fig. 2 (Zhong et al., 2022). Expression levels of (A)Neuropeptides (NP) and (B)Neuropeptide Receptors (NPR) in human PFC. The color code indicates the type of genes (orange, precursor; green, NP; blue, NPR). Red arrows in A and B point to the transcripts studied with ISH (in situ hybridization).

"And then a Plank in Reason, broke,"

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 “I am dead.”

 

In terms of possible delusions in living human beings, Le délire des négationsthe nihilistic delusion that one is dead evokes the most harrowing existence imaginable. The French neurologist Jules Cotard first described the syndrome that bears his name (1882, English translation):

I hazard the name of delirium of negations to designate the state of the patients ... in whom the negative disposition is carried to the highest degree. [They are] asked their name – they have no name; their age – they are ageless; where were they born – they were not born; ... if they have a headache, stomach ache, pain in some part of their body – they have no head, no stomach, some even have no body... For some the negation is universal, nothing exists anymore, they themselves are nothing.

 

Cotard presented the case of Miss X, a 43 year old woman with severe “melancholic anxiety” who tried to end her own life (1880, English translation):

...She affirms that she has neither brain nor nerves, nor chest, nor stomach, nor intestines; all that remains is the skin and bones of the body, disorganized (these are [her] own expressions). This delirium of negation extends even to the metaphysical ideas which were formerly the object of [her] firmest beliefs; She doesn't have a soul, God doesn't exist, neither does the devil. Miss X… being no more than a disorganized body, does not need to eat to live, she cannot die a natural death, she will exist eternally unless she is burned, fire being the only end...


Cotard delusion has been observed in a wide variety of psychiatric and neurological conditions, including psychotic depression, schizophrenia, encephalitis, subdural hemorrhage, arteriovenous malformations, migraine, Parkinson's disease, stroke, and epilepsy (Gerrans, 2022). From a neurobiological perspective, it's nearly impossible to construct a unified theory of the dysfunctional brain systems that underlie the delusion. Hence, some studies have focused on patients who manifest Cotard delusion after stroke, brain injury, or anti-NMDA receptor encephalitis for clues on potential brain regions that may be implicated in these cases. 

Two new papers describe the role of depersonalization an estrangement from one's body or self in Cotard delusion (Davies & Coltheart, 2022; Gerrans, 2022).


Absence disembodies — so does Death
Hiding individuals from the Earth
Superposition helps, as well as love —
Tenderness decreases as we prove —

Emily Dickinson


One prominent account of Cotard holds that people suffering from the delirium of negation are completely devoid of emotional responses. The nihilistic delusion is an attempt to make sense of this anomalous experience. Davies and Coltheart (2022) are critical of this view because there's no evidence that emotional reactivity is abolished in Cotard delusion. They also cite 12 case reports of patients who show a variety of affective states that collectively encompass anxiety, fear, guilt, distress, paranoia, aggression, agitation, anguish, despair, euphoria, grandiosity, irritability, sadness, and worry.

An alternate account places the anomalous experiences of depersonalization and derealization, rather than lack of emotion, as the central “surprising events” that trigger nihilistic delusions (Billon, 2016; Davies & Coltheart, 2022). These patients describe phenomena such as “I feel myself detached from my own body” and “feelings of unreality and difficulties in deciding whether events ... were real or just imagined”. The injured brain areas in these patients included insular cortex and right temporal-parietal regions.

A Death blow is a Life blow to Some
Who till they died, did not alive become —
Who had they lived, had died but when
They died, Vitality begun.

Emily Dickinson


In contrast, Gerrans (2022) proposes that depersonalization and Cotard delusion result from different ruptures in the sense of self. He provides an extensive and accessible review of the interoceptive active inference model and predictive coding of bodily states in the anterior insula cortex. Depersonalization may arise from imprecise interoceptive predictions, but reality testing remains intact. On the other hand, Cotard delusion represents a complete rupture from reality.

Within this framework, depersonalisation experience involves a selective failure to annex a class of experience to a largely intact hierarchical self-model. The Cotard delusion is a result of the destruction or degradation of that model. It is consistent with this view that there can be overlap between symptoms of depersonalisation disorder and Cotard syndrome, especially while the delusion develops because of nature of self-modelling. However the delusion reports the experience of human life without an intact regulatory self-model whereas in depersonalisation the self-model is largely intact.


A key component of the “depersonalization first, Cotard second” view should account for why the former is relatively common, while the latter is quite rare.

 

References

 
Cotard, J. (1880). Du Délire hypocondriaque dans une forme grave de la mélancolie anxieuse, mémoire lu à la Société médico-psychologique dans la séance du 28 juin 1880, par M. le Dr Jules Cotard.

Cotard, J. (1882). Du délire des négations. Arch de Neurol, 4, 282-296.
 
Davies, M., & Coltheart, M. (2022). Cotard delusion, emotional experience and depersonalisation. Cognitive Neuropsychiatry, 1-17.
 
 


 
I felt a Funeral, in my Brain,
And Mourners to and fro
Kept treading - treading - till it seemed
That Sense was breaking through -

And when they all were seated,
A Service, like a Drum -
Kept beating - beating - till I thought
My mind was going numb -

And then I heard them lift a Box
And creak across my Soul
With those same Boots of Lead, again,
Then Space - began to toll,

As all the Heavens were a Bell,
And Being, but an Ear,
And I, and Silence, some strange Race,
Wrecked, solitary, here -

And then a Plank in Reason, broke,
And I dropped down, and down -
And hit a World, at every plunge,
And Finished knowing - then -
 

Frankenstein's Hand

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Just in time for Halloween, I had a hideous surgery to repair a fractured elbow. This entailed receiving a nerve block that made my hand feel like a dead appendage, which was quite spooky indeed.

 


 Spooky Dead Hand

  

I'm supposed to keep the arm elevated above my heart (which isn't conducive to sitting here and typing), so that is all for now.

 

Happy Halloween!


Actual e-mail sent to the post-op contact person the night of my surgery:

 

 

OMFG, WHAT DID THEY DO TO ME WITH THIS DAMN TORTURE SLING?


Neuroscience Trend Forecasters

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As 2022 draws to a close, the SNL Trend Forecasters have agreed to divulge their predictions for the most — and the least exciting research fads for the New Year.


The Neurocritic: How do you guys predict today's most popular neuroscience trends? 

Trend Forecasters: Oh, well we have 4,000 computers, they're all big they all make charts and they beep LOUD.

TN: Let's get started!


In:posterior cingulate cortex

Hey Posterior Cingulate — we see you! You're fresh, you're mysterious, you're misunderstood. But we know you exist far beyond the default fashion mode. The new tripartite view proposes...

...that the broader PCC region contains three major subregions — the dorsal PCC, ventral PCC and retrosplenial cortex — that respectively support the integration of executive, mnemonic and spatial processing systems. This tripartite subregional view reconciles inconsistencies in prior unitary theories of PCC function and offers promising new avenues for progress.

 

Out:anterior cingulate cortex

Get behind me, you tired brain region. Think you can do everything? Well the list of your supposed functions is wildly implausible. We've looked at PubMed and found mental fatigue, prediction of non-violent felony rearrest in women, amyloid-β-related increases in empathic concern, experimental odontogenic pain, gravitational perception, chronic itch, RDoC social constructs, and modulation of synaptic plasticity in exercise interventions for post-stroke pain.

 


 

In:claustrum

Claustrum, we're in love with you and it's not only because of the holidays. You're connected to everything and everyone.

Santa Claustrum

 

Initial speculation claimed you were responsible for consciousness (Crick & Koch, 2015), but subsequent studies in human epilepsy patients showed no alterations in consciousness with unilateral or bilateral electrical stimulation (Bickel & Parvizi, 2019). Instead, you're critical for cognitive control. The fresh functional model is called network instantiation in cognitive control (Madden et al., 2022).

Researchers at the University of Maryland School of Medicine ... now posit that Crick may have been incorrect: They developed a new theory — built on data — that the claustrum behaves more like a high-speed internet router, taking in executive commands from “boss” areas of the brain’s cortex that forms complex thoughts to generate “networks” in the cortex.

 

The most exciting recent work (in mice) has shown that claustro-cortical circuits are organized into functional modules (McBride et al., 2022)...

  • Frontal areas are more inhibited, while posterior areas are more excited
  • Upper layers are more excited, while deeper layers are more inhibited 
...and connect cortical network motifs (Qadir et al., 2022)
  • Frontal cortices are synaptically connected to posterior cortices through claustrum
  • Two claustrum projection neuron subtypes support trans-claustral circuits
  • Trans-claustral circuits resemble a frontoposterior cortical network motif

Out: reinforcement learning and mesolimbic dopamine



 

Your superiority complex is tired, temporal difference error. We know you consider yourself the “biggest success story in computational neuroscience.” But every week a new finding prompts a mathematical tweak and an update of your impenetrable model.

‘teaching signal’ ‘learning model’ ‘model-free’ ‘cached values’ ‘ramps’ ‘bumps’ ‘belief states’ ‘vector RPE’ ‘DA dip of disappointment

Go to bed, TD. You have to get up early. For a flight TO HELL!



 
 

In:HippoCamera

You spent years developing your brilliant smartphone app that improves memory in older adults, drawing on the basic science of hippocampal replay (e.g., speeding up 24 sec video clips by 3×).



Autobiographical memory cues are created by recording an 8 sec audio cue to accompany a 24 sec video recording of a daily event, which is rated for significance. In your recent paper, fMRI scanning occurred after a two week or 10 week intervention. In comparison to baseline (non-reviewed) events, repeated replay of autobiographical memory cues enhanced episodic recollection and increased the differentiation of activity patterns in the hippocampus in older adults (Martin et al., 2022). Bravo, HippoCamera! Take a bow Barense, Honey, and Martin!

 

Out:Brain Behavior Quantification and Synchronization (BBQS)

BRAIN Initiative,2 you're so far behind the times that YOU ARE OUT. Didn't you get the memo that Neuroscience Needs Behavior back in 2017? Or read the review on Quantifying Behavior [in worms and flies] to Solve Sensorimotor Transformations, which covered papers going back to 2008 and earlier? The patentedHippoCamera was developed behind your back with funding from the Canadian government and private foundations. And the clever use of remote memories recorded by the 1 Second Everyday app (Bainbridge & Baker, 2022) was funded by NIH Intramural funds. The fact that you waited until 2023 to fully announce BBQS projects in humans and non-humans speaks volumes to the value you place on understanding behavior. GO TO BED!


In:neuropeptide maps of human prefrontal cortex

One recent uptick in human brain complexity was revealed from analysis of postmortem tissue in 17 subregions of prefrontal cortex (PFC). Zhong and colleagues (2022) found that 60 neuropeptides and 60 neuropeptide receptors are expressed in at least one of the PFC subregions. The data are freely available and incorporated into the Human Protein Atlas which has about 5 million individual web pages. The authors encouraged efforts to explore these neuropeptide receptors as potential targets for drug development in neurology and psychiatry, which has been neglected by pharmaceutical companies in recent years.


Out:functional neuroimaging in psychiatry
 

You're a failure, psychiatric neuroimaging!! Nour, Liu, and Dolan wrote a 20 page paper detailing your many shortcomings and faults. For instance, explanatory aspirations in resting-state studies are laughable:

“...bridging a gap between descriptive accounts of neural data and psychopathology requires a model that relates network properties ... to specific computational processes. Absent such a model, we argue that further large-scale data collection will be insufficient to yield breakthroughs in probing a fundamental understanding of cognition or psychiatric illness.

 We needn't go further than listing other direct quotes from their paper:

  • “...functional neuroimaging plays no role in clinical decision making.”
  • “While the computational psychiatry literature has identified associations between model-informed neural activity and psychiatric variables, effective clinical translation has been lacking.” 
  • “Casting a cold eye on the psychiatric neuroimaging literature invites a conclusion that despite 30 years of intense research and considerable technological advances, this enterprise has not delivered a neurobiological account (i.e., a mechanistic explanation) for any psychiatric disorder, nor has it provided a credible imaging-based biomarker of clinical utility.”
 
Ouch! You've done nothing for us, psychiatric neuroimaging. You haven't even embraced the correct level of analysis (i.e. manifolds). GO TO BED!

[In again:manifolds]


In:Synchron

Synchron, all the other billionaires are backing you, to the tune of $75 million! In a remarkable advance towards greater independence for paralyzed persons, the Stentrode, an endovascular brain computer interface (BCI), received Breakthrough Device designation from the FDA in August 2021. 

 

Stentrode™ (endovascular implant)

 

The minimally invasive BCI was developed with funding from DARPA (among others), and initial results from sheep were reported in Nature Biotechnology (Oxley et al., 2016). Its placement in the superior sagittal sinus (via the jugular vein) produces high-fidelity recordings from motor cortex without the need for risky cranial surgery. The brain.io™ motor neuroprosthesis transmits cortical signals from the Stentrode to a receiver implanted in the chest, and a machine learning algorithm decodes the neural activity and translates the signals to digital commands.

 

Oxley et al. (2021)

 

Two paralyzed participants with ALS achieved typing click selection accuracy of 93% within 86 days and 71 days of machine-learning supervised training (Oxley et al., 2021). Typing rate was relatively slow (13.8 and 20.1 correct characters per minute, respectively) in comparison to some other BCI cases, but those all entailed craniotomies.1 Nonetheless, both participants were able to text, e-mail, browse the internet, shop online, and manage finances (Oxley et al., 2021). The COMMAND Early Feasibility Study is an ongoing clinical trial of the Synchron device that will enroll six patients.


In:Mastodon

Because everyone needs an alternative social media site.


Out:Neuralink

Neuralink, you're out! So go back to hell. Stop flaunting your wealth, Neuralink. We all know you have to die for your hubris. You think you'll have FDA approval in six months, but that's what you said in 2019. Many of your claims are sheer fantasy, like you'll be able to cure everything from addiction to strokes.


from Neuralink Progress Update, Summer 2020

 

Your Fall 2022 update was more technically impressive, but still claimed your device will be able to restore vision prompting eminent vision scientist Brian Wandell to call out this BS:

He [Musk] specifically said this would work for the congenitally blind because they still have a visual cortex.

Two hundred years of experiments on site restoration in human, and many fundamental cellular experiments of visual development and the limits of adult plasticity, show this is false.


Potential ethical concerns have been noted by UPenn Prof Anna Wexler. Finally, you're under investigation for possible animal welfare violations. Neuralink, if I see you in the street I'll stab you in the face.




 
What are your favorite neuroscience trends for 2023? What should be kicked to the curb?

 

Footnotes

1 Most notable was BrainGate participant T5, with an astonishing 90 characters per minute. Two microelectrode arrays were implanted in the hand area of the precentral gyrus, and neural activity produced by imagined handwriting was decoded and translated into text in real time (Willett et al., 2021).

2 hat tip to Drug Monkey.


References

Bainbridge, W. A., & Baker, C. I. (2022). Multidimensional memory topography in the medial parietal cortex identified from neuroimaging of thousands of daily memory videos. Nature Communications, 13(1), 1-16.

Bickel, S., & Parvizi, J. (2019). Electrical stimulation of the human claustrum. Epilepsy & Behavior, 97, 296-303.

Calhoun, A. J., & Murthy, M. (2017). Quantifying behavior to solve sensorimotor transformations: advances from worms and flies. Current opinion in neurobiology, 46, 90-98.

Crick, F. C., & Koch, C. (2005). What is the function of the claustrum?. Philosophical Transactions of the Royal Society B: Biological Sciences, 360(1458), 1271-1279.

Foster, B. L., Koslov, S. R., Aponik-Gremillion, L., Monko, M. E., Hayden, B. Y., & Heilbronner, S. R. (2022). A tripartite view of the posterior cingulate cortex. Nature Reviews Neuroscience, 01 Dec 2022.

Han, J. J. (2021). Synchron receives FDA approval to begin early feasibility study of their endovascular, brain‐computer interface device. Artificial Organs, 45, 1134-1135.

Krakauer, J. W., Ghazanfar, A. A., Gomez-Marin, A., MacIver, M. A., & Poeppel, D. (2017). Neuroscience needs behavior: correcting a reductionist bias. Neuron, 93(3), 480-490. 

Madden, M. B., Stewart, B. W., White, M. G., Krimmel, S. R., Qadir, H., Barrett, F. S., ... & Mathur, B. N. (2022). A role for the claustrum in cognitive control. Trends in Cognitive Sciences.

Martin, C. B., Hong, B., Newsome, R. N., Savel, K., Meade, M. E., Xia, A., ... & Barense, M. D. (2022). A smartphone intervention that enhances real-world memory and promotes differentiation of hippocampal activity in older adults. Proceedings of the National Academy of Sciences, 119(51), e2214285119.

McBride, E. G., Gandhi, S. R., Kuyat, J. R., Ollerenshaw, D. R., Arkhipov, A., Koch, C., & Olsen, S. R. (2022). Influence of claustrum on cortex varies by area, layer, and cell type. Neuron (Nov 4).

Nour, M. M., Liu, Y., & Dolan, R. J. (2022). Functional neuroimaging in psychiatry and the case for failing better. Neuron, 110(16), 2524-2544.

Oxley, T. J., Yoo, P. E., Rind, G. S., Ronayne, S. M., Lee, C. S., Bird, C., ... & Opie, N. L. (2021). Motor neuroprosthesis implanted with neurointerventional surgery improves capacity for activities of daily living tasks in severe paralysis: first in-human experience. Journal of neurointerventional surgery, 13(2), 102-108.

Qadir, H., Stewart, B. W., VanRyzin, J. W., Wu, Q., Chen, S., Seminowicz, D. A., & Mathur, B. N. (2022). The mouse claustrum synaptically connects cortical network motifs. Cell Reports, 41(12), 111860.

Zhong, W., Barde, S., Mitsios, N., Adori, C., Oksvold, P., Feilitzen, K. V., ... & Hökfelt, T. (2022). The neuropeptide landscape of human prefrontal cortex. Proceedings of the National Academy of Sciences, 119(33), e2123146119.

 

I'm thinking about moving this blog...

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 ...to another platform.

 

Hi, it's been a while. I haven't written anything this year. My last post was December 31, 2022.

The main reason is that I've had to deal with more loss and grief in my life. Someone close to me was diagnosed with cancer, endured months of radiation and chemotherapy, and died anyway.1 I've also had some deflating garbage to wade through at work. My enthusiasm for doing anything has been rather low.

Besides all that, Blogger is a terrible platform for blogging. The interface changed a while a back and ever since then, composing in the little box has been unpleasant. It takes forever to get the formatting and spacing right. I could modernize the look from a “classic” theme 2 to one that has a “Layout” view...

 


...but that doesn't improve the writing experience.


So. I already have a WordPress blog. I may start posting there. The old neurocritic.blogspot.com site would become an archive of posts from 2006 2022.

 

The bigger question is whether I have anything relevant to say any more. 

 

Footnotes

1 ...less than three months later. If you ask me, the cause of death WAS the treatment (and its side effects). 

2“Hey there, 2004 wants their Rounders template back.” An SEO Guy even blogged about 11 Huge Reasons to AVOID Blogspot in 2023.

3 There are other platforms, sure. In a hilarious meta-example, a post on Medium provided a tutorial on Substack, which started as a platform for e-mail newsletters (whether monetized or not). But it also has a very blog-like look here's Margaret Atwood's, for example. Now they have Substack Notes, which is in the running as yet another Twitter replacement. Here's a thread on dumplings.

Why are "Love Languages" so popular, when they're completely inaccurate?

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I joined an online dating site a few months ago.1 Besides being asked about my sun, moon, and rising signs (?), I was puzzled by the following question.2



My love language? I'm supposed to choose only one answer? 

Gary Chapman has been a pastor at Calvary Baptist Church in Winston-Salem, NC for 50 years. In 1992, he published a book based on his experience of advising heterosexual couples on the best ways to have a harmonious marriage. His notion of 5 Love Languages is based on conservative Christian gender roles, although subsequent editions are less blatantly misogynistic. Nonetheless, the popularity of his ideas extends well beyond this initial demographic and has (ironically) invaded very Queer spaces.

Anyone can take the The Love Language® Quiz. I quit after the first question because it forces you to choose between a loving note/text/email for no special reason and a hug. Under any and all circumstances. 

Even my cat has more than one love language. There are three, which vary according to her needs:3

  • petting
  • play
  • food

And as humans, why must we limit ourselves to the five choices above, when the possibilities are endless? Here are some examples.4


New Love Languages
by James Folta and Kasey Borger

Deciding Where to Eat
Let your stressed-out partner know you’re for real by choosing a spot to eat. This is a love language that every single person desires, but almost no one can express. Looks like it’s frozen pizza again.

Talking About Your Commute
There is an extremely high concentration of individuals with this love language in New York and LA. Going on and on about trains, or highways, or traffic, or “I think it took me 25 minutes last time, but this time it took 35 — weird” is the only way this group can show their sweetie they care.

Explaining How You Feel About Facebook
Some people can only express their love by unpromptedly exclaiming that they’re going to delete their Facebook, and for real this time. Studies show this can be hard to discern as a love language because it is insufferable.

 

...and my personal favorite:

Replying to But Not Liking Tweets
This is a dark and horrific way to express affection, but we must begrudgingly acknowledge it.

Love Languages on a Likert Scale

As any decent social psychologist will tell you, The Love Language® Quiz has poor psychometric properties, meaning that the validity and reliability of the measurement instrument is very low. A remarkable number of studies have investigated the concept of love languages, and there is no empirical support for the idea, as recently reviewed by Impett, Park, and Muise (2023). A major issue is the way that Chapman frames his questions (as forced choices between two options). Instead, rating each item on continuous Likert-type scales reveals no correlation between scores on the quiz and scores on the continuous measure. These findings discount the notion that each person has a primary love language and illustrate that people value all five love languages but perhaps in different contexts, said Impett and colleagues.


So why are Love Languages so popular?
“If I had to pick one reason why I think many couples find Chapman’s book to be helpful,” says [co-author Haeyoung Gideon] Park, “it is not because they learned their own or their partner’s love language but because it gets people to identify any currently unmet needs in their relationship and opens up lines of communication to address those needs.”

 

Footnotes

1 I'm not saying which one. I'm in a demographic that absolutely no one cares about.

2 Clearly, I do not belong in my own demographic.

3 Sometimes, she enjoys more than one at the same time (e.g., petting while eating).

4 When forced to choose, my preferred love language is Sarcasm and Hyperbole, which does not make me popular with the online dating set.



Reference

Impett EA, Park HG, Muise A. (2023). Popular Psychology Through a Scientific Lens: Evaluating Love Languages From a Relationship Science Perspective. Current Directions in Psychological Science. 2023 Dec 7:09637214231217663.
 
- click to enlarge Table - 
 






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