A brain-enhancement amusement park mockumentary

“There was a level of undefined brain activity, about 30% higher, than the kids who stayed on the ground.”


The Centrifuge Brain Project is an awesome short film by Till Nowak, featuring a deadpan performance by Leslie Barany.





The fictitious website of the Institute for Centrifugal Research (ICR) is one of the best since LACUNA Inc. (which lives on at archive.org):

Welcome to the homepage of ICR - the world's leading research laboratory in the highly specialized field of spinning people around.

We are proud of our history - a chronicle of passion and pioneering achievements in the realms of brain manipulation, excessive G-Force and prenatal simulations. Established in 1976 by Dr. Matthew Brenswick and Dr. Nick Laslowicz, the institute has never stopped doubting the generally accepted laws of physics.

WEDDING CAKE CENTRIFUGE
established 1985.
Number of seats: 96
G-Force: 2.3
Model no. 810XN-96922

“Some of the test results that year were a little too extreme to be published.”

STEAM PRESSURE CATAPULT
established 2003.
Number of seats: 172
G-Force: 9
Model no. 01758X-KAZT

“Unpredictability was an important aspect of our work.”



Coming soon: Derealization during utricular stimulation.

ANISOMYCIN IS STRONG

In yesterday's story, EVERYTHING IS WRONG [...about protein synthesis and memory formation], The Neurocritic mentioned a potentially portentous new paper (Canal et al., 2007) that appears to question a [mostly] accepted theory that the formation of new memories requires de novo protein synthesis:

...the presumption is that protein synthesis inhibitors interfere with the establishment of enduring neural changes (i.e., those fundamental to memory, drug relapse, epilepsy, or motor cortex organization) by blocking mechanisms of neuronal and synaptic change that require de novo protein synthesis. Thus, evidence obtained with protein synthesis inhibitors has a pervasive influence on theories related to the fundamental mechanisms of not only memory formation but also a wide range of brain functions.

Fig. 3 (adapted from Canal et al., 2007). Effects of intraamygdala anisomycin (ANI) (n = 4) and vehicle (n = 4) injections on release of NE [norepinephrine; DA and 5-HT shown in original figure]. Microdialysis samples were collected every 45 min beginning 135 min before and ending 8 h after injections.

Although the protein synthesis view is predominant, the authors go on to cite data inconsistent with this notion (albeit data that's been basically ignored), and describe results so off the charts, it's surprising no one has noticed these effects before:

The findings described in the present article indicate that intraamygdala anisomycin injections result initially in extraordinarily large increases in release of biogenic amines near the site of injection, followed later by extensive and prolonged decreases in release of the amines. Additionally, blockade of amygdala beta-adrenergic receptors at the time of anisomycin injections, i.e., at the time of high release of biogenic amines, attenuates the amnesia produced by anisomycin as tested 48 h after training. Similarly, activation of beta2-adrenergic receptors during the time of amine depletion also attenuates anisomycin-induced amnesia assessed at 48 h after training. Moreover, a high dose of NE injected into the amygdala before training impairs memory to an extent similar to that seen after anisomycin injections. Together, these findings suggest that intraamygdala injections of anisomycin interfere with memory formation by inducing extraordinary changes in the release profiles of NE, DA, and 5-HT.

A critique of the microdialysis methods used in this study is beyond the scope of this blog, but any expert commentary is welcome.

Finally, appropriately timed administration of the beta-adrenergic antagonist propranolol and the beta-adrenergic agonist clenbuterol attenuated (but did not eliminate) the anisomycin-induced amnesia. Furthermore, a relatively high dose of norepinephrine injected into the amygdala 20 min before training produced amnesia for the inhibitory avoidance task when tested 48 hr later. No anisomycin necessary. At this stage, one can only speculate on the significance of these findings for the future of PTSD treatment.

Fig. 5 (from Canal et al., 2007).

Reference

Canal CE, Chang Q, Gold PE. (2007). Amnesia produced by altered release of neurotransmitters after intraamygdala injections of a protein synthesis inhibitor. Proc Natl Acad Sci. 104:12500-5.

Coda

And here's something akin to Lacuna Inc., perhaps?

* * *

anisomycin.com
"getting rid of bad memories"

The coundown has begun...

e-mail
info@anisomycin.com

Thoughts of Blue Brains and GABA Interneurons

An unsuccessful plan to 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 Hutton² undertook 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.

Gouwens et al., 2020

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 blog posts.

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

• from the transcript:

“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.

 

 

Brain in a box

Female Soldiers, PTSD, and Norepinephrine

Francisco Goya, The Disasters of War
[idea for using this image stolen from Mixing Memory's latest post on mirror neurons]

The 4th anniversary of the Iraq war was on Sunday, and some news outlets ran an obvious (but highly neglected) story: Violence takes severe mental toll on Iraqis.

Much more common are stories on the psychological toll of war in U.S. military personnel. There's a depressing article in the New York Times Magazine about post-traumatic stress disorder in women soldiers stationed in Iraq.

The Women’s War

By SARA CORBETT

Many female soldiers have lived through the terrible violence of the war in Iraq. Others have experienced sexual assault — or worse, a combination of the two. They have found themselves struggling to cope with their lives.

Among other examples, the article recounts the ordeal of Suzanne Swift, a 21-year-old Army specialist, who went AWOL rather than return to a second tour of duty in Iraq:

Despite the fact that military procedure for dealing with AWOL soldiers is well established - most are promptly court-martialed and, if convicted, reduced in rank and jailed in a military prison - Suzanne Swift's situation raised a seemingly unusual set of issues. She told Army investigators that the reason she did not report for deployment was that she had been sexually harassed repeatedly by three of her supervisors throughout her military service: beginning in Kuwait; through much of her time in Iraq; and following her return to Fort Lewis. She claimed too to be suffering from post-traumatic stress disorder, or PTSD, a highly debilitating condition brought on by an abnormal amount of stress. According to the most recent edition of The Diagnostic and Statistical Manual of Mental Disorders, used by mental-health professionals to establish diagnostic criteria, PTSD symptoms can include, among other things, depression, insomnia or "feeling constantly threatened." It is common for those afflicted to "re-experience" traumatic moments through intrusive, graphic memories and nightmares.

Given their current track record of providing adequate medical care to returning veterans, will the current administration find the funds to improve the standard of care not only for the physically wounded (see the Walter Reed debacle), but also for the astonishingly large number of vets (33%) diagnosed with mental illnesses?

The V.A. notes that as of last November, [almost] one-third [see Seal et al., 2007] of the veterans of Iraq and Afghanistan treated at its facilities were given diagnoses of a mental-health disorder, with PTSD being the most common. So far, the V.A. has diagnosed possible PTSD in some 34,000 Iraq and Afghanistan veterans; nearly 3,800 of them are women. Given that PTSD sometimes takes years to surface in a veteran, these numbers are almost assuredly going to grow.

What are the appropriate treatments for women with PTSD? Surely not this one:

While serving in a mostly male reserve unit in Kuwait, [another soldier] was sexually assaulted. After returning home to Michigan, she began exhibiting symptoms of PTSD - jumpiness, intrusive thoughts and nightmares - and promptly went to her local V.A. hospital for help. She was then put into group therapy - which has long been shown to be an economical and reasonably effective way of helping trauma survivors process their experiences - but her "group" was made up entirely of male Vietnam vets, some of whom were trying to work through sex crimes they committed during military service. Others came home from war and beat their wives. "I freaked out," the female reservist told me. "It sent me into a complete tailspin."

In addition to psychotherapy (including Exposure Therapy (Jaycox et al., 2002; Schnurr et al., 2007) -- a Cognitive Behavioral intervention -- and Eye Movement Desensitization and Reprocessing (Rothbaum et al., 2005; van der Kolk et al., 2007)) for those with PTSD, drugs that affect the neurotransmitter norepinephrine have been tested. A recent clinical trial of guanfacine was a complete failure (Neylan et al., 2006):

Neylan TC, Lenoci M, Samuelson KW, Metzler TJ, Henn-Haase C, Hierholzer RW, Lindley SE, Otte C, Schoenfeld FB, Yesavage JA, Marmar CR. (2006). No improvement of posttraumatic stress disorder symptoms with guanfacine treatment. Am J Psychiatry 163: 2186-8.

OBJECTIVE: The authors report an 8-week, double-blind, randomized controlled trial of guanfacine versus placebo for posttraumatic stress disorder (PTSD). METHOD: Veterans with chronic PTSD who were medication-free or receiving stable pharmacotherapy were randomly assigned to guanfacine (N=29) versus placebo (N=34). RESULTS: Guanfacine had no effect on PTSD symptoms, subjective sleep quality, or general mood disturbances. Guanfacine was associated with a number of side effects. CONCLUSIONS: These results do not support the use of alpha 2 agonists in veterans with chronic PTSD.

Guanfacine is an antihypertensive drug and an alpha-2 adrenergic agoninst that binds to autoreceptors on locus coeruleus (Berridge & Waterhouse, 2003) neurons [when administered at high doses¹], thereby inhibiting their activity and hence, the release of norepinephrine. When administered at low doses, guanfacine binds to post-synaptic alpha-2 receptors in places like the prefrontal cortex (Arnsten et al., 1988).

Another blood pressure medication, propranolol (a beta blocker), has been more widely used as a potential treatment for anxiety disorders and PTSD (e.g., Strawn & Geracioti, 2007). Similar to the use of alpha-2 agents, the idea behind propranolol is to normalize the hyperactive noradrenegic system in PTSD (a state produced by exposure to extreme levels of stress). Excessive norepinephrine (and the associated signal transduction activity) is thought to result in a trauma-induced enhancement of memory encoding for the harrowing event (Debiec & LeDoux, 2006).

Animal models of fear conditioning have been used to assess possible pharmacological treatments targeting the amygdala, a critical region for fear learning (Debiec & LeDoux, 2006). These treatments aim to impair memory consolidation and reconsolidation (reactivating a memory by retrieving it):

...propranolol, injected either systemically or directly into LA [lateral amygdala] lastingly impaired fear memory. Postreactivation propranolol significantly weakened fear responses measured 48 h later. ... Interestingly, our published findings indicate that propranolol disrupts reconsolidation of a memory 2 months after training. Therefore, even well-consolidated old fear memories undergo reconsolidation and may be disrupted by means of pharmacological manipulation.

For a more selective approach to PTSD, is it possible to

Wipe out a single memory (original source: Nature news) [??]

A single, specific memory has been wiped from the brains of rats, leaving other recollections intact.

The study adds to our understanding of how memories are made and altered in the brain, and could help to relieve sufferers of post-traumatic stress disorder (PTSD) of the fearful memories that disrupt their lives.

All very Lacuna Inc. (as other observers have noted). Original paper:

Doyere V, Debiec J, Monfils MH, Schafe GE, Ledoux JE. (2007). Synapse-specific reconsolidation of distinct fear memories in the lateral amygdala. Nat Neurosci. Mar 11; [Epub ahead of print].

When reactivated, memories enter a labile, protein synthesis–dependent state, a process referred to as reconsolidation. Here, we show in rats that fear memory retrieval produces a synaptic potentiation in the lateral amygdala that is selective to the reactivated memory, and that disruption of reconsolidation is correlated with a reduction of synaptic potentiation in the lateral amygdala. Thus, both retrieval and reconsolidation alter memories via synaptic plasticity at selectively targeted synapses.

In that experiment (and others like it), rats were treated with the MEK Inhibitor, U0126 [which inhibits the kinase activity of MAP kinase kinase, or MEK -- aka MKK or MAP2K²], not propranolol. U0126 is not exactly approved for human use³.

So what about propranolol for PTSD? According to Strawn & Geracioti (2007),

The utility of these anti-adrenergics in the clinical treatment of PTSD remains to be determined, though it is possible that they may prove to have primary roles in a disorder that is only modestly responsive to antidepressant treatment.

Footnotes

¹ Or so the story went, a story that motivated the idea of guanfacine treatment in the first place. However, recent work (Ramos & Arnsten, 2005; Arnsten & Li, 2007) has shown that alpha-2 receptors are much more prominent post-synaptically, and guanfacine is more selective for those than for pre-synaptic autoreceptors (and is selective to a greater extent than clonidine, another alpha-2 blood pressure med known to produce sedation).

² Also see the fun MAP Kinase Signal Transduction Animation by Dr. Vic Lemas.

³ We're getting way out of my league here, but apparently U0126 is in the very "early clinical phase" for cancer treatment (a "Target for the Future") and is viewed as a "radical approach to stroke therapy." The only published studies have been done with cell cultures, with a few in live rodents.


References

Arnsten AF, Cai JX, Goldman-Rakic PS. (1988). The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects: evidence for alpha-2 receptor subtypes. J Neurosci. 8:4287-98.

Arnsten AF, Li BM. (2005). Neurobiology of executive functions: catecholamine influences on prefrontal cortical functions. Biol Psychiatry 57:1377-84.

Berridge CW, Waterhouse BD. (2003). The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res Rev. 42:33-84.

Debiec J, LeDoux JE. (2006). Noradrenergic signaling in the amygdala contributes to the reconsolidation of fear memory: treatment implications for PTSD. Ann NY Acad Sci. 1071:521-4.

Jaycox LH, Zoellner L, Foa EB. (2002). Cognitive-behavior therapy for PTSD in rape survivors. J Clin Psychol. 58:891-906.

Ramos BP, Arnsten AF. (2007). Adrenergic pharmacology and cognition: Focus on the prefrontal cortex. Pharmacol Ther. 113:523-36.

Rothbaum BO, Astin MC, Marsteller F. (2005). Prolonged Exposure versus Eye Movement Desensitization and Reprocessing (EMDR) for PTSD rape victims. J Trauma Stress. 18:607-16.

Schnurr PP, Friedman MJ, Engel CC, Foa EB, Shea MT, Chow BK, Resick PA, Thurston V, Orsillo SM, Haug R, Turner C, Bernardy N. (2007). Cognitive behavioral therapy for posttraumatic stress disorder in women: a randomized controlled trial. JAMA 297:820-30.

Seal KH, Bertenthal D, Miner CR, Sen S, Marmar C. (2007). Bringing the war back home: mental health disorders among 103,788 US veterans returning from Iraq and Afghanistan seen at Department of Veterans Affairs facilities. Arch Intern Med. 167:476-82.

Strawn JR, Geracioti TD Jr. (2007). Noradrenergic dysfunction and the psychopharmacology of posttraumatic stress disorder. Depress Anxiety Mar 12; [Epub ahead of print].

van der Kolk BA, Spinazzola J, Blaustein ME, Hopper JW, Hopper EK, Korn DL, Simpson WB. (2007). A randomized clinical trial of eye movement desensitization and reprocessing (EMDR), fluoxetine, and pill placebo in the treatment of posttraumatic stress disorder: treatment effects and long-term maintenance. J Clin Psychiatry 68:37-46.