On The Agency Cortex

As previously reported, the mirror neuron system is a set of cortical circuits that are active both when an individual performs an act (picking up an apple, say) and when he observes that action being performed by another individual. This collection of cells is clearly important for understanding the intentions of others, and perhaps for learning by imitation. Furthermore, there is quite similar sensory activity associated with both active and passive limb movement (movement imposed on one's body).

This presents a problem. How do we attribute self-agency to our actions? This is a particularly important question if one subscribes to the theory (mentioned sporadically in this forum), that free will is not the cause of our actions, but the post-hoc assumption of agency for our actions. Even if one does take the stance that free will is the subjective experience of causing thoughts and acts, this question remains relevant since there must be some neural activity which distinguishes self-caused action from passively experienced action.

Of course, there is a wealth of non-cortical activity which accompanies moving one's arm (signals in the brain-stem and spinal column, in particular) which could provide this signal. However, because of the abstract nature of agency, some have the opinion that there must be a specialized cortical area whose job it is to integrate the diffuse, distributed neural activity associated with a single act and decide whether it was internally generated or externally imposed.

Writing in the pages of the Journal of Neuroscience, Zarinah Agnew and Richard J. S. Wise report that they've found an area of the brain that is a candidate for the job of agency detector, the Parietal Operculum¹.

This work pushes the boundaries of research into the nature of free will. One class of phenomena which motivates the free-will-as-post-hoc theory is the so-called automatisms: actions which are internally generated but feel as though they were caused by an outside agent. A well known example of automatism is the Ouija Board, where it is possible - most likely due to suggestion and the ability to ascribe agency directly to the other "players" - to feel as though one is not moving a planchette. Another is automatic writing, a phenomenon in which an individual composes pieces (in some cases entire novels) without any feeling of agency.

That the experience of will can break down in these ways is a very direct indication (along with a host of others) that our understanding of the phenomenon is minimal, at best. Localizing the brain areas responsible for the feeling of free will is one step towards understanding it.

References:
1. Agnew Z, Wise RJ. Separate areas for mirror responses and agency within the parietal operculum. J Neurosci 28: 12268-12273, 2008.

On The Ecosystem Within (UPDATE)

My last post was concerned with the way mice regulate the set of bacteria which reside in their intestines. Which specific bacteria are present in one's gut is known to be predictive of obesity, but new research suggests that it isn't the bacteria themselves that are important so much as the genes that they carry¹.

Scientists at Washington University in St. Louis studied the bacteria present in the intestines of pairs of twins (a useful methodology for exploring many kinds of similarities amongst individuals with similar genes) and their mothers, expecting to find that those who were obese would have similar species of gut flora (similarly expecting comparable special cross-sections in those who were not obese). Interestingly, they found that the set of bacteria differed widely, but that the core "bacteriome" (the set of all the genes in all the bacteria in a person's gut) was highly conserved across the obese (and separately across the non-obese). They further found that related individuals were more likely to harbor the same set of species.

This is not incredibly surprising. After all, the functional utility - in terms of digestive assistance, molecular synthesis, and nitrogen uptake - of these bacteria is defined by their genes. That is to say, bacteria can only be useful to us and our internal environment in that they are in possession of metabolic pathways that we lack. Furthermore, given the massive number of bacterial species, it is unsurprising that one person gets a specific part of the benefits from species A, while another person obtains that benefit from species B. It is a happy surprise to me that this research is progressing at an increasing pace. I hope it continues as such.

References:
1. Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, Sogin ML, Jones WJ, Roe BA, Affourtit JP, Egholm M, Henrissat B, Heath AC, Knight R, Gordon JI. A core gut microbiome in obese and lean twins. Nature [Epub ahead of print], 2008.

On The Ecosystem Within

BIOMED. IMAGING UNIT, SOUTHAMPTON GEN. HOSP./SPL


There are more microbial cells than human cells in your body; this is a good thing. Bacteria help us break down foodstuffs by fermentation, synthesize vital molecules, and help us get rid of excess nitrogenous wastes. Furthermore, it has been demonstrated that the kind of bacteria you have in your gut is predictive of obesity: the right bacteria can help keep you thin^{1, 2}. Thus, it is important to have a source of good microbes in your diet, like yogurt or kombucha (a fermented tea drink rich in microbes), especially if you're engaging in activities that tend to kill off these organisms, like drinking heavily or taking antibiotics which don't discriminate between the good & the bad bacteria.

While drugs may not be able to discriminate between good and bad bacteria, our bodies must be able to in order to maintain intestinal homeostasis; how this happens has been unclear, to-date. However, new research demonstrates how one type of "bad bacteria" - the so called gram-negative strains - are selectively targeted by the body's immune system³. These microbes present an excess of a type of molecule on their membranes (peptidoglycans) which the body recognizes. The detection of these molecules causes the body to generate lymphatic tissue that specifically targets these bacteria.

As we come to understand more and more about the relationship between gut flora and health in general, this type of research will prove invaluable because it facilitates our understanding of the body's innate ability to regulate the subset of flora residing within. In other words, there is surely a gradient of immune system function such that some individuals are better able to select which flora to keep and which to oust; understanding how the body achieves this feat will thus widen the scope of western medicine.

References:
1. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444: 1027-1031, 2006.
2. Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature 444(7122):1022-1023, 2006.
3. Bouskra D, Brézillon C, Bérard M, Werts C, Varona R, Boneca IG, Eberl G. Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature 456: 507-510, 2008.

On Anti-Aging

from reference 2


Throughout your life, your cells are continually replaced. The replacements are newly differentiated stem cells: cells which have somehow come to a decision regarding their fate in your body, and have thus undergone a transformation from a ready-to-become-something state, to a liver cell, a retinal cell, a skin cell, a brain cell (neuron). This further means that your stem cells (and others) are constantly dividing, a process called mitosis. The most fundamental operation in mitotic division is the replication (copying) of DNA. This is a multifaceted operation involving a large cast of molecular players including (amongst others) enzymes, cofactors, and nucleic acid building blocks.

When DNA is replicated, complementary nucleic acid bases are added one by one to each strand of the double helix as it is unwound, resulting in two copies of the original piece of DNA (chromosome). However, this presents a slight problem. The enzyme complex responsible for adding these base pairs (the process is called elongation) requires a bit of RNA at the end of the strand to get started. The solution is that part of the end of the DNA strand is snipped off and replaced with a chunk of RNA as a jumping off point. This would be an issue if these enzymes were chopping off pieces of "important" (functional) DNA; cells have so called "proofreading" mechanisms to look for the kinds of erroneous DNA sequences that would result from trimming parts off the end, which if found in large enough numbers, result in cellular suicide (apoptosis). Instead, and rather ingeniously, there are long sequences that cap the ends of the important parts of DNA called telomeres. The only function of these sequences is to be snipped apart, slowly ground down over time, by replication so that the important stuff in the middle doesn't get messed with in this process.

Telomeric DNA has been seen as a potential target for anti-aging therapy. The idea is simple: make telomeres longer, the animal lives longer because the animal's cells can replicate forever without ever being forced to snip "important" DNA during the replication part and ultimately apoptose. Furthermore, there is an enzyme whose job it is to lengthen telomeric DNA called, unsurprisingly, telomerase. Indeed, it is known that increased telomerase activity extends the lifespan of most human cell types in vitro¹. Sadly, high telomerase activity is correlated with the development of cancer, and the exploration of its use as an anti-aging therapy has thus been attenuated.

A recent study, published in the journal Cell, however, has explored the possibility of pumping-up telomerase activity in mice². The authors of this study enhanced telomerase activity in mice who had also been given a number of tumor-suppressing agents (p53, p16, and p19ARF) to render the rodents cancer resistant. This enhancement "improves the fitness of epithelial barriers, particularly the skin and the intestine, and produces a systemic delay in aging accompanied by extension of the median life span." (See figure, below.) The real significance of this study is that it is the first to demonstrate the ability of enhanced telomerase activity in extending lifespan in vivo, in a living organism.


from reference 2


Cells can only divide so many times before they become inviable (around 53 for humans). This hints at a fundamental limitation to the replication process. One component of this is surely that described herein of telomere shortening. However, there are many other ways that errors can accrue in DNA. On another note, it will be extremely intriguing to see how these sorts of aging stories regarding DNA and cell division relate to those concerning calorie restriction and associated metabolic pathways.

While the enhancement of telomerase activity is a piece of the aging puzzle, we have a long way to go in understanding the finite quality of cell division, and it may truly be inescapable, to say nothing of aging itself.

References:
1. Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, Harley CB, Shay JW, Lichtsteiner S, Wright WE. Extension of life-span by introduction of telomerase into normal human cells. Science 279: 349-352, 1998.
2. Tomás-Loba A, Flores I, Fernández-Marcos PJ, Cayuela ML, Maraver A, Tejera A, Borrás C, Matheu A, Klatt P, Flores JM, Viña J, Serrano M, Blasco MA. Telomerase reverse transcriptase delays aging in cancer-resistant mice. Cell 135: 609-622, 2008.

On The Ways That Brains Change

from reference 1


It is well known that nervous system plasticity (the mutable quality of brains) underlies animals' ability to change their behaviors. However, it has been widely thought that such plasticity consists mostly of changes at synapses, the sites of communication between neurons, or in the intrinsic excitability of individual neurons - how likely a cell is to increase or decrease its voltage or to fire action potentials. New research challenges this view by showing that another type of alteration can be at work: single neurons can change the type of neurotransmitter they release in response to stimulation¹.

Specifically, this work addresses tadpole camouflage. Tadpoles can rapidly change (increase or decrease) the amount of pigmentation in their skin in order to blend in with their surroundings. The research I here refer to demonstrates that when frog tadpoles (Xenopus laevis) are stimulated with bright light, the number of dopamine-secreting (dopaminergic) neurons in the animals' brains increases, allowing them to adapt more rapidly to subsequent exposure to light.

When exposed to just hours of direct light, dark-reared tadpoles responded by doubling the number off dopaminergic neurons within a part of their central nervous system called the suprachiasmatic nucleus (SCN). Furthermore, these new dopaminergic neurons seem to integrate into the existing pathways for changing pigmentation. The authors were able to selectively destroy existing SCN dopaminergic neurons, eliminating the tadpoles ability to change pigment, and then rescue this ability with light exposure.

It remains unclear if this phenomenon is purely a developmental one, operating only prior to adulthood, an important caveat. None the less, the ability to change cell type is an as-yet unexplored form of neural plasticity which will have widespread implications for neuroscience research. Furthermore, this work may have even more direct application to human experience.

In human beings, the malfunction of certain dopamine-mediated signalling cascades (cell-level combinations of molecular interactions) have been implicated in seasonal affective disorder (winter depression). It is also well known that dopamine is intrinsically involved in the rewarding feelings delivered by food, sex and drugs. It may thus simply be the case that a lack of light stimulation leads to a lack of dopaminergic neurons, and thus to fewer episodes of rewarding experience during the winter months.

References:
1. Dulcis D, Spitzer NC. Illumination controls differentiation of dopamine neurons regulating behaviour. Nature 456: 195-201, 2008.

On Presidents and Science

I'm not the first by far to point this out, but I'm so happy that Barack Obama has been elected that I had to do something to mark the occasion. In fact I was totally oblivious to this imagistic event until Jessica excitedly picked up the magazine from my desk and proclaimed: "You have it!" Below are the front and back cover images from the September 25th issue of Nature magazine. It's not clear if this move was in any way intentional on the publisher's part, but it's pretty hilarious.

---

On Art from Science

Copyright © 2005 Hunter O'Reilly


"Hunter O’Reilly obtained a Ph.D. in genetics from the University of Wisconsin-Madison and graduated cum laude from the University of California, Berkeley. Her abstractions have been shown internationally including galleries in New York, San Francisco, England, Italy, Japan, the Czech Republic, Indiana and Wisconsin."





"Observations in the laboratory and the world around her inspire the shapes in her abstract oil paintings. Hunter's abstract art hints at both organic matter at the highest level (human faces) and at the smallest level (single cells). This section includes many images of artwork."

"O'Reilly teaches biology and art at Loyola University Chicago. She created a course, Biology Through Art, where students have the opportunity to create innovative artworks in a biology laboratory. Students view microorganisms, use DNA as an artistic medium, create music based on DNA sequence and see anatomy as art. The course culminates in students creating their own biological self-portrait."

More images here.

On What's Possible

"... it's just over fifty years since the launch of Sputnik. This event started the "space race," and led President Kennedy to innaugurate the program to land men on the moon. Kennedy's prime motive was of course superpower rivalry -- cynics could deride it as a stunt. But it was an extraordinary technical triumph -- especially as NASA's total computing power was far less than that of a single mobile phone today." (my emphasis)

This is how we're investing our technological capital?

References:
1. Rees M. Science: The Coming Century. The New York Review of Books LV: 41-44, 2008.

On Staying In Touch

from reference 1


In the world of neurotechnology, the prospect of exploiting the brain's inherently electrical quality by interfacing it with our own devices has become fairly commonplace. However, the main problem with such techniques is that the methods we have for making connections with the brain are inherently short term (on the order of weeks). This makes the dream of using implanted electronic interfaces for applications like controlling robot prosthetics one relegated to the future.

However, a study recently published in Nature details an advance in this field. The authors of this study were able to use brain signals from the motor cortex of a monkey to control his own limb (they'd anesthetized the normal neural pathways to make sure the endogenous connections were inoperable during the test). The unique quality of this feat lay, however, in the device used to read the signals from the monkey's brain. The implanted electrode had small piezoelectric motors which allowed it to move around in the monkeys brain in small steps (1 micrometer at a time), so that it was able to move towards strong signals, and back off neurons when it got to close, to keep from damaging them.

The connections are still only maintainable for about a month, but this type of technology and thinking is exactly what is needed to turn long-term electrical interfacing with the human brain into a reality.

References:
1. Moritz CT, Perlmutter SI, Fetz EE. Direct control of paralysed muscles by cortical neurons. Nature, doi:10.1038/nature07418

On Anatomy, Physiology & IQ

from reference 1


Although the relationship between Spearman's IQ test scores (g) and the concept referred to as intelligence can be debated, there is no doubt about the clinical utility of such tests in diagnosing psychiatric disorder. Beyond this, IQ scores say something about human intellect, though perhaps not as much as we'd like.

A study published in the Journal of Neuroscience gives new insight into the biological basis of the subparts of the test, fluid (gF) and crystallizeed (gC) components¹. Specifically, using fMRI (a brain-scanning technique which indirectly measures blood-oxygenation and can also be utilized to estimate the size of pieces of brain-tissue), these researchers found that performance on the crystallized component of the test was better correlated with cortical thickness, while the fluid component was better correlated with the magnitude of the blood-oxygenation signal while performing test-tasks.

This finding represents an advance from a study that had previously explored the relationship between overall IQ and the volume/location of grey matter².

References:
1. Choi YY, Shamosh NA, Cho SH, DeYoung CG, Lee MJ, Lee J-M, Kim SI, Cho Z-H, Kim K, Gray JR, Lee KH. Multiple Bases of Human Intelligence Revealed by Cortical Thickness and Neural Activation. J Neurosci, 28: 10323-10329, 2008.
2. Haier RJ, Jung RE, Yeo RA, Head K, Alkire MT. Structural brain variation and general intelligence. Neuroimage, 23: 425-33, 2004.

On The Relationship Between Reviewers

This post is a bit of a departure for this blog, but I decided that the snatch of math it contains pushes it just over the line of suitability. It was several years ago that my then fellow graduate student, Ilana Deluca, neice of Giorgio Deluca, got me into the habit of trying out new restaurants on Friday night. Neither of us had a significant other at the time, and we enjoy each other's company, so we'd eagerly try and find cuisine that both fit our minimal budgets and tantalized our tongues; if no such establishment fit the bill, we'd grab a bottle of red wine and wait patiently at Angelica Kitchen (Ilana's a veggie-oriented individual and I am, I hope, accomodating). Since then, sampling New York City Restaurants (and those in other locales when possible) has become a minor obsession of mine. I do tend to rely heavily on reviews from Zagat, Michelin (since they began weighing in on the subject again), Frank, and Adam. Thus, I was excitedly awaiting the release of the new publications from both Michelin and Zagat. However, I've long wondered about the relationship between the two scoring systems, a musing that I know I'm not alone in. Since I had access to both data sources, I thought I'd do an extremely simple bit of analysis to explore this topic. The graphic above, described below, is the result.

I started with the list of Michelin-starred restaurants, and looked up the Zagat FOOD rating only for these places (quibble about this if you like, I considered more in depth analysis by some sort of combination of scores for Food, Decor & Service, which may actually be forthcoming, but this seemed a best first-pass). I had thought initially that I'd find the starred restaurant with the lowest Zagat Food score and use this as a sort of cut-off, using only restaurants with Food scores with this value or higher. However, the lowest Zagat Food score for a restaurant on the starred-list is 22, and there are fully 784 restaurants on the Zagat.com site with Food scores of 22 or greater. So, I decided to limit myself to the 88 restaurants that receive a 26 for food or better (42 of these have Michelin stars). Then I simply plotted these restaurants as dots on a graph with number of Michelin Stars as the ordinate and Zagat Food score as the abscissa. Because of the overlap, I scaled each of the 16 resulting points on the graph by the number of entries at each set of coordinates. The coloring is simply for a little jazz-up. Finally, I performed a linear and exponential fit to the data, which were identical. By this I mean, I found the line and the exponential curve which came closest to matching up with the data points in the least-squares sense. Interestingly, these both predicted that as the Zagat Food scores goes up, the number of Michelin stars goes down! This is obviously an artifact of the inclusion of just as many restaurants with high Zagat Food scores and no stars as those with stars. What this does show, I'm sure to nobody's surprise, is that these scales are really not strongly related. Here's another version of the figure with a smaller dynamic range on the dot size, but with numbers of restaurants at each point explicitly printed on the graph.





As a closing note, it is a well known fact that averaging the guesses of many non-experts is often a better estimate of some parameter than those of a few experts. Sir Francis Galton first famously demonstrated this at a livestock fair with the weight of a bull as the parameter. This would seem to suggest that Zagat's rating system should be trusted as it is the amalgamation of the votes of all those who care to contribute whereas the Michelin guide relies on a smaller number of experts. I do not say this as some sort of definitive endorsement of the Zagat Guide, but rather as food for thought, which goes great with... dinner!

On Circadian Rhythms & Physiology

from reference 1


Circadian rhythms govern our state of arousal, informing us when to go to sleep and (for some) pulling us up from the pleasant depths of slumber. Further, because the physiological goals of sleep are so different from wakefulness (learning while awake & consolidating memories while asleep, using muscles to do work during the day & repairing them at night, et cetera), the circadian rhythm is also used to regulate many bodily properties and dynamics. An example of this can be found in a recent paper published in the journal Cell¹. The authors of this study found that the degree of electrical coupling between rod cells and cone cells in mice and goldfish is modulated by circadian rhythms.

Rod cells are relatively color-insensitive cells in the eye while cone cells are color-sensitive (with different subtypes having being sensitive to different parts of the spectrum). Thus, for the purposes of accurate perception of the visual world, one wouldn't normally want to link the activity of rods and cones because this would mix the color-insensitive responses with the color-sensitive ones, effectively washing out color information. However, as the day goes on and it gets dark, the argument goes, color matters less, and the paucity of light leads to the strategy of pooling responses across all light-responsive retinal cells. This is what is achieved by such circadian-rhythm-induced electrical coupling, pooling of responses to illumination.

References:
1. Ribelayga C, Cao Y, Mangel SC. The circadian clock in the retina controls rod-cone coupling. Neuron, 59: 790-801, 2008.

On Martian Snow

As reported in the Washington Post, NASA's Phoenix Lander (pictured above) has detected snowfall on Mars. Using LASER based scanning technology, the remote probe was able to spot flakes in the atmosphere and track their descent for more than a mile. However, Phoenix was not able to discern whether the snow actually landed on the surface of the planet. The idea, however, of snow-fall on Mars is a romantic and beautiful one, it just blossoms in my imagination.

On the 2007 Science and Engineering Visualization Challenge

A runner-up in the photography category.

Each year, Science magazine and the National Science Foundation hold a competition to select the best of the best in scientific imagery. Awards are given in several categories, and the contents range from tiny sub-domains to entire galaxies. These renderings are freely available to all on Science Magazine's website.

On The Genetic Basis of Schizophrenia

"... what a narrow ridge of normality we all inhabit, with the abysses of mania and depression yawning to either side."¹


from reference 2


Schizophrenia is a debilitating condition, chronic in nature, that affects approximately 1 in a hundred people worldwide. Although able to strongly suggest a genetic basis, past research has not been truly successful in determining the hereditary underpinnings of this combined neurological and psychiatric disorder.


from reference 3


Two papers, published in the journal Nature, have pushed this field of research farther than ever before, establishing schizophrenia-relevant chromosomal loci and using larger numbers of patients than in the past, for stronger statistical power^2,3. These studies focused on two types of chromosomal abnormalities, single nucleotide polymorphisms (SNPs; changes to single bases) and copy-number variations (CNVs; changes in the number of copies of one or more whole genes). Both studies confirmed previous findings of a CNV locus associated with schizophrenia, and validated each other's implication of two new CNV loci. Although it is still unclear how such information might be used, this is a cause for enthusiasm regarding the treatment of schizophrenia, and the possibility of determining genetic basis for other psychiatric disorders.

References:
1. Sacks, O. A Summer of Madness. The New York Review of Books, LV(14): 57-61, 2008.

2. Stefansson H, Rujescu D, Cichon S, Pietiläinen OP, Ingason A, Steinberg S, Fossdal R, Sigurdsson E, Sigmundsson T, Buizer-Voskamp JE, Hansen T, Jakobsen KD, Muglia P, Francks C, Matthews PM, Gylfason A, Halldorsson BV, Gudbjartsson D, Thorgeirsson TE, Sigurdsson A, Jonasdottir A, Jonasdottir A, Bjornsson A, Mattiasdottir S, Blondal T, Haraldsson M, Magnusdottir BB, Giegling I, Möller HJ, Hartmann A, Shianna KV, Ge D, Need AC, Crombie C, Fraser G, Walker N, Lonnqvist J, Suvisaari J, Tuulio-Henriksson A, Paunio T, Toulopoulou T, Bramon E, Di Forti M, Murray R, Ruggeri M, Vassos E, Tosato S, Walshe M, Li T, Vasilescu C, Mühleisen TW, Wang AG, Ullum H, Djurovic S, Melle I, Olesen J, Kiemeney LA, Franke B, Sabatti C, Freimer NB, Gulcher JR, Thorsteinsdottir U, Kong A, Andreassen OA, Ophoff RA, Georgi A, Rietschel M, Werge T, Petursson H, Goldstein DB, Nöthen MM, Peltonen L, Collier DA, St Clair D, Stefansson K, Kahn RS, Linszen DH, van Os J, Wiersma D, Bruggeman R, Cahn W, de Haan L, Krabbendam L, Myin-Germeys I; Genetic Risk and Outcome in Psychosis (GROUP). Large recurrent microdeletions associated with schizophrenia. Nature, 455(7210):232-236, 2008.

3. Stone JL, O'Donovan MC, Gurling H, Kirov GK, Blackwood DH, Corvin A, Craddock NJ, Gill M, Hultman CM, Lichtenstein P, McQuillin A, Pato CN, Ruderfer DM, Owen MJ, St Clair D, Sullivan PF, Sklar P, Purcell SM, Stone JL, Ruderfer DM, Korn J, Kirov GK, Macgregor S, McQuillin A, Morris DW, O'Dushlaine CT, Daly MJ, Visscher PM, Holmans PA, O'Donovan MC, Sullivan PF, Sklar P, Purcell SM, Gurling H, Corvin A, Blackwood DH, Craddock NJ, Gill M, Hultman CM, Kirov GK, Lichtenstein P, McQuillin A, O'Donovan MC, Owen MJ, Pato CN, Purcell SM, Scolnick EM, St Clair D, Stone JL, Sullivan PF, Sklar P, O'Donovan MC, Kirov GK, Craddock NJ, Holmans PA, Williams NM, Georgieva L, Nikolov I, Norton N, Williams H, Toncheva D, Milanova V, Owen MJ, Hultman CM, Lichtenstein P, Thelander EF, Sullivan P, Morris DW, O'Dushlaine CT, Kenny E, Waddington JL, Gill M, Corvin A, McQuillin A, Choudhury K, Datta S, Pimm J, Thirumalai S, Puri V, Krasucki R, Lawrence J, Quested D, Bass N, Curtis D, Gurling H, Crombie C, Fraser G, Kwan SL, Walker N, St Clair D, Blackwood DH, Muir WJ, McGhee KA, Pickard B, Malloy P, Maclean AW, Van Beck M, Visscher PM, Macgregor S, Pato MT, Medeiros H, Middleton F, Carvalho C, Morley C, Fanous A, Conti D, Knowles JA, Ferreira CP, Macedo A, Azevedo MH, Pato CN, Stone JL, Ruderfer DM, Korn J, McCarroll SA, Daly M, Purcell SM, Sklar P, Purcell SM, Stone JL, Chambert K, Ruderfer DM, Korn J, McCarroll SA, Gates C, Daly MJ, Scolnick EM, Sklar P. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature, 455(7210):237-241, 2008

On Subconscious Action

from reference 1


The subconscious components of our minds are more powerful than many admit, or feel comfortable admitting. As we go about our lives, our subconsciousness learns about aspects of our existence that might otherwise clutter our thoughts with a distracting chatter of activity: what pressure must I apply to the coffee cup in order for it to remain in my grasp, what route must I take through the throng of commuters in Penn-station to avoid colliding with others, has my blood-sugar dropped below the threshold where I experience hunger, et cetera. In fact, to some extent, the subconscious mind has access to information that the conscious mind does not, as in the muscle tension and blood-sugar examples. Understanding how these abilities are segregated between conscious and unconscious, and to what extent that question even makes sense to ask at both a behavioral and neurophysiological level are of fundamental interest to the understanding of consciousness and human neurological function in general.

A recent study speaks to this topic by probing the extent to which the subconscious can learn about the association between briefly presented visual cues and a monetary reward¹. Specifically, Chris Frith & colleagues had subjects play a game where the ability to win money in a given turn of the game was predicted by a visual cue which was presented too briefly to be consciously perceived (see instructions below²). The results of this study suggest that humans are reliably able to subconsciously learn the rewarding value of these visual cues. Importantly, in a control experiment, the researchers demonstrated that the subjects were unable to discriminate between the stimuli without the monetary reward/punishment scheme.

Given the abilities of humans (sketched above) to relegate processing to the subconscious, this finding isn't that surprising. However, this paper demonstrates the importance of feedback (reward or punishment) for instructing the subconscious. Furthermore, the fact that something as arbitrary as the conscious perception of promised financial reward can serve as the feed-back signal suggests a fundamental role for this type of learning that isn't limited to certain acts, but might underlie the learning abilities of humans in general.

References/Notes:
1. Pessiglione M, Petrovic P, Daunizeau J, Palminteri S, Dolan RJ, Frith CD. Subliminal instrumental conditioning demonstrated in the human brain. Neuron, 59(4): 561-567, 2008.

2. "The aim of the game is to win money, by guessing the outcome of a button press.

At the beginning of each trial you must orient your gaze towards the central cross and pay attention to the
masked cue. You will not be able to perceive the cue which is hidden behind the mask.

When the interrogation dot appears you have 3 seconds to make your choice between
- holding the button down
- leaving the button up
If you change your mind you can still release or press the button until the 3 seconds have elapsed.

‘GO!’ will be written in yellow if, at the end of the 3 seconds delay, the button is being pressed.

Then we will display the outcome of your choice. Not pressing the button is safe: you will always get a
neutral outcome (£0). Pressing the button is of interest but risky: you can equally win £1, get nil (£0) or
lose £1. This depends on which cue was hidden behind the mask.

There is no logical rule to find in this game. If you never press the button, or if you press it every trial,
your overall payoff will be nil. To win money you must guess if the ongoing trial is a winning or a losing
trial. Your choices should be improved trial after trial by your unconscious emotional reactions. Just
follow your gut feelings and you will win, and avoid losing, a lot of pounds! "

On Tree Drinking

from reference 1


Plants don't have hearts to pump fluids throughout their systems, so how do they generate the pressure to move water against the force of gravity from their roots to their shoots (leaves)? Capillary action (the tendency of a fluid to move through small spaces due to it's molecular constituents cohesive properties or surface tension) can explain the movement of water over small distances, but it cannot account for the large scale movement of water from the bases to the tips of tall trees like the Giant Sequoia of Redwood Forest.

Instead, it has long been thought that evaporation of water at the leaves draws water up in a long continuous column from the root, a process known as transpiration. This hypothesis was recently verified in the form of an artificial model¹. Abraham Stroock and his graduate student at Cornell University built a small (10 cm) proof-of-concept tree model with artificial membranes representing roots and leaves and small "microfluidic" channels connecting them. Though small, this device demonstrates the functional capacity of the evaporation/water-column idea, and might eventually be used to test failures of this model (such as when air-bubbles intervene in the column) and to draw small amounts of water out of hard to reach places.

References:
1. Wheeler TD, Stroock AD. The transpiration of water at negative pressures in a synthetic tree. Nature, 455(7210): 208-212, 2008.

On the nth Sense

from reference 1


It is widely documented that pheromones effect the behavior of insects, fish and mammals. However, locating both the pheromone molecules themselves and the anatomy for detecting them has proven challenging. A recent study, however, has identified the cells responsible for detecting so-called 'alarm pheromones' in mice¹.

The image above shows the implicated structures at various levels of detail. In the upper left, you can see a section of a mouse head, with a box around the GG: the Gruenberg ganglion, named for Hans Gruenberg, who first identified the set of cells in 1973.

There is every reason to assume that human beings are susceptible to the effects of pheromones, especially since the ganglion identified in the study mentioned above is present in humans. The prospect of having our behavior (or physiology in general) manipulated by artificial use of these molecules is both exciting and scary.

References:

1. Brechbühl J, Klaey M, Broillet M-C. Grueneberg ganglion cells mediate alarm pheromone detection in mice. Science 321: 1092-1095, 2008.

On Memory and Experience

from reference 1

As reported in the New York Times, a new study has demonstrated an aspect of memory that has long been hypothesized. That being: the same neurons that fire during an experience fire during the memory of that experience. The research, published in the journal Science, relies on recordings from the brains of epileptic patients undergoing surgery to remove the parts of their brain which cause excesses of neuronal activity, essentially the only way to record the activity of neurons in awake human beings¹.

The authors of the study took an approach where they recorded the activity of single hippocampal brain cells while subjects were watching a variety of video clips. Unsurprisingly, certain cells responded best to certain clips. Then, after a brief interim during which the experimenters distracted the patients, they asked the subjects to recall the video clips. Not only did the activity of the neurons during recollection correlate with activity during first viewing, the experimenters were able to predict which video clip the subjects were remembering based on the recorded activity! Interestingly, however, the hippocampus (the area of the brain being recorded from in this study) is not required for the recall of long term memories. Thus, in some ways this work further deepens the mystery of how short term versus long term memories are encoded in the brain and the involvement of hippocampus in these processes; a subject previously touched on in this forum.

Reading about this research reminded me of my favorite definition of memory, as the ability to:

"repeat a mental or physical act after some time despite a changing context.... We stress repetition after some time in this definition because it is the ability to re-create an act separated by a certain duration from the original signal set that is characteristic of memory. And in mentioning a changing context, we pay heed to a key property of memory in the brain: that it is, in some sense, a form of constructive recategorization during ongoing experience, rather than a precise replication of a previous sequence of events.

...the key conclusion is that whatever its form, memory itself is a [property of a system]. It cannot be equated exclusively with circuitry, with synaptic changes, with biochemistry, with value constraints, or with behavioral dynamics. Instead, it is the dynamic result of the interactions of all these factors acting together, serving to select an output that repeats a performance or an act.

The overall characteristics of a particular performance may be similar to previous performance, but the ensembles of neurons underlying any two similar performances at different times can be and usually are different. This property ensures that one can repeat the same act, despite remarkable changes in background and context, with ongoing experience."²

References:

1. Gelbard-Sagiv H, Mukamel R, Harel M, Malach R, Fried I (2008) Internally Generated Reactivation of Single Neurons in Human Hippocampus During Free Recall. Science 10.1126/science.1164685
2. Edelman GM, Tononi G (2000) A Universe of Consciousness: How Matter Becomes Imagination, Basic Books, New York

On the Importance of Single Spikes

from reference 1


As mentioned numerous times before in this forum, neurons in the brain communicate by action potentials: pulses of voltage that usually propagate from the cell body (soma) down a specialized outcropping of membrane called the axon which synapses onto other neurons. Usually, these synapses link pre-synaptic axons to post-synaptic dendrites, cellular structures specialized for recieving input.

Until recently, it was thought impossible for a single action potential, initiated in soma, to cause a second, post-synaptic neuron to fire an action potential; rather, as has been extensively documented, single neurons require many simultaneous dendritic inputs which are summed together to cause an action potential to be initiated in the soma. Recent research, however, has identified a cell type found exclusively in the cerebral cortex of human beings which seems to contradict this generalization. These neurons, termed "chandelier cells" are able to cause a chain of post-synaptic events (action potentials in several cells) lasting up to, on average, 37 milliseconds, ten times longer than had been previously assumed possible¹.

The article reporting these findings, published in the estimable journal PLoS Biology, describes one feature that the authors feel is of paramount importance to this phenomenon. Apparently chandelier cells are much more likely to make axo-axonic connections. That is, they send their pulses of activity not to dentrites, but to other axons. The reason for this somewhat exotic type of connectivity is that chandelier cells normally turn off the output of other neurons by sending inhibitory signals that cancel action potentials being sent down axons of the chandelier's targets. It seems then, that single chandelier cell action potentials inhibit other cells which are themselves inhibitory, indirectly exciting the targets of these secondary inhibitory cells.

The relevance of these findings to human cognition or consciousness is unclear, but this represents a significant advancement for our understanding of the functional connectivity of the human brain.

References:
1. Molnár G, Oláh S, Komlósi G, Füle M, Szabadics J, et al. (2008) Complex Events Initiated by Individual Spikes in the Human Cerebral Cortex. PLoS Biol 6(9): e222 doi:10.1371/journal.pbio.0060222

On Behavioral Genetics (II)

from reference 1


Once again, an example of a gene that plays some role in determining a human behavior has been found. Vasopressin, a neuropeptide, has long been known to regulate monogamous behavior in male voles. As with all signalling molecules in the brain, the effects of vasopressin can be changed by variations in its receptors (the molecules that recognize the signal; the lock to the key). Interestingly, recent research indicates that vasopressin plays a similar regulatory role in humans. Specifically, research published in PNAS aimed to determine if there was variability in the pair-bonding behavior amongst men possessing variable copies (none, one or two) of a version of a gene that codes for one subtype of the vasopressin receptor. As can be read from the table above, the work reports that men with more copies of this gene were less likely to be married, and more likely to answer yes to the question: "Have you experienced marital crisis or threat of divorce within the last year?"

References:
1. Walum, H, Westberg, L, Henningsson, S, Neiderhiser, JM, Reiss, D, Igl, W, Ganiban, JM, Spotts, EL, Pedersen, NL, Eriksson, E, & Lichtenstein, P. (2008) Genetic variation in the vasopressin receptor 1a gene (AVPR1A) associates with pair-bonding behavior in humans. PNAS doi: 10.1073/pnas.0803081105

On Self Recognition

from reference 1


Ascribing human characteristics to animals based on behaviors that resemble our own is a dangerous game. However, scientists studying the brain and behavior are often left with little choice. Thus, the "spot-test" has become the best experiment we have for answering the question: "does a given species have the capacity for self-recognition." In this test, a colored spot is put on an animal, the animal is placed in front of a mirror, and the experimenter looks to see if the animal will attempt to remove the spot, thus associating the figure in the mirror with itself. So far, the four great apes, bottlenose dolphins, and Asian elephants have shown the ability to pass this test. New research adds the magpie to this list¹. An interesting commentary was also published in the same issue of PLoS Biology as the study itself, and I reproduce an excerpt from that commentary here:

"From an evolutionary perspective, it must be added that MSR [mirror self recognition] seems hardly interesting. It cannot be an important adaptation, since animals lacking this capacity have no trouble with reflective surfaces, such as standing pools of water. Animals certainly do not need to recognize themselves to survive. The importance of the mirror test rather resides in what it may tell us about how animals perceive themselves in relation to their environment, including their social partners. In other words, the mirror test is interesting not because it shows that an animal has the capacity for self-recognition but because of the cognitive abilities that are associated with MSR.

It has been speculated that MSR coincides with advanced social relationships, including the capacity to look at the world from another's viewpoint. Gallup already speculated about this connection, and more recently this idea has been connected to the various levels of empathy reached by mammals. The higher levels of empathy require individuals to grasp the situation in which another finds itself, hence looking at the situation from another's perspective. The same capacity may be reflected in MSR. This is known as the “co-emergence hypothesis,” according to which the capacities for MSR and perspective-taking appear in tandem during both evolution and development.

With regards to human development, this hypothesis is well-supported. Children begin to show perspective-taking abilities at around the same time that they first pass the mirror mark test, even after age has been controlled for. In the future, researchers may be able to address this issue more directly through neural investigation. In humans, for example, the right inferior parietal cortex, at the temporoparietal junction, underpins advanced empathy by helping distinguish between self- and other-produced actions. If mirror responses tap into the same self–other distinction, the mark test is obviously more than it appears.²"

References:
1. Prior H, Schwarz A, Güntürkün O (2008) Mirror-Induced Behavior in the Magpie (Pica pica): Evidence of Self-Recognition . PLoS Biol 6(8): e202 doi:10.1371/journal.pbio.0060202
2. de Waal FBM (2008) The Thief in the Mirror. PLoS Biol 6(8): e201 doi:10.1371/journal.pbio.0060201

On Rodent Parkinsons

The cover of the journal Brain


Therapies based on stem cells rely heavily on our ability to coax these blank-cellular-slates into taking on specific forms. Stem cells are exciting as possible sources of medicinal therapy because they have the potential to become any type of cell in the body, but in order for their utility to be realized, we must be able to reliably effect their fates. The process of turning a stem cell into a specific cell type is called, logically, differentiation. With the exception of the immune system, the brain has more cell-types than any other organ, not to mention some of the most differentiated (exotic or distinct) types. Thus, many scientists are busily engaged in the activity of deducing molecular algorithms for deterministic control of their cellular end-state.

One disease where there seems to be a clear connection between cell-type-specific disfunction and pathology is Parkinson's Disease. In this debilitating condition, the afflicted progressively loose motor function due to a lack of stimulation of their motor corticies (the area responsible for directing movement in the human brain) by dopaminergic neurons found in the amygdala (another brain region associated with emotion and reward). Further, it appears to be the case that the reason for this lack of stimulation is simply a lack of production of dopamine by these dopaminergic amygdalar neurons. The cell-type specificity of the disease makes it an an excellent candidate for treatment by replacing the existing hypoactive neurons with newly differentiated stem cell versions of their kind, which should have normal dopamine production abilities.

A recent paper appearing in the journal Brain reports the results of a study in which the researchers have achieved just such a therapeutic cell-type replacement in rats with a "model" of human Parkinson's disease (ref. 1). They report that motor function was restored by this approach, and further that the longevity of the differentiated cells was related to their restorative efficacy. Further examples of work like this promise to revolutionize the treatment of a host of diseases.

References:
1. Sanchez-Pernaute R, Lee H, Patterson M, Reske-Nielsen C, Yoshizaki T, Sonntag KC, Studer L, Isacson O. (2008) Parthenogenetic dopamine neurons from primate embryonic stem cells restore function in experimental Parkinson's disease. Brain.

On Curvature in Saccades

I study Saccade Adaptation, the process by which our saccades (rapid, point-to-point eye movements) are kept accurate. I am proud to report that something that I wrote (with a Post-Doc in the lab I currently do my work in) was published today in the Journal of Neuroscience. Take a look at the PDF if you're so inclined.

On the Positive Effects of Variability

from reference 1

An emerging idea in neuroscience is that noise is a good thing, in moderation. Neural activity is very noisy, there is a large degree of variability in the temporal and frequency domains of the spiking of brain cells. It is thought that this variability actually contributes to the robustness of the system. One concrete example is stochastic resonance. In that phenomenon, randomly perturbing neural activity can push it over some threshold such that a sensory event is detected, or an ambiguous decision is made, one way or the other. It may be difficult to see this as beneficial, but especially as we are fantastic learning machines, simply making a decision, or having a perceptual event occur (even when there has been none) contributes to the system's learning abilities far more than indecision or non-detection.

In a more macroscopic example, a recent paper analyzing variability in brain activity across several age groups has found it to be quite positive. "Behaviorally, children showed slower, more variable response times (RT), and less accurate recognition than adults. However, brain signal variability increased with age, and showed strong negative correlations with intrasubject RT variability and positive correlations with accuracy. Thus, maturation appears to lead to a brain with greater functional variability, which is indicative of enhanced neural complexity. This variability may reflect a broader repertoire of metastable brain states and more fluid transitions among them that enable optimum responses. Our results suggest that the moment-to-moment variability in brain activity may be a critical index of the cognitive capacity of the brain.¹"

References:
1. McIntosh AR, Kovacevic N, Itier RJ. (2008) Increased brain signal variability accompanies lower behavioral variability in development. PLoS Comput Biol. 4(7):e1000106.

On Language Influencing Non-verbal Thought

from reference 1

Does the language we speak influence our non-verbal thoughts? This question is a stratifying one: some think that language is synonymous with thought, while others consider it a component of our mental abilities or a type of output, no more representative of underlying cogitation than the way we walk or move our arms.

A paper published in the Proceedings of the National Academy of Science weighs in on this matter with experimental results indicating that individuals who speak very different languages (English, Turkish, Chinese, & Spanish) seem to non-verbally represent events in similar ways.

Specifically, in one task, the researchers asked their subjects to communicate an event such as "boy tilts glass" (read in each individual's native language) with gestures. In a second task, they were asked to reconstruct an event using pictures. In order to quantify performance in these tasks, the researchers examined the ordering that gestures or pictures were used. They reasoned that because grammatical structures dictate that words be used in potentially divergent ways depending on language, that this structure might extend to the order in which gestures or pictures are used as well. Interestingly, they found that there was no quantitative difference in performance between speakers of different languages, suggesting that there is a common underlying mode of event representation which is minimally influenced by spoken language.

References:
1. Goldin-Meadow S, So WC, Ozyürek A, Mylander C. (2008) The natural order of events: how speakers of different languages represent events nonverbally. Proc Natl Acad Sci USA. 105(27):9163-8.

On The Wiring Diagram

From reference 1


The human brain has roughly 100 Billion neurons and each neuron has between 1000 and 10000 synapses (connections), thus approximately 500 Trillion synapses. This makes the problem of determining the connectivity, or the wiring diagram of the brain absurdly complex. This is one of the most fundamental problems confronting neuroscientists today because the solution to many problems of how the brain works would be made much easier if we simply knew the structure that it is built on.

A recent piece of computational research (published a wonderful PLOS journal) suggests a novel statistical method to identify which synapses of a given neuron are active at a given time. The author of this study simulated the output of many single neurons when a particular subset of it's synapses were active. This characterization was based on the number of action potentials the neuron fired in response to the activity of these many specific synapses. Next, the author examined the changes in the output when a single additional synapse was activated along with the baseline subset. He found that if he simulated the addition of one synapse ~80 times, he could measure significant changes in the output of the simulated neuron such that it was possible in subsequent tests to reliably predict when this synapse was active.

The authors suggestion is that taking this technique out of the computer and into the world of real brains (or small slices of brain, as is commonly employed), would facilitate the task of elucidating the numerous connections in the brain. While this is true, it must be said that this method is good for asking the following question: Which neurons are connected to one neuron that I know very well? In other words, somebody interested in applying this work would have to have one neuron of interest and then stimulate every other neuron that might be connected to it in order to determine the connectivity. In this sense, the approach is a far cry from revealing the wiring of the brain, but it certainly does help.

References:
1. Bhalla US. (2008) How to record a million synaptic weights in a hippocampal slice. PLoS Comput Biol. 4(6):e1000098.

On The Brain In Your Face

Figure 1 (from reference 1) showing the employed stimuli (a) and a schematic of the model they used (b).

Commonly held wisdom says that processing of visual features such as lines, forms, and motion is limited to higher cortical areas (for example, the medial temporal lobe, or area MT). Recent research shows, however, that the retina itself can extract motion signals, underscoring the subtle computational prowess of the bit of your brain that lives in your eye.

References:
1. Baccus, S. A., Olveczky, B. P., Manu, M. & Meister, M. (2008) A Retinal Circuit That Computes Object Motion. The Journal of Neuroscience, 28(27):6807-6817

On Context & Priming

From Reference 1

Part of the paradox of free will is that it not only liberates us by giving us control over our own actions, it also requires us to take responsibility for decisions which we make subconsciously. Thus, it is important to be vigilant in monitoring and understanding ones own psychology, one's implicit rationale and underlying systematic reasoning so that taking responsibility for all acts is useful in correcting or maintaining patterns of behavior. However, we must also remember that there are things that will effect the way we interact with the world that may lie beyond our awareness. In this sense we must be able to forgive ourselves when those factors play a role in decisions we deem inappropriate in retrospect. Metaphysics aside, there is a great deal of research documenting the effects of context and priming on human behavior. The latest is from a study on how voting location can affect the way people vote¹. Specifically, psychology researchers found that those voting on a education tax increase initiative were significantly more likely to vote for the initiative if they were voting in a school. The values (in the table above) indicate that the differences were small, but the statistics indicate that these differences are real.

References:
1. Berger J, Meredith M, Wheeler SC. (2008) Contextual priming: Where people vote affects how they vote. Proc Natl Acad Sci U S A. 105(26):8846 – 8849

On, Robot Prosthetics

From Reference 1


Using signals from the brain to control robotic arms is no longer cutting edge, having been achieved several times in the last decade. However, in the latest research into this topic, the authors present a novelty: rapidly training monkeys to control an anthropomorphic (having a shoulder, elbow, and wrist joint as well as a gripper) in order to feed themselves¹. This kind of technology promises to eventually revolutionize prosthetics and give untold freedom to those who can no longer use their own limbs but do retain the brain areas that generate the signals that once controlled them. In order for this to become feasible, the implants used to record brain activity must be vastly improved (at present they are reliable for only a matter of weeks or months), the processing power must be reduced in size (it presently requires several computers), and the process must be automated (the systems must at present be tuned by a technician online).

References:
1. Velliste M, Perel S, Spalding MC, Whitford AS, Schwartz AB. (2008) Cortical control of a prosthetic arm for self-feeding. Nature. 453(7198):1098-101.

On Time Perception & Sleep

Courbet's Sleep


Why is it that our perception of the passage of time changes around and during periods of sleep? While it is known that there are diurnal variations in time perception¹, and that insomniacs have irregular perception of duration of sleep², this basic question remains.

In an article concerning regular and pathological conscious perception of time, Oliver Sacks speculates that "visual perception might in a very real way be analogous to cinematography, taking in the visual environment in brief, instantaneous, static frames, or 'stills,' and then, under normal conditions, fusing these to give visual awareness its usual movements and continuity³."

This suggests the possibility that our perception of time is a function of our ability to impose a sense of continuity on our own perceptions. Thus, in the absence of external stimuli for this continuity system to act on, we have no mechanism to calculate the passage of time, and instead estimate this variable in a noisy, post-hoc manner.

In any case, the fact that it's possible to drastically misestimate how long one a bout of sleep has lasted implies that there is something fundamental about the state of consciousness (wakefullness) and judgement of time perception which remains to be understood.

References:

1. Pöppel E, Giedke H. (1970) Diurnal variation of time perception. Psychol Forsch. 34(2):182-98.
2. Knab B, Engel RR. (1988) Perception of waking and sleeping: possible implications for the evaluation of insomnia. Sleep. 11(3):265-72.
3. Sacks, O. (2004) In the River of Consciousness. The New York Review of Books. 51(1):

On First Sightings

From NewScientist


A doctor performing a hysterectomy accidentally shot the first photos of a human egg emerging from an ovary. The process took some 15 minutes, far longer than some have proposed. The video isn't terribly exciting, but it's amazing that we have such imagery.

On Reading The Unreadable

Phaistos Disc


This is the Phaistos Disc. It is the first piece of printed writing and nobody can read it. It is loosely dated to 1900BC (the Greek Government will not allow it to be subjected to thermoluminescent testing which would clear up its time of origin). It is clearly printed in the sense that each character was stamped onto this piece of clay, not etched or written as all other pieces of writing from this period. Many attempts have been made to decipher it, but the prevailing feeling is that these have been unsuccessful. I find mysteries like this beautiful and exciting because they area great challenge and reminder of how much our knowledge relies on a kind of collective remembrance of things. Without such distributed knowledge, where would we be?

On Motivating the Anecdotal

I was recently asked the question: "Why do things taste better when they're free?" While this hardly constitutes a rigorous scientifically testable hypothesis, I thought I'd wax speculative about it for a moment.

The explanation of why some may have this experience lies in the fact that your brain has a unified reward system based on the small molecule dopamine. This system is responsible for many types of associative learning (including classical Conditioning a la Pavlov), and signals rewards to be gained from engaging in various behaviors such as eating, having sex, or doing drugs¹. Further, it seems likely that the dopamine system is responsible for making us feel happy about having received monetary returns¹.

In the free-food-tastes-better case, this system is double activated. There is a reward for having gotten something for free along with a reward for eating something. However, there is sometimes only one action to assign the reward to: eating. Perhaps when there is no immediate action to be applauded for providing the free-food-prize, the brain simply heaps all the praise on the eating itself, thus resulting in the delightful (and dangerous) experience of the free snack being extra desirable.

References:
1. Caplin, D & Dean M (2008) Dopamine, Reward Prediction Error, and Economics. The Quarterly Journal of Economics. 123(2), 663-701

On Dopamine and Ethics?

It has long been known that the hormone dopamine plays a key role in both addictive and learning behaviors. As with all neurotransmitters, “normal” functioning of these small molecules in the body depends on their receptors, of which there can be several types.

Two papers, published last year in the journal Science, both focus on particular dopamine receptor types, and behaviors associated with them. Work from Jeffrey Dalley’s lab¹ uses PET to demonstrate that impulsive rats have significantly lower availability of two dopamine receptor types in a certain brain area, and further, that such impulsivity predicts how effective cocaine is in reinforcing behaviors thatt cause its administration. Meanwhile, experiments conducted by Tilmann Klein² indicate that people with a certain allele of one type of dopamine receptor are significantly less able to learn a task via negative feedback.

The latter work, however, has implications beyond the nature of learning. This is the first example of a certain type of human behavioral trait about which one can make quantitative predictions through genomic analysis. This trait is one that has the potential to stratify people; categorize them before birth according their potential abilities.

This gene presents the possibility for exactly the sort of genetic profiling that many have predicted with dread. The former work mentioned above carries some of the same baggage, a PET scan based screening of individuals could potentially be done quite early, and it is not hard to imagine the development of genetic screens to forecast “dopamine receptor availability.” An interesting conclusion to the presentation of these ideas would be some exploration of the actual value of being able to learn from negative feedback. Are those less able to learn in this way simply more bold? Fearless? Risk-takers? More creative? Could there be some value in attempting to tailor one’s activities to one’s genetic disposition?

Just as the construction of the atomic bomb raised questions about the ethics of conducting certain types of research in the physical sciences, recent work such as that mentioned here does the same for neuroscience. As it gains widespread interest and makes increasingly strong predictions about human beings and their behaviors, the power of great neuroscientific research must be wielded as gingerly as any.

References:
1. Dalley, JW et al, (2007) Nucleus Accumbens D2/3 Receptors Predict Trait Impulsivity and Cocaine Reinforcement, Science, Vol. 315:1267-1270 | 
DOI: 10.1126/science.1137073

2. Klein, TA et al, (2007) Genetically Determined Differences in Learning from Errors, Science, Vol. 318:1642-1645 |
DOI: 10.1126/science.1145044

On the Dynamic and Ever Changing Brain

brain sites stimulated and measured; from Ref. 1

It is well accepted that the activity in our brains is not simply defined by the anatomical connectivity therein. However, one of the great mysteries of free will (if it actually does exist) is how a conscious state (the current pattern of electrical activity) is causally linked to subsequent states (the next pattern of activity). If it is truly deterministic, then free will may truly be an illusion.

A recent paper reporting results from an experiment in which awake human cortices were stimulated and responses measured, makes an implicit comment on these matters. In this experiment, patients going in for brain surgery volunteered to have their cerebral cortices experimented on. This is not as invasive as it sounds since the experiment involved only a reanalysis of data obtained from necessary pre-surgical procedures. The experimental paradigm consisted of simply electrically stimulating the cortex at various points and measuring the evoked activity at other sites. The authors were curious how regular these responses would be, and how they would vary over time.

They found that "The likelihood of an afterdischarge at an individual site after stimulation was predicted by spontaneous electroencephalographic activity at that specific site just prior to stimulation, but not by overall cortical activity" (ref. 1). The intriguing part about this is that the overall activity does not predict the subsequent activity, supporting the notion that there is something else (free will?) that intervenes or contributes to the causation involved in moving to another state of activity. However, it must be noted that the overall activity might not be predictive for another reason. Aggregate brain activity is made up of parts devoted to distinct cognitive functions. Thus if the brain area stimulated was one devoted to motor function and the subject happened to be thinking about a movie prior to stimulation, the activity devoted to the visual experience wouldn't necessarily be predictive of how the activity might spread through the brain from this motor area. Nonetheless, it may be the case that this sort of variation - the seemingly random, highly dynamic snatches of activity present in the brain at any given moment - contribute to our sense of free will, and the rich landscape of experience that we go through.

References:
1. Lesser RP, Lee HW, Webber WR, Prince B, Crone NE, Miglioretti DL. (2008) Short-term variations in response distribution to cortical stimulation. Brain, 131 :1528-1539