Tuesday, October 30, 2007

Will You Digg This PNAS Article On Digg?

Add to Digg Digg

Probably not. And even if you did, the collective Digg audience will forget about it in 69 minutes.
To study the dynamics of collective attention and its relation to novel inputs in a natural setting, we analyzed the behavioral patterns of 1 million people interacting with a news web site whose content is solely determined by its own users. Because people using this web site assign each news story an explicit measure of popularity, we were able to determine the growth and decay of attention for thousands of news stories and to validate a theoretical model that predicts both the dynamics and the statistical distribution of story lifetimes.
The authors (Wu & Huberman, 2007) go on to describe a model of decay culminating in this equation:


Wu F, Huberman BA. (2007). Novelty and collective attention. Proc Natl Acad Sci. Oct 25; [Epub ahead of print].

The subject of collective attention is central to an information age where millions of people are inundated with daily messages. It is thus of interest to understand how attention to novel items propagates and eventually fades among large populations. We have analyzed the dynamics of collective attention among 1 million users of an interactive web site, digg.com, devoted to thousands of novel news stories. The observations can be described by a dynamical model characterized by a single novelty factor. Our measurements indicate that novelty within groups decays with a stretched-exponential law, suggesting the existence of a natural time scale over which attention fades.

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...But My Subgenual Cingulate Is Sad

In the previous post, The Neurocritic discussed an article in Nature in which greater activity in the rostral anterior cingulate cortex (rACC) was associated with optimism1 (Sharot et al., 2007). "But wait!" you might say, "what about the sad cingulate?" Neuroimaging studies have shown that the sad subgenual cingulate (Brodmann area 25), located beneath the genu of the corpus callosum, is overly active in depression (Mayberg et al., 2000; see also Greicius et al., 2007). This excessive activity is dampened in those who respond to six weeks of fluoxetine treatment (Prozac, an SSRI antidepressant), but remains elevated in those who don't. Is this the same brain region in the two experiments? Let's take a look.

On the left is Fig. 2a of Mayberg et al. (2000), showing a decrease in area 25 (Cg25) activity in fluoxetine responders, as measured by PET. On the right is Fig. 2b of Sharot et al. (2007), showing the optimistic rACC region. At first glance, the two "hot spots" appear to be in quite similar locations. However, there are differences in the precise centers of mass, as indicated by the respective x y z coordinates (according to Talairach and Tournoux, a standard 3D atlas of the human brain), and in the designated Brodmann areas (numbered cortical regions based on cytoarchitecture).

x, y, z BA
Mayberg 10,22,-14 25
Sharot -11, 42, -1 32

The x coordinate indicates right or left hemisphere, y is anterior/posterior, and z is dorsal/ventral. Although activations in medial structures generally aren't discussed in terms of left/right hemisphere, because the margin of error is often greater than the distance from the midline (x = 0), here they're centered 10 mm right and 11 mm left of midline, respectively. Furthermore, the Sharot activation is 20 mm in front of the Mayberg activation. Finally, the activations are indicated by different Brodmann areas. Hmm, not the same.

More recently, Mayberg's group demonstrated that deep brain stimulation (DBS) in area 25 was effective in treating severe intractable depression in a small group of patients (Mayberg et al., 2005).
Each [of the six patients] met stringent criteria for treatment resistance defined as failure to response to a minimum of four different antidepressant treatments, including medications, evidence-based psychotherapy, or electroconvulsive therapy, administered at adequate doses and duration during the current episode.
In this procedure, a stimulating electrode is stereotaxically implanted in the targeted region. Dr. Helen Mayberg and her colleagues at Emory University are still recruiting patients with treatment resistant depression to participate in a clinical trial using chronic, high frequency stimulation of the subgenual cingulate white matter. To determine the anatomical connectivity of the sad cingulate region, a new study performed tractography (using diffusion-weighted magnetic resonance imaging) to trace the pathways mediating treatment response with DBS (Johansen-Berg et al., 2007). The authors compared the connections of the subgenual ACC (sACC, blue/cyan) and the perigenual ACC (pACC, red/yellow), which appears to be the optimistic rACC region of Sharot and colleagues.

Figure 3 (Johansen-Berg et al., 2007). Connectivity-based parcellation of ACC and location of electrode contacts. (A, B) Population probability maps of connectivity-defined sACC and pACC. Color scales represent the population probability of a voxel belonging to sACC (from 50% [dark blue] to 80% [light blue] probability) or pACC (from 50% [red] to 80% [yellow] probability). Also shown are the locations of effective electrode contacts from 9 patients overlaid in black. Effective electrode locations are mainly localized within the sACC subregion.

Can we directly link the "optimistic rACC" (pACC) to depression, as stated in the Nature paper? Or more specifically, to DBS efficacy [and Prozac efficacy], as indicated by the work of Mayberg and colleagues? Not really. The effective electrode contacts were in sACC. The critical comparison of sACC vs. pACC connectivity is illustrated below. Is the latter highly interconnected with the amygdala? Doesn't seem to be.

From Figure 4 (Johansen-Berg et al., 2007). Tracts from sACC and pACC regions. (A–F) Population maps of results of probabilistic tractography from the pACC and sACC subregions. Color scales represent the population probability of a voxel belonging to a pathway from pACC (A, B, red to yellow) or sACC (C–F, dark blue to light blue). Abbreviated labels indicate gray matter regions that are connected with sACC or pACC via these pathways. (A, B): Pathways from pACC connect with the anterior midcingulate cortex, AMCC (A); frontal pole, FP (A); nucleus accumbens, NAC (A); hypothalamus (A); and fornix (B). (C, D, E, F): Pathways from the sACC connect with the orbitofrontal cortex, OFC (C, F); NAC (C, D); hypothalamus (C, D); AMCC (C); fornix (C); and amygdala (E, F).

How do we account for these discrepancies in the Nature paper? The tractography article was published after the former went to press, but earlier work by Mayberg et al. was neglected. However, other results were cited (Drevets et al., 1997). These investigators found resting metabolic activity in ventral ACC to be reduced in both unipolar and bipolar depression, contrary to sad cingulate hyperactivity. What's up with that? Here's what Mayberg et al. (2005) suggest:
The baseline pattern of subgenual cingulate hyperactivity in combination with frontal hypoactivity described here in this TRD patient group is a finding that is in contrast to the hypoactivity reported in a more rostral region of subgenual medial prefrontal cortex in familial bipolar and unipolar depressed patients (Drevets et al., 1997). This distinction suggests important differences across subtypes of depression that are potentially relevant to the pathophysiology of major depressive disorders and perhaps their treatment.
What have we learned? Location matters. It's helpful to read the literature. So it goes...


1 Positive correlation with optimism was for the contrast imagine future events (positive) versus imagine future events (negative).


Drevets WC, Price JL, Simpson JR Jr, Todd RD, Reich T, Vannier M, Raichle ME. (1997). Subgenual prefrontal cortex abnormalities in mood disorders. Nature 386:824-7.

Greicius MD, Flores BH, Menon V, Glover GH, Solvason HB, Kenna H, Reiss AL, Schatzberg AF. (2007). Resting-state functional connectivity in major depression: abnormally increased contributions from subgenual cingulate cortex and thalamus. Biol Psychiatry 62:429-37

Johansen-Berg H, Gutman DA, Behrens TE, Matthews PM, Rushworth MF, Katz E, Lozano AM, Mayberg HS. (2007). Anatomical Connectivity of the Subgenual Cingulate Region Targeted with Deep Brain Stimulation for Treatment-Resistant Depression. Cereb Cortex. Oct 10; [Epub ahead of print]. free PDF

Chronic deep brain stimulation (DBS) of subgenual cingulate white matter results in dramatic remission of symptoms in some previously treatment-resistant depression patients. The effects of stimulation may be mediated locally or via corticocortical or corticosubcortical connections. We use tractography to define the likely connectivity of cingulate regions stimulated in DBS-responsive patients using diffusion imaging data acquired in healthy control subjects. We defined 2 distinct regions within anterior cingulate cortex based on anatomical connectivity: a pregenual region strongly connected to medial prefrontal and anterior midcingulate cortex and a subgenual region with strongest connections to nucleus accumbens, amygdala, hypothalamus, and orbitofrontal cortex. The location of electrode contact points from 9 patients successfully treated with DBS lies within this subgenual region. The anatomical connectivity of the subgenual cingulate region targeted with DBS for depression supports the hypothesis that treatment efficacy is mediated via effects on a distributed network of frontal, limbic, and visceromotor brain regions. At present, targeting of DBS for depression is based on landmarks visible in conventional magnetic resonance imaging. Preoperatively acquired diffusion imaging for connectivity-based cortical mapping could improve neurosurgical targeting. We hypothesize that the subgenual region with greatest connectivity across the distributed network described here may prove most effective.

Mayberg HS, Brannan SK, Tekell JL, Silva JA, Mahurin RK, McGinnis S, Jerabek PA. (2000). Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol Psychiatry 48:830-43.

Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, Schwalb JM, Kennedy SH. (2005). Deep brain stimulation for treatment-resistant depression. Neuron 45:651-60.

Sharot T, Riccardi AM, Raio CM, Phelps EA. (2007). Neural mechanisms mediating optimism bias. Nature. Oct 24; [Epub ahead of print].

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Saturday, October 27, 2007

My Amygdala Is Very Optimistic Today...

...and my rostral anterior cingulate cortex imagines a brighter tomorrow.

I don't know what all those pigs are doing in the posterior half of the brain, however. Oink.

Doesn't everyone love a forcefully-worded headline?
Source of ‘optimism’ found in the brain
Now we know! At least what counts as ‘optimism’ is put in quotes in the New Scientist headline above. Not so at Reuters:
Brain regions responsible for optimism located

By Will Dunham

WASHINGTON (Reuters) - Imagine receiving a big chunk of cash in the future. Or winning a prize.

Chances are, such optimistic thoughts are coming from two places in the brain that play an important role in enabling people to, as the old song says, accentuate the positive, New York University scientists said on Wednesday.

Pinpointing the brain regions involved in optimism and positive thinking about the future, the researchers said, may also have shed light on what might be going wrong in people with depression.
Does this count as being overly optimistic? Why yes, yes it does.

by Cory Morgan.
We Have Pie Charts.

The headlines were describing a new study on the "neural mechanisms of optimism bias" just published in Nature (Sharot et al., 2007). The amygdala! It's not just for fear any more. Now it's for optimism as well (although the current tally is 1,621 to 1). The amygdala (LeDoux, 2007) is indeed known for its role in fear conditioning.

Figure 4 (LeDoux, 2007). Auditory fear conditioning pathways. The auditory conditioned stimulus (CS) and somatosensory (pain) unconditioned stimulus (US) converge in the lateral amygdala (La). The La receives inputs from each system via both thalamic and cortical inputs. CS–US convergence induces synaptic plasticity in La such that after conditioning the CS flows through the La to activate the central amygdala (CE) via intraamygdala connections. Outputs of the Ce control the expression of emotional reactions involving behavioral (freezing) and autonomic and endocrine responses that are components of the fear reaction. Other abbreviations: B, basal amygdala; CG, central gray; LH, lateral hypothalamus; ITC, intercalated cells of the amygdala; PVN, paraventricular nucleus of the hypothalamus.

Imagining the Future

In the optimistic fMRI study (Sharot et al., 2007), participants were cued to either remember (past) or imagine (future) certain scenarios, for instance:
6. receiving a large amount of money
7. visiting a museum
8. going to a first session of a class
9. taking a day trip
10. meeting a significant other for the first time
11. car crash
Then each trial was classified as positive, negative, or neutral according to the subjects' ratings.
After scanning, participants rated their memories and projections on six factors related to their subjective experience. ... Finally, participants completed the LOT-R (Life Orientation Test-Revised) scale that measures trait optimism.

Previous studies with this sort of task have shown that remembering the past and imagining the future activate a similar network of brain regions (including medial prefrontal cortex, parahippocampal gyrus, posterior cingulate, and occipital cortex), with more extensive activity (premotor cortex, precuneus, and the cerebellum) generally observed in the future condition (Szpunar et al., 2007). The main contrasts in the current experiment are illustrated in the figure below. Four regions of interest were identified: rostral anterior cingulate cortex (rACC), posterior cingulate cortex (PCC), dorsal medial prefrontal cortex (DMPFC), and the right amygdala.

adapted from Fig 2 of Sharot et al. (2007): BOLD signals in both c, the amygdala and d, the rACC reduced while imagining negative future events [relative to positive future events and to all past events].

Still, it doesn't seem that those two areas are related to optimism per se. So the authors
...identified voxels within the four functional ROIs in which changes in BOLD signal during future positive trials relative to future negative trials were correlated with participants' optimism score on the LOT-R scale. We found a positive correlation in the rACC. No significant correlation with optimism was observed in the other ROIs. Finally, a functional connectivity analysis revealed a strong correlation between activity in the rACC and activity in the amygdala bilaterally while imagining future positive events; this correlation was weaker and less extensive when imagining future negative events.
This seems somewhat bizarre to me in light of previous studies. For example, high scores on trait rumination were associated with enhanced activity in rACC and right amygdala when participants were merely looking at negative pictures, relative to when they were trying to decrease their emotional responses, "consistent with the notion that ruminators may tend to chronically recruit medial prefrontal regions engaged in negative self-referential processing" (Ray et al., 2005). How does this relate to the optimistic rACC and amygdala in the current study? We don't really know. Nonetheless, the authors conclude:
These findings may provide insight to the mechanisms underlying depression. Depressive symptoms are associated with pessimism and with difficulties in creating detailed images of future events. It has been suggested that malfunction of a neural pathway incorporating the rACC and the amygdala may cause depression by leading to decreased regulatory affects of the rACC over the amygdala and other regions involved in emotional processing.
And how does this study really relate to rACC function in depression? Stay tuned!


LeDoux J. (2007). The amygdala. Current Biology 17: R868-R874.

Ray RD, Ochsner KN, Cooper JC, Robertson ER, Gabrieli JD, Gross JJ. (2005). Individual differences in trait rumination and the neural systems supporting cognitive reappraisal. Cog Affect Behav Neurosci. 5:156-68.

Sharot T, Riccardi AM, Raio CM, Phelps EA. (2007). Neural mechanisms mediating optimism bias. Nature. Oct 24; [Epub ahead of print].

Humans expect positive events in the future even when there is no evidence to support such expectations. For example, people expect to live longer and be healthier than average, they underestimate their likelihood of getting a divorce, and overestimate their prospects for success on the job market. We examined how the brain generates this pervasive optimism bias. Here we report that this tendency was related specifically to enhanced activation in the amygdala and in the rostral anterior cingulate cortex when imagining positive future events relative to negative ones, suggesting a key role for areas involved in monitoring emotional salience in mediating the optimism bias. These are the same regions that show irregularities in depression, which has been related to pessimism. Across individuals, activity in the rostral anterior cingulate cortex was correlated with trait optimism. The current study highlights how the brain may generate the tendency to engage in the projection of positive future events, suggesting that the effective integration and regulation of emotional and autobiographical information supports the projection of positive future events in healthy individuals, and is related to optimism.

Szpunar KK, Watson JM, McDermott KB. Neural substrates of envisioning the future. Proc. Natl. Acad. Sci. Published online before print January 3, 2007. OPEN ACCESS ARTICLE.

Flies are buzzing around my head
Vultures circling the dead
Picking up every last crumb
The big fish eat the little ones
The big fish eat the little ones
Not my problem give me some

-- Radiohead, Optimistic

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Tuesday, October 23, 2007

To die, to sleep;

To sleep: perchance to dream: ay, there's the rub;
For in that sleep of death what dreams may come
When we have shuffled off this mortal coil,
Must give us pause...

-- William Shakespeare - To be, or not to be
(from Hamlet 3/1)

Jacob's Dream woodcut, Lubeck Bible 1494

This week's Science Times in the New York Times has a series on sleep and dreaming, including articles on sleep deprivation, nightmares, and sleeping pills.

1888 woodcut, French astronomer Camille Flammarion

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Monday, October 22, 2007

Why Are Faces Special? Bruno Rossion on the N170 Controversy

Are faces special? This question has sparked endless debate among investigators who study object recognition, perceptual expertise, and developmental psychology. Neuroimaging experiments have demonstrated that specific fMRI activations (in the fusiform face area) and EEG responses (the N170 component) are larger for faces than for non-face objects. A controversial paper published in March (Thierry et al., 2007) claimed that the face selectivity shown in over 100 previous studies of the N170 was an artifact of differential interstimulus perceptual variance (ISPV). Namely, they argued that earlier experiments did not adequately control for variability across stimulus classes, i.e., face stimuli have been much more similar to each other than the non-face stimuli.

Dr. Bruno Rossion, a leading researcher in this area, has been highly critical of this finding, and his letter to the editor at Nature Neuroscience (Bentin et al., 2007) was previously covered by The Neurocritic and The Phineas Gage Fan Club. His latest comments on the matter first appeared here, and I have taken the liberty to repost them as a new entry.

A few months ago, you asked me to keep you updated on this issue. We have now in press (Neuroimage) a full paper deconstructing the claim of Thierry et al. that the N170 would not be larger to faces than other visual stimuli :

Rossion, B. & Jacques, C. (in press). Does physical interstimulus variance account for early electrophysiological face sensitive responses in the human brain? Ten lessons on the N170. NeuroImage. PDF

You can get it here : http://www.nefy.ucl.ac.be/Face_Categorisation_Lab.htm

The short reply that the editors of Nature Neuroscience allowed us to write was not enough, and gave the opportunity to Thierry and colleagues to throw more confusion on this issue (as also acknowledged by the comment on this website). So we thought it deserved a full commentary, deconstructing their paper, and trying to take the positives from this unfortunate publication (i.e. what can we learn about this for N170 research, suggest some kinds of guidelines, clarify a number of theoretical and methodological points).

In a nutshell, in our paper, we :

- Explain clearly the nature of their claim, why it’s ill defined and not to be confused with the real debate about the NATURE of the larger N170 to faces.
- Explain why their claim was not really plausible for reasons that are related to EEG/ERP analysis : an increase of intertrial variance should have delayed/smeared the N170, which is due to a fixed increase of power time-locked to the stimulus onset.
- Show that Thierry et al. were wrong with respect to previous studies not controlling for the factor they mention. In fact, ironically again, one of the few studies that suffered from such limitations, is their only published study before this one.
- Explain clearly why they failed to find a N170 effect in their study (we replicate this « finding » with the wrong electrodes considered)
- Show that they did not control for the factor that was supposed to be controlled and for which they were blaming other studies.
- Provide an account for their « ISPV » finding, which merely reflects a comparison of high-quality images to low quality image sets.
- Discuss why the N170 face effect is not related to low-level visual factors, whereas the earlier P1 effect (emphasized by Thierry et al.) is likely to be related to such factors.
- Emphasize that the larger N170 to faces is an important phenomenon for researchers to understand the time-course of face processing, and that this effect is in line with a large body of data from other sources.

I hope this will set the record straight. The paper of Thierry et al. was accepted in NN it seems precisely because, done by novices in this area it was very controversial and would make a lot of noise (i.e. citations). [NOTE: the title of the university press release is Neuropsychologists set for shock finding.] I believe it is not only intellectually dishonest, but reveal a dangerous trend in some « high impact factors » journals to publish papers first and foremost because they appear novel, catchy or controversial rather than on their scientific credibility.

Perhaps at some point you will be able to reformulate the question as « why are faces special » ?

All the best

Bruno Rossion


Bentin S, Taylor MJ, Rousselet GA, Itier RJ, Caldara R, Schyns P, Jacques C, Rossion B. (2007). Controlling interstimulus perceptual variance does not abolish N170 face sensitivity. Nature Neurosci. 10:801-802.

Thierry G, Martin CD, Downing P, Pegna AJ. (2007). Controlling for interstimulus perceptual variance abolishes N170 face selectivity. Nature Neurosci. 10:505-511.

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Friday, October 19, 2007

The Hunger:

The PYY and Dopamine Issue
Brain 'hunger pathways' pinpointed

12:05 15 October 2007
Anna Gosline

The brain circuitry that influences how much food a person will eat – whether they feel starving or full – has been revealed by a new imaging study. The results may help target new treatments against obesity, say researchers.

Rachel Batterham at University College London, UK, and her colleagues have previously shown that a hormone called peptide YY or PYY, which is released by the gut in proportion how many calories we eat, is a powerful appetite suppressant. Previous experiments show that treating normal and obese subjects with intravenous PYY decreases food intake by up to 30%.

Batterham's team used functional magnetic resonance imaging (fMRI) to investigate how PYY affects the brain. They scanned each of eight subjects twice, once while they were on an intravenous drip of PYY, mimicking its release after a meal, and once while just receiving a saline solution. All the subjects had fasted for 14 hours prior to the scans.

Half an hour after they left the scanner, Batterham dished out an all-you-can-eat buffet of each subjects' favourite meals, which included spaghetti Bolognese and macaroni cheese.

As expected, those who received PYY ate less – on average 25% fewer calories. The fMRI scans showed that PYY not only lit up the hypothalamus – the main hub for controlling metabolism, – but also increased activity in higher processing areas of the brain that are associated with reward and pleasure, notably the orbital frontal cortex (OFC). "I absolutely wasn't expecting it to affect the reward circuit," says Batterham.
In preparation for Halloween, two new treats provide potential ways to trick the nervous system into thinking the stomach is full (Batterham et al., 2007) or into reducing the reinforcing properties of highly palatable food (Epstein et al., 2007). In the first experiment, PYY or saline were administered in a double-blind crossover fashion and then fMRI and physiological measures were taken from 8 male participants. PYY, a peptide that belongs to the same family as neuropeptide Y (NPY), is secreted from cells in the intestinal mucosa within 15 min after eating (Ueno et al., 2007):
Via Y2 receptors, the satiety signal mediated by PYY inhibits NPY neurons and activates pro-opiomelanocortin neurons within the hypothalamic arcuate nucleus. Peripheral PYY(3-36) binds Y2 receptors on vagal afferent terminals to transmit the satiety signal to the brain. PYY(3-36) may have therapeutic potential in human obesity.
PYY may even be a "silver bullet" and "obesity's cause and cure" according to some experts (Tschöp & Ravussin, 2007). Miracle cure or no, the fMRI data from subjects treated with PYY showed increases in a laundry list of brain areas1 , relative to saline (Batterham et al., 2007). The a priori regions of interest that covaried positively with PYY plasma concentrations were the hypothalamus, substantia nigra (chock-full of dopamine neurons), and parabrachial nucleus (taste relay center in the brainstem), but not the nucleus accumbens (hedonia central) or the nucleus of the solitary tract (another brainstem taste center). Of particular note in the whole-brain analysis was the orbitofrontal cortex (OFC):
Thus, in the presence of PYY, a postprandial satiety factor, brain activity predicting caloric intake appeared to switch from a homeostatic area (hypothalamus) to a hedonic area (OFC).
Finally, the study participants treated with PYY ate 25% fewer calories at the all-you-can-eat buffet after the scanning session was over (see below, Fig. 1b of Batterham et al.)

The second study examined variations in the dopamine D2 receptor (DRD2) and dopamine transporter genes in 74 humans, fat and thin (Epstein et al., 2007). Obese individuals with the TaqI A1 allele were particularly susceptible to the reinforcing properties of food,
measured by determining the number of responses on a concurrent schedule task that participants made for food or food alternatives. The experimental environment included two computer stations with a swivel chair in the middle. At one station participants could earn points toward food, and at the other station they could earn points for time to spend reading the Buffalo News. [NOTE: because we all know how intrinsically rewarding this would be.] This alternative activity was provided to reduce the likelihood that participants would engage in responding out of boredom.
The authors discuss the usefulness of these results in tailoring obesity treatment plans to the needs of individuals with lower intrinsic dopamine activity.
Dopamine levels and appetite

Science has found one likely contributor to the way that some folks eat to live and others live to eat.

Researchers at the University at Buffalo, The State University of New York, have found that people with genetically lower dopamine, a neurotransmitter that helps make behaviors and substances more rewarding, find food to be more reinforcing than people without that genotype. In short, they are more motivated to eat and they eat more.
. . .

Epstein's team was particularly interested in the influence of the Taq1 A1 allele, a genetic variation linked to a lower number of dopamine D2 receptors and carried by about half the population (most of which carries one A1 and one A2; carriers of two A1 alleles are rare). The other half of the population carries two copies of A2, which by fostering more dopamine D2 receptors may make it easier to experience reward. People with fewer receptors need to consume more of a rewarding substance (such as drugs or food) to get that same effect.
. . .

Both obesity and the genotype associated with fewer dopamine D2 receptors predicted a significantly stronger response to food's reinforcing power. Perhaps not surprisingly, participants with that high level of food reinforcement consumed more calories.

The results also revealed a three-rung ladder of consumption, with people who don't find food that reinforcing, regardless of genotype, on the lowest rung. On the middle rung are people high in food reinforcement without the A1 allele. Atop the ladder are people high in food reinforcement with the allele, a potent combination that may put them at higher risk for obesity.

The reinforcing value of food, which may be influenced by dopamine genotypes, appeared to be a significantly stronger predictor of consumption than self-reported liking of the favorite food. What's more, obese participants clearly found food to be more reinforcing than non-obese participants. The authors conclude that, "Food is a powerful reinforcer that can be as reinforcing as drugs of abuse."

Editor's Note: Dr. Leonard Epstein is also a consultant to Kraft Foods.


1 Left orbitofrontal cortex, Midbrain PAG/VTA/SN, Right parabrachial nucleus, Right MSFG, Left MSFG, Right precentral gyrus, Middle frontal gyrus, Left posterior STG, Left posterior insula, Left anterior cingulate, Left inferior parietal lobule, Right lateral globus pallidus, right putamen, Right anterior lobe cerebellum, Left precentral gyrus (from Supplementary Table S1 of Batterham et al.).


Batterham RL, Ffytche DH, Rosenthal JM, Zelaya FO, Barker GJ, Withers DJ, Williams SC. (2007). PYY modulation of cortical and hypothalamic brain areas predicts feeding behaviour in humans. Nature Oct 14; [Epub ahead of print].

The ability to maintain adequate nutrient intake is critical for survival. Complex interrelated neuronal circuits have developed in the mammalian brain to regulate many aspects of feeding behaviour, from food-seeking to meal termination. The hypothalamus and brainstem are thought to be the principal homeostatic brain areas responsible for regulating body weight. However, in the current 'obesogenic' human environment food intake is largely determined by non-homeostatic factors including cognition, emotion and reward, which are primarily processed in corticolimbic and higher cortical brain regions. Although the pleasure of eating is modulated by satiety and food deprivation increases the reward value of food, there is currently no adequate neurobiological account of this interaction between homeostatic and higher centres in the regulation of food intake in humans. Here we show, using functional magnetic resonance imaging, that peptide YY(3-36) (PYY), a physiological gut-derived satiety signal, modulates neural activity within both corticolimbic and higher-cortical areas as well as homeostatic brain regions. Under conditions of high plasma PYY concentrations, mimicking the fed state, changes in neural activity within the caudolateral orbital frontal cortex predict feeding behaviour independently of meal-related sensory experiences. In contrast, in conditions of low levels of PYY, hypothalamic activation predicts food intake. Thus, the presence of a postprandial satiety factor switches food intake regulation from a homeostatic to a hedonic, corticolimbic area. Our studies give insights into the neural networks in humans that respond to a specific satiety signal to regulate food intake. An increased understanding of how such homeostatic and higher brain functions are integrated may pave the way for the development of new treatment strategies for obesity.

Epstein LH, Temple JL, Neaderhiser BJ, Salis RJ, Erbe RW, Leddy JJ. (2007). Food reinforcement, the dopamine D-sub-2 receptor genotype, and energy intake in obese and nonobese humans. Behav Neurosci. 121:877-86.

The authors measured food reinforcement, polymorphisms of the dopamine D2 receptor (DRD2) and dopamine transporter (DAT1) genes, and laboratory energy intake in 29 obese and 45 nonobese humans 18-40 years old. Food reinforcement was greater in obese than in nonobese individuals, especially in obese individuals with the TaqI A1 allele. Energy intake was greater for individuals high in food reinforcement and greatest in those high in food reinforcement with the TaqI A1 allele. No effect of the DAT1 genotype was observed. These data show that individual differences in food reinforcement may be important for obesity and that the DRD-sub-2 genotype may interact with food reinforcement to influence energy intake.

Tschop MH, Ravussin E. (2007). Peptide YY: Obesity’s Cause and Cure? Am J Physiol Endocrinol Metab. Sep 11; [Epub ahead of print]

Ueno H, Yamaguchi H, Mizuta M, Nakazato M. (2007). The role of PYY in feeding regulation. Regul Pept. Sep 18; [Epub ahead of print].

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Thursday, October 18, 2007


free brain scans for everyone!

This is your true brain, the emotions that run your life!

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Tuesday, October 16, 2007

The Real Iraq

"America, it has been five years. It's time to make a choice."

That quote concludes this editorial in today's Washington Post:
Today marks five years since the authorization of military force in Iraq, setting Operation Iraqi Freedom in motion. Five years on, the Iraq war is as undermanned and under-resourced as it was from the start. And, five years on, Iraq is in shambles.
The authors?

12 former Army captains: Jason Blindauer served in Babil and Baghdad in 2003 and 2005. Elizabeth Bostwick served in Salah Ad Din and An Najaf in 2004. Jeffrey Bouldin served in Al Anbar, Baghdad and Ninevah in 2006. Jason Bugajski served in Diyala in 2004. Anton Kemps served in Babil and Baghdad in 2003 and 2005. Kristy (Luken) McCormick served in Ninevah in 2003. Luis Carlos Montalván served in Anbar, Baghdad and Nineveh in 2003 and 2005. William Murphy served in Babil and Baghdad in 2003 and 2005. Josh Rizzo served in Baghdad in 2006. William "Jamie" Ruehl served in Nineveh in 2004. Gregg Tharp served in Babil and Baghdad in 2003 and 2005. Gary Williams served in Baghdad in 2003.
As Army captains who served in Baghdad and beyond, we've seen the corruption and the sectarian division. We understand what it's like to be stretched too thin. And we know when it's time to get out.

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Wednesday, October 10, 2007

The Joy of 5-HT4 Receptors

Move over, melanocortin receptors, 5-HT4 receptors are ready to take your place. Agonists of the 5-HT4 receptor, a subtype of the serotonin receptor family, seem to do the following, according to recently published reports:

(1) mediate the appetite-suppressing qualities of ecstasy (MDMA), and supposedly the self-reinforcing qualities of starving for individuals with anorexia nervosa (Jean et al., 2007). This paper was the one in PNAS mentioned the other day by The Neurocritic.
We [Jean et al., 2007] hypothesized that anorexia may involve altered signaling events within the nucleus accumbens (NAc), a brain structure involved in reward. We show here that direct stimulation of 5-HT4R in the NAc reduces the physiological drive to eat and increases CART (cocaine- and amphetamine-regulated transcript) mRNA levels in fed and food-deprived mice. ... Considering that CART may interfere with food- and drug-related rewards, we tested whether the appetite suppressant properties of MDMA involve the 5-HT4R. Using 5-HT4R knockout mice, we demonstrate that 5-HT4R are required for the anorectic effect of MDMA as well as for the MDMA-induced enhancement of CART mRNA expression in the NAc. ...
(2) act as a rapid-onset antidepressant (Lucas et al., 2007); no more waiting 3-6 weeks for treatment response from those pesky SSRIs. In a rodent model of depression, acute administration of 5-HT4 agonists was more effective than citalopram in reducing immobility in the forced swimming test.
Moreover, a 3 day regimen with such compounds modifies rat brain parameters considered to be key markers of antidepressant action, but that are observed only after 2–3 week treatments with classical molecules: desensitization of 5-HT1A receptors, and enhanced phosphorylation of the CREB protein and neurogenesis in the hippocampus. In contrast, a 3 day treatment with the SSRI citalopram remains devoid of any effect on these parameters.
(3) improve memory and affect amyloid metabolism (Lezoualc'h, 2007), making it a possible target for drugs to treat Alzheimer's disease (Maillet et al., 2004).

Fig. 1 (Lezoualc'h, 2007). In vivo and in vitro evidence for a beneficial effect of 5-HT4 receptor agonists in AD. 5-HT4 agonists facilitate ACh [acetylcholine] release in rat frontal and hippocampus and modulate different aspects of memory performance in behavioural experiments. In addition, they increase the extracellular release of sAPPα [non-amyloidogenic soluble form of APP] and decrease Aβ [amyloid β-peptide] secretion in primary neurons. sAPPα has potent memory-enhancing effects and displays neuroprotective and neurotrophic properties.

The one major thing the MC4R subtype of melanocortin receptors has over 5-HT4R is its potential as an aphrodisiac, in the form of PT-141 (company press release and PDF).


Alexandra Jean, Grégory Conductier, Christine Manrique, Constantin Bouras, Philippe Berta, René Hen, Yves Charnay, Joël Bockaert, and Valérie Compan (2007). Anorexia induced by activation of serotonin 5-HT4 receptors is mediated by increases in CART in the nucleus accumbens. PNAS published online October 3, 2007.

Lezoualc'h F. (2007). 5-HT4 receptor and Alzheimer's disease: the amyloid connection. Exp Neurol. 205:325-9.

Lucas G, Rymar VV, Du J, Mnie-Filali O, Bisgaard C, Manta S, Lambas-Senas L, Wiborg O, Haddjeri N, Pineyro G, Sadikot AF, Debonnel G. (2007 ). Serotonin-4 (5HT-4) receptor agonists are putative antidepressants with a rapid onset of action. Neuron 55:712-25.

Maillet M, Robert SJ, Lezoualc'h F. (2004). New insights into serotonin 5-HT4 receptors : a novel therapeutic target for Alzheimer's disease? Curr Alzheimer Res. 1(2):79-85.

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Tuesday, October 09, 2007

This is not a pipe

This is not a Bob Dylan movie, either.

Bob Dylan Approximately Top row, from left, Marcus Carl Franklin, Cate Blanchett and Ben Whishaw; bottom, Christian Bale, Heath Ledger and Richard Gere.

The New York Times Magazine has a long but interesting article on the latest film by American auteur Todd Haynes (who is strangely absent from Wikipedia's list of auteurs). Called I'm Not There after a song available only as a bootleg, it stars six actors of different ages, races, and sexes.
...Todd Haynes’s Dylan film isn’t about Dylan. ... Haynes was trying to make a Dylan film that is, instead, what Dylan is all about, as he sees it, which is changing, transforming, killing off one Dylan and moving to the next, shedding his artistic skin to stay alive. The twist is that to not be about Dylan can also be said to be true to the subject Dylan.
Haynes's reference points include Rimbaud, Fellini's , Fassbinder, Billy the Kid, and Godard as well as the more obvious Woody Guthrie.
This idea of changing identity is also where Haynes hooked into the idea of a Dylan film, one that would not even feature the words Bob or Dylan. It wasn’t just the music that got Haynes, though he was loving it. “I just found this refusal to be fixed as a single self in a single voice as a key to his freedom,” Haynes told me. “And he somehow escaped this process of being frozen into one fixed person.”
The treachery of identity, one might call it...

René Magritte, The Treachery Of Images

Coincidentally, another American director named Todd who is approximately the same age as Haynes and who is on the list of auteurs (Todd Solondz) made a very different film called Palindromes (which nobody saw) that cast eight actors of different ages, races, and sexes as the 13-year-old female protagonist.

Cambridge Encyclopaedia Of Astronomy, Fig. 6.7: Successive pulses from the first pulsar discovered, CP 1919, are here superimposed vertically. The pulses occur every 1.337 seconds. They are caused by a rapidly spinning neutron star.

A more straightforward biopic about a very different musician (Control, about the late Ian Curtis of Joy Division) has opened in UK theaters to very good reviews. Curtis, who suffered from epilepsy and depression, tragically killed himself at the age of 23.

She's Lost Control (1979/1980)

. . .

And she turned around and took me by the hand
And said I've lost control again.
And how I'll never know just why or understand
She said I've lost control again.
And she screamed out kicking on her side
And said I've lost control again.
And seized up on the floor, I thought she'd die.
She said I've lost control.
She's lost control again.
She's lost control.
She's lost control again.
She's lost control.

--Joy Division

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Monday, October 08, 2007

The Enforcer

Brain's 'social enforcer' centers identified

Researchers have identified brain structures that process the threat of punishment for violating social norms. They said that their findings suggest a neural basis for treating children, adolescents, and even immature adults differently in the criminal justice system, since the neural circuitry for processing the threat of such punishment is not as developed in younger individuals as it is in adults. The researchers also said that their identification of the brain’s “social norm compliance” structures also opens the way to exploring whether psychopaths have deficiencies in these structures’ circuitry.

Manfred Spitzer, Ernst Fehr, and colleagues published their findings in the October 4, 2007 issue of the journal Neuron, published by Cell Press.

“In this study, we sought to uncover the neural circuits involved in forced norm compliance,” wrote the researchers. “This question touches the very foundations of human sociality because the establishment of large-scale cooperation through social norms is a unique feature of the human species. Norm compliance among humans is either based on people’s voluntary compliance with standards of behavior that are viewed as normatively legitimate or on the enforcement of compliance through punishment. Although much compliance is voluntary, there can be little doubt that social order would quickly break down in the absence of punishment threats because a minority of noncompliers can trigger a process that leads to widespread noncompliance due to the conditional nature of many people’s compliance.

“To our knowledge, this is the first study [NOTE: it feels like the first time] that examines the brain processes involved in humans’ behavioral response to the threat of punishment for social norm violations,” wrote the researchers.
You know, I've been wondering about the brain's "social norm compliance structures" since, oh, September 13, 1848 (the date of Phineas Gage's infamous encounter with a tamping iron that exploded through his head). The accident resulted in bilateral damage to his prefrontal cortex and major changes in his personality. 1 From Wikipedia:
According to Gage's doctor, Dr. J.M. Harlow, whereas previously he had been hard-working, responsible, and popular with the men in his charge, his personality seemed to have been radically altered after the accident. His doctor reported that:

"Gage was fitful, irreverent, indulging at times in the grossest profanity (which was not previously his custom), manifesting but little deference for his fellows, impatient of restraint or advice when it conflicts with his desires, at times pertinaciously obstinate, yet capricious and vacillating, devising many plans of future operations, which are no sooner arranged than they are abandoned in turn for others appearing more feasible. A child in his intellectual capacity and manifestations, he has the animal passions of a strong man. Previous to his injury, although untrained in the schools, he possessed a well-balanced mind, and was looked upon by those who knew him as a shrewd, smart businessman, very energetic and persistent in executing all his plans of operation. In this regard his mind was radically changed, so decidedly that his friends and acquaintances said he was 'no longer Gage." (Harlow, 1868)
You can read more about the Phineas Gage story here and here (and of course, in Damasio et al., 1994). He even has a fan club.

OK, back to the new and novel study of Spitzer et al. (2007). From the abstract, here is a quick summary of their neuroimaging results:
Individuals’ increase in norm compliance when punishment is possible exhibits a strong positive correlation with activations in the lateral orbitofrontal cortex and right dorsolateral prefrontal cortex. Moreover, lateral orbitofrontal cortex activity is strongly correlated with Machiavellian personality characteristics. These findings indicate a neural network involved in social norm compliance that might constitute an important basis for human sociality.
So what were the social norms, and what was the "forced compliance"?? A gun to the head? A police station right around the corner? No, the social norm was financial fairness, and the threat was financial punishment. Their fMRI study used tasks popular in neuroeconomics (Sanfey et al., 2006): the dictator game (the no punishment condition) and the ultimatum game (the threat of punishment condition). More specifically,
Two players, A (in the scanner) and B, interacted anonymously with each other. Each knew that he was facing a human player. Player A received an endowment of 100 money units (MUs), which he could distribute freely between himself and player B. In the control [no punishment] condition, which resembles a dictator game, B was a passive recipient of A’s monetary transfer. In contrast, B could punish A in the punishment condition after having been informed of the latter’s decision. Each player received an additional endowment of 25 MUs in both conditions, for reasons of fairness and to make punishment possible. In the punishment condition, B could spend all or part of this amount to reduce A’s earnings; every MU B invested into punishment led to a reduction of A’s earnings by 5 MUs. ... Thus, the punishment condition resembles an ultimatum game, with the exception that player B has a larger set of available punishment actions.
Quite a few neuroimaging experiments have scanned subjects during the performance of those types of tasks (reviewed in Sanfey et al., 2006), 2 so what's different about the current paper? [besides its wild extrapolations to when the Vandals invaded and looted Rome, when the police went on strike in Liverpool and Montreal, and when ATM robberies in New York increased on September 11, 2001.]
...although important work examining the neural bases of economic choice, social cognition, moral judgment, social cooperation, and social punishment exists [NOTE: 16 references deleted for readability], the brain systems involved in forced norm compliance still remain unknown. In particular, the previous literature on social punishment examines the neural circuitry involved in the decision to punish whereas our work focuses on the neural circuitry involved in the processing and the response to punishment threats that are associated with norm violations.
So, what was predicted, and what were the results?
We therefore conjectured that during the decision phase, lateral prefrontal areas such as the dorsolateral prefrontal cortex (DLPFC), or the ventrolateral prefrontal cortex (VLPFC), which have been shown to be reliably involved in cognitive control and the inhibition of prepotent responses, will be more strongly activated in the punishment condition.
. . .

In the punishment condition player A also has to evaluate the sanctioning threat. Several studies suggest lateral orbitofrontal cortex (OFC) involvement in the evaluation of punishing stimuli that may lead to behavioral changes. These findings
led to the conjecture that the OFC might be more strongly activated in the punishment condition.
Previous transcranial magnetic stimulation (TMS) studies have shown that when the normal functioning of right DLPFC is transiently disrupted, participants accept a higher proportion of unfair offers (van't Wout et al., 2005; Knoch et al., 2006), so in general we know this region is important for decision-making in these types of tasks. In my view, what's most interesting is a brain region that was not activated (and not even mentioned by name in the entire paper): the anterior cingulate cortex, which has been associated with those same cognitive control functions described above. Why? We'll never know. Instead, as predicted, bilateral DLPFC, VLPFC, and OFC showed larger hemodynamic responses in the punishment condition than in the no punishment condition. Additionally, activitions in the right DLPFC and the Machiavellian lateral OFC were positively correlated with social norm compliance [the insula was also Machiavellian]. How were Machiavellian tendencies assessed, you ask? Before scanning, participants completed the Machiavelli questionnaire [not that this might have influenced their behavior in the study, oh no].

Interestingly, a brand new paper in Science (Jensen et al., 2007) demonstrated that chimpanzees (Pan troglodytes) behave rationally (i.e., according to models of rational economic decision making) in the ultimatum game: they do not reject unfair offers to punish the bad player. Unlike humans.

And what about Gage?

from Fig. 5 of Damasio et al. (1994): the white blobs indicate the estimated trajectory of the metal bar. The areas spared by the iron are highlighted in color: Broca, yellow; motor, red; somatosensory, blue; Wernicke, green.

Although he didn't play the ultimatum game (to our knowledge), other ultimatum game players with damage to the ventromedial prefrontal cortex (part of the OFC) are more likely to reject unfair offers than controls (Koenigs & Tranel, 2007). We don't know yet whether they would be more inclined to give skimpy offers despite the threat of punishment (i.e., when in the "player A" position), but one might imagine this would be the case (Fellows, 2007)...


1 But see this criticism of the popular story.

2 See also The Trust Game and Men are Torturers, Women are Nurturers...


Damasio H, Grabowski T, Frank R, Galaburda AM, Damasio AR. (1994). The return of Phineas Gage: clues about the brain from the skull of a famous patient. Science 264: 1102-5.

Fellows LK. (2007). Advances in understanding ventromedial prefrontal function: the accountant joins the executive. Neurology 68:991-5

Harlow, JM. (1868). Recovery from a Passage of an Iron Bar through the Head. Publications of the Massachusetts Medical Society 2: 327-347.

Jensen K, Call J, Tomasello M. (2007). Chimpanzees are rational maximizers in an ultimatum game. Science 318:107-9.

Knoch D, Pascual-Leone A, Meyer K, Treyer V, Fehr E. (2006). Diminishing reciprocal fairness by disrupting the right prefrontal cortex. Science 314:829-32.

Koenigs M, Tranel D. (2007). Irrational economic decision-making after ventromedial prefrontal damage: evidence from the Ultimatum Game. J Neurosci. 24:951-6.

Sanfey AG, Loewenstein G, McClure SM, Cohen JD. (2006). Neuroeconomics: cross-currents in research on decision-making. Trends Cog Sci. 10:108-16.

van't Wout M, Kahn RS, Sanfey AG, Aleman A. (2005). Repetitive transcranial magnetic stimulation over the right dorsolateral prefrontal cortex affects strategic decision-making. Neuroreport 16:1849-52.

Spitzer M, Fischbacher U, Herrnberger B, Grön G, Fehr E. (2007). The Neural Signature of Social Norm Compliance. Neuron 56: 185-196.

All known human societies establish social order by punishing violators of social norms. However, little is known about how the brain processes the punishment threat associated with norm violations. We use fMRI to study the neural circuitry behind social norm compliance by comparing a treatment in which norm violations can be punished with a control treatment in which punishment is impossible. Individuals' increase in norm compliance when punishment is possible exhibits a strong positive correlation with activations in the lateral orbitofrontal cortex and right dorsolateral prefrontal cortex. Moreover, lateral orbitofrontal cortex activity is strongly correlated with Machiavellian personality characteristics. These findings indicate a neural network involved in social norm compliance that might constitute an important basis for human sociality. Different activations of this network reveal individual differences in the behavioral response to the punishment threat and might thus provide a deeper understanding of the neurobiological sources of pathologies such as antisocial personality disorder.

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Thursday, October 04, 2007

Sinéad and Bipolar Disorder

Speaking of Sinéad O'Connor, she's making an appearance on Oprah today to discuss how she's suffered with bipolar disorder, which went undiagnosed until the age of 37 (she's 40 now). In one of her most famous (infamous) acts, she ripped up a picture of Pope John Paul II on Saturday Night Live in 1992:
Because it airs live, Saturday Night Live is an open invitation for troublemakers. ... But by far the show's biggest controversy was in 1992, when Sinead O'Connor followed her performance by declaring "Fight the real enemy!" and proceeding to rip a picture of Pope John Paul II in two.
The File Room, an illustrated archive on censorship, describes it thusly:
Description of incident

October 3, 1992: Sinéad O'Connor appears as the musical guest on "Saturday Night Live." Toward the end of the show O'Connor performs a remarkable a capella version of the Bob Marley song "War," which Marley wrote using words from a speech given by Ethiopia's last emperor, Haile Selassie, who died in 1975. The song basically says war is an appropriate response for victims of racial injustice, child abuse and other types of cruelty. At the song's conclusion O'Connor held up an 8" x 10" color photo of Pope John Paul II, ripped it into pieces and said, "Fight the real enemy."
Exclusive: Sinéad O'Connor Reveals Her Struggle with Bipolar Disorder

On the The Oprah Winfrey Show,
Sinéad says she used to feel suicidal but medication has given her a new outlook on life. "Everything just became too much, and the best way I can describe it to you is you're so sad, just terribly sad, that you're like a bucket of water with holes in it. Every pore of you is crying and you don't even understand why or what," Sinéad says. "I actually kind of died and got born again as a result of taking the meds and having a chance to, you know, build a life."
Now, you might be asking yourself the question, are those tabloid rumors about another famous female pop star with a shaved head true? While it's highly unethical for a mental health professional to speculate about a celebrity's possible psychiatric disorder [see They tried to make me talk about rehab but I said ‘no, no, no’ by Dr. Petra for a good discussion], Sinéad O'Connor can identify with the party in question:
Sinéad says she feels sorry for the scrutiny today's pop stars like Britney Spears live with. [NOTE: as do I.] "I think it's terrible what the media are doing to her here," Sinéad says. "I feel so sorry for celebrities in this country. It's absolutely impossible to live a normal life being followed around, poor girl. We all mess up, don't we, as moms. We never always get it right."

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